Metal-Catalyzed Spiroketalizations of Monoallylic Ketodiols

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Title:
Metal-Catalyzed Spiroketalizations of Monoallylic Ketodiols
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1 online resource (193 p.)
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english
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Palmes, Jean A
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University of Florida
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Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
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University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Aponick, Aaron Steven
Committee Members:
Mcelwee-White, Lisa A
Stewart, Jon D
Dolbier, William R
Sloan, Kenneth B

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Subjects / Keywords:
catalyzed -- ketodiols -- metal -- monoallylic -- spiroketals
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
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theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
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Abstract:
Spiroketals are found in a myriad of natural products that show potential biological activity.Traditional methods to prepare spiroketals require harsh conditions. An alternative approach is to use mild reaction conditions associated with metal-catalysis. As an expansion of our group’s interest in the formation of heterocycles by p-activation of allylic alcohols, the method presented in this thesis aims to prepare spiroketals from monoallylic ketodiols. Gold(I),palladium(II), and platinum(II) compounds were demonstrated to catalyze the transformation of monoallylic ketodiols to a-vinyl spiroketals, but PdCl2(CH3CN)2determined to be the optimal catalyst. The newly-developed Pd(II)-catalyzed spiroketalization conditions efficiently converts various monoallylic ketodiolsto 6,6-, 6,5- and 5,6-spiroketal systems in high yields (60-90%) and diastereoselectivities up to 20:1. The presence of substituents in either of the spiroketal rings is also tolerated even at low (5 mol%) catalyst loadings. The Pd(II)-catalyzed transformation was also applied to the stereoselective construction of spiroketals. The method proves to be successful in accessing either anomeric or nonanomeric spiroketals by simply varying the absolute configuration of the allylic alcohol and the geometry of the olefin.Even in highly substituted monoallylic ketodiol precursors, nonanomeric spiroketals can be synthesized starting with an (R)-E- or (S)-Z-monoallylic ketodiol.  However, the spiroketalization of E-olefin substrates is generally faster and high yielding than the Z-olefin counterparts. The stereocomplementary nature of this methodology will be useful in natural product synthesis especially for compounds in which the absolute configuration of the spiroketal is not known.
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Includes vita.
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Statement of Responsibility:
by Jean A Palmes.
Thesis:
Thesis (Ph.D.)--University of Florida, 2012.
Local:
Adviser: Aponick, Aaron Steven.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-02-28

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1 METAL CATALYZED SPIROKETALIZATION OF MONOALLYLIC KETODIOLS By JEAN ALCARAZ PALMES A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2012

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2 2012 Jean Alcaraz Palmes

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3 To my family

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4 ACKNOWLEDGMENTS I sincer e ly thank Dr. Aaron Aponick, my advisor, for his support patience and guidance throughout my graduate studies. He encouraged me to not only grow as an experimentalist and a chemist but also as an independent thinker. I will forever be grateful to my undergraduate mentors, Dr. Evelyn Rodriguez, Dr. Cleofe Calanasan and Dr. Milagros Peralta, for making me love organic c hemistry. I thank Dr. Davidson for inspiring me to be a good teacher for my students. I appreciate the unique experience I had working in the Aponick lab not only because of the knowledge and experience I gained but also because of the special group of pe ople I worked with: Berenger (Dr. Biannic), Dr. Li, John, Carl, Nick, Thomas, Justin, Flavio, Barry, Romain and Paulo. Special thanks goes to John and Nick for proofreading my manuscript. To Marisa and Leonardo, the undergrads I worked with, for the wonder ful mentoring experience I had with them. I am grateful to Dr. Sukwon Hong and the former Hong group members, for the intellectual discussions on Friday meetings and letting me use the HPLC. I would like to thank my friends whom I meet in Gainesville. T o t he ladies in Chemistry: Pam Paula Egle, Claudia, Danniebelle and Marie, for the la outside the lab; t o my Pinoy_uf comm unity, for bringing a taste of home t o Gainesville; t o Ethel, Star, Edward, Natasha, Ian and Jill, for all the fun times we h ad during our dinners and trips, the memories we shared will forever be cherished. Special thanks to Cris for always being supportive of me and to Dr. S. J. K. for the wonderful times we shared together and for always believing in my capabilities. I a to have a mother you can always count on in this foreign land. Her lov e and support are

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5 unconditional, and most of all, I want to thank my family for the support and unwavering lov e; t o Ate Malou, for being such a good listener to Ate Minda and Nonoy for being ve ry supportive and understanding. I thank my parents for their faith in me and allowing me to follow my dreams

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6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURE S ................................ ................................ ................................ ........ 10 LIST OF SCHEMES ................................ ................................ ................................ ...... 11 LIST OF ABBREVIATIONS ................................ ................................ ........................... 17 ABSTRACT ................................ ................................ ................................ ................... 20 CHAPTER 1 RECENT ADVANCES IN TRANSITION METAL CATALYZED SPIROKETALIZATIONS ................................ ................................ ......................... 22 1.1 Spiroketals in Nature ................................ ................................ ......................... 22 1.2 Conformational Aspects of Spiroketal Structures ................................ .............. 23 1.3 Traditional Approaches to Spiroketal Synthesis ................................ ................ 24 1.4 Transition Metal Catalyzed Spiroketalization ................................ .................... 25 1.4.1 Dihydroalkoxylatio n of Alkynediols ................................ .......................... 25 1.4.2 Spiroketalization of Monopropargylic Triols ................................ ............. 33 1.4.3 Intramolecular Reaction of Epoxy Alkynes ................................ .............. 34 1.4.4 Tandem Propargyl Claisen Rearrangement/Spiroketalization of Propargyl Vinyl Ethers ................................ ................................ ................... 38 1.4.5 Oxycarbonylation of Dienones ................................ ................................ 39 1.4.6 Transposition of Allylic A lcohols ................................ .............................. 40 1.4.7 Hetero Diels Alder Reaction ................................ ................................ .... 42 1.4.8 Cyclization of Monoacetylated Ketodiol ................................ ................... 47 1.4.9 Ring Closing Metathesis ................................ ................................ .......... 48 1.4.10 [2+2+2] Cycloaddition of C alkynyl carbohydrates ................................ 50 1.4.11 Cyclization/Cross Bromoketals and Aryl Iodides ................................ ................................ ................................ ... 51 1.4.12 Applications to Natural Product Synthesis ................................ ............. 53 1.4.12.1 Dihydroalkoxylation of alkynediols ................................ ............... 53 1.4.12.2 Spiroketalization of monopropargylic triols ................................ ... 59 1.4.12.3 Cyclization of mono protected ketodiols/hemiketals ..................... 60 1.4.12.4 Ring closing metathesis ................................ ............................... 60 1.5 Outlook ................................ ................................ ................................ ............. 62 2 METAL CATALYZED SPIROKETALIZATION OF MONO ALLYLIC KETODIOLS ................................ ................................ ................................ ........... 63

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7 2.1 Introduction ................................ ................................ ................................ ....... 63 2.2 Preliminary Studies ................................ ................................ ........................... 68 2.2.1 Initial Results ................................ ................................ ........................... 68 2.2.2 Improvements in Substrate Synthesis ................................ ..................... 72 2.3 Optimization of Spiroketalization Conditions ................................ ..................... 76 2.3.1 Spiroketalization using Gold Catalysts ................................ .................... 77 2.3.2 Spiroketalization using Pd(II) and Pt(II) Catalysts ................................ ... 79 2.4 Substrate Scope of Pd(II) catalyzed Spiroketalization ................................ ...... 81 2.4.1 Effect of Ring Size ................................ ................................ ................... 81 2.4.2 Effect of Substituents on Ring A ................................ .............................. 83 2.4.3 Effect of Substituents on Ring B ................................ .............................. 89 2.5 Summary ................................ ................................ ................................ .......... 92 2.6 Other Spirocyclizations Studied ................................ ................................ ........ 92 2.6.1 Pd(II) catalyzed Bis spiroketalization of Monoallylic Diketodiols ............. 92 2.6.2 Metal catalyzed Spiroaminal Formation ................................ .................. 96 3 PALLADIUM(II) CATALYZED STEREOSELECTIVE SPIROKETAL FORMATION ................................ ................................ ................................ .......... 99 3.1 Introduction ................................ ................................ ................................ ....... 99 3.2 Synthesis of Nonanomeric Spiroketals ................................ ........................... 100 3.2.1 Substrate control Approach ................................ ................................ ... 100 3.2.2 Chiral catalyst based Approach ................................ ............................ 103 3.3 Project Aim ................................ ................................ ................................ ..... 106 3.3.1 Effect of Allylic Alcohol Chirality ................................ ............................ 107 3.3.2 Effect of Olefin Geometry ................................ ................................ ...... 112 3.3.3 Rationale for Stereoselectivity Observed ................................ ............... 114 3.3.3.1 ( S ) E monoallylic ketodiols ................................ ........................... 116 3.3.3.2 ( R ) E monoallylic ketodiols ................................ .......................... 117 3.3.3.3 ( S ) Z monoallylic ketodiols ................................ ........................... 118 3.3.3.4 ( R ) Z monoallylic ketodiols ................................ ........................... 119 3.4 Summary and Outlook ................................ ................................ .................... 120 4 CONCLUSION AND OUTLOOK ................................ ................................ ........... 121 5 EXPERIMENTAL SECTION ................................ ................................ ................. 122 5.1 General Remarks ................................ ................................ ............................ 122 5.2 Expe rimental Procedures ................................ ................................ ................ 123 5.2.1 Synthesis of 2 vinyl 1,6 dioxaspiro[4.5]decane ( 2 50 ). .......................... 123 5.2.2 Synthesis of 2 vinyl 1,7 dioxaspiro[5.5]decane ( 2 52 ) ........................... 125 5.2.3 Synthesis of 7 vinyl 1,6 dioxaspiro[4.5]decane ( 2 78 ) ........................... 130 5.2.4 Synthesis of 2 butyl 8 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 67 ) ........... 133 5.2.5 Synthesis of 2 isopropyl 8 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 115 ) .. 137 5.2.6 Synthesis of 11 propyl 2 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 117 ). .... 142 5.2.7 Synthesis of 9,9 dimethyl 2 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 116 ). ................................ ................................ ................................ ............ 146

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8 5.2.8 Synthesis of tert butyldimethyl 8 vinyl 1,7 dioxaspiro[5.5]undecan 4 yloxy)silane ( 2 119 ). ................................ ................................ .................... 150 5.2.9 Synthesis of 3 methyl 2 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 134 ). ..... 156 5.2.10 Synthesis of 4 methyl 2 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 135 ). ... 159 5.2.11 Synthesis of 2 phenethyl 8 (( E ) prop 1 enyl) 1,7 dioxaspiro[5.5]undecane ( 3 55 3 56 and 3 57 ) ................................ .......... 163 5.2.12 Synthesis of glucose derived spiroketals 3 62 3 63 and 3 64 ............ 172 5.2.13 Synthesis of 2 cyclohexylvinyl) 8 phenethyl 1,7 dioxaspiro[5.5]undecane ( 3 70 3 72 and 3 73 ) ................................ .......... 178 LIST OF REFERENCES ................................ ................................ ............................. 187 BIOGRAPH ICAL SKETCH ................................ ................................ .......................... 193

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9 LIST OF TABLES Table page 1 1 Metal catalyzed spiroketalization of monoprotected 4 alkynols .......................... 27 1 2 Metal catalyzed hydroalkoxylation of 4 alkynols ................................ ................. 27 1 3 Ir and Rh catalyzed synthesis of spiroketals from alkynediols ........................... 29 1 4 Ir(I) and Rh(I) single and dual catalyzed synthesis of spiroketals ...................... 31 1 5 Hg(II) catalyzed spiroketalization of internal alkyne diols ................................ ... 33 1 6 Au(I) and Hg(II) catalyzed spiroketalization of monopropargylic triols ............... 35 1 7 HDA of 3,4 epoxy 2 methylenetetrahydrofuran with oxodienes .......................... 44 2 1 Optimization of desilylation step ................................ ................................ ......... 75 2 2 Optimization of conditions for spiroketalization using Gold catalysts .................. 78 2 3 Optimization of conditions for spiroke talization using Palladium(II) and Platinum(II) catalysts ................................ ................................ .......................... 80 2 4 Catalyst screening for spiroaminal formation ................................ ...................... 97

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10 LIST OF FIGURES Figure page 1 1 Spiroketal containing natural products ................................ ............................... 22 1 2 Possible positions of an electronegative substituent at the tetrahydropyran anomeric carbon ................................ ................................ ................................ 23 1 3 Possible conformations of a spiroketal ................................ ............................... 24 1 4 Acid catalyzed spiroketalization ................................ ................................ .......... 25 1 5 ................................ ................................ .................. 26 1 6 Ir(I) and Rh(I) catalysts used by Messerle ................................ .......................... 29 1 7 Au(I) catalyzed cycloisomerization of epoxy alkynes ................................ .......... 36 1 8 ................................ ........................ 46 2 1 Isomers of compound 2 52 with two anomeric relat ionships .............................. 83 2 2 Substrate 2 93 ................................ ................................ ................................ .... 85 3 1 Natural products with nonanomeric spiroketal cores ................................ .......... 99

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11 LIST OF SCHEMES Scheme page 1 1 Regioselectivity in Pd(II) catalyzed dihydroalkoxylation of alkynediols ............... 26 1 2 Proposed mechanism of Pt(II) catalyzed dihydroalkoxylation of alkynes ........... 28 1 3 Proposed dual metal catalyzed dihydroxyalkoxylation of alkynediols ................. 32 1 4 Spiroketalization of monopropargylic triols ................................ ......................... 34 1 5 Au(I) catalyzed spiroketalization of homopropargylic epoxy alkynes .................. 36 1 6 Substrate scope of Au(I) catalyzed spiroketalization of homopropargylic epoxy alkynes ................................ ................................ ................................ ..... 37 1 7 Plausible mechanism of Au(I) catalyzed spiroketalization of homopropargylic epoxy alkynes ................................ ................................ ................................ ..... 37 1 8 Au(I) catalyzed spiroketalization of vinyl propargyl ethers with pendant alcohol nucleophile ................................ ................................ ............................. 39 1 9 Possible intermediate for the spiroketalization of propargyl vinyl ethers ............. 39 1 10 Pd(II) catalyzed oxycarbonylation of dienones ................................ ................... 40 1 11 Re 2 O 7 mediated allylic transposition leading to leucascandrolide A ................... 40 1 12 Re(VII) catalyzed spiroketalization of a diol acetal ................................ ............. 41 1 13 Re 2 O 7 catalyzed allylic alcohol transposition (primary vs secondary alcohol) .... 42 1 14 Re 2 O 7 catalyzed remote 1,9 stereochemical induction ................................ ....... 42 1 15 Hetero Diels Alder approach to spiroketals ................................ ........................ 43 1 16 Isomerization of exo vinyl ethers ................................ ................................ ........ 43 1 17 Origin of diastereoselectivity of HDA ................................ ................................ .. 45 1 18 Enantioselective spiro carbohydrates synthesis ................................ ................. 45 1 19 Model HDA reaction for synthesis of reveromycin A ................................ ........... 46 1 20 HDA approach to the spiroketal core of reveromycin A ................................ ...... 47 1 21 FeCl 3 catalyzed spiroketal formation ................................ ................................ .. 47

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12 1 22 Spiroketalization via cross metathesis of tetraene acetals ................................ 48 1 23 Proposed mechanism for the spiroketalization via cross metathesis of tetraene acetals ................................ ................................ ................................ .. 49 1 24 metathesis approach to spiroketals ................................ ............. 50 1 25 Metal catalyzed [2+2+2] cycloaddition to form spirocarbohydrate derivatives. ... 51 1 26 Ni(II) ca talyzed intramolecular cyclization/intermolecular reductive coupling ..... 51 1 27 Ni(II) catalyzed tandem intramolecular cyclization/re ductive coupling ................ 52 1 28 Proposed mechanism for the Ni(II) catalyzed spiroketalization .......................... 52 1 29 Pd(II) catalyzed synthesis of the spiroketal core of (+) Broussonetine ............... 53 1 30 Pd(II) catalyzed synthesis of the spiroketal moiety of Spirolaxine Methyl Ether ................................ ................................ ................................ ................... 54 1 31 Pd(II) catalyzed synthesis of the spiroketal core of Cephalosphorides ............... 54 1 32 of Hippuristanol ............................... 55 1 33 Proposed mechanism for the Hg(II) catalyzed spiroketalization ......................... 56 1 34 ................................ ........................ 56 1 35 Metal catalyzed spiroketalization en route to Ushikulide A ................................ 57 1 36 Au(I) catalyzed spiroketalization as key step in Spirastrellolide F Methyl Ester synthesis ................................ ................................ ................................ ............ 58 1 37 Au(I) spiroketalization of 1 217 ................................ ................................ ........... 58 1 38 Au(I) catalyzed spiroketalization of 1 219 and 1 223 ................................ .......... 59 1 39 Pd(II) catalyzed synthesis of spiroketal 1 225 ................................ ................... 60 1 40 .............................. 61 1 41 closing metathesis approach to the spiroketal moiety of Spirastrellolide A ................................ ................................ ................................ 61 2 1 Activation of allylic alcohols by allyl complex formation ................................ .. 63 2 2 Activation of allylic alcohols by coordination to olefin and alcohol ...................... 63 2 3 Activation of allylic alcohols by coordination to the olefin ................................ ... 64

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13 2 4 Activation of allylic alcohols by allyl cation formation ................................ .......... 64 2 5 Selected examples of metal catalyzed cyclization of monoallylic diols ............... 65 2 6 Au(I) catalyzed sy nthesis of tetrahydropyrans ................................ .................... 65 2 7 Proposed Au(I) catalyzed spiroketalization ................................ ........................ 66 2 8 Pd(II) catalyzed cyclizations involving hemiacetal intermediates ........................ 67 2 9 Retrosynthesis for the synthesis of spiroketal precursor 2 21 ............................ 68 2 10 Addition of Grignard reagent 2 26 to lactone 2 25 ................................ .............. 68 2 11 Revised retrosynthesis of the spiroketal precursor ................................ ............. 69 2 12 Synthesis of Weinreb amide 2 36 ................................ ................................ ....... 70 2 13 Synthesis of bromides 2 43 and 2 44 ................................ ................................ 70 2 14 Addition of organometallic reagents to 2 43 and 2 44 ................................ ........ 70 2 15 Deprotection of 2 46 and 2 47 ................................ ................................ ............ 71 2 16 Preliminary reaction condition screening results ................................ ................. 71 2 17 Synthesis of 2 53 ................................ ................................ ................................ 72 2 18 Cross metathesis NaBH 4 reduction sequence en route to 2 55 ......................... 72 2 19 Cross metathesis of 2 53 and allyl alcohol using G2 catalyst ............................. 73 2 20 Synthesis of 2 49 ................................ ................................ ................................ 73 2 21 Synthesis of 2 61 using different chemoselective reduction conditions .............. 74 2 22 Optimized synth esis of monoallylic ketodiol 2 62 ................................ .............. 77 2 23 Formation of hemiketal 2 71 ................................ ................................ ............... 79 2 24 Synthesis of unsubstituted monoallylic ketodiols ................................ ................ 81 2 25 Pd(II) catalyzed spiroketalization of unsubstituted monoallylic ketodiols ............ 82 2 26 Cyclization to form ring A substituted spiroketals ................................ ............... 83 2 27 Synthesis of mo noallylic ketodiols with alkyl substituents on ring A ................... 84 2 28 Attempts to synthesize 2 97 or 2 99 ................................ ................................ ... 85

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14 2 29 Attempts to synthesize compound 2 93 ................................ .............................. 86 2 30 Synthesis of 2 114 ................................ ................................ ............................. 87 2 31 Pd(II) catalyzed spiroketalization to form ring A substituted spiroketals ............. 88 2 32 Pd(II) catalyzed spiroketalization to obtain ring B substituted spiroketals .......... 89 2 33 Synthesis of alkenyl bromides 2 122 and 2 124 ................................ ................. 90 2 34 Synthesis of monoallylic ketodiols 2 132 and 2 133 ................................ ........... 90 2 35 Pd(II) catalyzed spiroketalization to form ring B substituted spiroketa ls ............. 91 2 36 Three possible diastereomers of 2 134 ................................ .............................. 92 2 37 Proposed Pd(II) catalyzed bis spiroketalization ................................ .................. 93 2 38 Synthesis of monoallylic diketodiol 2 143 ................................ ........................... 94 2 39 Attempted bis spiroketalization of 2 143 ................................ ............................. 94 2 40 Synthesis of monoallylic diketodiol 2 136 ................................ ........................... 95 2 41 Attempted bis spiroketalization of 2 136 ................................ ............................. 95 2 42 Proposed metal catalyzed spiroaminal formation ................................ ............... 96 2 43 Synthesis of spiroa minal precursor 2 154 ................................ .......................... 97 3 1 ............. 101 3 2 Non anomeric spiroketals via methanol induced kinetic spiroketalization of syn glycal epoxides ................................ ................................ .......................... 102 3 3 Non anomeric spiroketals via Ti(O i Pr) 4 induced kinetic spiroketalization of anti glycal epoxides ................................ ................................ .......................... 103 3 4 catalyzed spiroketalization ................................ ............. 104 3 5 ori .................... 105 3 6 ori tive spiroketalization ................................ .............. 105 3 7 catalyzed diastereoselective spiroketalization ................ 106 3 8 Proposed stereoselective spiroketal synthesis ................................ ................. 107 3 9 Preparation of synthetic intermediate 3 50 ................................ ....................... 108

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15 3 10 Preparation of 3 53 and 3 54 ................................ ................................ ............ 109 3 11 Spiroketalization of 3 53 and 3 54 ................................ ................................ .... 110 3 12 Diagnostic nOe or NOESY correlation observed for spiroketalization products 110 3 13 Synthesis of 3 60 and 3 61 ................................ ................................ ............... 111 3 15 Diagnostic nOe or NOESY peaks observed for spiroketalization products 3 23 3 24 and 3 25 ................................ ................................ ............................. 112 3 16 Preparation of Z monoallylic ketodiols 3 68 and 3 69 ................................ ....... 113 3 17 Spiroketalization of Z monoallylic ketodiols 3 68 and 3 69 ............................... 114 3 18 Origin of stereoselectivity in the spiroketalization of ( S ) E monoallylic ketodiols (R = CH 2 CH 2 Ph) ................................ ................................ ................ 116 3 19 Origin of stereoselectivity in the spiroketalization of ( R ) E monoallylic ketodiols (R = CH 2 CH 2 Ph) ................................ ................................ ................ 117 3 20 Origin of stereoselectivity in the spiroketalization of ( S ) Z monoallylic ketodiols (R = CH 2 CH 2 Ph) ................................ ................................ ................ 118 3 21 Origin of stereoselectivity in the spiroketalization of ( R ) Z monoallylic ketodiols (R = CH 2 CH 2 Ph) ................................ ................................ ................ 119 3 22 Stereoselectivity in Pd(II) catalyzed spiroketalization ................................ ....... 120 5 1 Synthesis of 2 48 ................................ ................................ .............................. 123 5 2 Sy nthesis of 2 49 ................................ ................................ .............................. 127 5 3 Synthesis of 2 77 ................................ ................................ .............................. 131 5 4 Sy nthesis of 2 62 ................................ ................................ .............................. 13 5 5 5 Synthesis of 2 91 ................................ ................................ .............................. 139 5 6 Synthesis of 2 90 ................................ ................................ .............................. 144 5 7 Sy nthesis of 2 92 ................................ ................................ .............................. 148 5 8 Synthesis of 2 114 ................................ ................................ ............................ 153 5 9 Synthesis of 2 132 ................................ ................................ ............................ 157 5 10 Synthesis of 2 133 ................................ ................................ ............................ 160

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16 5 11 Synthesis of 3 48 ................................ ................................ .............................. 165 5 12 Synthesis of 3 66 ................................ ................................ .............................. 178 5 13 Synthesis of 3 68 ................................ ................................ .............................. 180 5 14 Synthesis of 3 69 ................................ ................................ .............................. 183

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17 LIST OF ABBREVIATION S A C acetyl B n benzyl Boc t butoxycarbonyl Brsm based on recovered starting material Bu n butyl Bz benzoyl Cat. catalytic Conc. concentration CSA camphorsulfonic aci d DBU 1,8 diazabicyclo[5.4.0]undec 7 ene DCM dicholoromethane DDQ 2,3 dichloro 5,6 dicyano 1,4 benzoquinone dr diastereomeric ratio DIBAL H diisobutylaluminum hydride DIPT diisopropyl tartrate DMAP N N 4 dimethylaminopyridine DMF dimethylformamide EDCI 1 ethyl 3 (3 dimethylaminopropyl)carbodiimide hydrochloride ee enantiomeric excess equiv equivalent Fmoc 9 fluorenylmethoxycarbonyl Imid imidazole IPA isopropyl alcohol LAH lithium aluminum hydride

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18 LDA lithium diisopropylamide m CPBA meta chloroperbenzoic acid Mes mesitylene MS molecular sieves n normal (e.g. unbranched alkyl chain) NMO N morpholine oxide NMR nuclear magnetic resonance NR no reaction Nuc nucleophile (general) Ph phenyl PMB p methoxybenzyl PPTS pyridinium p toluenesulfonate TsOH p toluenesulfonic acid Pyr pyridine r.t. room temperature R f retention factor (in chromatography) TBAB tetra n butylammonium bromide TBAF tetra n butylammonium fluoride TBAI tetra n butylammonium iodide TBS t butyldimethylsilyl TBDPS t butyldiphenylsilyl TEMPO 2,2,6,6 tetramethyl 1 piperidinyloxy free radical TfOH trifluromethanesulfonic acid THF tetrahydrofuran THP 2 tetrahydrofuranyl

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19 TMS trimethylsilyl Ts p toluenesulfonyl

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20 Abstract of Dissertation Presented to the Graduate School of the University of F lorida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy METAL CATALYZED SPIROKETALIZATION OF MONOALLYLIC KETODIOLS By Jean Alcaraz Palmes August 2012 Chair: Aaron Aponick Major: Chemistry Spiroketals are found in a myriad of natural products that show potential biological activity. Traditional methods to prepare spiroketals require harsh conditions. An alternative approach is to use mild reaction conditions associated with metal catalysis. As an expansion activation of allylic alcohols, the method presented in this thesis aims to prepare spiroketals from monoallylic ketodiols. Gold(I), palladium(II), and platinum(II) compounds were demonstrated vinyl spiroketals, but PdCl 2 (CH 3 CN) 2 determined to be the optimal catalyst. The newly developed Pd( II) catalyzed spiroketalization conditions efficiently converts various monoallylic ketodiols to [6,6] [6,5] and [5,6] spiroketal systems in high yields (60 90%) and diastereoselectivities up to 20:1. The presence of substituents in either of the spirok etal rings is also tolerated even at low (5 mol%) catalyst loadings. The Pd(II) catalyzed transformation was also applied to the stereoselective construction of spiroketals. The method proves to be successful in accessing either anomeric or nonanomeric sp iroketals by simply varying the absolute configuration of the allylic alcohol and the geometry of the olefin. Even in highly substituted monoallylic

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21 ketodiol precursors, nonanomeric spiroketals can be synthesized starting with an ( R ) E or ( S ) Z monoallyli c ketodiol. However, t he spiroketalization of E olefin substrates is generally faster and high yielding than the Z olefin counterparts. The stereocomplementary nature of this methodology will be useful in natural product synthesis especially for compounds in which the absolute configuration of the spiroketal is not known.

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22 CHAPTER 1 RECENT ADVANCES IN T RANSITION METAL CATALYZED SPIR OKETALIZATION S 1.1 Spiroketals in Nature Spiroketals are cyclic ketals in which two rings are connected to a single carbon atom called the spiro carbon. Each of the ketal oxygens joined by the spiro atom belongs to one of the rings. The spiroketal ring system is an important synthetic target beca use it exists as a structural feature in a myriad of natural products of biological interest ranging from insect pheromones, polyether ionophores, macrolide antibiotics Figure 1 1. Spiroketal containing natural products

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23 and steroidal saponins. 1 For example, t automycin 1 1 3 okadaic acid 1 2 4 and spongistatins 1 3 2 and 1 4 5 which are protein phosphatase inihibitors, all contain spiroketals in their structural manifold (Figure 1 1) To date, the stereoselective synthesis of spiroketals still remains a challenge for synthetic chemists T hese fragments often serve as pharmacophores in biological sy s tems owing to the conformational constraints brought about by the rigidity of the s e moieties 6 1.2 Conformational Aspects of Spiroketal Structures The stereochemistry o f spiroketals is influenced largely by anomeric effect. 7 However, intramolecular hydrogen bonding, steric interactions, and chelation also contribute to the relative configuration and stabilities of these bicyclic systems. 8 The anomeric effect is defined a s the tendency of an electronegative atom at the anomeric carbon of a pyranose ring to assume an axial orientation. This orientation allows the axial lone pair of oxygen to interact with the antibonding orbital of the C O bond (Figure 1 2A). This overla p is not possible if the substituent X is in an equatorial position (Figure 1 2B). Each anomeric interaction contributes a stabilization of approximately 1.4 2.4 kcal/mol to the total energy of the molecule. 9 Figure 1 2. Possible positions of an electronegative substituent at the tetrahydropyran anomeric carbon. A) axial. B) equatorial The 6,6 spiroketal core can have four different conformations interconverted by ring flipping (Figure 1 3). 1f The first conformation A has two anomeric interactions and

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24 is the most thermodynamically stable isomer. Two possible conformations exhibit one anomeric effect (Figure 1 3 B and C ) and one with no anomeric relationship (Figure 1 3 D ). Figure 1 3. Possible conformations of a spiroketal 1.3 Traditional Approaches to Spiroketal Synthesis The most common method to prepare spiroketals is by the acid catalyzed cyclization of dihydroxyketones 1 5 (Figure 1 4) 1e With this methodology, the most thermodynamically stable spiroketal stereoisomers, which benefit from conformational anomeric effects, are easily obtained. 7 Most natural products have this conformation and sometimes this method is often effective for their synthesis However, the presence of acid labile functional groups in the same molecule becomes a limitation of the reaction scope. Moreover, synthesis of nonanomeric or contrathermodynamic spiroketals is very challenging using this route.

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25 Figure 1 4. Acid catalyzed spiroketalization 1.4 Transition M etal Catalyzed Spiroketalization Due to the harsh conditions and multi step synth esis associated with spiroketal synthesis through traditional methods, transition metal catalyzed spiro keta lization methods have been developed in the past two decades. Recent developments mostly involved metal catalyzed spiroketali zation of alkyne diols u sing Au ( I ) Au ( III ) Pd ( II ) Hg ( II ) Ir ( I ) and Rh ( I ) Novel transformations leading to formation of spiroketals catalyzed by Re ( VII ) Eu ( III ) Fe ( III ) Ni ( II ) and Ru ( II ) have also been reported. 1.4.1 Dihy droalkoxylation of Alkynediols Alkyne diols can be considered a dihydroxyketone equivalent. The alkyne serves as a masked ketone that is relatively inert toward many transformations. Utimoto et al. pioneered the use of Pd(II) in the hydroalkoxylation of internal alkynediols to form spir oketals based on the observation that in the presence of catalytic amount of PdCl 2 (PhCN) 2 alcohols react with dihydropyran to form dihy d ropyranyl ethers. When solutions of alkynediols were treated with PdCl 2 (PhCN) 2 or PdCl 2 smooth conversion to spiroke tals were attained (Figure 1 5) 10 In the case of 4 nonyne 1,9 diol 1 11 the 5,7 spiroketal 1 10 was selectively obtained De Brabander and coworkers also studied the cyclization of 1 11 and obtained a mixture of 1 10 and 1 12 spiroketals in a 2 :1 ratio 11 This regioselectivity can be attributed to the possibility of both endo dig 1 13 or exo dig 1 14 attack of the primary alcohols to the alkyne moiety (Scheme 1 1)

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26 Figure 1 5 Scheme 1 1. Regioselectivity in Pd(II) catalyzed dihydroalkoxylation of alkynediols In an attempt to address the regioselectivity issue and to favor the formation of 6,6 spiroketal 1 12 De Brabander and coworkers subjected the THP monoprotected alkynediol 1 15 to a catalyst screening (Table 1, entries 1 6). A mixture of 6 exo dig 1 12 and 7 endo dig 1 10 products were obtained for each catalyst. Low yields (36 52%) and regioselectivities ( 1 12 : 1 10 up to 2.2:1) were observed for PdCl 2 (Table 1 1, Entry 1), cationic gold(I) (Entries 2 and 3) and AuCl 3 (Entry 4). Pt( II ) catalysts, on the other hand, gave spiroketals in high yields and regioselectivity favoring 1 12 (Entries 5 & 6). 2 Pt( CH 2 CH 2 )] 2 was chosen as the best catalyst owing to shorter reaction time albeit lower selectivity compared to PtCl 2 (30:1 vs 116:1, Entry 5 vs 6). When the protecting group was changed to TBS, a slight decrease in regioselectivity was observed (20:1 vs 30 :1) but higher overall yield (83% vs 75%) (Entry 7).

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27 Table 1 1. Metal c ata lyzed s pirok etalization of monoprotected 4 a lkynols Entry R Catalyst Time (h) Yield (%) [a] Product ratio [a ] ( 1 12 : 1 10 ) 1 [b] THP 1% PdCl 2 1.5 52 2:1 2 THP 1% MeAuPPh 3 10% TfOH 0.5 40 1.3:1 3 THP 5% AuClPPh 3 /AgOTf (1:1) 0.5 36 2:1 4 THP 5% AuCl 3 0.5 41 2.2:1 5 THP 2% PtCl 2 24 [c ] 64 116:1 6 THP 1% [Cl 2 Pt(CH 2 CH 2 )] 2 0.5 75 30:1 7 TBS 1% [Cl 2 Pt(CH 2 CH 2 )] 2 0.5 83 20:1 [ a] Yields (at >95% conversion) and ratios ( 1 12 : 1 10 ) determined by GC with an external standard [b] MeCN was used as solvent [c] <5% conversion at 30 min. Table 1 2. Metal catalyzed h ydroalkoxylation of 4 alkynols Entry R Catalyst (mol%) Time (h) Product ratio [a } ( 1 12 : 1 10 ) Yield (%) [a ] 1 THP 1% [Cl 2 Pt(CH 2 CH 2 )] 2 [b] 0.5 11:1 70 2 THP 1% [Cl 2 Pt(CH 2 CH 2 )] 2 0.5 9:1 60 3 TBS 1% [Cl 2 Pt(CH 2 CH 2 )] 2 0.5 3.7:1 58 4 H 3% PdCl 2 (PhCN) 2 3 1:2 >95 5 H 1% MeAuPPh 3 /AgPF 6 [c] 0.5 1:3.7 92 6 TBS 5% MeAuPPh 3 /AgPF 6 [c] 13 1:6.6 73 [a] Determined by GC. [b] solvent is dioxane [c] solvent is i Pr 2 O The 4 alkynols 1 16 were also subjected to metal catalysis to determine the which conditions favor the formation of 5 exo dihydroalkoxylation ( Table 1 2) Pt ( II ) favored the formation of 6 endo spiroketal 1 12 in moderate yields ( E ntries 1 3), whereas Pd ( II ) only

PAGE 28

28 slightly favored the formation of the 5 exo product 1 10 (E ntry 4). Au ( I ) gave the best yields in favor of the 5 exo spiroketal 1 10 (E ntries 5 6). Scheme 1 2. Proposed mechanism of Pt(II) catalyzed dihydroalkoxylation of alkynes T he authors proposed a mechanism for the spiroketalization which involves the intramolecular attack of the alcohol to Pt (II) activated alkyne 1 17 to give rise to either endo 1 1 8 or exo 1 1 9 adducts (Scheme 1 2) The platinated oxycarbenium species 1 21 and 1 2 2 are then formed from tautomerization of 1 18 and 1 1 9 Intramolecular attack of the pendant alkoxy functionality to the oxycarbenium species give the spiroketals 1 12 and 1 10 after de metallation Messerle et al reported the use of Ir ( I ) 1 2 3 an d Rh ( I ) 1 2 4 catalysts with bidentate ligands in the formation of spiroketals via intramolecular dihydroalkoxylation of alkynediols (Figure 1 6) 12

PAGE 29

29 Figure 1 6 Ir (I) and Rh (I) catalysts used by Messerle Table 1 3. Ir and Rh catalyzed synthesis of spiroketals from alkynediols E ntry Catalyst, mol% S ubstrate Product % Conv.(hrs) [a] 1 2 Ir I 5.0 Rh I 5.0 >98 (22) 1 26 : 1 2 7 = 50:50 >98 (15) 1 26 : 1 2 7 = 37:63 3 4 Ir I 5.0 Rh I 5.0 >98 (174) >98 (21) 5 6 Ir I 5.0 Rh I 5.0 >98 (22) >98 (5.5) 1 31 : 1 32 = 87:13 [a] Performed in C 2 D 2 Cl 4 at 120 C Treatment of internal alkyne diols with the catalysts led to the formation of desired spiroketals (Table 1 3). Rh(I) 1 24 was shown to be a more effective catalyst than Ir(I)

PAGE 30

30 1 23 in the conversion of alkynediols 1 25 1 28 and 1 30 to spiroketals. When Rh (I) was used in the cyclization of 1 30 a side product 1 32 resulting from dehydration was observed (Entry 6 ). Messerle and coworkers expanded their work by conducting a detailed investigation on Rh ( I ) and Ir ( I ) single and dual metal catalyzed dihydroalkoxylation reactions of alkynediols ( Table 1 4 ) 1 3 After a series of studies on the effect of ligand and counterions, [Rh(bpm) ( CO ) 2 ]BAr F 4 1 2 4 and [Ir(bpm) ( CO ) 2 ]BAr F 4 1 2 3 proved to be the most efficient catalysts Ir ( I ) complex 1 23 was a better catalyst in the formation of 5,5 spiroketal 1 8 whereas Rh ( I ) complex 1 24 promote d the formation of 6,6 spiroketal 1 3 5 (Entries 1 3 vs. Entries 4 6 ) In substrates where the cyclization can proceed with the simultaneous ring closure to both 5 exo and 6 endo rings, the use of the dual metal catalyst system enhanced the reactivity compared to individual single metal catalysis ( Entries 7 1 5 ) The reactiv ity of the cyclization is not dependent on the nature of the substituents (aromatic or aliphatic) but rather on the size of the ring formed. T he authors proposed a dual metal activation mechanism composed of two C O bond formation cycles ( Scheme 1 3 ). The coordination of the metal (Rh/Ir) to the alkyne to generate the intermediate 1 38 The nucleophilic alcohol then attacks the activated alkyne through a 5 exo (i) or 6 endo (ii) cyclization, the rates of which are controlled by the re spective Rh or Ir complexes. The catalytic species 1 23 and 1 24 are regenerated after protodemetallation and the intermediate furan 1 4 1 or pyran 1 4 2 coordination of the complex to the enol Nucleophilic att ack of the pendant alcohol followed by rearrangement and

PAGE 31

31 protonation affords the spiroketals 1 2 7 and 1 2 6 I solation of monocyclized products 1 41 and 1 4 2 as minor products provided a n experimental evidence for this mechanism Table 1 4. Ir(I) and Rh(I) single and dual catalyzed synthesis of spiroketals Entry Substrate Product Catalyst time, h TOF 1 Rh 0.15 714 2 Ir 0.18 1126 3 Rh + Ir 0.11 1014 4 Rh 0.28 794 5 Ir 1.73 177 6 Rh + Ir 0.59 435 7 Rh 8.2 56 8 Ir 7.2 45 9 Rh + Ir 2.10 122 10 Rh 1.03 381 11 Ir 0.55 372 12 Rh + Ir 0.32 556 13 Rh 0.22 (0.7:1)* 961 14 Ir 0.58(0.9:1)* 374 15 Rh + Ir 0.13(0.8:1)* 1694 Reaction conditions : 1 mol% catalyst, CD 2 Cl 2 100 C, NMR scale ; *product ratio ( 1 27 : 1 26 ) Deslongchamps et al. reported the use of Hg(OTf) 2 catalyzed spiroketalization of a monoprotected alkyne diol in the synthesis of Hippuristanol 14 and studied the scope and limitations of this cyclization process. 15 1 1 5 was used as a

PAGE 32

32 benchmark for the reaction. Treatment of substrate with 10 mol% of Hg(OTf) 2 in aqueous CH 3 CN at ambient temperature formed spir oketal 1 12 exclusively. Interestingly, compounds ( 1 11 1 16 1 49 and 1 50 ) all gave 6,6 spiroketals despite the possibility of 5 exo dig cyclizations (Table 1 5, Entries 1 5). This implies the preference of this catalyst system to favor the 6 exo dig cyclization rather than 7 endo or 5 exo dig cyclizations. Spiroketalization of substrates 1 53 and 1 54 to give 5,6 spiroketal 1 55 also proceeded smoothly in high yields and short reaction times (Entries 6 7). Scheme 1 3. Proposed dual metal catalyzed dihydroxyalkoxylation of alkynediols

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33 Table 1 5 Hg(II) catalyzed s piroketalization of i nternal a lkyne d iols entry substrate product [a] time yield [b] % 1 45 min 90 [c] 2 1 12 45 min 92 [d] 3 1 12 45 min 90 [c] 4 1 49 R = H 45 min 94 [d] 5 1 50 R = THP 1 52 45 min 90 [c] 6 1 53 R = H 10 min 92 [d] 7 1 54 R = THP 1 55 10 min 90 [c] [a] all products were prepared as racemic mixtures [b] isolated yields [c] procedure A [d] procedure B 1 .4.2 Spiroketalization of Mono propargylic Triols The spiroketalizations described above involved acetylenic diols and pose a challenge because of inherent regioselectivity issues. Whereas metal catalyzed dihydroalkoxylation of alkyne diols can lead to a mixture of spiroketals 1 10 and 1 12 (Scheme 1 1), cyclization of homopropargylic triols are regioselective. With an appropriate propargylic alcohol, the double bond can be strategically positioned (Scheme1 4).

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34 Scheme 1 4. Spiroketalization of monopropargylic triols In 2008, Aponick and coworkers reported the dehydrative cyclization of monopropargylic triols 1 56 to monounsaturated spiroketals 1 57 in the presence of a cationic gold complex. 16 Good to excellent yields were obtained with 2 mol% of Au[P( t Bu) 2 ( o biphenyl]Cl/AgOTf and the reaction was tolerant of different substitution patterns (Table 1 6). In 2011, Deslongchamps et al. repeated this work and showed that Hg(II) can also catalyze the conversion of monopropargylic triols to monounsaturated spiroketals. 15 Treatment of compound 1 58 with Hg(OTf) 2 in CH 3 CN at room temperature gave a smooth conversion to 1 59 (9 0 % yield) in 5 minutes. Examin ation of different substrates under the standard conditions revealed short reaction times and excellent yields (Table 1 6). It should be noted that 10 mol% Hg(II) catalyst is employed in comparison to 2 mol% of the original Au(I) salt. 1.4.3 Intramolecular Reaction of Epoxy Alkynes P revious work by Shi and coworkers demonstrated that exocyclic vinyl ethers 1 73 can be obtained by intermolecular addition of nucleophiles to epoxy alkynes 1 72 in the presence of gold (I) (Figure 1 7) 17 The reaction was extended to the intramolecular reaction of homopropargylic alcohols with epoxides to afford spiroketals. 18 In the presence of 5 mol% of [AuClPPh 3 ]/AgSbF 6 and 30 mol% p TsOH in EtOH at room temperature, the epoxy alcohol 1 74 was converted to the desired spiroketal 1 7 5 in moderate yield and diastereoselectivity along with side product 1 76 TsOH was

PAGE 35

35 Table 1 6 Au (I) and Hg (II) catalyzed spiroketalization of monopropargylic triols Entry Substrate Product Cond [a] Time (min) Yield (%) [b] 1 A B 60 5 81 90 2 A 105 88 3 A 25 81 4 A B 80 5 80 96 5 A 35 99 6 A 60 74 7 B 5 90 [a] A 1 6 : 2 mol% Au[P( t Bu) 2 ( o biphenyl)]Cl/AgOTf, THF, MS 4, 0 C; B 1 5 : 10 mol% Hg(OTf) 2 CH 3 CN, r.t. [b] Isolated yields.

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36 believed to facilitate oxirane ring opening (Scheme 1 5). Figure 1 7 Au ( I ) catalyzed cycloisomerization of epoxy alkynes T he diastereoselectivity decreased as the alcohol nucleophile became bulkier (MeOH, d.r. 12:88 vs i PrOH, d.r. 35:65). When very bulky alcohols such as t BuOH and neopentyl alcohol were used, the side product 1 76 was exclusively obtained and in low yield (Scheme 1 5) Substitution at the homopropargylic position favor s the formation of the side product (Scheme 1 6, Equation 1) whereas the presence of a phenyl group substituent in the of the oxirane ring led to the smooth conversion to the desired spiroketal 1 86 in high yield and diastereoselectivity (Scheme 1 6, Equation 2) Scheme 1 5. Au(I) catalyzed spiroketalization of homopropargylic epoxy alkynes

PAGE 37

37 (1) (2) Sc heme 1 6. Substrate scope of Au(I) catalyzed spiroketalization of homopropargylic epoxy alkynes Scheme 1 7. Plausible mechanism of Au(I) catalyzed spiroketalization of homopropargylic epoxy alkynes

PAGE 38

38 A plausible reaction mechanism was proposed based on experimental results (Scheme 1 7) Nucleophilic attack of the pendant alcohol to the activated alkyne gives the intermediate 1 88 which upon attack of EtOH gives rise to k etal 1 89 This intermediate was isolat ed in an experiment using standard reaction condition s with omission of TsOH Intermolecular attack by EtO H to the TsOH or cationic gold complex activated oxirane ring and subsequent ketalization gives rise to interm ediates 1 90 and 1 92 Spiroisomerization favoring the formation of the anomeric spiroketal 1 93 via intermediate 1 94 accounts for the observed diastereoselectivity of the reaction. 1.4.4 Tandem Propargyl Claisen Rearrangement/Spiroketalization of Proparg yl Vinyl Ethers Toste et al. reported a stereoselective synthesis of dihydropyran hemiketal s through a Au(I) catalyzed rearrangement of propargyl vinyl ethers in the presence of water. 19 When an alcohol nucleophile was instead tethered to the substrate, an intramolecular reaction between the alcohol and the propargyl vinyl ether provided an entry to spiroketal structures. Treatment of 1 9 6 and 1 9 7 with 1 mol% of [(Ph 3 PAu) 3 ]OBF 4 1 9 5 provided the anomerically stabilized spiroketals 1 98 and 1 99 respectively, with complete stereocontrol over three stereogenic centers (Scheme 1 8 Equation 1). Additionally, complete chirality transfer was observed when the enantiomerically enriched propargyl vinyl ether 1 100 was converted to spiroketal 1 101 u sing the standard reaction conditions (Scheme 1 8 Equation 2). The reaction is believed to proceed through an oxocarbenium intermediate 1 103 which is trapped by the pendant alcohol nucleophile (Scheme 1 9 ).

PAGE 39

39 Scheme 1 8 Au(I) catalyzed spiroketalization of vinyl propargyl ethers with pendant alcohol nucleophile Scheme 1 9 Possible intermediate for the spiroketalization of propargyl vinyl ethers 1.4.5 Oxycarbonylation of Dienones Yadav et al. reported the construction of bifunctional spiroketals by the Pd (II) catalyzed double cyclization of dienones. 20 Using a catalytic amount of PdCl 2 in the presence of CuCl 2 CO, MeOH and trimethylorthoformate, dienone 1 105 and 1 106 were converted to spiroketal s 1 107 and 1 108 respectively, with simultaneous introduction of two carboxymethyl groups in the side chain ( Scheme 1 10 Equation 1). The product was believed to form from the intermediate dimethyl acetals of dienones

PAGE 40

40 that were formed in situ In a control experiment where 1 109 was treated in the same reaction conditions, the dienone dimethyl acetal gave the spiroketal 1 110 (Scheme 1 10 Equation 2). (1) (2) Scheme 1 10 Pd(II) catalyzed oxycarbonylation of dienones 1.4.6 Transposition of Allylic Alcohols Scheme 1 1 1. Re 2 O 7 mediated allylic transposition leading to leucascandrolide A During the synthesis of leucascandrolide A, Floreancig et al. subjected the allylic alcohol 1 111 to Re 2 O 7 mediated allylic alcohol transposition. 21 They found that exposing the C19 epimer 1 112 to the same conditions led to the same product 1 113 indicating that epimerization occurs during the transposition and therefore any epimer of the allylic alcohol ca n be used for the transposition (Scheme 1 1 1 ).

PAGE 41

41 Floreancig et al. investigated the applicability of this dynamic thermodynamic stereocontrol process to the synthesis of vinyl lactols via transposition/ hemiketal formation and vinyl tetrahydropyrans through a tandem transposition/oxa Michael addition sequence. In most cases, high stereocontrol w as achieved with ketal substrates and secondary allylic alcohols. 22 These results can be explained by the greater stability of the oxocarbenium ion from the ionizatio n of ketals and the ease of ionization of secondary alcohols. The strategy was extended to the formation of spiroketals. Diol acetal 1 115 was subjected to Re 2 O 7 mediated allylic alcohol transposition and provided a mixture of spiroketals 1 116 and 1 117 in 30 minutes in a 1:1 ratio. Increasing the reaction time to 12 hours greatly improved t he diastereoselectivity (dr > 20:1) and the thermodynamic product with two anomeric effects and both vinyl groups equatorial 1 116 was preferentially formed (Scheme 1 1 2 ). Scheme 1 12 Re(VII) catalyzed spiroketalization of a diol acetal Ketodiol 1 118 with primary allylic alcohol s react slowly under the reaction condition s and also demand the use of MeOH, which was postulated to help in the ring opening during the equilibration process ( Scheme 1 13 Equation 1). In contrast, secondary alcohol 1 119 reacted rapidly under the standard conditions to yield a single diastereomer (Scheme 1 13 Equation 2).

PAGE 42

42 (1) (2) Scheme 1 1 3 Re 2 O 7 catalyzed allylic alcohol transposition (primary vs secondary alcohol) Scheme 1 1 4 Re 2 O 7 catalyzed remote 1,9 stereochemical induction The process was also shown to promote a remote 1,9 stereoinduction. When enantiomerically pure ketodiols 1 121 and 1 122 were subjected to the reac tion, a single diastereomer of 1 123 and 1 124 respectively, was observed with minimal racemization ( Scheme 1 14 ). 1.4.7 Hetero Diels Alder Reaction Hetero Diels Alder (HDA) reactions are a convergent way to prepare spiroketals. 23 The [4+2] cycloaddition of enone/enal 1 125 methylene furan 1 126 or pyran 1 127 will provide the 6,5 and 6,6 spiroketals 1 128 and 1 129 respectively (Scheme 1

PAGE 43

43 1 5 ) A challenge for an HDA approach to spiroketals is the isomeriz ation of exo vin yl ether 1 130 to the more stable endo vinyl ether 1 131 under mildly acidic conditions ( Scheme 1 16 ). Scheme 1 1 5 Hetero Diels Alder approach to spiroketals Scheme 1 1 6 Isomerization of exo vinyl ethers The first metal catalyzed spiroketalization using HDA approach was reported by Pale et al. in 1988 in the reaction of acrolein derivatives with 3,4 epoxy 2 methylenetetrahydrofuran. 24 a ,b The oxirane substrates were prepared from the MCPBA epoxidation of Z 2 pent 4 yn 1 ol derivatives followed by a s ilver ion catalyzed i ntra m o l ecu l ar cyclization 24 b The epoxy group was installed for a variety of reasons: 1) to prevent isomerization and enhance double bond reactivity of the exo vinyl ether due to electronic effects, 2) for diastereoinduction and 3) ease of functional group manipulation. Different Lewis acids were screened for the reaction (Table 1 7 ). The presence of mild Lewis acids increased the rate of reaction, however, Yb(OTf) 3 (Entry 2) was ineffective. SnCl 2 (Entry 3) was almost as effective as ZnCl 2 but ZnCl 2 was chosen as the reagent of choice THF was determined as the best solvent. High

PAGE 44

44 diastereoselectivity was observed for HDA reactions of substituted acrolein derivatives 1 135 and 1 136 (Entries 5 7). Table 1 7 HDA of 3,4 epoxy 2 methylenetetrahydrofuran with oxodienes Entry Dienophile Diene [a] Condition (solvent/ cat) Time (d) Adduct Yield (%) 1 neat 8 45 2 1 132 1 133 neat/ Yb(fod) 3 4 1 134 21 3 1 13 2 1 133 PhH/ SnCl 2 2 1 13 4 70 4 1 132 1 133 PhH/ ZnCl 2 18 1 13 4 84 5 1 13 2 THF/ ZnCl 2 2 53 6 1 132 THF/ ZnCl 2 3 63 7 1 133 THF/ ZnCl 2 2 70 a. 3 equivalents of diene was used (except Entry 1 which used only 1 equivalent) The diastereoselectivity can be explained by the end o transition state 1 141 of the cycloaddition, and the approach anti to the allyl ic epoxy substituent (Scheme1 1 7 ).

PAGE 45

45 Scheme 1 17 Origin of diastereoselectivity of HDA (1) (2) Scheme 1 1 8 Enantioselective spiro carbohydrates synthesis Jrgensen reported the preparation of optically active spiro carbohydrates via enantioselective HDA approach. 25 unsaturated keto esters 1 142 and 1 143 methylene furan 1 145 in the presence of t Bu Box Cu(OTf) 2 gave the endo spiroketals 1 146 and 1 148 as the major diastereomers in 74% and 76% ee,

PAGE 46

46 respectively ( Scheme 1 1 8 Equation 1). Further manipulation of 1 149 gave the carbohydrate like spiroketal 1 150 (Scheme 1 1 8 Equation 2). In the synthesis of reveromycin A, Riccazasa and coworkers proposed a stereoselective HDA between the oxodiene and the optically pure dienophile. 2 6 It was envisioned that the [4+2] cy cloaddition will proceed through the axial approach of the carbonyl oxygen (Figure 1 8 ). Figure 1 8 A model system was studied using a simple methylenepyran. In previous studies, K 2 CO 3 was shown to be effective in suppressing the isomerisation of and promoting the HDA of 1 152 with simple heterodienes. 27 However, with th ese condition s poor yields were obtained because of the base sensit ivity of the diene. The use of Lewis acid was then studied and it was found that Eu(fod) 3 was the most effective and hexanes as the best solvent for the HDA between 1 151 and 1 152 to give 1 153 (Scheme 1 1 9 ). Scheme 1 1 9 Model HDA reaction for synthesis of reveromycin A

PAGE 47

47 However, using the methylene pyran 1 154 needed for the synthesis, a neat mixture and higher catalyst loading (15 mol%) had to be used to promote the cycloaddition (Scheme 1 20 ). The desired spiroketal 1 155 was obtained as a single diastereomer in moderate yield together with a side product 1 156 from an ene reaction. The spiroketal was further manipulated to get ( ) reveromycin A. Scheme 1 20 HDA approach to the sp iroketal core of reveromycin A 1.4.8 Cyclization of Monoacetylated Ketodiol In 2010, Cossy reported a FeCl 3 catalyzed diastereoselective formation of hydroxy a lcohols. 2 8 The cyclization was proposed to occur via a carbocation intermediate.This was supported by the fact that treatment of isomeric Scheme 1 2 1 FeCl 3 catalyzed spiroketal formation allylic alcohols to the reaction conditions gave the same diastereoselectivities.The method was extended to the formation of vinyl spiroketal using hydroxyketones. The

PAGE 48

48 spiroketal 1 158 was obtained in good yield and excellent diastereoselectivity (Scheme 1 2 1 ). 1.4.9 Ring Closing Metathesis All transformations described previously involved C O bond formation in one of the two rings of the spiroketal structure. Harrity et al. employed a different approach whereby C=C of spiroketals where formed from selective ring closing metathesis reaction of tetraene acetals. 2 9 As shown in Scheme 1 2 2 the formation of 5 membered dihydrofuran spiroketal 1 161 was favored over formation of seven membe red ring closure. Cyclic acetal 1 160 also provided 1 161 after ring closing metathesis using 1 catalyst I Scheme 1 2 2 Spiroketalization via cross metathesis of tetraene acetals It was postulated that the catalyst coordinates to the less hindered alkene. This can be followed by the formation of 5 membered spirocycl e 1 165 or alternatively, the competing 7 membered ring 1 166 formation (Scheme 1 2 3 ). The observed selectivity was attributed to the kinetically favored 5 membered ring formation based on the result obtained above where the 7 membered cyclic acetal proved to be less reactive and slowly reversible at harsher conditions.

PAGE 49

49 Scheme 1 2 3 Proposed mechanism for the spiroketalization via cross metathesis of tetraene acetals Hsung et al. reported a different ring closing metathesis approach using ketal tethered diene substrates to access spiroketals (Scheme 1 2 4 ). 30 Diene 1 167 was subjected to ring closing st generation catalyst in CH 2 Cl 2 at room temperature to give the unsaturated spiroketal 1 168 in 83% yield. Subsequent dihydroxylation provided a single diastereomer of 1 169 in 87% yield with retention of chirality of the spirocenter (Scheme 1 2 4 Equation 1). A single diastereomer was also obtained after ring closing metathesis dihydroxylation sequence of 1 170. To confirm the relative stereochemistry of the dihydroxylation product of 1 17 1 the diol was protected as diphenyl methylid e ne acetal (Scheme 1 2 4 Equation 2). The X ray struc ture revealed the nonanomeric spiroketal structure 1 172 however, in CDCl 3 the doubly anomeric spiroketal 1 171 was the major diastereomer based on coupling constants of H2 and H3. Subjecting 1 1 71 and 1 17 2 to acidic conditions gave a 1:1

PAGE 50

50 mixture of the two spiroketals confirming that these two diastereomers have almost the same stability. (1) (2) Scheme 1 2 4 cross metathesis approach to spiroketals 1.4.10 [2+2+2] Cycloaddition of C alkynyl carbohydrates Metal catalyzed alkyne cyclotrimerization rea ctions were developed by the Mc Donald 31 and Yamamoto 32 groups to gain access to an important group of C arylglycosides and C arylribosides, respectively. In 1995 McDonald and coworkers subjected the C alkynyl O propargyl substrate 1 174 to an ethanolic solution of acetylene in the arylglycoside 1 175 in excellent yield (Scheme 1 2 5 Equation 1). 31 The rea ction occurs via a [2+2+2] cycloaddition of the propargyl alkyne moieties with acetylene. In 2006, Yamamoto reported the application of their Ru(II) catalyzed cyclotrimerization to the synthesis of C arylribosides (Scheme 1 2 5 Equation 2). 32 The ribose derived diyne 176 reacted in a [2+2+2] fashion with acetylene using 1 mol% of Cp*RuCl(cod) in 1,2 dichloroethane to give a mixture of and anomers of 1 177 in 74% and 8% yield, respectively.

PAGE 51

51 (1) (2) Scheme 1 2 5 Metal catalyzed [2+2+2] cycloaddition to form spirocarbohydrate derivatives 1.4.11 Cyclization/Cross Bromoketals and Aryl Iodides Scheme 1 2 6 Ni(II) catalyzed intramolecular cyclization/intermolecular reductive coupling Recently, Peng et al reported a Ni mediated double C C bond formation via an bromoketals 1 178 and 1 181 and aryl iodides to yield [5,5] and [6,5] spiroketals 1 180 and 1 182 with one anomeric stabili zation (Scheme 1 2 6 ). 33

PAGE 52

52 Scheme 1 2 7 Ni(II) catalyzed tandem intramolecular cyclization/reductive coupling The methodology was also successfully extended to the unprecedented stereospecific tandem intramolecular cyclization/reductive cross coupling reaction, albeit the use of stoichiometric amount of NiCl 2 and excess of ethyl crotonate (Scheme 1 2 7 ). Scheme 1 2 8 Proposed mechanism for the Ni(II) catalyzed spiroketalization A radical mechanism pathway was proposed to rationalize the tandem reactions exemplified in Schemes 1 2 6 and 1 2 7 First, the radical species I is generated from the halide by a single electron transfer from the [Ni 0 2ECPy] complex (Scheme 1 28) The alkyl species adopts a pseudochair conformation while the alkoxy subsitutuent preferably adopts an axial position which is also favored b y the anomeric effect. A 5 exo trig radical cyclization follows forming species II with two stereocenters defined.

PAGE 53

53 Coordination of II with [L n Ni I Br] results into intermediate III which is reduced by stoichiometric Zn. Oxidative addition of the Ni I species V and coupling with ArI 1 185 forms 1 186 which subsequently undergoes reductive elimination to give the cross coupled product, in this case, the spiroketal 1 187 The Ni 0 catalyst is regenerated from oxidation of Zn to Zn 2+ 1.4.12 Application s to Natural Product Synthesis 1.4.12.1 Dihydro alkoxy lation of a lkyne d iols For alkynediols where only one regioisomer can possibly be formed, Pd(II) catalysis proved to be useful in total synthesis In 2003, Trost et al synthesized the spiroketal intermediate 1 189 o f (+) Broussonetine G via dihydroxyalkoxylation of alkynediol 1 188 in the presence of PdCl 2 (PhCN) 2 in good yield and excellent diastereoselectivity (d.r. 97:3) with the anomeric product as the major diastereomer ( Scheme 1 2 9 ). 34 Trost et al. applied the same strategy to construct the spiroketal substructure of (+) Spirolaxine methyl ether from the alkynediol 1 191 in good yield and moderate diastereoselectivity (Scheme 1 30 ). 35 Scheme 1 2 9 Pd(II ) catalyzed synthesis of the spiroketal core of (+) Broussonetine

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54 En route to the synthesis of ( ) Cephalosphoride E and (+) Cephalosphoride F, Gonnade et al obtained the spiroketal 1 194 in moderate yield by treating alkynediol 1 193 with catalytic PdCl 2 (CH 3 CN) 2 in CH 3 CN (Scheme 1 3 1 ). The inseparable mixture leading to the desired natural products were separated after the deprotection step. 36 Scheme 1 30 Pd(II) catalyzed synthesis of the spiroketal moiety of Spirolaxine Methyl Ether Scheme 1 3 1 Pd( II) catalyzed synthesis of the spiroketal core of Cephalosphorides Deslongchamps reported the Hg(II) catalyzed spiroketalization of the [5,5] spiroketal core of the anti proliferative agent hippuristanol ( Scheme 1 3 2 ). The mono protected 3 alkyn 1,7 diol 1 197 was treated with Hg(OTf) 2 in aqueous CH 3 CN gave the desired spiroketal in 90% yield. Debenzylation with lithium and liquid ammonia furnished

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55 22 epi Hippuristanol 1 198 as a single diastereomer which upon treatment with PPTS in CHCl 3 was converted to Hippu ristanol. 1 4 Scheme 1 3 2 The authors proposed a mechanism where the first step is the oxymercuration of the triple bond by the C16 hydroxyl group followed by olefin isomerisation to form the oxonium ion 1 200 (Scheme 1 33 ). Demercuration, and subsequent THP deprotection gave 1 204 The exclusive formation of epi hippuristanol was attributed to the attack of the free hydroxyl group to the less hindered side of the oxonium ion 1 204 ( anti to the neighboring hydroxyl group) or presumably, equilibration of the other diastereomer to the epi product 1 205 because of the acidic reaction condition. 1 4 a

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56 Scheme 1 3 3 Pro posed mechanism for the Hg(II) catalyzed spiroketalization In the synthesis of Ushikulide A, Trost et al conditions (10 mol% PdCl 2 (CH 3 CN) 2 CH 3 CN/ THF reflux) to form the spiroketal 1 207 from compound 1 206 (Scheme 1 3 4 ). Unfortunately, no desired product was formed. When the solvent was changed to acetone, the acetonide resulting from protection of the 1,3 anti diol was obtained. When AuCl was employ ed as a catalyst, careful selection of protecting group ( OH vs OBz) and additives (CSA vs PPTS) was necessary to favor the formation of the desired spiroketal 1 209 instead of the elimination product 1 210 (Scheme 1 3 5 ). The latter product was formed via dehydrative cyclization of a monopropargylic triol 16 derivative having the OBz as the leaving group. However, no product from a competing pathway, 5 exo dig cyclization, was observed. 37 Scheme 1 3 4

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57 Scheme 1 3 5 Metal catalyzed spiroketalization en route to Ushikulide A In 2011, F rstner et al. reported their second generation synthesis of Spirastrellolide F Methyl Ester utilizing a gold catalyzed dihydroalkoxylation strategy to install the spiroketal as a key step (Scheme 1 3 6 ) Unexpectedly the use of simple AuCl or AuCl SMe 2 to promote the dihydroalkoxylation of the alkynediol 1 212 furnished the undesired regioisomer from the 5 e xo dig attack of the alcohol to the alkyne. An unstable tetrahydrofuran enol ether intermediate was formed that needed to be trapped with MeOH to prevent decomposition upon workup and provide 1 213 in 36% yield. The use of the gold catalyst 1 214 with a bu lky ligand promoted the desired 6 endo cyclization to form an intermediate dihydropyran enol ether which after treatment of PPTS furnished the spiroketal 1 215 in 81% yield over two steps. This intermediate 1 215 was carried forward in the synthesis of Spi rastrellolide F Methyl Ester 1 216 38

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58 Scheme 1 3 6 Au (I) catalyzed spiroketalization as key step in Spirastrellolide F Methyl Ester synthesis moieties via Au(I) catalyzed spiroketalizations. The spiroketal 1 218 was derived from dihydroalkoxylation of the sugar derived alkynediol 1 217 (Scheme 1 3 7 ). Partial deprotectio n of the anisylidene group was observed in the process. Addition of tosic acid was required to complete the deprotection and obtain an excellent yield of 1 218 39 Scheme 1 3 7 Au(I) spiroketalization of 1 217

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59 1.4.12.2 Spiroketalization of m onopropargylic t riols Scheme 1 3 8 Au(I) catalyzed spiroketalization of 1 219 and 1 223 The other spiroketal intermediate 1 219 of okadaic acid was synthesized from the gold(I) catalyzed dehydration of monopropargylic triol (Scheme 1 3 8 ) 16 The diastereomers 1 219 and 1 223 were obtained in the course of the total synthesis. As previously observed in Aponic 1,3 diol is important in the outcome of the reaction. T he syn diol 1 219 gave the desired unsaturated spiroketal 1 220 as a minor product in 13% yield. The major products, anomers 1 221 and 1 222 came from the 5 exo dig attack of the OH group in C31 to C33 instead of the 6 exo dig cyclization (to C34), elimination addition sequence that furnishes the unsaturated spiroketal desired. The anti diol precursor 1 223 on the other hand, gave the desired spiroketal 1 220 in 65% yield. 39

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60 1 .4.12.3 Cyclization of mono protected ketodiols/ hemiketal s Hirai and coworkers employed the Pd(II) catalyzed cyclization of intermediate hemiketal 1 224 to form the spiroketal core 1 225 en route to the synthesis of Spiro C Arylglycoriboside 1 226 ( Scheme 1 3 9 ) 40 The spiroc yclization occurs through the attack of the hemiketal hydroxyl group to the Pd(II) activated olefin followed by elimination of PdCl(OTHP). A high catalyst loading (20 mol%) and low solvent concentration (0.01 M) was necessary to obtain a high yield (91%) o f the spiroketal 1 225 Scheme 1 3 9 Pd(II) catalyzed synthesis of spiroketal 1 225 In their synthesis of Bistramides and and their analogues, Cossy et al. constructed the spiroketal core through a diastereoselective FeCl 3 catalyzed spiroketalization of a unsaturated lactol 1 227 (Scheme 1 40 ). 41 Although this method relies on cation formation, excellent selectivity was observed. The resulting spiroketal core 1 228 was then functionalized to get the advanced intermediates for the different Bistramides. 1.4.12.4 Ring c losing metathesis The ring closing metathesis spiroketal synthesis approach was applied by Hsung in their synthetic effort to make the C11 C23 fragment of the PP2A inhibitor Spirastrellolide A (Scheme 1 4 1 ). T he glucose derived lactol 1 231 and homoallylic alcohol 1 232 were coupled and the resulting diene 1 233 was treated with the standard

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61 conditions to successfully obtain the desired spiroketal 1 234 with most spectroscopic data matching that reported for Sp irastrellolide A except for epi C22. 30 Scheme 1 40 approach to the synthesis of Bistramide analogues Scheme 1 4 1 r ing closing metathesis approach to the spiroketal moiety of Spirastrellolide A

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62 1.5 Outlook The use of transition metal catalysts in spiroketalization is gaining attention in the syntheti c community because of the mild conditions employed in the reactions. In the last 5 years, these methodologies have been used in the synthesis of spiroketal moieties of complex natural products. A recent trend and still a challenging area has been the de velopment of enantio and diastereoselective spiroketalization processes to easily gain access to different spiroketal diastereomers. It is expected that new methodologies will continue to be developed and applied in natural product synthesis as nature rev eals compounds whose complexity requires alternative strategies.

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63 CHAPTER 2 METAL CATALYZED SPIROKETAL IZATION OF MONO ALLYLIC KETODIOLS 2.1 Introduction The activation of allylic alcohols towards inter or intramolecular nucleophilic substitution reactions catalyzed by transition metals have been reported. Four modes of activation are possible: a) activation through a allyl complex formation with Pd(0), 4 2, 43 Rh(I), 44 Pt(0) 45 or Ru(II) 46 (Scheme 2 1) ; b) coordination to the olefin and hydroxyl groups of the allylic alcohol with Pd(II) (Scheme 2 2); 47 c) coordination to the olefin with Au(I) (Scheme 2 3); 48 d) formation of a stabilized allyl cation with B i(III) 49 or Fe(III) 28,4 1 (Scheme 2 4). Scheme 2 1. Activation of allylic alcohols by allyl complex formation Scheme 2 2. Activation of allylic alcohols by coordination to olefin and alcohol

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64 Scheme 2 3. Activation of allylic alcohols by coordination to the olefin Scheme 2 4. Activation of allylic alcohols by allyl cation formation Uenishi et al. reported the use of Pd(II) catalyst to convert monoallylic diol 2 1 to vinyl tetrahydropyran 2 2 in high yield and diastere oselectivity. 47 They suggest a mechanism characteristic of activation mode in Scheme 2 2. Kitamura et al. investigated an asymmetric version of this dehydrative cyclization to form 2 4 from 2 3 in high yield and enantioselectivity using Ru(II) catalyst [Cp Ru(CH 3 CN) 3 ]PF 6 in combination with their newly designed ligand 2 5 46 Cossy and coworkers demonstrated the same transformation is possible with catalytic FeCl 3 28 However, in this case, an allyl cation intermediate was proposed for the cyclization. When t he allylic alcohols 2 6 and 2 8 were subjected to the standard cyclization conditions, the same diastereoselectivity was observed for the formation of products 2 7 and 2 9 respectively (Scheme 2 5).

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65 Scheme 2 5 Selected examples of metal catalyzed cyclization of monoallylic diols O ur group also developed t he first gold catalyzed reaction cyclization of mono allylic diols to obtain vinyl substituted tetrahydropyrans and furans in excellent yields with catalyst loading s as low as 0.1 mol % (Scheme 2 6 ). 48 Scheme 2 6 Au(I) catalyzed synthesis of tetrahydropyrans

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66 Scheme 2 7 Proposed Au(I) catalyzed spiroketalization In an effort to expand the utility of our reaction, we hypothesized that a mono allylic keto diol 2 12 could undergo the same Au(I) catalyzed mode of cyclization to provide vinyl substituted spiroketal 2 15 In our Au catalyzed cyclization of monoallylic diols, a mechanism that involve s the c omplexation of Au(I) to the alkene of the allylic alcohol and subsequent attack of the pendant alcohol to give the product with loss of H 2 O is proposed For spiroketalization, the spiroketal could be formed from the attack o f the pendant alcohol to the ketone to form a hemiketal 2 13 followed by the nucleophilic attack of the resu lting intermediate to the gold activated allylic alcohol to gi ve vinyl substituted spiroketal 2 15 (Scheme 2 7 pathway a) The feasibility of the of the hemiketal C bonds has been demonstrated 50 51 work (Scheme 2 8). The intermolecular attack of alcohol nucleophiles to alkynyl or allylic alcohol tethered aldehydes 2 16 and 2 17 gav e rise to

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67 activated alkyne 50 or allylic alcohol 51 to furnish cyclic alkenyl ethers 2 17 and 2 1 9 or substituted tetrahydropyrans 2 20 respectively. Alternatively, the ketone oxygen may also attack the activated allylic alcohol to give rise to the oxocarbenium intermediate 2 14 (Scheme 2 7, pathway b) Attack of the pendant alcohol to this intermediate will produce the spiroketal product 2 15 Scheme 2 8 Pd(II) catalyzed cyclizations involving hemiacetal intermediates Compared to spiroketalization methods involving alkyne diols discussed earlier (Section 1.4.1), our proposed spiroketalization will eliminate issues of regioselectivity in cyclizations since no competing cyclization pathways are possible It also has the p otential to be diastereoselective depending on which face of the olefin the nucleophile attacks 48 The presence of exocyclic double bond in the spiroketal product 2 15 will also be advantageous as it offers a site for further functional group manipulatio n.

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68 2.2 Preliminary Studies 2.2.1 Initial Results As a proof of concept, the short synthesis of racemic monoallylic hemiketal s of type 2 21 was designed. The precursors were envisioned to come from reaction between a lactone 2 23 and a Grignard reagent 2 24 of a suitable bromoalkene The olefinic hemiketal formed would be subjected to cross metathesis with crotonaldehyde unsaturated aldehyde 2 2 2 Reduction of the aldehyde to the allylic alcohol using NaBH 4 would furnish the required spir oketal precursor 2 21 This synthesis has the advantage of being protecting group free and therefore, should be a short route to the desired spiroketal precursor 2 21 (Scheme 2 9). S cheme 2 9 Retrosynthesis for the synthesis of spiroketal precursor 2 21 Unfortunately, the first step of this reaction sequence, which involved the addition of the Grignard reagent 2 26 to the lactone 2 25 proved to be difficult. Lactones are cyclic est ers, so it was a challenge to control the reaction to stop at the mono alkylation stage even at low reaction temperatures (Scheme 2 10). Polymerization of the lactone was also observed under the reaction conditions. Scheme 2 10. Addition of Grignard reagent 2 26 to lactone 2 25

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69 A different strategy was then explored. It was desire able to form ketone 2 30 through the attack of the Grigna rd or l ithium reagent 2 32 to the amide 2 31 (Scheme 2 11) Scheme 2 11. Revised retrosynthesis of the spiroketal precursor Instead of using a lactone, the Weinreb amide 2 36 52 was prepared from 1,5 pentanediol 2 33 in three steps by monoprotection of the diol, oxidation of the resulting alcohol 2 34 to the acid 2 35 and finally coupling with N O dimethylhydroxylamine hydrochloride (Scheme 2 12) The Grignard or lithium reagent would be generated from bromoalkene derivatives 2 43 or 2 44 which were obtained from corresponding bromoalkenes 2 37 or 2 38 through cross metathesis, reduction and prot ection of the resulting alcohol (Scheme 2 13). However, attempts to couple fragments 2 43 and 2 36 were not very successful. Treatment of bromides 2 43 and 2 44 with t BuLi followed by the addition of Weinreb amide 2 36 yield ed the desired ketones 2 46 and 2 47 in 27% and 54 % respectively (Scheme 2 14). In an effort to improve the yield, preparation of the Grignard reagent from 2 43 was attempted but unfortunately failed. It is possible that reaction between 2 43 and t BuLi me talates the silyl methyl in TB S, 53 hence, the silyl protecting group was changed to TBDPS (Scheme 2 11). Deprotection of the silyl protecting groups gave the desired spiroketal precursors 2 48 and 2 49 in 28 and 67% yield, respectively (Scheme 2 15).

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70 Scheme 2 12. Synthesis of Weinreb amide 2 36 Scheme 2 13. Synthesis of bromides 2 43 and 2 44 Scheme 2 14. Addition of organometallic reagents to 2 43 and 2 44

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71 Scheme 2 15. Deprotection of 2 4 6 and 2 4 7 With the spiroketal precursors finally in hand, the gold catalyzed s piroketalization was attempted. Treatment of 2 48 under the reaction conditions used for our synthesis of 2 vinyl tetrahydropyrans 48a gave the desir ed 6,5 spiroketal 2 50 in 50% yield (d.r. 1:1.3) after 3.5 h (Scheme 2 16, Equation 1). Compound 2 49 on the other hand, took 4.5 h to furnish the doubly anomeric 6,6 spiroketal 2 52 in 41% yield and high diastereoselectivity (Scheme 2 16, Equation 2). Cha nging to THF, a coordinating solvent, proved detrimental to the reaction (Scheme 2 16, Equation 3). These results were encouraging; h owever, due t o problems encountered in the synthesis of these substrates, and thus, minimal amount of material in hand, opt imization of reaction condition was performed using a different substrate. Scheme 2 1 6 Preliminary reaction condition screening results

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72 2.2.2 Improvements in Substrate Synthesis With the hypothesis that the TBS group protecting the allylic alcohol was the cause of poor yield in the halogen metal exchange, formation of a Grignard reagent from commercially available 5 bromo 1 pentene 2 38 was attempted. Gratifyingly, a Grignard reagent was obtained which upon addition to Weinreb amide 2 36 gave a yield of 75 % of 2 53 (Scheme 2 17 ). Scheme 2 17. Synthesis of 2 53 Having overcome the challenging halogen metal exchange, a cross metathesis with crotonaldehyde followed by unsaturated aldehyde to allylic alcohol was envisioned (Scheme 2 18). The cross metathesis of keto olefin 2 53 with crotonaldehyde to obtain aldehyde 2 54 worked well with 86% yield, however, u nsaturated aldehyde to the allylic alcohol using NaBH 4 gave compound 2 55 in very poor yield It is possible that the ketone functionality was also reduced in the process to yield a diol which upon aqueous work up could have been lost in the aqueous phase Scheme 2 1 8 Cross metathesis NaBH 4 reduction sequence en route to 2 55

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73 Cross metathesis of 2 53 with allyl alcohol was also attempted since it w ould reduce the synthesis by one step by getting to compound 2 55 directly but the yield was low as well (Scheme 2 19) Posed with this proble m, another route was explored (Scheme 2 20) A cross metathesis methodology developed by Grubbs et al. using Grubbs 1 st generation catalyst 2 59 and TBS protected cis butenediols looked promising due to its trans selecti vity 54 This m ethod was explored and protected ketodiol 2 57 was obtained in good yield. While deprotection of the TBS groups gave the spiroketal precursor 2 49 the starting protected diol 2 56 was difficult to separate from 2 57 and had to be carried forward. T he pres ence of the latter during deprotection pose d a problem because 2 49 and the resulting butenediol 2 58 were very difficult to separate. Scheme 2 19. Cross metathesis of 2 53 and allyl alcohol using G2 catalyst Scheme 2 20. Synthesis of 2 4 9

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74 After experiencing difficulties in alternative cross metathesis routes, and since cross metathesis of 2 53 with crotonaldehyde gives the best yield (Scheme 2 18), we focused on finding chemoselective reduction conditions. Additionally, the synthesis of monoallylic ketodiol 2 61 was pursued for the reaction optimization step. This time using substrate 2 60 the reduction using NaBH 4 in wet silica under solvent free conditions developed by Zeynizadeh and coworkers was employed (Scheme 2 21a) 55 Compound 2 61 was obtained in up to 70% yield; however, this reaction was not consistently reproducible (due to overreduc tion) likely owing to inefficient mixing. Reduction using 0.25 eq uiv of NaBH 4 in MeOH at 0 C gave up to 58% yield of allylic alcohol 2 6 1 but the reaction was difficult to control to the reduction of the aldehyde alone (Scheme 2 21b). Scheme 2 21 Synthesis of 2 6 1 using different chemoselective reduction conditions

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75 Sodium triacetoxy borohydride, NaBH(OAc) 3 which is usually employed for reductive amination, 56 was then used for chemoselective reduction of 2 60 (Scheme 2 21c) To our delight, even with the use of an excess of this reagent (2 equivalents), no overreduction was observed, and yields as high as 84% of 2 61 were obtained. Maximum yield was obtained when 2.5 equivalent s of the reducing agent was used. Desilylation 57 of TBS protected ketodiol 2 61 proved to be more challenging than expected. Either the starting material decomposes or forms hemiketal that is difficult to isolate by column chromatography. A variety of rea gents were used to remove the TBS group from 2 61 (Table 2 1). Table 2 1. Optimization of desilylation step Entry Reagent Solvent Temp Time (hr) Isolated yield (%) R emarks 1 4 eq TBAF THF r. t. 48 23 44 2 4 eq. TBAF, AcOH THF r. t. 168 50 3 4 eq. TBAF, AcOH THF 40 C 72 43 Recovered 24% SM 4 (HF pyridine) x CH 2 Cl 2 0 C to r. t. 4 0 SM decomposed 5 3HF Et 3 N THF r. t. 24 12 6 3HF Et 3 N, Et 3 N CH 3 CN 0 C to r. t. 120 48 7 10 eq CsF CH 3 CN/H 2 O(4:1) reflux 24 N. R. 8 4 eq TBAF, MS 4 THF r.t. 5 71

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76 Deprotection using TBAF (Table 2 1, Entry 1) yield ed only 23 44% of the ketodiol 2 62 We speculated that the poor result s might be due to the basicity of the fluoride reagent used, so AcOH was added to buffer the reaction (Entries 2 & 3), however, no sign ificant increase in the yield was observed even when longer reaction times were employed Next, the less basic reagent HFpyridine was used (Entry 4) but the reaction resulted in complex mixtures. The use of the milder reagent HFEt 3 N (Entry 5) was explore d to effect the desilylation, however, only 12% yield was obtained It was then buffered using additional Et 3 N (Entry 6) and the yield improved to 48%. Use of CsF was also explored (Entry 7) but no reaction was observed. Finally, since TBAF gave the best r esults, one further modification was employed. A ddition of molecular sieves to the solution of substrate in THF followed by addition of TBAF gave the product in up to 71% yield in 5 hours (Entry 8). Using TBAF which was previously dried in activated molecu lar sieves prior to use also gave the same result but with a much easier work up procedure. 2.3 Optimization of Spiroketalization Conditions The synthesis of 2 6 4 was improved and shortened to two steps by subjecting lactone 2 6 3 to Merck conditions to obt ain the Weinreb amide 58 followed by TBS protection of the free alcohol. A larger quantity of ketodiol 2 62 was obtained after the synthetic steps for its preparation were optimized (Scheme 2 22) thus, it was used for optimization of conditions f or spiroke tal synthesis. T he addition of the butyl group as a substituent was advantageous as the increased molecular weight of the spiroketal product helped prevent erroneous results due to volatility problems Also, the presence of only one proton in the methine c arbon would simplify nOe analysis.

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77 Scheme 2 22. Optimized synthesis of monoallylic ketodiol 2 6 2 2.3.1 Spiroketalization using Gold Catalysts At the onset of this project, our goal was to use gold catalysis to demonstrate the feasibility of our prop osed spiroketalization of monoallylic ketodiols. The catalyst system 2 51 /AgOTf in DCM was first employed for spiroketalization since it previously gave high yield (Table 2 2, Entry 1). Under these conditions, product 2 67 was obtained in 55% yield after 2 4 h at room temperature. Changing the solvent from DCM to THF resulted in a lower yield (Entry 2). No product was obtained when AuCl was used (Entry 3). The use of the cationic gold(I) complex derived from AuClPPh 3 /AgOTf in DCM resulted in a 45% yield with shorter reaction time (Entry 4), however, no reaction was observed when the solvent was changed to THF (Entry 5). No significant change was observed when AgBF 4 was used as the silver salt (Entry 6). It is worth mentioning that all the spiroketalizations t ried thus far gave excellent diastereoselectivities (dr 20:1). Based on Table 2 2 it can be concluded that the cationic gold (I) complex is the active species in the cyclization since the use of Br o nsted acid such as PPTS (Entry 7) or AuCl (Entry 8) did no t yield the desired spiroketal. The addition of TsOH resulted in poor yields (Entries 9 and 10).

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78 Table 2 2 Optimization of c onditions for s piroketalization using Gold catalysts Entry Catalyst Catalyst loading Solvent Temp. Reaction time, h Isolated yield Remarks 1 2 51 AgOTf 5 DCM rt 24 h 55 2 2 51 AgOTf 5 THF rt 24 h 25 3 AuCl 5 THF r t 24 h 0 a 4 AuClPPh 3 ,AgOTf 5 DCM r t 80 min 45 5 AuClPPh 3 ,AgOTf 5 THF rt 5 h, then 40 C 24 h 0 b 6 AuClPPh 3 AgBF 4 5 DCM r t 1 h 32 7 PPTS 10 DCM rt 1 h 0 c 8 AuCl 5 CH 3 CN rt 1 h 0 Used MS 3 9 AuClPPh 3 AgBF 4 5 DCM rt 1 h <10 d With 10 mol% TsOH 10 AuClPPh 3 AgBF 4 5 DCM rt 1 h <1 0 d With 2 mol% TsOH 11 2 68 AgBF 4 5 DCM rt 24 h 24 12 2 69 1.6 DCM rt 48 h 78 Poor d.r. 13 2 69 1.6 DCM reflux 48 h 93 Poor d.r. 14 AuClPPh 3 ,AgOTf 5 DCM rt 2 h 32 Filtered AgCl 15 2 70 2.5 DCM rt 5 h 55 *Entries 1 8: used DCM to flush sil ica plug on work up, entries 8 15 used ether.; **mixture of diastereomers dr>20:1; a= hemiketal formed; b= no new spot in TLC; c = SM was consumed based on TLC before work up; d = based on crude 1 H NMR

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79 For all entries except Entry 1 1 TLC analysis indicated that there was another product that is more polar than the spiroketal product, but less polar than the starting material. This product was difficult to obtain by column chromatography, and we speculate d based on crude NMR data that this is the hemiketal We a lso observed that after the work up (passing the reaction mixture over a silica plug), the starting material spot appears again even though TLC analysis of the reaction mixture before workup indicated its absence. We infer from this observation that the he miketal is unstable and the ketodiol is reformed under acidic condition s such as passing through silica (Scheme 2 23). Scheme 2 23. Formation of hemiketal 2 71 Among the gold catalysts used, AuClPPh 3 /AgOTf or AgBF 4 gave the shortest reaction time in ter ms of disappearance of the starting material; however, the yield was still low due to the incomplete conversion of the hemiketal to the desired product. The use of catalyst 2 69 gave 93% yield but with poor diastereoselectivity (2:1) and long reaction time (Entry 13). 2.3.2 Spiroketalization using Pd(II) and Pt(II) Catalysts In our effort to obtain better yield and diastereoselectivity for the spiroketalization of monoallylic ketodiols, we explored other metal catalysts. When the spiroketalization of 2 6 2 to 2 6 7 was performed using 10 mol % PdCl 2 (PhCN) 2 (Table 2 3 ), complete consumption of starting material was observed after 10 min and only the product spot

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80 was observed (no hemiketal spot) with 59% isolated yield (Table 2 3 Entry 1). Lowering the catalyst loading to 2 mol % PdCl 2 (PhCN) 2 gave the product in 83% yield after 15 minutes (Entry 2). Because PhCN was observed after purification of the spiroketal obtained, the use of PdCl 2 (CH 3 CN) 2 was explored (Entries 3 11). U sing 5 mol% of PdCl 2 (C H 3 CN) 2 at 0 C without using molecular sieves, gave the product cleanly in 82% yield in 1.5 h (Entry 11) and these conditions were dubbed optimum Experimental results using solvents such as benzene and CH 2 Cl 2 were found to be inferior (Entries 6 and 7) P tCl 2 in toluene (Entry 12) also gave a satisfactory yield of spiroketalization desired, however, we opted to use PdCl 2 (CH 3 CN) 2 because of the harsher conditions required for PtCl 2 Table 2 3 Optimization of conditions for s piroketalization using Palladiu m(II) and Platinum(II) catalysts Entry Catalyst Catalyst loading Solvent Temp. Reaction Time Isolated yield* Remarks 1 PdCl 2 (PhCN) 2 10 THF r t 10 min 59 2 PdCl 2 (PhCN) 2 2 THF rt 15 min 83 3 PdCl 2 (MeCN) 2 2 THF r t 24 h 83 No MS 4 PdCl 2 (PhCN) 2 2 THF rt 1 h 64 5 1) PPTS, then 2)PdCl 2 (MeCN) 2 2 THF rt 1) 1 h 2) 2 h 0 6 PdCl 2 (MeCN) 2 2 benzene rt 2 h 18 7 PdCl 2 (MeCN) 2 5 DCM rt 48 h 4 8 PdCl 2 (MeCN) 2 10 THF 0 C 1 h 89 With unknown impurity 9 PdCl 2 (MeCN) 2 5 THF 0 C 2 h 67 10 PdCl 2 (MeCN) 2 5 THF 0 C 1.5 h 8 3 No MS 11 PdCl 2 (MeCN) 2 5 THF 78 C to rt 3 h; 16 h 74 No MS 12 PtCl 2 5 Toluene 40 C 24 h 83 dr>20:1 for all entries with yields.

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81 2.4 Substrate Scope of Pd(II) catalyzed Spiroketalization The scope of the Pd(II) catalyzed spiroketalization reaction was investigated by varying the ring size and substituents on each spiroketal ring. Since most spiroketal containing natural products have either alkyl or hydroxyl groups in the ring, spiroketal precursors with these substituents were evaluated. 2.4.1 Effect of Ring Size The unsubstituted mono allylic ketodiols 2 77 2 48 and 2 49 which are precursors in the formation of 5,6 6,5 and 6,6 vinyl spiroketals were prepared starting from commercially available lactones 2 72 and 2 73 The same six step synthetic sequence as the formation of optimization substrate 2 62 (Scheme 2 24 ) was employed to obtain the desired substrates. Scheme 2 24. Synthesis of unsubstitut ed monoallylic ketodiols The substrates were treated under the standard spiroketalization conditions (5 mol% PdCl 2 (CH 3 CN) 2 THF, 0 C) to yield the desired spiroketals. The 6,6 spiroketal 2 5 2 was obtained in 83% yield and high diastereoselectivity (Scheme 2 25, Equation 1). The formation of the 6,5 spiroketal 2 50 was very fast (~40 minutes) and high yielding,

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82 however, the diastereoselectivity was very low (Scheme 2 25, Equation 2). In contrast, the 5,6 spiroketal 2 7 8 required a longer reaction time and p rovided the product in lower yield (52% vs 84%) but exhibited a higher d.r. than was observed for 6,5 spiroketal 2 50 (Scheme 2 25, Equation 3). The low diastereoselectivities for forming 2 50 and 2 7 8, compared to other spiroketals formed, can be attributed to the five lack of clearly defined axial or equatorial bonds. The rapid formation of 2 50 may also indicate that the formation of the ring B is the rate determining step of the spiro ketalization (Equation 1 vs Equation 2). Scheme 2 25 Pd(II) catalyzed spiroketalization of unsubstituted monoallylic ketodiols The spiroketals were characterized based on NMR data. For example, spiroketal 2 5 2 has two possible isomers, both of whi ch have two anomeric relationships ( Figure 2 1 ) The two isomers can be easily be differentiated by 1 H NMR, 2 5 2 a is predicted to have a 2 H coupling value corresponding to J 8ax,7ax and J 8ax,7eq whereas 2 5 2 b will only

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83 have J 8eq,7ax and J 8eq,7eq values. Additionally, an NOE correlation should also be observed between 8 H ax and 2 H ax Figure 2 1 Isomers of compound 2 5 2 with two anomeric relationships We predict that 2 5 2 a will be the thermodynamic product based on anomeric and steric factors. Compound 2 5 2 b will not be favored due to steric strain between 2 H (ax) and the axial vinyl group. NMR analysis of spiroketal 2 5 2 showed a characteristic anomeric 8 H resonance H 4.13 (dddd J 8ax,7ax 11.7 Hz, J 8ax,2eq 2.3 Hz) which indicated that the vinyl substituent ad opted an equatorial position. 13 1g also confirms the presence of anomeric spirocarbon C6 and a n n O e correlation between 2 H ax and 8 H ax also confirmed a bis anomerically stabilized spiroketal 2 5 2 a system. 2.4.2 Effect of Substituents on Ring A To determine the tolerance of the spiroketalization conditions to substitution on ring, the formation of ring A substituted spiroketals was invest igated (Scheme 2 26). T Scheme 2 26. Cyclization to form ring A substituted spiroketals Alkyl substituted monoallylic ketodiols 2 90, 2 91 and 2 92 were synthesized (Scheme 2 27). The synthesis started with conversion of lactones 2 81 and 2 82 or

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84 ester 2 83 to Weinreb amides (Scheme 2 27). These Weinreb amides were then reacted with pent 4 enylmagnesium bromide 2 65 to yield the corresponding keto ol efins in 39 85% yields. Cross metathesis with crotonaldehyde followed by reduction and deprotection gave the furnished the desired spiroketal precursors. Scheme 2 27. Synt hesis of monoallylic ketodiols with alkyl substituents on ring A The monoallylic ketodiol substrate 2 93 which has a hydroxyl substituent was also desired. Some spiroketalization strategies have taken advantage of the chelating/H bonding properties of an OH group to obtain the desired anomeric or nonanomeric spiroketals. 1f

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85 Figure 2 2 Substrate 2 9 3 The first attempt to make the substrate was through an iterative alkylation of the acetone N N dimethylhydrazone 2 95 (Scheme 2 29). 58 This route was attractive since the intermediate 2 9 7 or 2 9 9 can be obtained in a three step, one pot reaction starting from condensation of acetone and N N dimethylhydrazine. Scheme 2 28. Attempts to synthesize 2 9 7 or 2 9 9 Stepwise alkylation of 2 9 5, initially with 4 bromobutene 2 37 follow ed by aldehyde 2 9 6 and then hydrolysis of the hydrazone using wet silica gave intermediate 2 9 7 in 13% yield over three steps (Scheme 2 28, Equation 1). When aldehyde 2 9 8 was used as the electrophile, the hydroxyketo olefin 2 9 9 was never obtained. When

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86 the product from the first alkylation of 2 9 5 with 2 37 was isolated, a 72% yield was obtained. Considering that alkylation with aldehyde 2 9 8 did not work, it can be concluded that the second alkylation was the lowest yielding st ep for this one pot reaction sequence. Scheme 2 29. Attempts to synthesize compound 2 9 3 Another route was then investigated. The alcohol 2 101 was prepared starting with the aldol r eaction of known Weinreb amide 2 100 and TBS protected alkoxy aldehyde 2 9 6 to give the adduct 2 101 in 71% yield (Scheme 2 29). Before the Grignard addition was attempted, the free alcohol was protected. Benzylation using benzyl trichloroacetamidate or be nzyl bromide was unfortunately unsuccessful. PMB protection using PMB acetimidate gave 41% of 2 10 5 However, addition of pent 4

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87 enylmagnesium bromide 2 65 to 2 105 yielded only 24 26% of the desired product hydroxyketo olefin 2 106 and an elimination product 2 10 7 was observed. To our delight, addition of an excess of Grignard reagent to unprotected keto alcohol 2 101 gave 2 10 8 in 38 55% yield. Methylation of the free alcohol and subjecting 2 10 9 to conditions similar to the synthe sis of previous substrates gave intermediate 2 1 10 in moderate yield. However, deprotection of the TBS group with TBAF only gave the elimination product 2 1 11 instead of the desired spiroketal precursor. A synthetic sequence similar to Scheme 2 2 9 was explored instead, starting with the aldol reaction of 2 100 with a PMB protected alkoxy aldehyde 2 9 8 which furnished 71% of 2 1 12 (Scheme 2 30 ). Addition of Grignard reagent 2 65 to Weinre b amide 2 112 produced hydroxyketo olefin 2 9 9 in 51% yield. Protection of the free alcohol gave 2 11 3 in 95% yield. Cross metathesis with crotonaldehyde, reduction of the aldehyde and deprotection of the PMB group with DDQ afforded not the open chain form of the monoallylic ketodiol, but the hemiketal 2 11 4 in 27% yield as a mixture of anomers. Scheme 2 30. Synthesis of 2 11 4

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88 The substituted monoallylic keto diols 2 90 2 9 1 2 9 2 and 2 11 4 were subjected to the standard spiroketalization conditions to obtain ring A substituted spiroketals (Scheme 2 31). Compound 2 91 and 2 9 2 proceeded smoothly to obtain thermodynamic spiroketals 2 11 5 and 2 11 6 in 86% and 82% yields, respectively, and with high diastereoselectivities (Scheme 2 31, Equations 1 and 2). Compound 2 9 2 which is a gem dimethyl substituted substrate, reacted faster than the unsubstituted 6,6 spiroketal precursor 2 48 (5 h vs. 4 h) presumably because of the Thorpe Ingold effect. 59 Scheme 2 31. Pd(II) catalyzed spiroketalization to form ring A substituted spiroketals

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89 Alkyl substitution at the position of the ketone (compound 2 90 ) tends to slow down the reaction and lower the diastereoselect ivity (Scheme 2 31, Equation 3). This could be due to steric hindrance near the reaction site. The product observed was also a mixture of nonanomeric spiroketals with both propyl groups in equatorial positions. The TBS protected alcohol substituted hemik etal 2 11 4 under the standard reaction conditions reacted in 3 h to give a mixture of diastereomers of 2 11 9 (dr 3:1:0.6) in 60% yield (Scheme 2 31, Equation 4). Since the starting substrate has additional stereocenter, four diastereomers of the substrate could be present in the starting material (confirmed by 13 C NMR of the substrate), this could explain the very poor diastereoselectivity observed. In an effort to increase the diastereoselectivity and yield, the substrate was treated with a higher catalys t loading (10 mol %) and was also run at a lower concentration (0.05 M). The yield increased to 79%, however, there was no significant increase in the diastereoselectivity. 2.4.3 Effect of Substituents on Ring B Next, we investigated the effect of substitu ents on the formation of ring B substituted spiroketals: Scheme 2 32. Pd(II) catalyzed spiroketalization to obtain ring B substituted spiroketals For this purpose, methyl substituted bromopentenes 2 12 5 and 2 12 7 were synthesized (Scheme 2 30). Crotyl alcohol 2 122 was reacted with triethylorthoformate through a Johnson orthoester Claisen rearrangement 60 to yield alkenyl ester 2 12 4 in 70% yield. M e thylpent 4 enoate s 2 12 4 and 2 12 6 were reduced to corresponding

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90 alcohols using LAH. The alcohols were converted into tosylates which were then subjected to S N 2 reaction with LiBr to furnish bromides 2 12 5 and 2 12 7 in 52% and 60% yield, respectively. Scheme 2 33. Synthesis of alkenyl bromides 2 122 and 2 124 Starting from bromides 2 12 5 and 2 12 7 and Weinreb amide 2 36 the monoallylic ketodiols 2 1 32 and 2 13 3 were obtained through a protocol similar to the previous substrate synthesis (Scheme 2 34). Scheme 2 34. Synthesis of monoallylic ketodiols 2 1 32 and 2 1 33 Pd( II) catalyzed spiroketalization of 2 1 32 and 2 13 3 under standard conditions were high yielding and diastereoselective (Scheme 2 35). Methyl substituted

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91 monoallylic ketodiol 2 1 33 was converted to spiroketal 2 13 5 in 1 h and 90% yield as a single diastereo mer. Scheme 2 35. Pd(II) catalyzed spiroketalization to form ring B substituted spiroketals Spiroketal precursor 2 1 32 which has an allylic methyl group, took a longer time (7 h) to cyclize but was also furnis hed in 85% yield of the desired product 2 134 Interestingly, the methyl group was oriented axial ly From the 13 C NMR of 2 13 4 the spiro carbon has a resonance of 95.7 ppm, which suggests a doubly anomeric spiroketal (compared to anomeric spiroketals 2 11 5 2 116 and 2 135 which has 96.0, 95.3, and 96.0 ppm, respectively; and nonanomeric spiroketal 2 117 with 98.2 ppm) 1g Based on the coupling constants of proton H a it can be deduced that it can be in an axial equatorial or equatorial equatorial relatio nship to the neighboring proton. From th e s e data, three possible diastereomers for 2 13 4 can be proposed ( Scheme 2 36 ). However, nOe data revealed a weak correlation between proton H a and H b Based on this, the structure of 2 13 4 was assigned to 2 13 4 c

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92 Scheme 2 3 6 Three possible diastereomers of 2 13 4 2.5 Summary In this chapter, it was demonstrated that various transition metal catalysts can activate monoallylic ketodiols towards formation of spiroketals. Among the catalysts screened, optimum results were obtained with PdCl 2 (CH 3 CN) 2 in THF under mild reaction cond itions ( 0 C to rt). The spiroketalization method proved to be tolerant of different substitution patterns (60 90% yield), however, the presence of a substituent alpha to the ketone or allylic alcohol dramatically slowed down the reaction ( 2 117/2 118 and 2 134 24 h and 7 h, respectively). This is probably due to steric effects near the reaction center. For most of the substrates, the major product obtained is the doubly anomeric spiroketal except for 2 117/2 118 which are nonanomeric. In the next chapter, efforts towards the stereoselective construction of spiroketals will be discussed. 2.6 Other Spirocyclizations Studied 2.6.1 Pd(II) catalyzed Bis spiroketalization of Monoallylic Diketodiols As discussed earlier in this chapter, we were able to demonstra te that monoallylic ketodiols can undergo dehydrative spiroketalization in the presence of PdCl 2 (CH 3 CN) 2 We hope to extend this methodology in the construction of bis spiroketals. Compared to the spiroketal counterparts, there are only a limited of synthe tic methods available for the formation of the tricyclic bis spiroketal ring systems. 61 However, these scaffolds can be found in a wide range of biologically active natural products such as pinnatoxins, 62

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93 spirolides, 63 azaspiracids 64 and spirastrellolides 65 Thus, synthesis of bis spiroketals is emerging as an active research. Our approach towards the synthesis of the bis spiroketal system 2 137 will take advantage of the ability of palladium(II) to activate allylic alcohols (Scheme 2 37). If we have a subs trate such as 2 136 which contain a diketone functionality and a pendant alcohol nucleophile, a cascade of reaction can be envisioned. The pendant alcohol can attack the first ketone forming a hemiketal ; the hemiketal attack the s econd carbonyl forming a bicyclic hemiketal The third ring will be formed by the attack of the hemiketal 2 137 Scheme 2 37. Proposed Pd(II) catalyzed bis spiroketalization The synthesis of the bis spiroketal precursor monoallylic diketodiol 2 143 started with the alkylation of the double enolate formed from ethyl acetoacet ate 2 138 with the alkene 2 37 (Scheme 2 35). Conjugate addition of ketoester 2 139 to 2 140 furnished the diketoalkenyl compound 2 141 in 98% yield. Cross metathesis of alkene 2 141 with 2 45 followed by chemo sel ective reduction using NaBH(OAc) 3 gave the allylic alcohol 2 142 in 72% yield. Deprotection of 2 142 afforded the desired bis spiroketal precursor 2 143 Compound 2 143 was treated initially with 10 mol % of PdCl 2 (CH 3 CN) 2 in THF at 0 C (Scheme 2 35). Another 10 mol % catalyst was added and the reaction was warmed to room temperature before a new spot in TLC was observed. After 24 h, the reaction

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94 was stopped, however, no desired product was obtained based on analysis of the crude reaction 1 H NMR. Scheme 2 38. Synthesis of monoallylic diketodiol 2 143 Scheme 2 39. Attempted bis spiroketalizatio n of 2 143 To eliminate the possibility that the acidic proton alpha to the ester substitutent of 2 143 was the reason for the cyclization to fail, the unsubstituted precursor 2 136 was prepared (Scheme 2 40). Transesterification of ethyl ester 2 139 with allyl alcohol furnished the allyl ketoester 2 145 in 80% yield followed by conjugate addition to 2

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95 140 to give 2 146 in 78% yield Decarboxylative deallylation 66 of diketoester 2 146 produced 2 147 in quantitative yield. Compound 2 147 was subjec ted to reaction sequence similar to 2 141 to obtain the desired bis spiroketal precursor 2 136 However, under the standard spiroketalization conditions, 2 136 failed to cyclize to 2 137 (Scheme 2 41). No further experiments were done to optimize the spiro ketalization of 2 136 Scheme 2 40. Synthesis of monoallylic diketodiol 2 136 Scheme 2 41. Attempted bis spiroketalization of 2 136

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96 2.6.2 Metal catalyzed Spiroaminal Formation Spiroaminals or spiro N,O spiroketal systems exist as substructures occur in a number of biologically active comp ounds such as azaspiracid, 64 marineosins A and B, 67 and tomatidine. 68 Compared to its oxygen analogues, there are fewer methods to construct spiroaminal motifs. 69 As a continuing effort in our lab to explore new strategies in spirocycle formation that invo lve activation of unsaturated alcohols, we turned our attention to the synthesis of spiroaminals. It was envisioned that if a nitrogen nucleophile instead of an alcohol was tethered to the monoallylic ketodiol substrate used for spiroketal synthesis and ob tain a system similar to 2 149 the nitrogen can attack the ketone to form an intermediate hemiaminal. The hemiaminal can then act as nucleophile and attack the activated allylic alcohol to furnish the spiroaminal 2 15 1 (Scheme 2 42). Scheme 2 42 Proposed m etal catalyzed s piro a minal f ormation To test our hypothesis, the spiroaminal precursor 2 154 was synthesized in three synthetic steps starting from valerolactam 2 152 ( Scheme 2 43). Protection of the nitrogen with Boc 2 O followed by addition of Grignard reagent 2 65 produced 2 153 in 74% yield. Cross metathesis of 2 153 catalyst 2 45 follo wed by chemoselective reduction gave the target compound 2 154 in 63% yield over 2 steps.

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97 Scheme 2 43 Synthesis of spiroaminal precursor 2 154 The spiroaminalization of compound 2 154 was screened under a variety of conditions, metal catalysts and additives (Table 2 4). Table 2 4. Catalyst screening for spiroaminal formation Entry Catalyst Cat. Loading (mol%) Solvent Temp Time Yield % Remarks 1 PdCl 2 (MeCN) 2 15 THF 0 C rt 24 h trace 2 a) TsOH 5 THF rt 1 h No new spot b) PdCl 2 (MeCN) 2 5 THF rt 24 h 2 3 new spots 3 a) K 2 CO 3 (1 eq), PdCl 2 (MeCN) 2 5 THF t. 2 h 0 4 a) CSA 10 THF rt 1 h 0 No new spot b) PdCl 2 (MeCN) 2 5 THF rt to 50 C 24 h 0 5 a)Yb(OTf) 3 10 DCM 0 C 1 h 0 No new spot b) PdCl 2 (MeCN) 2 5 DCM 0 C rt 3 d 0 6 BF 3 OEt 2 20 DCM 0 C 1 h 0 No new spot PdCl 2 (MeCN) 2 5 DCM 0 C rt 3 d 0

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98 Table 2 Entry Catalyst Cat. Loading (mol%) Solvent Temp Time Yield % Remarks 7 PdCl 2 (MeCN) 2 5 1,4 dioxane 80 C 3 d 0 8 Yb(OTf) 3 MeOH (1eq) 10 THF 0 C 2 h 0 No new spot b) PdCl 2 (MeCN) 2 5 THF 0 C rt 3 d 0 9 Yb(OTf) 3 TsOH, MeOH (1eq) 10, 10 DCM 0 C 2 h 0 No new spot b) PdCl 2 (MeCN) 2 5 DCM 0 C rt 0 PdCl 2 (CH 3 CN) 2 which has been shown to promote the cyclization of an aminoallylic alcohol to vinyl piperidines, 47 and Yb(OTf) 3 were tested as catalysts for the cyclization, however, no spiroamination was observed even at high catalyst loading (20 mol %). Additives such as K 2 CO 3 and other Lewis acids which we thought will activate the ketone or aid in the hemiaminal formation, we re also employed. Although the spiroamination attempts were not successful, it could be that the reaction failed to work because the Boc protecting group renders the nitrogen electron poor to act as a nucleophile. Changing the protecting group to Ts or Cb z could improve the reactivity of the nitrogen. Also, this spiroamination was not explored using gold catalyst. This project was set aside to prioritize the spiroketalization project but this is a promising transformation and deserves to be revisited.

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99 CHAPTER 3 PALLADIUM(II) CATALYZED STEREOSELE CTIVE SPIROKETAL FOR MATION 3.1 Introduction The spiroketal motif contains an acid sensitive ketal group and can therefore can exist and equilibrate in different configurations (Figure 1 3). While most natural products contain the thermodynamically favored doub ly anomeric structures, a number of them contain nonanomeric spiroketals. Some examples include spongistatin 1 (Figure 1 1), 2 spirofungin B, 70 aplysiatoxins 71 and reveromycin A 72 (Figure 3 1). From a synthetic standpoint, the stereoselective construction o f nonanomeric spiroketals are more challenging because unlike their doubly anomeric counterparts, they are thermodynamically less stable Figure 3 1. Natural products with nonanomeric spiroketal cores

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100 3.2 Synthesis of Nonanomeric Spiroketals The challenge of having a flexible synthesis of stereodefined spiroketals has lead to innovative approaches to access either the anomeric or nonanomeric spiroketals. The classical approach takes advantage of equilibrat ing conditions to dictate the spiroketal stereochemistry; however, these methods usually provide the anomeric spiroketals. For the thermodynamically less stable nonanomeric spiroketals to be obtained under equilibrating conditions, chelation effects 73 and intramolecular hydrogen bonding have typically been utilized. 74 A few general methods are available for stereoselective construction of spiroketals that give access to nonanomeric spiroketals. These can be classified as: a) substrate controlled; 75, 76 or b) chiral catalyst based spiroketalizations. 77, 78 All of these spiroketalizations, however, rely on having one of the rings already preformed. 3.2.1 Substrate c ontrol A pproach In 2005, Rychnovsky et al. reported a reductive cyclization strategy towards no nanomeric spiroketals (Scheme 3 1). 75 Cyanoacetals are treated with lithium di tert butylbiphenylide (LiDBB) creating an organolithium intermediate, which then attacks the tethered alkyl halide (or any suitable leaving groups) to form the nonanomeric produ ct 3 7 Initial single electron transfer (SET) followed by C CN bond scission generates radical intermediate 3 9 This radical can equilibrate to the axial or equatorial position. However, due to anomeric effect the axial radical is favored. A second SET f orms the alkoxy alkyllithium intermediate 3 10 which is followed by an intramolecular alkylation to form the nonanomeric spiroketal 3 7 Some of the limitations of this method are the laborious preparation of the substrates which require at least 8 synth etic steps; and base sensitive or radical sensitive substrates cannot be used.

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101 Scheme 3 1. Ry The Tan group developed a different approach to access nonanomeric spiroketals. 76a Their methanol induced kinetic spiroketalization takes advantage of the stereoinduction provided by the stereoselective epoxidation preceding the cyclization. The epoxide ring opening occurs with inv ersion of configuration and for syn glycals such as 3 11 this gives rise to a nonanomeric spiroketal 3 14 (Scheme 3 2). Conversely, upon warming the reaction, a mixture of the anomeric 3 16 and nonanomeric spiroketal 3 14 was obtained. The authors discove red that formation of the nonanomeric spiroketal 3 14 is favored by adding MeOH at low temperatures to the initial solvent used in the preceding epoxidation, while addition of TsOH equilibrated the mixture and favored the anomeric spiroketal 3 16 with rete ntion of configuration at the anomeric carbon C1 To prove that the MeOH induced spiroketalization is kinetically controlled, the anomeric spiroketal 3 16 was subjected to the same conditions (DMDO, 78 C; then MeOH, 63 C) and no conversion to 3 14 was observed. The authors speculate that a MeOH hydrogen bonding catalysis could be involved since the spirocyclization did not proceed

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102 when polar aprotic solvents (acetone, THF, DMF or ethyl acetate; 78 C ) were employed. Scheme 3 2. Non anomeric spiroketals via methanol induced kinetic spiroketalization of syn glycal epoxides The same stereocomplementary kinetic spiroketalization approach was also developed for the anti glycal series (Scheme 3 3). 76b In this case, the product of the spontaneous spiroketalization of anti glycal 3 17 under methanolic conditions favored the C1 inversion pathway resulting in the anomeric spiroketal 3 2 0 On the contrary, the presence of Ti (O i Pr) 4 gave the 3 22 A transition state 3 21 where the oxygens are chelated to the Lewis acid accounted for the locked conformation which favors the formation of the nonanomeric spiroketal 3 22

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103 Scheme 3 3. Non anomeric spiroketals via Ti(O i Pr) 4 induced kinetic spiroketalization of anti glycal epoxides to gain access to stereocomplementary anomeric and nonanomeric spiroketals, it has drawbacks. For instance, an allylic hydroxyl group must be present in the first ring to direct the stereoselective epoxidation. 3.2.2 Chiral catalyst based A pproach Deslong champ and coworkers 8b studied the acid catalyzed spiroketalization from different cyclic enol ethers and this serves as the basis for the stereoselective construction of spiroketals using chiral acid catalysts. In these studies, a thorough explanation for the different stereoc hemical outcomes using transition state models was proposed. Treatment of 3 23 with TFA in benzene gave a 1:1 racemic mixture of

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104 anomeric 3 24 and nonanomeric 3 25 spiroketals However, in the presence of AcOH, it formed a mixture of 3 24 3 25 and 3 26 i n 1.5:2.5:1 ratio. Scheme 3 catalyzed spiroketalization Upon treatment with acid, the cyclic enol ether 3 27 forms a planar oxo carbenium ion 3 28 (Scheme 3 5). In the presence of an achiral acid, the hydroxyl group can attack either face of the ion with an equal probability which will lead to a racemic mixture. ori ge of the Coulombic interaction between the negatively charged bulky chiral catalyst and the positively charged oxo carbenium ion. 77 They developed Br nsted acids with an imidodiphosphoric acid motif. Reaction of this chiral acid with the cyclic enol ether generates the anion (X ) which selectively blocks one face of the oxocarbenium ion and dictates which isomer is formed (Scheme 3 5, inset). For substituted enantiopure enol ethers such as 3 34 and 3 35 this can result in the formation of the nonanomeric 3 36 or anomeric 3 37 spiroketal (Scheme 3 6). This method can be used with simple substrates lacking polar functional groups which are oftentimes necessary for Br nsted acid catalysis.

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105 Scheme 3 5. ori Scheme 3 6. ori ation Shortly after ori Br nsted acid catalyzed stereoselective spiroketalization. 78 Their approach utilized a BINOL derived chiral phosphoric acid (CPAs) to promote stereochemical induction. Treatment of cyclic enol ether 3 38 with 5 mol % of ( S ) 3 41 produced 87% yield with the nonanomeric product 3 39 (dr 95:5) as the major diastereomer (Scheme 3 7).

PAGE 106

106 However, ( R ) 3 41 and achiral (PhO) 2 (P=O)OH gave 76% and 89% yield of almost racemic mixture, respectively. The authors reported that treatment of 3 39 with (PhO) 2 (P=O)OH resulted in complete isomerization of 3 39 to 3 40 Scheme 3 7 catalyzed diastereoselective spiroketalization The authors proposed a mechanism involving a concerted proton transfer and C O bond formation, contrary to the accepted inter mediacy of oxo carbenium intermediate in the acid catalyzed spiroketalization of cyclic enol ethers (Scheme 3 7). They based this hypothesis on the observation that the reaction proceeds faster and yields higher stereocontrol in nonpolar solvents such as p entane. 3.3 Project Aim In Chapter 2, the Pd(II) catalyzed spiroketalization of racemic monoallylic ketodiols was discussed. From these results, it can be deduced that the sterics of the substrate influences the conformation of the transition state and th ereby the stereochemistry of the products. Uenishi and coworkers have extensively studied chirality transfers in the

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107 cyclizations of monoallylic diols catalyzed by Pd(II) in an S N 47 Their proposed mechanism shows Pd(II) complexed to both the ol efin and alcohol of the allylic alcohol as well as the incoming nucleophile We hypothesize that we could alter the configuration of C10 by varying the absolute configuration of C12 or the geometry of the olefin (Scheme 3 8). If our hypothesis proves righ t, this process would illustrate the versatility of our spiroketalization strategy to efficiently prepare either anomeric or nonanomeric spiroketals by a minor structural change in the substrate. Scheme 3 8. Proposed stereoselective spiroketal synthesis 3.3.1 Effect of Allylic Alcohol Chirality To test our hypothesis, both epimers of monoallylic ketodiols were necessary. The substrates with the same olefin geometry should be available by cross metathesis using 2 different allylic alcohols and a common terminal olefin intermediate. The synthesis of inter mediate keto olefin 3 50 commenced with the alkynylation of aldehyde 3 44 followed by Swern oxidation to obtain the ynone 3 45 (Scheme 3 9). Asymmetric transfer hydrogenation of 3 45 under modified Noyori conditions 79 using RuCl[( R R ) Ts DPEN(mesitylene) a nd consequent TBS protection of the resulting propargyl alcohol furnished 3 46 in 81% yield (over 2 steps) and 97% ee. Hydrogenation of 3 46 reduced

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108 the alkyne and cleaved the benzyl protecting group; the resulting alcohol was oxidized to obtain acid 3 47 in a 65% yield. Coupling of 3 47 with N methoxy N methylamine produced the Weinreb amide 3 48 in 77% yield. Finally, addition of Grignard reagent 23 49 to the Weinreb amide furnished the common intermediate keto olefin 3 50 in 76% yield. The epimeric monoa llylic ketodiols 3 53 and 3 54 were accessed by cross metathesis of 3 50 with either of the allylic alcohols 3 51 or 3 53 derived from Sharpless kinetic resolution. 80 Compounds 3 53 and 3 54 were obtained in 60% and 55% yield, respectively, after TBS deprotection (Scheme 3 10). Scheme 3 9. Preparation of synthetic intermediate 3 50

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109 Scheme 3 10 Preparation of 3 53 and 3 54 With the ketodiols 3 53 and 3 54 in hand, Pd(II) catalyzed spiroketalization was performed using the standard reactions conditions (5 mol% PdCl 2 (MeCN) 2 THF, 0 C) (Scheme 3 11). Whereas the ( R ) epimer 3 54 smoothly converted to the anomeric spiroketal 3 57 in 75 minutes with an 89% yield, the ( S ) epimer 3 53 was not completely consumed under the standard conditions after several hours. However, when the catalyst loading was increased to 10 mol% and the reaction was warmed to room temperature, the nonanomeric spiroketals 3 55 and 3 56 were obtained in a combined yield of 70%. Nonanomeric spiroketals 3 55 and 3 56 were found to equilibrate even in trace amounts of acid from CD Cl 3 with a ratio of 1:1 after complete equilibration. The configurations of spiroketals 3 55 3 56 and 3 57 were confirmed by 2D NMR experiments. Several diagnostic NOESY cross peaks clearly differentiated 3 55 from 3 56 (Scheme 3 12).

PAGE 110

110 Scheme 3 11. Spiroketalization of 3 53 and 3 54 Scheme 3 12. Diagnostic nOe or NOESY correlation observed for spiroketalization products From the results of the spiroketalizations described above, it is evident that the allylic alcohol chirality has an infl uence on the stereochemistry of the products formed. It was necessary to further investigate if control of chirality by the allylic alcohol can override inherent steric bias in the substrate. For this purpose, the protected glycal

PAGE 111

111 derivatives 3 60 and 3 61 were synthesized (Scheme 3 13). Protecting the glucose derivative as a benzylidene acetal would lock this ring in a fixed conformation where all the substituents are locked in the equatorial position. Treatment of gluconolactone 3 58 with lithiated bromop entene 3 49 afforded the hemiketal 3 59 in 74% yield. Cross metathesis of alkenyl hemiketal 3 59 with TBS protected allylic alcohols 3 52 or 3 51 followed by deprotection with PPTS in MeOH gave 3 60 and 3 61 in 37% and 30% yield, respectively, over 2 steps. Interestingly, these compounds exist primarily in the cyclic form, in contrast to the previous substrates. Scheme 3 13. Synthesis of 3 60 and 3 61 The diastereomers 3 60 and 3 61 were subjected to the standard reactions conditions. (Scheme 3 14). The ( R ) epimer 3 60 was completely converted to the anomeric spiroketal 3 62 after 45 minutes to give an 86% yield. The ( S ) epimer 3 61 took a longer time to react, furnishing the nonanomeric spiroketals 3 63 3 64 and an

PAGE 112

112 unknown diastereomer in 82% combined yield and 62:34:4 dr after 10 h at room temperature. The configurations of compounds 3 62 3 63 and 3 64 were confirmed by 2D NMR experiments. A diagnostic NOESY cross peak clearly differentiated 3 63 and 3 64 (Scheme 3 15). Scheme 3 14. Spiroketalization of 3 21 and 3 22 Scheme 3 15. Diagnostic nOe or NOESY peaks observed for spiroketalization products 3 23 3 24 and 3 25 3.3.2 Effect of Olefin Geometry We have shown in Section 3.3.1 that the absolute configuration of the allylic alcohol has an influence on the stereochemical outcome of the spiroketalization. To

PAGE 113

113 confirm if the cyclization is controlled solely by the allylic alcohol or a combination of bot h allylic alcohol chirality and olefin geometry epimeric monoallylic ketodiols 3 69 and 3 70 with a Z olefin configuration were synthesized (Scheme 3 16). Thus, a Grignard reagent from (5 bromopent 1 ynyl)trimethylsilane 3 65 was added to Weinreb amide 3 48 to obtain a TMS protected keto alkyne in 70% yield. Cleavage of the TMS group using K 2 CO 3 in methanol furnished terminal alkyne 3 66 in 86% yield. Asymmetric alkynylation of cyclohexane carboxaldehyde 3 67 with 3 66 conditions 8 1 using t he appropriate N methyl ephedrine (NME) enantiomer, followed by Lindlar reduction and deprotection with TBAF provided the Z monoallylic ketodiols 3 68 and 3 69 in 58% and 35%, respectively. Scheme 3 16 Preparation of Z monoallylic ketodiols 3 68 and 3 69

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114 Scheme 3 1 7 Spiroketalization of Z monoallylic ketodiols 3 68 and 3 69 3.3.3 Rationale for Stereoselectivity Observed An analysis of the possible transition states for the spiroketalization of the different monoall ylic ketodiols are presented in Schemes 3 18 to 3 21. The observed products are highlighted for each scheme. The spiroketal products obtaine d are E olefins, so these transition state analyses do not take into account alternative conformations that would gi ve rise to Z olefin products. 47 the Pd(II) metal coordinates syn to the alcohol of the allylic moiety. Assuming that this mechanism of coordination is true for our reaction, the next step in the spiroketalization would be the attack of the nucleophile to the activated olefin. The hemiketal alcohol can attack on the sam e face of the metal and the allylic alcohol ( syn oxypalladation) or from the opposite face ( anti oxypalladation). This will be followed by syn elimination of the metal and the alcohol

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115 leaving group to give the vinyl spiroketal. The mechanism of formation o f the observed products for all substrates revealed a syn oxypalladation, syn elimination sequence. It should be noted that whenever the nucleophile is set for an anti oxypalladation, the expected product is not observed experimentally ( Scheme 3 18, Equat ion 1, Scheme 3 19, Equations 2 4, Scheme 3 20, Equations 2 4, and Scheme 3 21, Equation 1). For the ( S ) E and ( R ) Z monoallylic ketodiol substrates, a syn oxypalladation, syn elimination sequence is also possible when the hemiketal alcohol is axial (Sche mes 3 11 and 3 14, Equation 2). The expected product would be doubly anomeric, which is favored by electronics. The sterically encumbered transition state with axial vinyl substituent inhibits this formation and the product is not observed experimentally.

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116 3.3.3.1 ( S ) E monoallylic ketodiols Scheme 3 18. Origin of stereoselectivity in the spiroketalization of ( S ) E monoallylic ketodiol s (R = CH 2 CH 2 Ph)

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117 3.3.3.2 ( R ) E monoallylic ketodiols Scheme 3 19. Origin of stereoselectivity in the spiroketalization of ( R ) E monoallylic ketodiol s (R = CH 2 CH 2 Ph)

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118 3.3.3.3 ( S ) Z monoallylic ketodiols Scheme 3 20. Origin of stereoselectivity in the spiroketalization of ( S ) Z monoallylic ketodiol s (R = CH 2 CH 2 Ph )

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119 3.3.3.4 ( R ) Z monoallylic ketodiols Scheme 3 21. Origin of stereoselectivity in the spiroketalization of ( R ) Z monoallylic ketodiol s (R = CH 2 CH 2 Ph)

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120 3.4 Summary and Outlook The stereoselective construction of spiroketals remains a challenging area for synthetic chemists, only a few general methods are available to date. In this work on Pd(II) catalyzed spiroketal formation from monoally lic ketodiols, we were able to demonstrate that even with highly substituted substrates we can selectively obtain anomeric or nonanomeric spiroketals by changing the geometry of the olefin and the chirality of allylic alcohols. This complementary approach to access different diastereomers will allow flexibity in the synthesis of the cyclization precursors, especially in totally synthesis application. An ( S ) Z monoallylic ketodiol or ( R ) E monoallylic ketodiol, for example, could be used as starting material for the spiroketalization to access a doubly anomeric spiroketal (Scheme 3 22). An analysis of the possible reaction mechanisms was presented to account for the formation of the observed products. Scheme 3 22. Stereoselectivity in Pd(II) catalyzed spiroketalization

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121 CHAPTER 4 CONCLUSION AND OUTLOOK The abundance of spiroketals in natural products continues to inspire synthetic chemists to be innovative in constructing these moieties. The development of spiroketalization methods using transition m etal s started two decades ago, and in the past five years, its application in total synthesis has been increasing in numbers. In this work, we have demonstrated that mono allylic ketodiols can be efficiently converted to spiroketals using Pd(II) catalysis in high yields and diastereoselectivities. The reaction tolerate d a wide range of substitution patt erns for both spiroketal rings. Moreover, we were able to show that the stereochemistry of the spiroketal formed is dependent on both the olefin geometry and chirality of the allylic alcohol in the starting material. The newly developed stereoselective spiroketalization method will pave a way to access anomeric or nonanomeric spiroketals by a simple structural change in the monoally lic ketodiol substrate. The application of this Pd(II) catalyzed spiroketalization to natural product synthesis is underway in our laboratory. Despite the emerging progress in metal catalyzed spiroketalizations, the stereoselective version to construct sp iroketals remain s a challenge. Th e work reported herein could be considered as one of the few metal catalyzed stereoselective spiroketalization method s available to date However, further investigation is necessary to obtain exclusively one nonanomeric spi roketal after spiroketalization. In the future, metal catalyzed spiroketalization is expected to be competitive with traditional methods of spiroketalization owing to the mild reaction conditions needed for the construction of complex molecules.

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122 CHAPTE R 5 EXPERIMENTAL SECTION 5 .1 General Remarks All reactions were carried out under an atmosphere of nitrogen unless otherwise specified. Anhydrous solvents were transferred via syringe to flame dried glassware, which had been cooled under a stream of dry ni trogen. Anhydrous tetrahydrofuran (THF), acetonitrile, ether, dichloromethane, pentane were dried using a mBraun solvent purification system. Gel 60 F 254 pre coated plates (EMD Chemicals Inc.). Flash column chromatography was performed using 230 400 Mesh 60A Silica Gel (Whatman Inc.). The eluents employed are reported as volume:volume percentages. Proton nuclear magnetic resonance ( 1 H NMR) spectra were rec orded using Varian Mercury 300 MHz or Inova 500 or 600 downfield relative to tetramethylsilane (TMS, 0.0 ppm) or CDCl 3 (7.2 6 ppm). Coupling constants ( J ) are reported in Hz. Multi plicities are reported using the following abbreviations: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; qn, quintet; m, multiplet; br, broad; Carbon 13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded using a Varian Un ity Mercury 300 spectrometer at 75 MHz or Inova spectrometer at 125 MHz or 150 MHz .Chemical shift is reported in ppm relative to the carbon resonance of CDCl 3 (77.00 ppm). Enantiomeric excesses were determined by high performance liquid chromatography (HPLC) using Shimadzu instrument. Specific optical rotations were obtained on a JASCD P 2000 Series Polarimeter (wavelength = 589 nm).

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123 5 .2 Experimental Procedure s 5 .2.1 Synthesis of 2 vinyl 1,6 dioxaspiro[4.5]decane (2 50). Scheme 5 1. Synthesis of 2 48 ( E ) 10 ( tert butyldimethylsilyloxy) 6 oxodec 2 enal (S1) A solution of 2 76 (647 mg, 2.4 mmol) and crotonaldehyde (0.99 mL, 12 mmol) in dry CH 2 Cl 2 (1 mL) was added to a solution of Grubbs 2 nd generation catalyst (41 mg, 0.048 mmol, 2 mol%) in dry CH 2 Cl 2 (1 mL). The mixture was stirred at reflux for 4 hours and then allowed to sti r at room temperature for 30 minutes. The solution was filtered through a silica plug, which was then washed with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (5% to 20% EtOAc in hexanes) to give the al dehyde product S1 as a yellow oil (576 mg, 80%). 1 H NMR (500 MHz, Chloroform J = 7.8, 0.7 Hz, 1H), 6.86 6.76 (ddd, 15.8, 6.4, 6.4 Hz, 1H), 6.06 (dddd, J = 15.7, 7.8, 1.5, 0.8 Hz, 1H), 3.57 (t, J = 6.3 Hz, 2H), 2.63 2.52 (m, 4H), 2.42 (t, J = 7.3 Hz, 2H), 1.65 1.58 (m, 2H), 1.51 1.40 (m, 2H), 0.84 (d, J = 0.6 Hz, 9H), 0.07 0.06 (m, 6H). 13 C NMR (126 MHz, CDCl 3 42.6 40.1, 32.1, 26.4, 25.9, 20.3, 18.3, 5.3

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12 4 ( E ) 1 ( tert butyldimethylsilyloxy) 10 hydroxydec 8 en 5 one (S2). To a stirring solution of aldehyde S2 (571 mg, 1.9 mmol) in benzene (19 mL) was added NaBH(OAc) 3 (1.06 g, 4.8 mmol). The mixture was refluxed for 16 hours and quenched with 25 mL satur ated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with ether (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10 % to 20% EtOAc in hexanes) to give the allylic alcohol S2 as a colorless oil (489 mg, 86%) ; 1 H NMR (500 MHz, CDCl 3 5.60 (m, 2H), 4.09 4.05 (m, 2H), 3.60 (t, J = 6.3 Hz, 2H), 2.50 (dd, J = 7.3, 0.6 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.35 2.29 (m, 3H), 1.68 1.58 (m, 2H), 1.54 1.45 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H). 13 C NMR (126 MHz, CDCl 3 32.2, 26.3, 25.6, 20.3, 18.3, 5.3 ( E ) 1,10 dihydroxydec 8 en 5 one (2 48). To a stirring solution of S4 (477 mg, 1.6 mmol) in THF (8 ml) was added 3.2 mL of 1.0 M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of starting material (3 hour). Silica was added to the reaction mixture and concentrated i n vacuo. The resulting mixture was purified by flash column chromatography (30% 50% EtOAc in hexanes) to give 218 mg (73%) of colorless oil. R f = 0.2 (EtOAc) 1 H NMR (299 MHz, CDCl 3 5.60 (m, 2H), 4.10 (m, 2H), 3.60 (t, J = 6.3Hz, 2H), ), 2.43 (t, J = 7.4 Hz, 2H), 2.35 2.29 (m, 2H), 1.80 1.70 (bs, 2H), 1.68 1.58 (m, 2H), 1.54 1.45 (m, 2H). 3 C NMR (126 MHz, CDCl 3 25.9, 19.7 HRMS (ESI) calculated for C 10 H 18 O 3 [M+Na] + = 209.1148, found 209.1147.

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125 2 vinyl 1,6 dioxaspiro[4.5]decane (2 50). To a stirred solution of monoallylic ketodiol 2 48 (55.9 mg, 0.3 mmol) in THF (1 ml) at 0 C was added PdCl 2 (MeCN) 2 (3.9 mg, 0.015 mmol). After 40 min, the starting material was completely consumed as monitored by TLC. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography ( hexanes to 5% EtOAc in hexanes) to yield 42.6 mg of the spiroketal (84%) as a mixture of diastereomers (dr 1.5:1). Rf = 0.9 (EtOAc). 1 H NMR (500 MHz, Chloroform 5.78 (m, 0.6H), 5.22 (ddd, J = 17.1, 1.8, 1.2 Hz, 0.4H), 5.17 (ddd, J = 17.1, 1.7, 1.0 Hz, 0.60H), 5.07 (ddd, J = 10.3, 1.8, 1.1 Hz, 0.6H), 5.04 (ddd, J = 10.2, 1.7, 0.9 Hz, 0.4H), 4.52 4.42 (m, 1H), 3.88 (dddd, J = 17.3, 11.7, 11.2, 2.9 Hz, 1H), 3.62 3.53 (m, 1H), 2.18 (ddd, J = 12.1, 8.7, 7.6 Hz, 1H), 2.06 1.95 (m, 1H), 1.92 1. 77 (m, 2H), 1.75 1.44 (m, 8H), 1.31 1.16 (m, 1H). 13 C NMR (126 MHz, CDCl 3 115.1, 105.9, 105.7, 81.9, 78.9, 61.7, 61.5, 38.8, 37.4, 34.1, 33.9, 33.8 30.5, 30.2, 25.3, 25.2, 22.3, 20.2, 20.1, 14.0 HRMS (ESI) calculated for C 10 H 16 O 2 [M+H] + = 169.2223, found 169.1219. 5 .2.2 Synthesis of 2 vinyl 1,7 dioxaspiro[5.5]decane (2 52)

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126 5 ( tert butyldimethylsiloxy) N methoxy methylpentanamide (2 36) 52 To a suspension of valerolactone 2 73 (1.2 mL, 10.0 mmol) and N O dimethylhydroxyamine hydrochloride (2.4g, 25.0 mmol) in 50 mL THF at 2 0 C was added dropwise over a period of 30 minutes a solution of i PrMgCl (25 mL, 50.0 mmol). The mixture was stirred at 2 0 C for 2 hours, then quenched with 25 mL of saturated NH 4 Cl solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated in vacuo The crude product was purified by flash chromatography (80 100% EtOAc in hexanes) to yield the amide 5a as colorless oil (1.25g, 78%). R f 0.3 (EtOAc). To a solution of the alcohol (1.3g, 8.1 mmol) in 30 mL of DCM at 0 C was added imidazole (1.1g, 16.2 mmol) followed by TBSCl (1.2g, 8.1 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 20 mL H 2 O. The layers were separated and the aqueous layer was extracted three times with DCM. The combined organic layers was washed with 1N HCl (15mL), saturated N aHCO 3 and finally with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 15% EtOAc in hexanes) to yield 2.07g of 6a (93%) of colorless oil that satisfactory matched all previously reporte d data. 1 ( tert butyldimethylsilyloxy)dec 9 en 5 one ( 2 53 ). To a suspension of Mg (159 mg, 6.5 mmol) in THF (2 mL) at room temperature was added dropwise over a

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127 period of 10 minutes, a solution of 5 bromo 1 pentene 2 38 (0.52 mL, 4.4 mmol) in THF (2.2 mL). The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solution of 2 36 (600 mg, 2.2 mmol) in THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 5 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a colorless oil (549 mg, 89%). R f 0.5 (10% EtOAc in hexanes). 1 H NMR (299 MHz, CDCl 3 J = 16.9, 10.2, 6.7 Hz, 1H), 5.03 4.90 (m, 2H), 3.58 (t, J = 6.2 Hz, 2H), 2.42 2.34 (m, 4H), 2.02 (ddd, J = 7.9, 6.2, 1.4 Hz, 2H), 1.70 1.54 (m, 4H), 1.52 1.41 (m, 2H), 0.86 (s, 9H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ) 211.0, 138.0, 115.2, 62.8, 42.6, 41.8, 33.1, 32.27, 25.9, 22.8, 20.3 18.3 5.3 Scheme 5 2. Synthesis of 2 49 ( E ) 11 (tert butyldimethylsilyloxy) 7 oxoundec 2 enal ( S 3 ) A solution of 2 53 ( 1.17 g 4.1 mmol) and crotonaldehyde ( 1.7 mL, 20.5 mmol) in dry CH 2 Cl 2 ( 14 mL) was added to a solution of Grubbs 2 nd generation catalyst ( 70 mg, 0.082 mmol) in dry

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128 CH 2 Cl 2 ( 7 mL). The mixture was stirred at reflux for 4 hours and then allowed to stir for 30 minutes. The solution was filtered through a silica plug, washed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chr omatography (5% to 3 0% EtOAc in hexanes) to give the aldehyde product as a yellow oil ( 1.17g 91 %). Rf = 0.5 (20% EtOAc in hexanes); 1 H NMR (299 MHz, CDCl 3 ) J = 7.8 Hz, 1H), 6.79 (dd, J = 15.7, 6.8 Hz, 1H), 6.10 (ddd, J = 15.6, 7.8, 1.5 Hz, 1H ), 3.58 (t, J = 6.2 Hz, 2H), 2.42 (dd, J = 9.3, 7.4 Hz, 4H), 2.32 (ddd, J = 8.1, 7.0, 1.5 Hz, 3H), 1.78 (p, J = 7.2 Hz, 2H), 1.67 1.55 (m, 3H), 1.52 1.42 (m, 3H), 0.87 (s, 9H), 0.02 (s, 6H). ( E ) 1 (tert butyldimethylsilyloxy) 11 hydroxyundec 9 en 5 one (S 4 ) .To a stirring solution of aldehyde S 3 ( 1.16 g, 3.7 mmol) in benzene ( 35 m L) was added NaBH(OAc) 3 ( 2.06 g 9.25 mmol). The mixture was refluxed for 16 hours and quenched with 25 mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with ether (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% Et OAc in hexanes) to give the allylic alcohol S 4 as a colorless oil ( 963 mg, 83 %). Rf = 0.3 (30% EtOAc in hexanes ); 1 H NMR (299 MHz, CDCl 3 5.57 (m, 2H), 4.07 4.01 (m, 2H), 3.57 (t, J = 6.2 Hz, 2H), 2.43 2.33 (m, 4H), 2.06 1.94 (m, 2H), 1.76 (s, 1H), 1.69 1.53 (m, 4H), 1.51 1.42 (m, 2H), 0.85 (s, 9H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 42.6, 41.8, 32.2, 31.5 25.9, 23.0, 20.3, 18.3, 5.4 ( E ) 1,11 dihydroxyundec 9 en 5 one ( 2 49 ). To a solution of S 4 (434 mg, 1.0 mmol) in 2 mL of THF at room temperature was added TBAF (5 mL, 5.0 mmol). The

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129 solution was allowed to stir for 4 hours and then quenched with 4 mL of H 2 O. The mixture was extracted four times with EtOAc, The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (80% EtOAc in hexanes to pure EtOAc) to give the product as a yellow oil, (119 mg, 60%). R f : 0.3 (EtOAc) ; IR (neat) 3376, 2937, 1703, 1408, 1370 .53, 1002 cm 1 ; 1 H NMR (500 MHz, Chloroform 5.54 (m, 2H), 4.09 3.99 (m, 2H), 3.58 (t, J = 6.3, 2H), 2.41 (t, J = 6.1 Hz, 2H), 2.39 (t, J = 6.2 Hz, 2H), 2.08 1.98 (m, 2H), 1.92 (s, 2H), 1.70 1.56 (m, 4H), 1.56 1.44 (m, 2H). 13 C NMR (126 MHz, CDCl 3 19.8 HRMS (ESI) calculated for C 11 H 20 O 3 [M+Na] + = 223.1305, found 223.1301. 2 vinyl 1,7 dioxaspiro[5.5]decane ( 2 52 ). To a stirred solution of monoallylic ketodiol 2 49 (55 mg, 0.27 mmol) in THF (2.7 ml) at 0 C was added PdCl 2 (MeCN) 2 (3.5 mg, 0.0135 mmol). After 5 h, TLC showed complete consumption of starting material. The mixt ure was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo and purified by flash chromatography (pentane to 2% ether in pentane) to yield 40.9 mg of the spiroketal 2 52 (83 %). R f : 0.7 (5% EtOAc) 1 H NMR (500 MH z, CDCl 3 ) 5.89 (1H, ddd, J = 17 .3, 10.55, 5.3 Hz), 5.28 (1H, dd J = 17.3, 1.7 Hz), 5.10 (1H, d d J =10.6, 1.6 Hz), 4.13 (1H, dddd J = 11.7, 5.4, 2.3, 1.3 Hz), 3.68 (1H, ddd, J = 11.0, 11.9, 3.0 Hz), 3.60 (1H, ddd, J = 11.0, 4.6, 1.8 Hz), 1.81 2.01 (2H, m), 1.21 1.72 (13H, m) 13 C NMR (75 MHz, CDCl 3 ) 139.7, 114.2, 95.7, 69.7, 60.4, 35.7,

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130 35.1, 30.7, 25.3, 18.7, 18.5 HRMS (ESI) calculated for C 11 H 18 O 2 [M+H] + = 183.1380, found 183.1374. 5 .2.3 Synthesis of 7 vinyl 1,6 d ioxaspiro[4.5]decane (2 78) 1 ( tert butyldimethylsilyloxy)non 8 en 4 one (2 75) To a suspension of Mg (241mg, 9.9 mmol) in THF (2 mL) at room temperature was added dropwise over a period of 10 minutes, a solution of 5 bromo 1 pentene (9 84 mg, 6.60 mmol) in THF (4.6 mL). The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solut ion of 2 74 (863 mg, 3.3 mmol) in THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 5mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a colorless oil (802 mg, 90%) ; 1 H NMR (500 MHz, CDCl 3 5.79 5.69 (m, 1H), 5.02 4.92 (m, 2H), 3.58 (dd, J = 6.1, 0.5 Hz, 2H), 2.47 2.43 (m, 2H), 2.40 (dd, J = 7.7, 7.1 Hz, 2H), 2.06 2.00 (m, 2H), 1.78 1.72 (m, 2H), 1.66 (p, 2H), 0.86 (s, 9H), 0.01 (s, 6H). 13 C NMR (126 MHz, CDCl 3 1 15 .1, 62.2, 41.9, 39.1, 33.1, 26.8, 25.9, 22.8, 18.3, 5.4

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131 Scheme 5 3. Synthesis of 2 77 ( E ) 10 ( tert butyldimethylsilyloxy) 7 oxodec 2 enal (S5) A solution of 2 75 (793 mg, 2.9 mmol) and crotonaldehyde (1.2 mL, 14.7 mmol) in dry CH 2 Cl 2 (10 mL) was added to a solution of Grubbs 2 nd generation catalyst (50 mg, 0.059 mmol, 2 mol%) in dry CH 2 Cl 2 (4 mL). The mixture was stirred at reflux for 2 hours and then allowed to s tir for 30 minutes. The solution was filtered through a silica plug, washed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (5% to 20% EtOAc in hexanes) to give the aldehyde product as a yellow oil (802 mg, 93 %). R f = 0.4 (20% EtOAc in hexanes ); 1 H NMR (500 MHz, CDCl 3 ) J = 15.6, 6.8 Hz, 1H), 6.10 (ddd, J = 15.6, 7.8, 1.5 Hz, 1H), 3.58 (t, J = 6.1 Hz, 2H), 2.48 2.43 (m, 5H), 2.32 (ddd, J = 7.7, 6.8, 1.5 Hz, 2H), 1.83 1.71 (m, 4H), 0.86 (s, 9H), 0.01 (s, 6H). 13 C NMR (126 MHz, CDCl 3 62 .1, 41.6, 39.2, 32.0, 26.8, 25.9, 21.7, 18.3, 5.4 ( E ) 1 ( tert butyldimethylsilyloxy) 10 hydroxydec 8 en 4 one (S6) To a stirring solution of aldehyde S5 (790 mg, 2.6 mmol) in benzene (26 mL) was added NaBH(OAc) 3 (1.48 g, 6.6 mmol). The mixture was refluxed for 16 hours and quenched with 15mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with ether (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give the allylic alcohol S6

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132 as a colorless oil (612 mg, 78%). R f = 0.3 (30% EtOA c in hexanes ); 1 H NMR (500 MHz, CDCl 3 5.55 (m, 2H), 4.06 (dd, J = 2.7, 0.9 Hz, 3H), 3.59 3.56 (m, 3H), 2.45 (t, J = 7.3 Hz, 2H), 2.40 (t, J = 7.4 Hz, 4H), 2.05 1.99 (m, 2H), 1.78 1.71 (m, 2H), 1.69 1.60 (m, 3H), 0.86 (s, 9H), 0.01 (s, 6H) 13 C NMR (126 MHz, CDCl 3 132.1, 129.8, 63.6, 62.2, 42.0, 39.1, 31.6, 26.8, 25.9, 23.1, 18.3, 5.4 ( E ) 1,10 dihydroxydec 8 en 4 one (2 77) To a stirring solution of S6 (600 mg, 2 mmol) in THF (10 ml) was added 4.0 mL of 1.0M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of starting material (1 hour). Silica was added to the reaction mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography (30% 50% EtOAc in hexanes) to give 259 mg (69%) of colorless oil. R f = 0.3 (EtOAc); 1 H NMR (500 MHz, CDCl 3 5.48 (m, 2H), 4.12 3.92 (m, 2H), 3.62 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 6.9 Hz, 2H) 2.42 (t, J = 7.2 Hz, 2H), 2.06 2.01 (m, 4H), 1.85 1.77 (m, 2H), 1.67 (m, 2H). 13 C NMR (126 MHz, CDCl 3 39.6 31.6, 26.4, 22.9 7 vinyl 1,6 dioxaspiro[4.5]decane (2 78 ). To a stirred solution of monoallylic ketodiol 2 77 (47 mg, 0.25 mmol) in THF (5 ml) at 0 C was added PdCl 2 (MeCN) 2 (6.5 mg, 0.025 mmol). After 24 h, no further progress in the reaction was observed as monitored by TLC. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield 22 mg of the spiroketal (52%). R f = 0.9

PAGE 133

133 (EtOAc) ; 1 H NMR (500 MHz, CDCl 3 J = 17.3, 10.5, 5.8 Hz, 1H), 5.19 (dd, J = 17.3, 1.6 Hz, 1H), 5.04 (ddd, J = 10.5, 1.8, 1.3 Hz, 1H), 4.23 (dddd, J = 11.7, 5.6, 2.6, 1.4 Hz, 1H), 3.88 (t, J = 7.0 Hz, 2H), 2.09 1.98 (m, 1H), 1.96 (ddd, J = 12.4, 8.7, 3.6 Hz, 1H), 1.91 1.78 (m, 3H), 1.74 1.60 (m, 6H), 1.36 1.15 (m, 2H). 13 C NMR (126 MHz, CDCl 3 6 2 3.7, 20.2 HRMS (ESI) calculated for C 10 H 16 O 2 [M+Na] + = 209.1148, found 209.1154. 5 .2.4 Synthesis of 2 butyl 8 vinyl 1,7 dioxaspiro[5.5]undecane (2 67) 5 ( tert butyldimethylsiloxy) N methoxy methylnonamide (2 64) To a suspension of 6 butyltetrahydro 2H pyran 2 one (3.19 g, 20.0 mmol) and N O dimethylhydroxyamine hydrochloride (4.88 g, 50.0 mmol) in 100 mL THF at 2 0 C was added dropwise over a period of 30 minutes a solution of i PrMgCl (25 mL, 50.0 mmol). The mixture was stirred at 2 0 C for 3 hours, then quenched with 50mL of saturated NH 4 Cl solution. The layers were separated and the aqueous layer was extra cted three times with EtOAc. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated in vacuo The crude product was purified by flash chromatography (80 100% EtOAc in hexanes) to yield the amide as colorless oil R f 0.3 (EtOAc). 1 H NMR (300 MHz, CDCl 3 3.53 (m, 1H), 3.18 (s, 3H), 2.53 2.38 (m, 4H), 1.83 1.68 (m, 2H), 1.55 1.37 (m, 4H), 1.37 1.24 (m, 2H), 0.93 0.84 ( m, 3H ) To a solution of the crude alcohol in 130 mL of DMF at 0 C wa s added imidazole (3.89 g, 57.2 mmol) followed by TBSCl (3.91 g, 26.0 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched

PAGE 134

134 with 20 mL H 2 O. The layers were separated and the aqueous layer was extracted three times with DCM. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 15% EtOAc in hexanes) to yield 7.44 g of 6a (86%) of colorless oil tha t satisfactory matched all previously reported data 1 H NMR (300 MHz, CDCl 3 m 4 H), 1.63 (m, 2H), 1.35 1.49 (m, 4H), 1.18 1.33 (m, 5 H), 0.85 (s, 9H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl3) 174.5, 72.1, 61.1, 36.7, 32.1, 27.4, 25.9, 22.8, 22.6, 20.5, 18.1, 14.1, 4.5. 10 ( tert butyldimethylsilyloxy)tetradec 1 en 6 one (2 65) A solution of 5 bromo 1 pentene (2.60 mL, 22.0 mmol) in THF (12 mL) was added dropwise over a period of 10 minutes to a suspension of Mg (802 mg, 33.0 mmol ) in THF (10 mL) at room temperature.The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a sol ution of 2 64 (3.64 g, 11.0 mmol) in 15 mL of THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 30 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated in vacuo The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a pale yellow oil (3.05 g, 81%). R f = 0.5 (5% EtOAc in hexanes). 1 H NMR (299 MHz, CDCl 3 J = 16.9, 10.2, 6.7 Hz, 1H),

PAGE 135

135 5.08 4.82 (m, 2H), 3.71 3.48 (m, 1H), 2.37 (dd, J = 7.4, 4.6 Hz, 4H), 2.14 1.93 (m, 2H), 1.71 1.50 (m, 4H), 1.46 1.32 (m, 3H), 1.25 (ddd, J = 8.4, 6.9, 3.0 Hz, 3H), 0.86 (s, 12H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ) 211.0, 138.0, 115.1, 72.0 43.1, 41.8, 36.7, 36.5 33.1 27.4, 25.9, 22.9, 22.8, 19.7, 18.1, 14.1 4. 5. Scheme 5 4. Synthesis of 2 62 ( E ) 11 (tert butyldimethylsilyloxy) 1 hydroxypentadec 2 en 7 one (S7). A solution of 2 65 (1.28 g, 3.8 mmol) and crotonaldehyde (1.6 mL, 19 mmol) in dry CH 2 Cl 2 (10 mL) was added to a solution of Grubbs 2 nd generation catalyst (64 mg, 0.075 mmol, 2 mol%) in dry CH 2 Cl 2 (9 mL). The mixture was stirred at reflux for 4 hours and then allowed to stir at room temperature for 30 minutes. The solution was filtered throug h a silica plug, washed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (hexanes to 20% EtOAc in hexanes) to give the aldehyde product as a yellow oil (1.39 g, 87%). R f 0.3 (20% EtOAc in hexanes). IR (KBr pellet) 2995 (s), 2858 (s), 1715 (s), 1693 (s), 1462 (m) cm 1. 1 H NMR (300 MHz, CDCl 3 J = 7.9 Hz, 1H), 6.79 (dd, J = 15.7, 6.7 Hz, 1H), 6.09 (ddd, J = 15.6, 7.8, 1.5 Hz, 1H), 3.61 (m, 1H), 2.49 2.23 (m, 6H), 1.84 1.72 (m, 2H), 1.68 1.46 (m, 2H), 1.45 1.31 (m, 4H), 1.29 1.17 (m, 4H), 0.86 (s, 12H), 0.03 0.03 (m, 6H). 13 C NMR (75 MHz, CDCl 3 3 6.7, 36.4, 32.0, 27.4, 25.9, 22.9, 21.6, 19.7, 18.1, 14.1, 4.4, 4.5

PAGE 136

136 ( E ) 11 ( tert butyldimethylsilyloxy) 1 hydroxypentadec 2 en 7 one (2 61). To a stirring solution of aldehyde S7 (749 mg, 2.0 mmol) in benzene (20 mL) was added NaBH(OAc) 3 (1.12 g, 5.0 m mol). The mixture was refluxed for 16 hours and quenched with 25mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concen trated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give the allylic alcohol 2 61 as a colorless oil (741 mg, 80%). R f 0.5 (30% EtOAc) 1 H NMR 1 H NMR (299 MHz, CDCl 3 5.63 (ddd, J = 3.4, 2.3, 0.9 Hz, 2H), 4.06 (dd, J = 2.7, 1.0 Hz, 2H), 3.60 (p, J = 5.7 Hz, 1H), 2.52 2.25 (m, 5H), 2.03 (dddd, J = 7.8, 6.9, 4.6, 2.3 Hz, 2H), 1.74 1.45 (m, 4H), 1.42 1.29 (m, 4H), 1.28 1.16 (m, 4H), 0.99 0.76 (m, 12H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ) 211.0, 132.1, 129.8, 72.0, 63.6, 43.1 41.8 36.7, 36.5, 31.6, 27.4, 25.9, 23.0, 22.8, 19.7, 18.1, 14.1, 4.4, 4.5 ( E ) 1,11 dihydroxypentadec 2 en 7 one (2 62). To a stirring solution of 2 61 (2.12 g, 5.7 mmol) in THF (57 ml) was added 17 mL of 1.0M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of starting material (1 hour). Silica was added to the reaction mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography (30% 50% EtOAc in hexanes) to give 949 mg (65%) of colorless oil. Rf = 0.3 (EtOAc); 1 H NMR (300 MHz, CDCl 3 ) 5.57 5.73 (m, 2H ), 4.09 (dd, J =3.2 1. 2 Hz, 2H), 3.56 (dd, J =7.62, 4.69 Hz, 1H), 2.36 2.48 (m, 4H), 2.00 2.12 (m, 2H), 1.16 1.75 (m, 21H), 0.83 0.95 (m, 3H). 13 C NMR (75 MHz, CDCl 3 ) 211.4, 131.6 130.0 71.3, 63.3, 42.6, 41.7, 37.1,

PAGE 137

137 36.7, 31.5, 27.8, 24.1, 22.9, 22.7, 19.7, 14.0 HRMS (ESI) calculated for C 15 H 28 O 3 [M H] = 255.1966, found 255.1967. 2 butyl 8 vinyl 1,7 dioxaspiro[5.5]undecane ( 2 67 ). To a stirred solution of monoallylic ketodiol 2 62 ( 102.4 mg, 0.4 mmol) in THF ( 4.4 ml) at 0 C was added PdCl 2 (MeCN) 2 ( 5.2 mg, 0.02 mmol). Aft er 1.5 h, complete consumption of starting material was observed by TLC. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purif ied by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield 79 mg of the spiroketal ( 83 %). Rf: 0.7 (5% EtOAc) ; IR (neat) 2935, 2868, 1456, 1225, 990 cm 1 ; 1 H NMR (300 MHz, CDCl 3 J =17.2 10. 6, 5.4 Hz, 1H), 5.22 (dd, J =17. 4 1. 6 Hz,1H), 5.02 5.09 (m, 1H), 4.00 ( dd J = 11.5, 2.5 Hz, 1H), 3.52 ( dd J = 11.5, 2.2 Hz, 1H), 1.80 1.99 (m, 2H) ,1.07 1.68 (m, 6 H), 0.89 (t, J = 7.04 Hz, 3H) 13 C NMR (75 MHz, CDCl 3 139.8, 114.2, 96.1, 69.7, 69.1, 36.1, 35.4, 35.3, 31.3, 30.8, 28.1 22.8, 18.9, 18.8, 14.1. HRMS (APCI) calculated for C 15 H 16 O 2 [M+H] + = 239.2006, found 239.2010. 5 .2.5 Synthesis of 2 isopropyl 8 vinyl 1,7 dioxaspiro[5.5]undecane (2 115) 5 ( tert butyldimethylsilyloxy) N methoxy N ,6 dimethylheptanamide (2 86) To a suspension of 6 isopropyltetrahydro 2H pyran 2 one (1.65 g, 11.6 mmol) and N O

PAGE 138

138 dimethylhydroxyamine hydrochloride (2.83 g, 29.0 mmol) in 58 mL THF at 2 0 C was added dropwise over a period of 30 minutes a solution of i PrMgCl (29 mL, 58 mmol). The mixture was stirred at 2 0 C for 3 hours, then quenched with 25mL of saturated NH 4 Cl solution and allowed to warm to room temperat ure. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers was washed with brine, dried with anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (40 8 0% EtOAc in hexanes) to yield the amide as colorless oil (2.06 g, 87%). R f = 0.3 (60% EtOAc). 1 H NMR (300 MHz, CDCl 3 3.56 (m, 2H), 3.32 3.20 (m, 1H), 3.12 (d, J = 2.7 Hz, 2H), 2.46 2.35 (m, 2H), 2.31 2.19 (m, 1H), 1.80 1.52 (m, 1H), 1.52 1.29 (m, 1H), 0.84 (dd, J = 6.7, 2.8 Hz, 4H). 13 C NMR (75 MHz, CDCl 3 17.2 To a solution of the alcohol (2.0 g 9.8 mmol) in 30 mL of DMF at 0 C was added imidazole (1.47 g, 21.6 mmol) followed by TBSCl (1.47 g, 9.8 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 20 mL H 2 O. The layers were separated and the aqueous layer was extracted three times with DCM. The combined organic layers w as washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 10% EtOAc in hexanes) to yield 2.60g of 2 86 (84%) of colorless oil. 10 ( tert butyldimethylsilyloxy) 11 methyldodec 1 en 6 one (2 89) A solution of 5 bromo 1 pentene (1.2 mL, 10.0 mmol) in THF (6 mL) was added dropwise over a

PAGE 139

139 period of 10 minutes to a suspension of Mg (365 mg, 15.0 mmol) in THF (4 mL) at room temperature.The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes a t room temperature. This Grignard reagent was added to a solution of 2 86 (1.59 g, 5.0 mmol) in 8 mL of THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 2 hours. The reaction was quenched with 10 mL of saturated NH 4 Cl. The laye rs were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO4 and concentrated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hex anes) to yield a pale yellow oil (1.38 g, 85%). 1 H NMR (29 9 MHz, CDCl 3 (ddd J = 16.9, 10.1, 6.7 Hz, 1H), 5.06 4.86 (m, 2H), 3.40 ( d d, J = 5.7, 4.5 Hz, 1H), 2.36 ( d d, J = 7.3, 5.6 Hz, 5H), 2.15 1.93 (m, 2H), 1.78 1.41 (m, 4H), 1.41 1.24 (m, 2H), 1.02 0.74 (m, 1 6 H), 0.13 0.13 (m, 5H). Scheme 5 5. Synthesis of 2 91 ( E ) 11 ( tert butyldimethylsilyloxy) 1 hydroxy 12 methyltridec 2 en 7 one (S9) A solution of 2 89 (1.37 g, 4.2 mmol) and crotonaldehyde (1.7 mL, 21.0 mmol) in dry CH 2 Cl 2 (7 mL) was added to a solution of Grubbs 2 nd generation catalyst (71 mg, 0.084

PAGE 140

140 mmol, 2 mol%) in dry CH 2 Cl 2 (14 mL). The mixture was stirred at reflux for 2 hours and then allowed to stir at room temperature for 30 minutes. The solution was filtered through a silica plug, washed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (5% to 30% EtOAc in hexanes) to give the aldeh yde product S8 as a yellow oil (1.31 g) which was immediately taken up in benzene (35 mL). To this solution was added NaBH(OAc) 3 (2.05 g, 9.2 mmol). The mixture was refluxed for 16 hours and quenched with 15mL saturated NaHCO 3 solution. The layers were sep arated and the aqueous phase was extracted with ether (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give the al lylic alcohol S9 as a colorless oil (1.125 g, 86%) 1 H NMR (299 MHz, Chloroform 5.54 (m, 2H), 4.10 4.03 (m, 2H), 3.39 ( d d, J = 5.7, 4.6 Hz, 1H), 2.36 ( d d, J = 7.3, 5.8 Hz, 4H), 2.06 1.98 (m, 2H), 1.74 1.57 (m, 3H), 1.57 1.42 (m, 2H), 1.38 1.28 (m, 2H), 0.85 (s, 7H), 0.81 (t, J = 6.8 Hz, 5H), 0.05 0.04 (m, 4H). 13 C NMR (75 MHz, CDCl 3 132.1, 129.8, 63.6, 43.1, 41.8, 32.6, 31.6, 25.9, 23.0, 19.9, 18.1, 18.0, 17.6, 4.5 ( E ) 1,11 dihydroxy 12 methyltridec 2 en 7 one (2 91) To a stirring solution of S9 (1.097 g, 3.08 mmol) in THF (30 ml) was added 12 mL of 1.0M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of starting material (4 hour s ). Silica was added to the reaction mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography (30% 50% EtOAc in hexanes) to give 359 mg (48%) of colorless oil (mixture of open chain and hemiketal ) IR (neat) 3419, 2942, 2872, 1713, 1456, 1367,

PAGE 141

141 1183, 1015, 971 cm 1 ; 1 H NMR (300 MHz, Chloroform 5.52 (m, 2H), 4.11 3.98 (m, 3H), 3.28 (ddd, J = 8.8, 5.2, 3.5 Hz, 1H), 2.39 (q, J = 7.1 Hz, 4H), 2.07 1. 97 (m, 4H), 1.97 1.82 (m, 2H), 1.78 1.48 (m, 6H), 1.46 1.24 (m, 3H), 0.84 (t, J = 7.0 Hz, 10H). 13 C NMR (75 MHz, CDCl 3 76.2, 75.0, 74.7, 63.6, 63.4, 60.1, 42.7, 41.7, 33.5, 31.5 22.9 20.1, 18.7, 17 .2 HRMS (ESI) calculated for C 14 H 26 O 3 [M+Na] + = 265.1774, found 265.1773. 2 isopropyl 8 vinyl 1,7 dioxaspiro[5.5]undecane (2 115). To a stirred solution of monoallylic ketodiol 2 91 (27 mg, 0.11 mmol) in THF (1.1 ml) at 0 C was added PdCl 2 (MeCN) 2 (1.4 mg, 0.0056 mmol). After 3 h, the s tarting material was completely consumed as monitored by TLC. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (pentanes to 5% ether in pentanes) to yield 21.3 mg of the spiroketal (86%). Rf = 0.9 (20% EtOAc in hexanes); 1 H NMR (300 MHz, CDCl 3 5.73 (m, 1H), 5.31 5.17 (m, 1H), 5.13 4.96 (m, 1H), 4.14 3.99 (m, 1H), 3.18 (ddd, J = 11.6, 7.4, 2.1 Hz, 1H), 2.00 1.76 (m, 2H), 1.67 1.46 (m, 4H), 1.46 1.21 (m, 4H), 1.21 1.02 (m, 1H), 0.96 (d, J = 6.7 Hz, 2H), 0.87 (d, J = 6.8 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 22 .3, 19.0, 18.9, 18.9, 14.1

PAGE 142

142 5 .2.6 Synthesis of 11 propyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 117). 5 ( tert butyldimethylsilyloxy) N methoxy N methyl 2 propylpentanamide (2 84) To a suspension of 3 propyltetrahydro 2H pyran 2 one 82 (1.14 g, 8.0 mmol) and N O dimethylhydroxyamine hydrochloride (1.95 g, 20.0 mmol) in 40 mL THF at 2 0 C was added dropwise over a period of 30 minutes a solution of i PrMgCl (20 mL, 40 mmol). The mixt ure was stirred at 2 0 C for 2 hours, then quenched with 25mL of saturated NH 4 Cl solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated in vacuo The crude product was purified by flash chromatography (40 100% EtOAc in hexanes) to yield the amide as colorless oil (1.33 g, 76%). R f 0.3 (EtOAc). To a solution of the alcohol (1.3 g, 6.0 mmol) in 30 mL of DCM at 0 C was added imidazole (946 mg, 13.9 mmol) followed by TBSCl (903 mg, 6.0 mmol) and DMAP (147 mg, 1.2 mmol) The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 20 mL H 2 O. The layers were separated and the aqueous layer was extracted three times with DCM. The combined organic layers was washed with 1N HCl (15mL), saturated NaHCO 3 and finally with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 1 0% EtOAc in hexanes) to yield 1.77 g of 2 84 (93%) of colorless oil 1 H NMR (300 MHz, CDCl 3 3.50

PAGE 143

143 (m, 2H), 3.16 (s, 3H), 1.76 1.11 (m, 9H), 0.97 0.69 (m, 12H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 34.9 30.8, 28.8, 25.9, 25.6, 20.8, 18.3 14. 2 5.3. 1 ( tert butyldimethylsilyloxy) 4 propyldec 9 en 5 one (2 87) A solution of 5 bromo 1 pentene ( 0.24 mL, 2.0 mmol) in THF (2 mL) was added dropwise over a period of 10 minutes to a suspension of Mg (73 mg, 3.0 mmol) in THF (1 mL) at room temperature.The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solution of 2 84 (317.5 mg, 3.0 mmol) in 1 mL of THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 2 hours. The reaction was quenched with 5 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and con centrated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a pale yellow oil (127 mg, 39 %). 1 H NMR (300 MHz, CDCl 3 ) J = 16.9, 10.2, 6.7 Hz, 1H), 5.12 4.81 (m, 2H), 3.54 (t, J = 6.1, 0.8 Hz, 3H ), 2.57 2.28 (m, 4H), 2.13 1.92 (m, 3H), 1.78 1.06 (m, 7 H), 0.98 0.70 (m, 12 H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 33.9, 33.1, 30.6, 27.9, 25.9, 22.5, 20.7, 18.3, 14.2

PAGE 144

144 Scheme 5 6. Synthesis of 2 90 ( E ) 11 ( tert butyldimethylsilyloxy) 7 oxo 8 propylundec 2 enal (S10) A solution of 2 87 (354 mg, 1.08 mmol) and crotonaldehyde (0.45 mL, 5.4 mmol) in dry CH 2 Cl 2 (2 mL) was added to a solution of Grubbs 2 nd generation catalyst (18 mg, 0.02 mmol, 2 mol%) in dry CH 2 Cl 2 (3 mL). The mixture was stirred at reflux for 2 hours and then allowed to stir for 30 minutes. The solution was filtered through a silica plug, washe d the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (5% to 20% EtOAc in hexanes) to give the aldehyde product as a 328 mg (86%) yellow oil which was immediately taken up in 9 mL of benze ne. 1 H NMR (300 MHz, CDCl 3 ) 9.49 (d, J = 7.8 Hz, 1H), 6.79 (dd, J = 15.7, 6.8 Hz, 1H), 6.10 (dddd, J = 15.7, 7.9, 1.5, 0.6 Hz, 1H), 3.55 (t, J = 5.9 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.38 2.25 (m, 2H), 1.84 1.69 (m, 2H), 1.63 1.49 (m, 3H), 1.4 8 1.30 (m, 4H), 1.27 1.16 (m, 2H), 0.86 (d, J = 0.7 Hz, 12H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 193.9, 157.6, 133.3, 62.8, 51.9, 40.9, 33.9, 32.1, 30.5, 27.9, 25.9, 21.5, 20.7, 18.3, 14.2, 5.3 Allylic alcohol S11 To a stirring solution of aldehyde S10 (322 mg, 0.9 mmol) in benzene was added NaBH(OAc) 3 (502 mg, 2.25 mmol). The mixture was refluxed for 16 hours and quenched with 10mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extra cted with ether (3 x 25mL), and the combined organic

PAGE 145

145 layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give allylic alcohol S11 (245 mg, 69%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3 ) 5.55 (m, 2H), 4.06 (d, J = 4.6 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 2.55 2.27 (m, 3H), 2.15 1.92 (m, 1H), 1.75 1.49 (m, 6H), 1.48 1.28 (m, 3H), 1.26 1.12 (m, 2H), 0.95 0.65 (m, 12H), 0.01 (s, 6H). ( E ) 1,11 dihydroxy 4 propylundec 9 en 5 one (2 90). To a stirring solution of S11 (240 mg, 0.67 mmol) in THF (6.7 ml) was added 2.70 mL of 1.0M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of startin g material (3 hours). Silica was added to the reaction mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography to obtain (127 mg, 78%) of yellow oil R f = 0.5, 100% EtOAc. 1 H NMR (300 MHz, CDCl 3 ) ppm 5.73 5. 46 (m, 2H), 4.19 3.95 (m, 2H), 3.59 (t, J = 6.2 Hz, 2H), 2.58 2.33 (m, 3H), 2.19 1.93 (m, 2H), 1.66 (m, 5H), 1.59 1.40 (m, 3H), 1.39 1.32 (m, 2H), 1.31 1.19 (m, 2H), 0.88 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 214.5, 132.2, 129.9, 63.6, 62.6, 51.8, 41.1, 34.0, 31.4, 30.5, 27.6, 22.5, 20.6, 14.2 11 propyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 117) To a stirred solution of monoallylic ketodiol 2 90 (52 mg, 0.21 mmol) in THF (2 ml) with MS 3 (600 mg) at room temperature was added PdCl 2 (MeCN) 2 (2.8 mg, 0.01 mmol). The reaction was stirred for 24 hours. The mixture was filtered through a short plug of silica. The solution

PAGE 146

146 of crude product was concent rated in vacuo and purified by flash chromatography (pentane to 5% ether in pentane) to yield 28 mg of the spiroketal as a mixture of diastereomers ( 60 %). Rf = 0 .85, 20% EtOAc in hexanes 1 H NMR (500 MHz, Chloroform J = 17.3, 10.6, 5.2 Hz, 1H), 5.25 (dt, J = 17.2, 1.8 Hz, 1H), 5.08 (minor) (ddd, J = 10.6, 1.9, 1.4 Hz, 1H), 5.04 (major) (ddd, J = 10.6, 2.0, 1.4 Hz, 1H), 4.15 4.11 (m, 1H), 4.10 4.06 (m, 1H), 3.67 (ddd, J = 11.9, 11.0, 3.1 Hz, 1H), 3.62 3.52 (m, 2H), 2.52 2.36 (minor) (m, 1H), 2.11 2.03 (m, 1H), 1.97 1.86 (m, 1H), 1.84 1.71 (m, 1H), 1.68 1.10 (m, 12H), 0.89 (d, J = 7.2 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 33.1, 31.0, 26.1, 24.3, 20.5, 18.8, 14.3 13 C NMR (126 MHz CDCl 3 40.9, 31.3, 31.1, 30.7, 29.1 21.1 20.6, 20.3 18.8 14.2 5 .2.7 Synthesis of 9,9 dimethyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 116). 5 ( tert butyldimethylsilyloxy) N methoxy N methyl 2 propylpentanamide (2 85) To a suspension of ester 2 83 (1.94 g, 7.1 mmol) and N O dimethylhydroxy l amine hydrochloride (1.73 g, 17.7 mmol) in 36 mL THF at 2 0 C was added dropwise over a period of 30 minutes a solution of i PrMgCl (17.8 mL, 35.5 mmol). The mixture was stirred at 2 0 C for 2 hours, then quenched with 25mL of saturated NH 4 Cl solution. The layers were separated and the aqueous layer was extracte d three times with EtOAc. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated in vacuo. The crude product was purified by flash chromatography

PAGE 147

147 (hexanes to 20% EtOAc in hexanes) to yield the amide 2.04 g (95%) as c olorless oil R f 0.6 (30% EtOAc). 1 H NMR (300 MHz, CDCl 3 3.65 (3 H, s), 3.23 (2 H, s), 3.15 (3 H, s), 2.29 2.42 (2 H, m), 1.49 1.60 (2 H, m), 0.86 (9H, s) 0.83 (6 H, s), 0.01 (6 H, s). 13 C NMR (75 MHz, CDCl 3 174.0, 71.5, 61.2, 35.0, 33 .54, 25.9, 23.8, 18.3, 5.6 1 ( tert butyldimethylsilyloxy) 2,2 dimethyldec 9 en 5 one (2 88) A solution of 5 bromo 1 pentene (1.51 mL, 12.8 mmol) in THF (8 mL) was added dropwise over a period of 10 minutes to a suspension of Mg (447 mg, 19 .2 mmol) in THF (5 mL) at room temperature.The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solution of 2 85 (1.95 g, 6.4 mmol) in 8 mL of THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 5 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted th ree times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a colorless oil (1.74 g, 87%). R f 0.5 (5% EtOAc in hexanes). 1 H NMR (299 MHz, CDCl 3 5.59 (m, 1H), 5.10 4.83 (m, 2H), 3.21 (s, 2H), 2.47 2.26 (m, 4H), 2.08 1.95 (m, 2H), 1.72 1.57 (m, 2H), 1.52 1.43 (m, 2H), 0.86 (s, 9H), 0.79 (s, 6H), 0.00 (s, 6H). 13 C NMR (75 MHz, CD Cl 3 7, 138.0, 115.1, 71.4, 41.8, 38.1, 34.5, 33.1, 32.5, 25.9, 23.9, 22.9, 18.2, 5.6

PAGE 148

148 Scheme 5 7. Synthesis of 2 92 ( E ) 11 ( tert butyldimethylsilyloxy) 10,10 dimethyl 7 oxoundec 2 enal (S12) A solution of 2 88 (1.72 g, 5.5 mmol) and crotonaldehyde (2.3 mL, 27.5 mmol) in dry CH 2 Cl 2 (17 mL) was added to a solution of Grubbs 2 nd generation catalyst (93 mg, 0.11 mmol, 2 mol%) in dry CH 2 Cl 2 (11 mL). The mixture was stirred at reflux for 2 hours and then allowed to stir for 30 minutes. The solution was filtered through a silica plug, washed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (5% to 2 0% EtOAc in hexanes) to give the aldehyde product as a 1.47 g (79%) yellow oil which was immediately taken up in 26 mL of benzene. 1 H NMR (300 MHz, CDCl 3 ) 9.48 (d, J = 7.9 Hz, 1H), 6.78 (dd, J = 15.7, 6.8 Hz, 1H), 6.09 (ddd, J = 15.6, 7.8, 1.5 Hz, 1 H), 3.20 (s, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.39 2.24 (m, 4H), 1.77 (p, J = 7.3 Hz, 2H), 1.56 1.41 (m, 2H), 0.86 (s, 9H), 0.79 (s, 6H), 0.01 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ) 133.3, 71.3, 41.4, 38.3, 34.8, 32.6 32.0 25.9 23.9, 21.7, 18.3, 5.6. ( E ) 1 ( tert butyldimethylsilyloxy) 11 hydroxy 2,2 dimethylundec 9 en 5 one (S13). To a stirring solution of aldehyde S12 (1.46 g, 4.3 mmol) in benzene (26 mL) was

PAGE 149

149 added NaBH(OAc) 3 (2.4 g, 10.75 mmol). The mixture was refluxed for 16 hours and quenched with 15mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with ether (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was p urified by flash chromatography (10% to 20% EtOAc in hexanes) to give allylic alcohol S13 (1.20 g, 82%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3 ) ppm 1 H NMR (300 MHz, Chloroform 5.54 (m, 1H), 4.25 3.91 (m, 2H), 3.21 (s, 2H), 2.51 2.2 4 (m, 4H), 2.12 1.92 (m, 4H), 1.71 1.61 (m, 2H), 1.53 1.43 (m, 2H), 0.87 (s, 9H), 0.80 (s, 6H), 0.00 (s, 6H). 13 C NMR (75 MHz, CDCl 3 129.7, 71.4, 63.7, 41.8, 38.1, 34.8, 32.6, 31.6, 25.9, 23.9, 23.1, 18.3, 5.5 (E ) 1,11 dihydroxy 2,2 dimethylundec 9 en 5 one (2 92) To a stirring solution of S13 (1.19 g, 3.47 mmol) in THF (35 ml) was added 35.0 mL of 1.0M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of start ing material (1 hour). Silica was added to the reaction mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography to obtain (397 mg, 50%) of yellow oil. R f = 0.3, 60% EtOAc. IR (neat) 3397, 2948, 2868, 1713, 1449, 1364, 1201, 1039 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ) 1 H NMR (299 MHz, Chloroform 5.46 (m, 1H), 4.12 3.97 (m, 1H), 3.65 (minor) (dd, J = 10.9, 0.8 Hz, 0H), 3.18 (minor) (s, 0H), 3.06 (dd, J = 11.0, 2.6 Hz, 0H), 2.39 (dt, J = 12.2, 7.6 Hz, 1H), 2.07 1.96 (m, 1H), 1.74 1.58 (m, 1H), 1.29 1.19 (m, 1H), 0.95 (minor) (s, 1H), 0.81 (d, J = 8.4 Hz, 2H). ) 13 C NMR (75 MHz, CDCl 3 ) 212.2, 132.6, 131.8(minor), 129.9(minor), 129.4, 96.0 (minor), 70.7, 70.7, 63.6, 63.4, 41.2 41.8, 37.8, 34. 8 34.7, 32.2, 32.1(minor), 31.5, 31.4(minor), 29.3, 29.1 (minor), 27.0,

PAGE 150

150 24.0, 23.0, 22.8, 22.8 HRMS (ESI) calculated for C 13 H 24 O 3 [M+Na] + = 251.1618, found 251.1618. 9, 9 dimethyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 116) To a stirred solution of monoallylic ketodiol 2 92 (46 mg, 0.0.2 mmol) in THF (2 ml) at 0 C was added PdCl 2 (MeCN) 2 (2.6 mg, 0.01 mmol). The reaction was stirred for 4 h. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (pentane to 5% ether in pentane) to yield 34.4 mg of the spiroketal 2 116 (74%). R f = 0.85, 20% EtOAc in hexanes ; IR (neat) 2950, 2870, 1714, 1450, 1366, 983, 922 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ) J = 16.8, 10.5, 5.4, 0.7 Hz, 1H), 5.32 5.19 (m, 1H), 5.08 (dd, J = 10.5, 1.6 Hz, 1H), 4.15 4.02 (m, 1H), 3.42 (dd, J = 10.8, 0.9 Hz, 1H), 3.08 (dd, J = 10.8, 2.6 Hz, 1H), 1.90 (dd, J = 12.8, 4.4 Hz, 1H), 1.78 1.66 (m, 1H), 1.65 (s, 1H), 1.45 (dd, J = 13.2, 4.5 Hz, 1H), 1.37 1.16 (m, 3H), 1.02 (s, 3H), 0.91 0.85 (m, 1H), 0.81 (s, 3H). 13 C NMR (75 MHz, CDCl 3 32.2, 31.8, 30.6, 29.3, 27.2, 23.1, 18.9, 14.0 HRMS (APCI) calculated for C 13 H 22 O 2 [M+H] + = 211.1693, found 211.1688. 5 .2.8 Synthesis of tert butyldimethyl 8 vinyl 1,7 dioxaspiro[5.5]undecan 4 yloxy)silane (2 119). 3 hydroxy N methoxy 5 (4 methoxybenzyloxy) N methylpentanamide (2 112) A flame dried round bottom flask was charged with 21 mL of THF and diisopropylamine

PAGE 151

151 (1.42 mL, 10.1 mmol mmol) and then cooled to 78 C. n BuL i solution (2.5M in hexanes, 9.4 mmol) was added dropwise to the solution of amine over 10 min. The resulting solution of LDA was stirred for 1 hr. A solution of N methoxy N methylacetamide (884 mg, 8.6 mmol) in 5 mL of THF was added dropwise. After 1 h, a solution of aldehyde 2 98 (1.51 g, 7.8 mmol) in THF (5 mL) was added and the mixture is stirred for 25 min. The reaction was quenched by addition of 20 mL saturated NH4Cl, stirred for 30 min, and then transferred to a separatory funnel and extracted wit h EtOAc (3 x 30 mL. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. 3 hydroxy 1 (4 methoxybenzyloxy)dec 9 en 5 one (2 99) A solution of 5 bromo 1 pentene (0.95 mL, 8 mmol) in THF (8 mL) was added dropwise over a period of 10 minutes to a suspension of Mg (292 mg, 12 mmol) in THF (5 mL) at room temperature.The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solution of 2 112 (595 mg, 2.0 mmol) in 8 mL of THF at 0 C, the mixture was stirred for 1 hour. The reactio n was quenched with 10 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purifi ed by flash chromatography (hexanes to 40% EtOAc in hexanes) to yield a colorless oil (313 mg, 51%). Rf = 0.7 (50% EtOAc) 1 H NMR (300 MHz, CDCl 3 ) ppm

PAGE 152

152 7.37 7.11 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.75 (ddd, J = 17.6, 10.1, 6.7 Hz, 1H), 5.13 4.81 (m, 2H), 4.44 (s, 3H), 4.23 (ddd, J = 9.2, 4.7, 2.3 Hz, 1H), 3.80 (d, J = 0.8 Hz, 4H), 3.68 3.55 (m, 2H), 3.39 (d, J = 3.1 Hz, 1H), 2.62 2.51 (m, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.05 (ddd, J = 7.7, 6.6, 1.4 Hz, 2H ), 1.82 1.59 (m, 2H). 13 C NMR (125 MHz, CDCl 3 ) 55.2, 49.3, 42.7, 36.1 33.0, 22.5 3 ( tert butyldimethylsilyloxy) 1 (4 methoxybenzyloxy)dec 9 en 5 one (2 113) The alcohol 2 112 (328 mg, 1.07 mmol) was dissolved in DCM and cooled to 45 C. To the mixture was added 2,6 lutidine (0.25 mL, 2.14 mmol), followed by slow addition of TBSOTf. After 5 0 minutes, the reaction was quenched with 7 mL saturated NaHCO 3 The layers were separated and the aqueous phase was extracted with ether (3 x 25mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixtu re was purified by flash chromatography (hexanes to 30% EtOAc in hexanes) and the product (400 mg, 95%) was obtained as colorless oil. R f = 0.7 (30% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 ) ppm 7.33 7.15 (m, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.82 5.62 (m, 1H), 5.04 4.89 (m, 2H), 4.45 4.33 (m, 2H), 4.29 (dd, J = 6.8, 5.6 Hz, 1H), 3.78 (s, 3H), 3.55 3.30 (m, 2H), 2.56 (dd, J = 15.4, 6.8 Hz, 1H), 2.52 2.44 (m, 1H), 2.37 (dd, J = 7.2, 1.4 Hz, 2H), 2.09 1.95 (m, 3H), 1.7 4 (q, J = 6.3 Hz, 2H), 1.66 1.57 (m, 2H), 0.82 (d, J = 0.3 Hz, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) 115.1, 113.7, 72.6, 66.6, 66.3, 55.3, 50.4, 43.6, 37.4, 33.0, 25.8, 22.4 18.0, 4.8, 4.7

PAGE 153

153 Scheme 5 8. Synthesis of 2 114 ( E ) 3 ( tert butyldimethylsilyloxy) 1,11 dihydroxyundec 9 en 5 one (S14) A solution of 2 113 (292, 0.7 mmol) and crotonaldehyde (0.29 mL, 3.5 mmol) in dry CH 2 Cl 2 (2.5 mL) was added to a solution of Grubbs 2nd generation catalyst (11.9 mg, 0.014 mmol) in dry CH 2 Cl 2 (1 mL). The mixture was stirred at reflux for 3 hours and then allowed to stir for 30 minutes. The solution was filtered through a silica plug, washed the silica plug with ether and the solvent was removed in vacuo. The crude product was purified by flash chromatography (5% to 20% EtOAc in hexanes) to give the aldehyde product as a yellow oil (278 mg, 89%) which was immediately taken up in 6 mL of benzene. Rf = 0.4 (30% EtOAc); 1 H NMR (500 MHz, CDCl 3 ppm 9.47 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 8.8, 0.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.76 (dd, J = 15.7, 6.8 Hz, 1H), 6.08 (dddd, J = 15.7, 7.8, 1.5, 0.3 Hz, 1H), 4.41 4.34 (m, 2H), 4.29 (dd, J = 6.8, 5.7 Hz, 1H), 3.78 (d, J = 0.3 Hz, 3H), 3.47 (ddd, J = 9.4, 6.3 Hz, 2H), 2.60 2.46 (m, 2H), 2.42 (ddd J = 7.1, 2.2 Hz, 2H), 2.32 2.23 (m, 2H), 1.77 1.68 (m, 4H), 0.82 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13 C NMR (125 MHz, CDCl 3 193.9, 159.1, 157.55, 133.3, 130.5, 129.2, 113.7, 72.6, 66.7, 66.2, 55.3, 50.3, 43.3, 37.3, 31.9, 25.8, 21.4, 18.0, 4.7

PAGE 154

154 ( E ) 3 (tert butyldimethylsilyloxy) 11 hydroxy 1 (4 methoxybenzyloxy)undec 9 en 5 one (S15) To a stirring solution of aldehyde S14 (270 g, 0.6 mmol) in benzene (6 mL) was added NaBH(OAc) 3 (335 mg, 1.5 mmol). The mixture was refluxed for 16 hours and quenched with 15mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with ether (3 x 10mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give allylic alcohol S15 (224 mg, 83%) as a pale yellow oil. Rf = 0.3 (30% EtOAc); 1 H NMR (500 MHz, Chloroform 7.24 7.21 (m,2H), 6. 85 (d, J = 8.7 Hz, 2H), 5.67 5.53 (m, 2H), 4.43 4.32 (m, 2H), 4.29 (dd, J = 6.8, 5.7 Hz, 1H), 4.05 (dd, J = 2.4, 1.0 Hz, 2H), 3.78 (s, 3H), 3.47 (ddd, J = 9.4, 6.4 Hz, 2H), 2.56 (dd, J = 15.4, 6.8 Hz, 1H), 2.49 (dd, J = 15.4, 5.5 Hz, 1H), 2.37 (dd, J = 7.2, 1.3 Hz, 2H), 2.03 1.96 (m, 2H), 1.74 (ddd, J = 6.4, 5.7 Hz, 2H), 1.65 1.56 (m, 3H), 0.82 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13 C NMR (126 MHz, CDCl 3 130.5, 129.8, 129.2, 113.7, 72.6, 66.6, 66.2, 63.6, 55.2, 50.4, 43.6, 3 7.3, 31.5, 25.8, 22.6, 18.0, 4.8, 4.7 ( E ) 4 ( tert butyldimethylsilyloxy) 2 (6 hydroxyhex 4 enyl)tetrahydro 2H pyran 2 ol (2 114). The allylic alcohol S15 (67 mg, 0.15 mmol) obtained above was dissolved in DCM/H 2 O (18:1) and cooled to 0 C, then DDQ (45 mg, 0.2 mmol) was added. After 2.5 h, 7 mL of saturated NaHCO 3 was added. The layers were separated and the aqueous phase was extracted with DCM (3 x 10mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crud e mixture was purified by flash column chromatography (hexanes to 10% EtOAc in hexanes) and the product was obtained as colorless oil (18 mg, 36%). Rf = 0.2 (50% EtOAc); 1 H NMR

PAGE 155

155 (500 MHz, Chloroform 5.55 (m, 2H), 4.31 (h, J = 2.8 H z, 1H), 4.05 (d, J = 5.6 Hz, 2H), 3.66 3.59 (m, 1H), 2.09 1.99 (m, 4H), 1.86 1.74 (m, 2H), 1.66 (dd, J = 13.7, 2.7 Hz, 1H), 1.55 (d, J = 16.3 Hz, 5H), 0.90 (s, 9H), 0.09 (d, J = 0.4 Hz, 3H), 0.08 (d, J = 0.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 113.5, 98.0, 69.5, 65.0, 58.9, 45.6, 35.6, 34.8, 30.7, 25.9, 18.8, 18.1, 4.57. tert butyldimethyl 8 vinyl 1,7 dioxaspiro[5.5]undecan 4 yloxy)silane ( 2 119 ) To a stirred solution of monoallylic ketodiol 2 114 (46 mg, 0.2 mmol) in THF (1 ml) at 0 C was added PdCl 2 (MeCN) 2 (1.4 mg, 0.0054 mmol). After 1 h, the starting material was completely consumed as monitored by TLC. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (he xanes to 5% EtOAc in hexanes) to yield 13.4 mg of the spiroketal (79%). Rf = 0.4 (5% EtOAc in hexanes); 1 H NMR (mixture of diastereomers) (500 MHz, Chloroform J = 17.2, 10.4, 6.7 Hz, 0.3H), 5.81 (dddd, J = 17.5, 10.6, 5.1, 1.8 Hz, 1H), 5.23 5.15 (m, 1H), 5.09 4.95 (m, 1H), 4.23 (minor) (dddd, J = 10.2, 5.2, 2.5, 1.3 Hz, 0.3H), 4.10 (ddd, J = 10.8, 10.8, 4.8 Hz, 1H), 4.06 3.90 (m, 1H), 3.71 3.53 (m, 2H), 3.47 3.37 (minor) (m, 0.3H), 2.31 (minor) (ddd, J = 13.1, 4.5, 2.1 Hz, 0.3H), 1.92 (ddd, J = 12.6, 4.8, 2.0 Hz, 1H), 1.88 1.83 (m, 1H), 1.77 1.70 (m, 1H), 1.68 (d, J = 5.0 Hz, 1H), 1.63 (ddd, J = 5.0, 2.5, 1.4 Hz, 1H), 1.61 1.58 (m, 1H), 1.57 1.45 (m, 1H), 1.41 (dd, J = 13.6, 4.6 Hz, 1H), 1.34 (dd, J = 12.7, 10.9 Hz, 1H), 1.30 1.21 (m, 1H), 0.87 (s, 1H), 0.86 (s, 7H), 0.04 (d, J = 0.7 Hz, 4H), 0.02 (s,

PAGE 156

156 1H), 0.00 (s, 1H). 13 C NMR ( 125 MHz CDCl 3 98.0, 96.7, 77.2, 74.3, 70.3, 69.5, 65.0, 65.0, 64. 7, 60.0, 58.9, 57.1, 45.6, 43.9, 40.6, 35.8, 35.6, 35.6, 34.8, 33.9, 33.1, 30.7, 30.5, 30.4, 25.9, 25.8, 18.8, 18.5, 18.1, 4.5, 4.6, -4.7, 4.9. IR (neat) 2930, 2857, 1463, 1380, 1252, 1072, 986 cm 1 ; HRMS (APCI) calculated for C 17 H 32 O 3 Si [M+Na] + = 335. 2013, found 335.2016. 5 .2.9 Synthesis of 3 methyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 134). 1 (tert butyldimethylsilyloxy) 8 methyldec 9 en 5 one (2 128) To a suspension of Mg (292 mg, 12.0 mmol) in THF (3 mL) at room temperature was added dropwise over a period of 10 minutes, a solution of 5 bromo 3 methylpent 1 ene (1.30 g, 8.0 mmol) in THF (5 mL). The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solution of 2 36 (1.10 g, 4.0 mmol) in THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 5 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a colorless oil (970mg, 79%). 1 H NMR ( 500 MHz, CDCl 3 d ) J =17.16, 10.30, 7.82 Hz, 2 H ), 4.86 4.98 (m, 2 H ), 3.57 (t, J =6.38 Hz, 2 H), 2.29 2.43 (m, 5 H ), 1.99 2.12 (m, 1 H,), 1.54 1.63 (m, 3 H,), 1.42 1.52

PAGE 157

157 (m, 3 H ), 0.78 1.00 (m, 14H), 0.02 0.05 (m, 6H). ). 13 C NMR (125 MHz, CDCl 3 ) 211.1 143. 8 113. 4, 62.8, 42.6, 40.4 37. 6 32. 4, 30.1 25.9 20.3, 18.3, 5.3 HRMS (ESI) calculated for C 1 7 H 34 O 2 Si [M+Na] + = 321.2231 found 321.2215 Scheme 5 9. Synthesis of 2 132 ( E ) 11 (tert butyldimethylsilyloxy) 4 methyl 7 oxoundec 2 enal (S16) A solution of 2 128 (898 mg, 3.0 mmol) and crotonaldehyde (1.25 mL, 15 mmol) in dry CH 2 Cl 2 (6 mL) was added to a solution of Grubbs 2 nd generation catalyst (127 mg, 0.15 mmol, 5 mol%) in dry CH 2 Cl 2 (9 mL). The mixture was stirred at reflux for 4 hours and then allowed to stir for 30 minutes. The solution was filtered through a silica plug, wash ed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (hexanes to 20% EtOAc in hexanes) to give the aldehyde product as a yellow oil (386 mg, 39%) and unreacted alkene starting material ( 434 mg, 48%). 1 H NMR (500 MHz, CDCl 3 d J =7.82 Hz), 6.66 (1 H, dd, J =15.65, 7.82 Hz), 6.05 (1 H, dd, J =15.65, 7.82 Hz), 3.57 (3 H, t, J =6.25 Hz), 2.38 (7 H, q, J =7.28 Hz), 1.69 (3 H, dt, J =13.62, 6.85 Hz), 1.52 1.63 (3 H, m),

PAGE 158

158 1.41 1.51 (3 H, m), 1.18 1.27 (1 H, m), 1.09 (4 H, d, J =6.73 Hz), 0.86 (13 H, s), 0.01 (8 H, s) ( E ) 1 (tert butyldimethylsilyloxy) 11 hydroxy 8 methylundec 9 en 5 one (S17) To a stirring solution of aldehyde S16 (380 mg, 1.2 mmol) in benzene (12 mL) was added NaBH(OAc) 3 (669 mg, 3.0 mmol). The mixture was refluxed for 16 hours and quenched with 25 mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase was extracted with ether (3 x 25 mL), a nd the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give the allylic alcohol S17 as a colorless oil (307 mg, 78%). 1 H NMR (500 MHz CDCl 3 ) 5.61 (1 H, m), 5.44 5.51 (1 H, m), 4.07 (2 H, d, J =5.77 Hz), 3.58 (3 H, t, J =6.38 Hz), 2.37 (5 H, dt, J =17.12, 7.43 Hz), 2.06 2.16 (1 H, m), 1.55 1.63 (5 H, m), 1.49 (4 H, s), 0.98 (4 H, d, J =6.73 Hz), 0.84 0.89 (12 H, m), 0. 01 (7 H, s) 13 C NMR (125 MHz, CDCl 3 ) 137.8, 128.1, 63.6, 62.8, 42.6 40. 5, 36.1 32. 3 30. 4 25.9, 20. 5, 20.3, 18.3, 5.3 ( E ) 1,11 dihydroxy 8 methylundec 9 en 5 one (2 132) To a stirring solution of S17 (299 mg, 0.9 mmol) in THF (4.5ml) was added 2.7mL of 1.0 M TBAF in THF. The mixture was allowed to stir at room temperature until TLC showed complete consumption of starting material (2 hour). Silica was added to the reaction mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography (30% 50% EtOAc in hexanes) to give 136 mg (71%) of colorless oil. 1 H NMR (500 MHz, CDCl 3 5.63 (5 H, m), 5.43 5.51 (1 H, m), 4.07 (2 H, d, J =5.49 Hz), 3.59 (2 H, t, J =6.25 Hz), 2.34 2.4 6 (4 H, m), 2.05 2.16 (1 H, m), 1.45

PAGE 159

159 1.82 (10 H, m), 0.98 (3 H, d, J =6.73 Hz) 13 C NMR (125 MHz, CDCl 3 96.8, 63.6, 62.2, 42.4, 40.5, 36.2, 32.1, 30.3, 20.6, 19.8. 3 methyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 134) To a stirred solution of monoallylic ketodiol 2 132 (70 mg, 0.33 mmol) in THF (3.3 ml) at 0 C was added PdCl 2 (MeCN) 2 (4.2 mg, 0.016 mmol). The reaction wa s stirred for 7 h. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (pentane to 5% ether in pentane) to yield 34.4 mg of the spiroketal 2 134 (74%). R f = 0.7 ( 10% EtOAc in hexanes ) 1 H NMR 5.81 (1 H, ddd, J = 17.36, 10.64, 4.80 Hz), 5.29 (1 H, dt, J =17.30, 1.78 Hz), 5.10 (1 H, dt, J =10.60, 1.84 Hz), 3.55 3.68 (3 H, m), 2.07 2.16 (1 H, m), 1.85 1.99 (2 H, m), 1.74 (1 H, ddt, J =6.97, 4.67, 2.49, 2.4 9 Hz), 1.67 1.70 (1 H, m), 1.65 1.67 (1 H, m), 1.47 1.64 (6 H, m), 1.46 (1 H, d, J =4.26 Hz), 1.38 1.44 (3 H, m), 0.91 (4 H, d, J =7.00 Hz), 0.86 0.88 (1 H, m), 0.82 (1 H, d, J =6.59 Hz) 13 C NMR (126 MHz, CDCl 3 113.8 95. 7 71. 3, 60.4, 35 .6, 30.9, 29.8, 26.0, 25.3, 18.6, 11.2 5 .2.10 Synthesis of 4 methyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 135). 1 ( tert butyldimethylsilyloxy) 7 methyldec 9 en 5 one (2 129) To a suspension of Mg (146 mg, 6.0 mmol) in THF (1 mL) at room temperature was added dropwise over a period of 10 minutes, a solution of 5 bromo 4 methylpent 1 ene (652 mg, 4.0 mmol) in THF (3 mL). The mixture started refluxing after addition of half of th e bromide solution.

PAGE 160

160 After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was added to a solution of 2 36 (551 mg, 2.0 mmol) in THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 5mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concen trated. The crude product was purified by flash chromatography (hexanes to 5% EtOAc in hexanes) to yield a colorless oil (244 mg, 41%). 1 H NMR (299 MHz, CDCl 3 5.63 (m, 1H), 4.99 ( m 1H), 4.95 (d d d, J = 3.6, 2.2, 1.2 Hz, 1H), 3.57 (t, J = 6.2 Hz, 2H), 2.43 2.32 (m, 3H), 2.19 (d, J = 7.7 Hz, 1H), 2.15 2.00 (m, 2H), 2.00 1.91 (m, 2H), 1.66 1.53 (m, 2H), 1.52 1.41 (m, 2H), 0.86 (s, 13H), 0.04 0.02 (m, 5H). 13 C NMR (75 MHz, CDCl 3 7 136. 7 136. 5 116. 7 116. 4 62.8, 49. 3 46. 2 43. 2 41. 2 38.2, 33.0 32. 6 28. 9 26.0 20. 3 19. 8 18.3, 5.3. Scheme 5 10. Synthesis of 2 133 ( E ) 11 (tert butyldimethylsilyloxy) 5 methyl 7 oxoundec 2 enal (S18) A solution of 2 129 (582 mg, 1.9 mmol) and crotonaldehyde (0.8 mL, 9.7 mmol) in dry CH 2 Cl 2 (4 mL) was added to a solution of Grubbs 2 nd generation catalyst (32 mg, 0.038 mmol, 2 mol%) in dry CH 2 Cl 2 (6 mL). The mixture was stirred at reflux for 2 hours and

PAGE 161

161 then allowed to stir for 30 minutes. The solution was filtered through a silica plug, washed the silica plug with ether and the solvent was removed in vacuo The crude product was purified by flash chromatography (5% to 20% EtOAc in hexanes) to give the al dehyde product as a yellow oil (619 mg, 87%). 1 H NMR (299MHz, CDCl 3 d ppm 9.60 9.42 (m, 2H), 6.78 (d d d, J = 15.5, 7.1, 1.3 Hz, 1H), 6.10 (dd d J = 15.6, 7.9, 1.5 Hz, 1H), 3.74 3.49 (m, 2 H), 2.56 2.18 (m, 7H), 1.70 1.42 (m, 8H), 1.10 0.82 (m, 29H), 0.22 0.04 (m, 6 H). 13 C NMR (75 MHz, CDCl 3 193. 8 156. 4 134. 5 62.75, 49. 1 43.2, 39.7, 32. 2 28.3, 25.9, 20.2, 19. 9 18.3, 5.3. ( E ) 1 (tert butyldimethylsilyloxy) 11 hydroxy 7 methylundec 9 en 5 one (S19) To a stirring solution of aldehyde S18 (530 mg, 1.6 mmol) in benzene (16 mL) was added NaBH(OAc) 3 (905 mg, 4.0 mmol). The mixture was refluxed for 16 hours and quenched with 15 mL saturated NaHCO 3 solution. The layers were separated and the aqueous phase w as extracted with ether (3 x 25 mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated. The crude mixture was purified by flash chromatography (10% to 20% EtOAc in hexanes) to give the allylic alcohol S19 as a colorl ess oil (488 mg, 92%) 1 H NMR (500 MHz, CDCl 3 d 5.66 5.56 (m, 2H), 4.07 (d, J = 3.0 Hz, 2H), 3.58 (t, J = 6.3 Hz, 2H), 2.40 2.33 (m, 4H), 2.22 2.15 (m, 1H), 2.13 2.04 (m, 1H), 2.02 1.90 (m, 2H), 1.63 1.55 (m, 2H), 1.51 1.43 (m, 2H), 1 .34 (s, 1H), 0.87 (d, J = 8.3 Hz, 12H), 0.04 0.00 (m, 6H). 13 C NMR (75 MHz, CDCl 3 ) 1 130. 7 63.6, 62.8, 49.3, 43. 2 39. 5 32.2, 29. 1 26.0 20. 3 19. 9 18.33, 5.3. ( E ) 1,11 dihydroxy 7 methylundec 9 en 5 one (2 133) To a stirring solution of S19 (476 mg, 1.45 mmol) in THF (7 ml) was added 4.3 mL of 1.0M TBAF in THF. The

PAGE 162

162 mixture was allowed to stir at room temperature until TLC showed complete consumption of starting material (2 hour). Silica was added to the reacti on mixture and concentrated in vacuo. The resulting mixture was purified by flash column chromatography (30% 50% EtOAc in hexanes) to give 197 mg (63%) of colorless oil. IR (neat) 3419, 2950, 1709, 1375, 1180, 986 cm 1 ; 1 H NMR (500 MHz, CDCl 3 5.53 (m, 2H), 4.09 4.01 (m, 2H), 3.58 (t, J = 6.3 Hz, 2H), 2.43 2.35 (m, 3H), 2.18 (ddd, J = 16.2, 7.6, 0.5 Hz, 1H), 2.08 (dq, J = 13.5, 6.7 Hz, 1H), 1.98 1.83 (m, 5H), 1.66 1.58 (m, 2H), 1.55 1.47 (m, 2H), 0.87 (d, J = 6.7 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 131. 1, 130.4 63.4, 62. 2, 49.3, 42.9 39. 5 32.0, 29. 1 20.0, 19.7 HRMS (ESI) calculated for C 12 H 22 O 3 [M+Na] + = 237.1461, found 237.1470. 4 methyl 2 vinyl 1,7 dioxaspiro[5.5]undecane (2 135) To a stirred solution of monoallylic ketodiol 2 133 (85 mg 0.40 mmol) in THF (4 ml) at 0 C was added PdCl 2 (MeCN) 2 (5.1 mg, 0.020 mmol). After 60 min, TLC showed complete consumption of starting materia l. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (pentane to 2% ether in pentane) to yield 70.0 mg of the spiroketal 2 135 (90%). Rf = 0.7; IR (neat) 2 928, 1266, 710, 703 cm 1 ; 1 H NMR (500 MHz, CDCl 3 5.92 5.76 (m, 1H), 5.32 5.15 (m, 1H), 5.06 (ddd, J = 10.5, 1.9, 1.4 Hz, 1H), 4.16 4.00 (m, 1H), 3.64 (ddd, J = 12.0, 11.0, 2.6 Hz, 1H), 3.57 3.49 (m, 1H), 2.04 1.95 (m, 1H), 1.92 1.84

PAGE 163

163 (m, 1H), 1.66 1.57 (m, 3H), 1.57 1.41 (m, 3H), 0.98 (dd, J = 13.4, 12.3 Hz, 1H), 0.93 0.88 (m, 1H), 0.86 (d, J = 6.6 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 95. 6 69.8 60.5, 43.9, 39.3, 35.6, 25.3 25. 1 22.0, 18. 6 HRMS (ESI) calculated fo r C 12 H 20 O 2 [M+Na] + = 219.1356, found 219.1359. 5 .2.11 Synthesis of 2 phenethyl 8 (( E ) prop 1 enyl) 1,7 dioxaspiro[5.5]undecane (3 55, 3 56 and 3 57) 7 (benzyloxy) 1 phenylhept 4 yn 3 one (3 45) To a solution of ((but 3 ynyloxy)methyl)benzene 3 43 (3.20 g, 20.0 mmol) inTHF (25 mL) was added n butyllithium (2.5 M in hexanes; 9.6 mL, 24.0 mmol) at 78 C under nitrogen atmosphere. After the mixture was s tirred for 30 min at 78 C, a solution of hydrocinnamaldehyde (2.63 mL, 20.0 mmol) inTHF (25.0mL) was added. The reaction mixture was allowed to come to room temperature, stirred for overnight, and quenched with saturated aqueous NH 4 Cl. The organic materi als were extracted with ether, and the combined organic extracts were washed with H 2 O several times and then brine, dried over MgSO 4 and evaporated in vacuo. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to give 7 (benzylo xy) 1 phenylhept 4 yn 3 ol (5.60 g, 95%) as a pale yellow oil. R f 0.6 (30% EtOAc in hexanes ) To a cooled solution of DMSO (2.84 mL, 40.0 mmol) in 20 mL DCM was added dropwise via syringe over 15 min, a solution of oxalyl chloride (10.0 mL, 20.0 mmol) at 78 C. The reaction mixture was stirred at 78 C for 20 min and then a solution of alcohol (2.94 g, 10.0 mmol) in 13 mL of DCM was added dropwise over 10 min. The reaction mixture was stirred at 78

PAGE 164

164 C for 1.5 h and then triethylamine (0.7 mL, 50.0 mmol ) was added via syringe in one portion. The reaction mixture was stirred at 78 C for 2 h and then the dry ice acetone bath was replaced with an ice bath and the reaction mixture was stirred at 0 C for 10 min. The reaction was quenched with water, organi c materials were extracted with DCM, and the combined organic extracts were washed with H 2 O several times and then brine, dried over MgSO 4 and evaporated in vacuo The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give a pale yellow oil of 7 (benzyloxy) 1 phenylhept 4 yn 3 one (2.65 g, 91%). Rf = 0.6 (10% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 7.32 (m, 2H), 7.31 7.25 (m, 1H), 7.22 7.16 (m, 1H), 4.55 (s, 1H), 3.63 (t, J = 6.8 Hz, 2H), 3.00 2.94 (m, 2H), 2.87 (ddd, J = 8.1, 7.0, 1.0 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 3 137. 7 128. 3 127.6, 91.2, 81.3, 73.1, 67.1, 46.9, 29. 9 20. 5 ( R ) ( 7 (benzyloxy) 1 phenylhept 4 yn 3 yloxy)(tert butyl)dimethylsilane (3 46) Noyori catalyst [( R R ) TsDPEN Ru(mesitylene)Cl] (54.6 mg, 0.079 mmol) was added to a mixture of 3 45 sodium formate (5.37 g, 79 mmol), and TBAC (659 mg, 2.37 mmol,) in CH 2 Cl 2 (20 m L) and deionized H 2 O (20 mL). The biphasic mixture was strongly stirred for 20 hours at room temperature, diluted with water (10 mL) and extracted with CH 2 Cl 2 (2 x 40 mL). The organic layers were dried over MgSO 4 and then purified by flash chromatography ( gradient; 5%, 10%, 20% EtOAc/Hexanes) to give the product as a colorless oil (1.8319 g, 79%). R f D = 74.4 ( c 1.00, CH 2 Cl 2 ); To a solution of alcohol (1.30 g, 4.4 mmol) and imidazole (661 mg, 9.7

PAGE 165

165 mmol) in dry CH 2 Cl 2 (22 mL) at 0 C was added portion wise TBSCl (685 mg, 4.4 mmol). The reaction was stirred at r.t. overnight, then 20 mL water was added. The aqueous layer was extracted with CH 2 Cl 2 (3x30 mL). The combined extracts were dried over MgSO 4 and then purified by fl ash chromatography (10% EtOAc /Hexanes) to give the product as a colorless oil (1.55 g, 86%) 1 H NMR (500 MHz, CDCl 3 7.31 (m, 2H), 7.30 7.24 (m, 2H), 7.18 (ddd, J = 7.7, 1.4, 0.7 Hz, 2H), 4.56 4.52 (m, 2H), 4.38 4.33 (m, 1H), 3.59 (t, J = 7.1 Hz, 2H), 2.83 2.65 (m, 2H), 2.53 (ddd, J = 7.1, 2.0, 0.7 Hz, 2H), 2.03 1.83 (m, 2H), 0.91 (s, 9H), 0.10 (d, 6H). 13 C NMR (126 MHz, CDCl 3 142.1 138. 4, 128.7, 128.6 128. 6, 127.9 127. 9, 126.0 83.0 81. 7 73.2, 68.8, 62.8, 40.7 31. 8, 26.1, 20.42 1 8.5, 4.1, 4.7 Enantiomeric excess (97%) was determined by HPLC analysis (Chiralcel AD, 3% i PrOH in hexanes, 0.6 mL/min, 254 nm), t r 22.6 (minor), 25.7 (major). HRMS (ESI) Calcd for C 26 H 36 O 2 Si (M+Na) + : 431.25; found 431.2367. Scheme 5 11. Synthesis of 3 48 ( S ) 5 ( tert butyldimethylsilyloxy) 7 phenylheptanoic acid (3 47) Pd/C was added to a solution of 3 46 (1.53 g, 3.74 mmol) in dry EtOH (9.5 mL). The reaction mixture was stirred 1.5 h under H 2 (1 atm). After filtration over celite and removal of the solvent, the crude product was purified by flash chromatography (hexanes 30%

PAGE 166

166 EtOAc in hexanes) to obtain a pale yellow oil alcohol S20 (992 mg, 82%). R f 0.4 (20% EtOAc in hexanes). According to a known procedure 83 : TEMPO (4.7 mg, 0.03 mmol, 1 mol%), Aliquat 336 (0.014 M in CH 2 Cl 2 13 mL, 0.182 mmol, 6 mol%), potassium bromide (0.28 M in H 2 O, 1.6 mL, 0.456 mmol), sodium hypochlorite (1.7 M in H 2 O, 26 mL, 18.24 mmol, 6 eq.) and sat. aq. NaHCO 3 (5.2 ml) were added sequentially to a solution of S20 (980 mg, 3.04 mmol, 1 eq.) in CH 2 Cl 2 (68 ml) at 0 C. After stirring at 0 C for 30 min, the reaction mixture was poured onto a mixture of CHCl 3 (14 ml) and 1 M aq. HCl (15 ml) and the layers separated. The aqueous layer was extracted with DCM (3 25 ml) and the combined organic fractions washed with brine (2 5 ml) and dried (Na 2 SO 4 ). Concentration of the filtrate in vacuo and purification by flash column chr omatography (hexanes 30% EtOAc) afforded 3 47 (853 mg, 84%). Rf = 0.4 (30% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 7.26 (m, 1H), 7.19 7.15 (m, 3H), 3.74 (p, J = 5.7 Hz, 1H), 2.72 2.55 (m, 3H), 2.36 (t, J = 7.4 Hz, 2H), 1.81 1.61 (m, 4H), 1.59 1.49 (m, 2H), 0.91 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). ( S ) 5 ( tert butyldimethylsilyloxy) N methoxy N methyl 7 phenylheptanamide ( 3 48 ). To a solution of carboxylic acid 3 47 (363 mg, 1.07 mmol) in DCM (5 mL) was added (MeO)NH 2 MeCl (157 mg, 1.6 mmol) and DMAP (13 mg, 0.107 mmol). The mixture was cooled to 0 C before adding triethylamine (0.25 mL, 1.82 mmol) and EDCI (419 mg, 2.14 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight, then quenc hed with 10 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted three times with DCM. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated in vacuo The crude product was purified b y flash chromatography (hexanes 10% EtOAc

PAGE 167

167 in hexanes) to yield the amide as colorless oil (1.64 g, 85%). R f 0. 6 ( 10% EtOAc in hexanes ). 1H NMR (500 MHz, Chloroform J = 5.7, 2.4 Hz, 2H), 7.17 (d, J = 7.3 Hz, 3H), 3.74 (t, J = 5.7 Hz, 1H), 3. 67 (s, 3H), 3.18 (s, 3H), 2.64 (ddd, J = 32.9, 9.2, 8.3, 6.0 Hz, 1H), 2.42 (d, J = 8.3 Hz, 2H), 1.85 1.48 (m, 6H), 0.91 (s, 9H), 0.06 (s, 6H). ( S ) 10 ( tert butyldimethylsilyloxy) 12 phenyldodec 1 en 6 one (3 50). A solution of 5 bromo 1 pentene (0.66 mL, 5.6 mmol) in THF (3.6 mL) was added dropwise over a period of 10 minutes to a suspension of Mg (204 mg, 8.4 mmol) in THF (2 mL) at room temperature.The mixture started refluxing after addition of half of the bromide solution. After complete addition, the mixture was allowed to stir for another 30 minutes at room temperature. This Grignard reagent was add ed to a solution of 3 48 (1.06 g, 5.6 mmol) in 8 mL of THF at 78C, after 5 minutes, the mixture was warmed to 0 C and stirred for 1 hour. The reaction was quenched with 5 mL of saturated NH 4 Cl. The layers were separated and the aqueous layer was extract ed three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and concentrated. The crude product was purified by flash column chromatography (hexanes to 3% EtOAc in hexanes) to yield a colorless oil (823 mg, 76%) R f 0.5 (5% EtOAc in hexanes) 1 H NMR (500 MHz, CDCl 3 7.29 (m, 1H), 7.22 7.17 (m, 3H), 5.79 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.06 4.98 (m, 2H), 3.74 (p, J = 5.7 Hz, 1H), 2.65 (dddd, J = 37.3, 13.6, 10.1, 6.4 Hz, 3H), 2.46 2.37 (m, 6H), 2.14 1.97 (m, 3H), 1.84 1.74 (m, 2H), 1.74 1.55 (m, 5H), 1.52 1.46 (m, 2H), 0.93 (s, 9H), 0.08 (s, 3H),

PAGE 168

168 0.07 (s, 3H). 13 C NMR (126 MHz, CDCl 3 142. 6 138.0, 128.3, 128.3 125. 7 115. 2 71.6 43.0, 41.8 38. 9, 36.4, 33.1, 31.6, 25.9 22. 8 19. 7, 18.1 HRMS (ESI) calculated for C 24 H 40 O 2 Si [M+Na] + = 411.2432, found 411.2432. (3 S ,13 R E ) 3,13 dihydroxy 1 phenyltetradec 11 en 7 one. To a stirring solution of ( R ) (but 3 en 2 yloxy)(tert butyl)dimethylsilane (50% solution in hexane, 3.0 mmol) and keto alkene 3 50 (389 mg, 1.0 mmol) in DCM (20 mL) was added 42 mg of xture was refluxed for 2 h. After cooling to room temperature, the mixture was passed over a short silica plug, and the solvent was concentrated in vacuo. Purication of the residue by flash column chromatography (5% EtOAc in hexanes) afforded a yellow oil (185 mg, 67%). 1 H NMR (300 MHz, CDCl 3 7.35 7.23 (m, 3H), 7.17 (ddd, J = 6.0, 2.0, 1.1 Hz, 4H), 5.52 5.38 (m, 2H), 4.33 4.14 (m, 1H), 3.71 (p, J = 5.6 Hz, 1H), 2.72 2.53 (m, 3H), 2.38 (t, J = 7.3 Hz, 6H), 2.00 (ddd, J = 8.1, 6.8, 5.1 Hz, 3H), 1.8 3 1.68 (m, 3H), 1.68 1.58 (m, 4H), 1.52 1.41 ( m, 3H), 1.18 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 5.3 Hz, 18H), 0.05 (dd, J = 2.8, 1.6 Hz, 12H). The diprotected monoalllylic diol was immediately taken in THF (1.7 mL). TBAF (1.0 M in THF, 1.4 mL) was added and the mixture was stirred overnight at room temperature. Silica gel was added to the mixture and the solvent was concentrated in vacuo. Flash column chromatography (50% EtOAc in hexanes) afforded the title compound as colorless oil (79 mg, 73%). 1 H NMR (500 MHz, CDCl 3 7.27 (m, 1H), 7.21 7.17 (m, 2H), 5.66 5.44 (m, 2H), 4.30 4.20 (m, 1H), 3.64 3.51 (m, 1H), 2.78 (ddd, J = 13.8, 9.1, 6.3 Hz, 1H), 2.67 (ddd, J = 13.6, 9.1, 6.9 Hz, 1H), 2.47 2.34 (m, 4H), 2.08

PAGE 169

169 1.95 (m, 3H), 1.80 1.71 (m, 2H), 1.70 1.62 (m, 2H), 1.50 1.36 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H). 1 135. 1 129. 8 128.4 128.4 128.3 125. 8, 70.7, 68.7, 42., 42.5 41. 9, 39.0, 36.9 32. 2 31.4, 23. 5, 23.0 19. 6 HRMS (ESI) calculated for C 19 H 28 O 3 [M+Na] + = 341.2 08 7, found 341.2077. (2 S ,6 S ,8 S ) 2 phenethyl 8 (( E ) prop 1 enyl) 1,7 dioxaspiro[5.5]undecane (3 57) To a stirred solution of monoallylic ketodiol (75 mg, 0.24 mmol) in THF (2.4 ml) at 0 C was added PdCl 2 (MeCN) 2 (3.1 mg, 0.0118 mmol) After 75 min, TLC showed complete consumption of starting material. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (hexanes to 2% ether in hexanes) to yield 63.3 mg of the spiroketal 3 57 (89%). IR (neat) 2936, 1456, 1224, 1200, 1084, 981 cm 1 ; 1H NMR (500 MHz, CDCl 3 7.24 (m, 2 H), 7.23 7.20 (m, 1H), 7.17 ( d d, J = 7.1, 1.5 Hz, 1 H), 5.55 (d d d, J = 15.3, 6.2, 1.0 Hz, 1 H), 5.46 (ddq, J = 15.3, 6.3, 1.4 Hz, 1 H), 4.00 3.96 (m, 1 H), 3.62 (dddd, J = 11.0, 8.5, 4.3, 2.2 Hz, 1 H), 2.90 (ddd, J = 13.8, 10.3, 5.8 Hz, 1 H), 2.64 (ddd, J = 13.9, 10.1, 6.2 Hz, 1H), 1.92 ( d ddd, J = 17.5, 13.4, 8.8, 4.1 Hz, 1H), 1.84 1.72 (m, 1H), 1.68 (dd, J = 6. 3, 1.2 Hz, 3 H), 1.65 1.51 (m, 2H), 1.40 ( d dd, J = 13.3, 4.5, 3.4 Hz, 1H), 1.35 1.28 (m, 1 H), 1.27 1.17 (m, 1H). 13 C NMR (126 MHz, CDCl 3 ) 8 128. 5 128.4, 126.6, 125. 6 96. 3 69.8, 68. 7 38. 1 35. 6 35.4, 32. 4 31.4,

PAGE 170

170 31. 2, 19.0 18.0 HRMS (ESI) calculated for C 20 H 28 O 2 [M+H] + = 301.2162, found 301.2148. (3 S ,13 S ,E) 3,13 dihydroxy 1 phenyltetradec 11 en 7 one (3 53) To a stirring solution of ( S ) (but 3 en 2 yloxy )(tert butyl)dimethylsilane (60% solution in hexane, 2.9 mmol) and keto alkene 3 50 (375 mg, 0.97 mmol) in DCM (19 mL) was added 41 mg of temperature, the mixture was passed o ver a short silica plug, and the solvent was concentrated in vacuo. Purication of the residue by flash column chromatography (5% EtOAc in hexanes) afforded a yellow oil (290 mg, 55%). Rf = 0.5 (50% EtOAc in hexanes); 1 H NMR (500 MHz, CDCl 3 7.27 ( m, 1H), 7.21 7.17 (m, 2H), 5.66 5.44 (m, 2H), 4.30 4.20 (m, 1H), 3.64 3.51 (m, 1H), 2.78 (ddd, J = 13.8, 9.1, 6.3 Hz, 1H), 2.67 (ddd, J = 13.6, 9.1, 6.9 Hz, 1H), 2.47 2.34 (m, 4H), 2.08 1.95 (m, 3H), 1.80 1.71 (m, 2H), 1.70 1.62 (m, 2H), 1. 50 1.36 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H). 13 C NMR ( 125 MHz CDCl 3 8, 70.7, 68.7, 42. 9, 42.5, 41.9, 39.0, 36.9, 32.2, 31.4, 23.5, 23.0, 19.6. HRMS (ESI) calculated for C 19 H 28 O 3 [M+Na] + = 341.2087, found 341.2077.

PAGE 171

171 (2 S ,6 R ,8 R ) 2 phenethyl 8 (( E ) prop 1 enyl) 1,7 dioxaspiro[5.5]undecane (3 55) and (2 S ,6 S ,8 R ) 2 phenethyl 8 ((E) prop 1 enyl) 1,7 dioxaspiro[5.5]undecane (3 56). To a stirred solution of monoallylic ketodiol 3 53 (75 mg, 0.24 mmol) in THF (2.4 ml) at 0 C was added PdCl 2 (MeCN) 2 (3.1 mg, 0.0118 mmol). After 75 min, TLC showed complete consumption of starting material. The mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (hexanes to 2 % ether in hexanes) to yield 49.5 mg of the spiroketals 3 55 and 3 56 (70%). Structural assignments done by 2D NMR: HSQC, HMBC, COSY and NOESY. 3 55: Rf = 0.40 (5% EtOAc); D = +67. 368 ( c 1.00, CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 7.25 (m, 2H), 7. 23 7.14 (m, 3H), 5.70 (ddd, J = 15.4, 6.5, 1.1 Hz, 1H), 5.49 (ddq, J = 15.4, 6.7, 1.6 Hz, 1H), 4.55 4.51 (m, 1H), 3.52 3.43 (m, 1H), 2.93 (ddd, J = 13.8, 10.6, 5.4 Hz, 1H), 2.62 (ddd, J = 13.8, 10.4, 6.0 Hz, 1H), 2.23 (dd, J = 13.8, 1.5 Hz, 1H), 1.94 (m, 1H), 1.82 1.71 (m, 2H), 1.71 1.50 (m, 8H), 1.40 1.24 (m, 3H), 1.17 (dd, J = 13.7, 4.1 Hz, 1H), 0.97 (d, J = 6.6 Hz, 1H), 0.92 0.84 (m, 1H). 13 C NMR (126 MHz, CDCl 3 128. 3, 126.8, 125.6 97. 6, 72.3, 70.9 38. 2 36.3, 32.4, 31.4, 31.0, 28.1, 20.0 18.1 17.8 3 56: Rf = 0.45 (5% EtOAc in hexanes); D = 1.695 ( c 0.37, CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 7.24 (m, 3H), 7.23 7.13 (m, 2H), 5.75 5.61 (m, 2H), 4.05 3.97 (m, 2H), 2.72 (ddd, J = 13.7, 10.9, 5.5 Hz, 1H), 2.64 (ddd, J = 13.6, 10.8, 6.0 Hz, 2H), 2.06 (d, J = 13.6 Hz, 1H), 1.91 1.76 (m, 2H), 1.73 1.66 (m, 4H), 1.68 1.61 (m, 2H), 1.61 1.54 (m, 3H), 1.30 1.17 (m, 4H), 0.97 (d, J = 6.6 Hz, 0H), 0.92 0.82 (m, 1H). 13 C NMR (126 MHz, CDCl 3 6 132.2 128.3 ,125. 8 125. 7

PAGE 172

172 125.61, 96. 1 69. 1, 68.5, 65.3 38. 4 38.0, 35.5, 35.4, 35.3 32.5, 32.2, 31.3, 31.2 31.0 18.8, 18.7 13.4 1 H NMR (500 MHz, C 6 D 6 7.12 (m, 13H), 7.08 7.03 (m, 1H), 5.80 (ddq, J = 15.3, 6.8, 1.6 Hz, 1H), 5.61 (ddd, J = 15.3, 6.5, 1.1 Hz, 1H), 4.13 (dddd, J = 11.5, 7.6, 4.8, 2.3 Hz, 1H), 3.95 3.88 (m, 1H), 2.81 (ddd, J = 13.5, 10.4, 5.2 Hz, 1H), 2.70 (ddd, J = 13.6, 10.4, 6.5 Hz, 1H), 2.11 1.95 (m, 1H), 1.94 1.74 (m, 4H), 1. 59 (ddd, J = 6.5, 1.6, 0.8 Hz, 3H), 1.41 1.25 (m, 3H), 1.20 1.04 (m, 2H). 13 C NMR (126 MHz, C 6 D 6 134. 3 129. 3 128. 7 128. 3 126.2 97.3 73.8, 69.4, 39.3, 36. 9 32.7, 32.0, 31.6, 19.3 19.0, 18.2 5 2.12 Synthesis of glucose derived spiroketals 3 62, 3 63 and 3 64 (2 R ,4a R ,7 R ,8 S ,8a R ) 7,8 bis(benzyloxy) 6 (pent 4 enyl) 2 phenylhexahydropyrano[3,2 d][1,3]dioxin 6 ol (3 59) A solution of 5 bromo 1 pentene (191 mg, 1.29 mmol) in ether (2.5 mL) was cooled to 78 C. t BuLi was added dropwise and the resulting solution was stirred for 10 minutes before a solution of lactone 3 58 84 (173 mg, 0.39 mmol) in 8 mL of ether was added The mixture was stirred for 10 minutes, then quenched with saturated NH 4 Cl solution. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers was washed with brine, dried with anhydrous MgSO 4 and c oncentrated. The crude product was purified by flash chromatography (hexanes to 3% EtOAc in hexanes) to yield a colorless oil (149 mg, 74%). Rf = 0.3 (20% EtOAc) 1 H NMR (500

PAGE 173

173 MHz, CDCl 3 7.47 (m, 2H), 7.41 7.27 (m, 11H), 5.74 (ddd, J = 16.9, 10. 2, 6.6 Hz, 1H), 5.58 (s, 1H), 5.03 (m, 1 H), 4 .98 (d, J = 7.7 Hz, 1H), 4.76 (d, J = 7.7 Hz, 1H), 4.69 (d, J = 7.7 Hz, 1H), 4.30 (dd, J = 10.2, 5.0 Hz, 1H), 4.09 4.00 (m, 2H), 3.70 (dd, J = 10.3, 10.3 Hz, 1H), 3.64 (dd, J = 9.5, 9.5 Hz, 1H), 3.46 (d, J = 8.7 Hz, 1H), 2.82 (s, 1H), 2.01 1.91 (m, 2H), 1.64 (ddd, J = 13.7, 11.3, 5.0 Hz, 2H), 1.53 1.43 (m, 1H), 1.37 1.28 (m, 1H). 13 C NMR (126 MHz CDCl 3 5 138. 4 137.7 137. 5 128. 9, 128.4 128. 4, 128.2, 128.1, 128.0 127. 7, 126.0 114. 8 101. 2 99. 2 82. 5 80. 7 80. 5 75.6, 75. 2 69. 2 63. 1 38. 3 33.6, 21. 8 (2 R ,4a R ,7 R ,8 S ,8a R ) 7,8 bis(benzyloxy) 6 (( R E ) 6 hydroxyhept 4 enyl) 2 phenylhexahydropyrano[3,2 d][1,3]dioxin 6 ol (3 60). To a stirring solution of ( R ) (but 3 en 2 yloxy)(tert butyl)dimethylsilane (50% solution in hexane,1.17 mmol) and keto alkene 3 59 (200 mg, 0.39 mmol) in DCM (7.8 mL) was added 33 mg (0.039 temperature, the mixture was passed over a short silica plug, and the solvent was concentrated in vacuo. Pu rication of the residue by flash column chromatography (5% EtOAc in hexanes) afforded a yellow oil (169 mg, 64%). A portion of the product (154 mg, 0.23 mmol) was immediately taken in MeOH (4.6 mL). PPTS (58 mg, 0.23 mmol) was added and the mixture was sti rred overnight at room temperature. Silica gel was added to the mixture and the solvent was concentrated in vacuo. Flash column chromatography (50% EtOAc in hexanes) afforded the title compound as colorless oil (70.7 mg, 55%). 1 H NMR (500 MHz, CDCl 3 5 7.44 (m, 2H), 7.40 7.20 (m,

PAGE 174

174 13H), 5.57 (s, 1H ), 5.56 5.45 (m, 2H), 4.99 (d J = 7.7 Hz, 1 H), 4. 98 (d J = 7.7 Hz, 1 H), 4.76 (d, J = 7.7 Hz, 1H), 4.69 (d, J = 7.7 Hz, 1H), ( 4.30 (dd, J = 10.2, 5.0 Hz, 1H), 4.26 4.20 (m, 1H), 4.08 4.00 (m, 2H), 3 .70 (dd, J = 10.3 Hz, 1H), 3.63 (dd, J = 9.5 Hz, 1H), 3.45 (d, J = 8.7 Hz, 1H), 2.86 (s, 1H), 1.98 1.86 (m, 2H), 1.70 1.55 (m, 3H), 1.52 1.41 (m, 1H), 1.39 1.36 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 5 137.7, 137. 5 134.6 130.3 128. 9, 128.4 128. 4, 128.3, 128.2 128. 1, 128.1 127. 7 126.0 101. 2 99.1, 82. 5, 80.7, 80.5 75. 6 75. 2 69. 2 68.8, 63. 1 (2 S ,2' R ,4a' R ,6S,7' R ,8' S ,8a' R ) 7',8' bis(benzyloxy) 2' phenyl 6 (( E ) prop 1 enyl)octahydro 4'H spiro[pyran 2,6' pyrano[3,2 d][1,3]dioxine] (3 62) To a stirred solution of diol 3 60 (64 mg, 0.11 mmol) in THF (1.1 ml) at 0 C was added PdCl 2 (MeCN) 2 (1.5 mg, 0.0059 mmol). The reaction was monitored by TLC. After 45 min, the starting material was completely consumed (as monitored by TLC). The solution was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo and purified by flash column chromatography (hexanes to 5% ether in hexanes) to yield the spiroketal as a colorless oil (51.2 mg, 86%) dr = 89:7:4 IR (neat) 2932, 2865, 1497, 1453, 1365, 10 62, 1021, 956, 743 cm 1 ; 1 H NMR (600 MHz, CDCl 3 J = 8.1, 1.7 Hz, 2H), 7.42 7.27 (m, 13H), 5.65 (dqd, J = 15.4, 6.3, 0.9 Hz, 1H), 5.60 (s, 1H), 5.55 (dddd, J = 13.8, 6.7, 3.2, 1.7 Hz, 1H), 5.00 (d, J = 11.6 Hz, 1H), 4.97 (d, J = 11.1 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.34 4.30 (m, 1H), 4.20 (dd, J = 9.2 Hz, 1H), 4.04 3.97 (m, 1H), 3.79 3.75 (m, 2H),

PAGE 175

175 3.68 (dd, J = 9.1 Hz, 1H), 3.28 (d, J = 9.2 Hz, 1H), 2.10 2.01 (m, 0H), 1.89 1.81 (m, 1H), 1.81 1.74 (m, 1H), 1.68 (ddd, J = 6.4, 0.7 Hz, 3H), 1.57 (s, 2H), 1.44 1.35 (m, 1H), 1.26 1.21 (m, 1H). 13 C NMR (126 MHz, CDCl 3 139.0 138.4, 137. 7 132. 1 129.0 128. 6 128. 5 128. 4 128.3, 128. 2 127.8, 127.7, 127. 3 126. 1 101.2 100. 2 83. 4 8 2.8, 79. 6 77.4, 77. 4 77. 2 76.9, 75.6, 75.4, 71.2, 69.5, 62. 6, 30.6 29. 7 18.6, 17. 9 Structural assignments done by 2D NMR: HSQC, HMBC, COSY and NOESY. HRMS (ESI) calculated for C 34 H 38 O 6 [M+Na] + = 565.2061, found 565.2554. (2 R ,4a R ,7 R ,8S,8a R ) 7,8 bis(benzyloxy) 6 (( S E ) 6 hydroxyhept 4 enyl) 2 phenylhexahydropyrano[3,2 d][1,3]dioxin 6 ol (3 61). To a stirring solution of ( S ) (but 3 en 2 yloxy)(tert butyl)dimethylsilane (50% solution in hexane,1.17 mmol) and keto alkene 3 50 (200 mg, 0.39 mmol) in DCM (7.8 mL) was added 33 mg (0.039 temp erature, the mixture was passed over a short silica plug, and the solvent was concentrated in vacuo. Purication of the residue by flash column chromatography (5% EtOAc in hexanes) afforded a yellow oil (182 mg, 69%). A portion of the product (170 mg, 0.25 mmol) was immediately taken in MeOH (5 mL). PPTS (63 mg, 0.25 mmol) was added and the mixture was stirred overnight at room temperature. Silica gel was added to the mixture and the solvent was concentrated in vacuo. Flash column chromatography (50% EtOAc i n hexanes) afforded the title compound as colorless oil (81.6 mg, 58%). IR (neat) 3393, 2925, 1719, 1454, 1371, 1040, 1027, 971 cm 1 1 H

PAGE 176

176 NMR (500 MHz, CDCl 3 7.45 (m, 2H), 7.39 7.25 (m, 13H), 5.56 (s, 1H), 5.54 5.51 (m, 1H), 5.49 5.44 (m, 1H ), 4.98 (d, J = 7.6 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 4.76 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.28 (dd, J = 10.2, 5.0 Hz, 1H), 4.22 (t, J = 7.3 Hz, 1H), 4.06 3.97 (m, 2H), 3.68 (dd, J = 10.3, 10.3 Hz, 1H), 3.62 (dd, J = 9.5, 9.5 Hz, 1H), 3 .44 (d, J = 8.7 Hz, 1H), 2.81 (s, 1H), 1.91 (h, J = 6.6 Hz, 2H), 1.67 1.57 (m, 2H), 1.49 1.39 (m, 1H), 1.33 (d, J = 5.5 Hz, 1H), 1.25 (d, J = 7.1 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 9 137.6, 134. 8 130. 5 129. 1 128.6, 128. 6 128. 5 128. 4 128. 3 128.2, 127. 9 126. 2, 101.3 99.3, 82.6, 80. 9, 80.6, 77.4 75.3 69.3, 69.0, 63.2, 38.5, 32.1 23. 6, 22.2 14. 4 HRMS (ESI) calculated for C 34 H 40 O 7 [M+Na] + = 583.2666, found 583.2670. Spiroketals 3 63 and 3 64. To a stirred solution of diol 3 61 (75 mg, 0.13 mmol) in THF (1.3 ml) at 0 C was added PdCl 2 (MeCN) 2 (1.7 mg, 0.0067 mmol). The reaction was monitored by TLC. After 10 h, the starting material was completely consumed (as monitored by TLC). The solution was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo a nd purified by flash column chromatography (hexanes to 5% ether in hexanes) to yield a mixture of the spiroketal as a colorless oil (58.1.2 mg, 82%) dr = 62:34:4 Structural assignments of both diastereomers were done using 2D NMR: HSQC, HMBC, COSY and NO ESY

PAGE 177

177 (2 S ,2' R ,4a' R ,6 R ,7' R ,8' S ,8a' R ) 7',8' bis(benzyloxy) 2' phenyl 6 (( E ) prop 1 enyl)octahydro 4'H spiro[pyran 2,6' pyrano[3,2 d][1,3]dioxine] (3 63) Rf = 0.25 (10% EtOAc in hexanes) ; 1 H NMR (600 MHz, CDCl 3 7.49 (m, 2H), 7.41 7.27 (m, 14H), 5.92 (ddd, J = 15.2, 9.2, 1.7 Hz, 1H), 5.68 (dq, J = 15.2, 6.5 Hz, 1H), 5.56 (s, 1H), 4.98 (d, J = 11.3 Hz, 1H), 4.96 (d, J = 11.1 Hz, 1H), 4.78 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.44 (ddd, J = 8.6, 5.5, 2.3 Hz, 1H), 4.18 (dd, J = 10.1, 5.0 Hz, 1H), 4.13 (dd, J = 9.3 Hz, 1H), 3.94 (ddd, J = 10.1, 10.2, 5.0 Hz, 1H), 3.69 (dd, J = 10.8, 11.4 Hz, 1H), 3.66 (dd, J = 10.2, 9.6 Hz, 1H ), 3.21 (d, J = 9.3 Hz, 1H), 1.96 1.90 (m, 1H), 1.88 (dd, J = 12.7 4.2 Hz, 1H), 1.86 1.79 (m, 1H), 1.70 (dd, J = 6.5, 1.6 Hz, 3H), 1.68 1.65 (m, 1H), 1.51 (dd, J = 11.7, 3.8 Hz, 1H), 1.39 1.34 (m, 1H). 13 C NMR (126 MHz, CDCl 3 8, 137.6 131. 8 128. 8 128.6 128.5, 128.3 128. 3, 128.2, 128.1, 127.7 127. 6, 12 6.0 101.0, 99.7, 83. 5, 83 .0 80.0 75.9, 75.3, 74. 5 69. 1 62. 8 30. 4 28.5, 17.8, 14. 2 (2 R ,2' R ,4a' R ,6 R ,7' R ,8' S ,8a' R ) 7',8' bis(benzyloxy) 2' phenyl 6 (( E ) prop 1 enyl)octahydro 4'H spiro[pyran 2,6' pyrano[3,2 d][1,3]dioxine] (3 64) Rf = 0.3 ; 1 H NMR (500 MHz, CDCl 3 7.46 (m, 2H), 7.40 7.25 (m, 13H), 5.71 (ddd, J = 15.4, 6.5, 1.1 Hz, 1H), 5.47 (ddd, J = 15.4, 6.5, 1.6 Hz, 1H), 4.89 (d, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.78 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.4 1 ( dd J = 10.5, 6.8 Hz, 1H), 4.33 (dd, J = 10.3, 4.9 Hz, 1H), 3.80 (dd, J = 10.2, 9.7 Hz, 1 H), 3.72 (dd, J = 9.2, 8.4 Hz, 1H), 3.51 (d, J = 8.4 Hz, 1H), 1.93 (d, J = 14.1 Hz, 1H), 1.90 1.81 (m, 1H), 1.79 1.71 (m, 1 H), 1.70 (ddd, J = 6.5, 1.7, 0.8 Hz, 3H), 1.6 8 1.61 (m, 1H), 1.40 (dd, J = 13.0, 4.1 Hz, 0H), 1.35 (dd, J = 12.7, 4.2 Hz, 1 H). 13 C NMR (126 MHz, CDCl 3 138.9, 138.8 132. 3, 129.0, 128.4, 128.3 128. 3 128. 2, 128.1, 127.7, 127.6 126. 6

PAGE 178

178 126. 2 10 2 0 101. 4 99. 9, 85.3, 82.2, 79.2, 77.4 75.0 74. 9 72. 4 69. 7 65.0 31.7, 24.1, 18.0 17. 7 key NOESY correlations for 3 64 5 .2.13 Synthesis of 2 cyclohexylvinyl) 8 phenethyl 1,7 dioxaspiro[5.5]undecane (3 70, 3 72 and 3 73) Scheme 5 12. Synthesis of 3 66 ( S ) 10 ( tert butyldimethylsilyloxy) 12 phenyl 1 (trimethylsilyl)dodec 1 yn 6 one (S21) To a a flame dried flask was added Mg (192 mg, 7.9 mmol), dibromoethane (39 mg, 0.21 mmol) and THF (5.3 mL). A solution of (5 bromopent 1 ynyl)trimethylsilane in THF (5.0 mL was added to the mixture dropwise over a period of 10 min. The resulting mixture was r efluxed for 30 min, then slowly cooled 0 C by which time the mixture looked like a suspension. A solution of the Weinreb amide 3 48 (800 mg, 2.1 mmol) in THF (10 mL) was added dropwise. The mixture was stirred for 1.5 hours before quenching with saturated NH 4 Cl solution. The organic materials were extracted

PAGE 179

179 with ether, and the combined organic extracts were washed with brine, dried over MgSO 4 and evaporated in vacuo The residue was purified by flash column chromatography (20% EtOAc in hexanes) and obtain ed (771 mg, 81%) as a pale yellow oil. R f 0.5 (5% EtOAc in hexanes). 1 H NMR (500 MHz, CDCl 3 7.27 (m, 2H), 7.19 7.15 (m, 2H), 3.72 (p, J = 5.7 Hz, 2H), 2.67 (ddd, J = 13.7, 9.9, 7.0 Hz, 2H), 2.59 (ddd, J = 13.6, 9.8, 6.5 Hz, 2H), 2.52 (t, J = 7. 3 Hz, 2H), 2.45 2.38 (m, 2H), 2.26 (t, J = 6.9 Hz, 2H), 1.83 1.71 (m, 4H), 1.69 1.57 (m, 2H), 1.51 1.43 (m, 1H), 0.91 (s, 9H), 0.14 (s, 9H), 0.06 (d, J = 0.4 Hz, 3H), 0.05 (s, 3H). 13 C NMR (126 MHz, CDCl 3 6 142.84, 128.6, 128. 5 106.6, 100.0 85. 6, 77.5 71. 8 43. 3 41. 4 39.1, 36. 7 31. 9 26. 2 26.1, 22. 7 19. 9 19. 5 18. 4, 0.41, 0.35, 4.1 ( S ) 10 ( tert butyldimethylsilyloxy) 12 phenyldodec 1 yn 6 one (3 66). T o a stirring solution of the product above (750 mg, 1.63 mmol) in MeOH (5.4 mL) was added K 2 CO 3 (45 mg, 0.33 mmol). The mixture was stirred overnight, concentrated in vacuo and taken up in saturated NaHCO 3 solution. The aqueous phase was extracted with DCM (3 x 10 mL), and the combined organic layers were washed with brine, dried with MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography and yield a colorless oil (559 mg, 89%). 1 H NMR (500 MHz, CDCl 3 7.25 7.21 (m, 1H), 7.14 7.09 (m, 3H), 3.66 (p, J = 5.7 Hz, 1H), 2.61 (ddd, J = 13.7, 9.8, 7.1 Hz, 1H), 2.57 2.51 (m, 1H), 2.49 (t, J = 7.2 Hz, 2H), 2.39 2.33 (m, 2H), 2.17 (ddd, J = 6.9, 2.7 Hz, 2H), 1.89 (t, J = 2.7 Hz, 1H), 1.77 1.67 (m, 4H), 1.65 1.50 (m, 3H), 1.45 1.38 (m, 2H), 0.85 (s, 9H), 0.00 (d, J = 0.4 Hz, 3H), 0.01 (s, 3H). 13 C NMR (126 MHz, CDCl 3 142. 6 128.30, 128. 3, 125.6 83. 6 71. 6 69.0, 43.0, 40.9

PAGE 180

180 38. 9 36. 4, 31.6, 25.9 22. 2, 19.6, 18.1, 17.7 4. 4. HRMS (ESI) calculated for C 24 H 38 O 2 Si [M+Na] + = 409.2533, found 409.2533. Scheme 5 13. Synthesis of 3 68 (1 S ,11 S ) 11 ( tert butyldimethylsilyloxy) 1 cyclohexyl 1 hydroxy 13 phenyltridec 2 yn 7 one (S 22) A 50 mL flask was charged with Zn(OTf) 2 (553 mg, 1.49 mm ol) and ( ) N methylephedrine (296 mg, 1.63mmol) was added. To the flask was added toluene (4.5 mL) and triethylamine (0.23 mL, 1.63 mmol,). The resulting mixture was stirred for 2 h at r.t. before the alkyne 3 66 (524 mg, 1.36 mmol) in toluene (1 mL) was added in one portion. After stirring for 0.25 h at r oom temperature, cyclohexane carboxaldehyde (0.16 mL, 1.35 mmol) was added in one portion. The reaction mixture was stirred at r.t. for 20 hours. The reaction w as quenched by addition of NH 4 Cl (sat.) (3 mL). The reaction mixture was poured into a separatory funnel containing diethyl ether (10 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined ethereal p ortion was washed with NaCl (sat.) (10 mL), dried over anhydrous MgSO 4 filtered and concentrated in vacuo The crude material was purified by flash chromatography (gradient; 5,10%

PAGE 181

181 EtOAc/hexanes) to give the product as a colorless oil (547 mg, 81%); Rf = 0 .5 (10% EtOAc/hexanes ). 1 H NMR (500 MHz, CDCl 3 7.25 (m, 1H), 7.21 7.14 (m, 3H), 3.72 (p, J = 5.7 Hz, 1H), 2.67 (ddd, J = 13.7, 9.9, 7.1 Hz, 1H), 2.59 (ddd, J = 13.7, 9.9, 6.6 Hz, 1H), 2.52 ( dd J = 7.2 7.2 Hz, 2H), 2.42 (ddd, J = 8.3, 6.3, 1.3 Hz, 3H), 2.26 (td, J = 6.9, 2.0 Hz, 2H), 1.88 1.80 (m, 1H), 1.79 1.73 (m, 3H), 1.70 1.54 (m, 4H), 1.53 1.44 (m, 2H), 1.29 1.18 (m, 3H), 1.19 1.01 (m, 3H), 0.91 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13 C NMR (126 MHz, CDCl 3 3 142. 6, 128.3, 128.3 125. 7 85. 2 81.0, 71.6 67. 4 44.3, 43.0, 41. 3 38. 9 36.4, 31. 6 28. 6 28.1, 26.4, 25. 9 22. 6, 19.6 18. 2, 18.1, 4. 4. (1 S ,11 S ,Z) 1 cyclohexyl 1,11 dihydroxy 13 phenyltridec 2 en 7 one (S22) Lindlar catalyst (5% palladium on calcium carbo nate, poisoned with lead, 52 mg) was added to a solution of S22 (517 mg, 1.03 mmol) and quinoline (52 mg) in dry EtOH (1 mL). The reaction mixture was stirred 1.5 h under H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was purified by flash column chromatography and obtained the product contaminated with quinoline. The quinoline was distilled by Kuhgelhror. A colorless oil S22 (389 mg, 78%) was obtained and used in the next step. 1 H NMR (500 MHz, CDCl 3 7.23 (m, 2H), 7.21 7.12 (m, 3H), 6.20 (dd, J = 11.5, 1.6 Hz, 1H), 6.05 (dd, J = 11.5, 7.4 Hz, 1H), 3.78 3.66 (m, 1H), 2.67 (ddd, J = 13.6, 9.9, 6.9 Hz, 1H), 2.63 2.55 (m, 2H), 2.45 2.36 (m, 5H), 2.36 2.28 (m, 1H), 1.86 1.63 (m, 5H), 1.59 1.53 (m, 1H), 1.49 1.41 (m, 2H), 1.36 1.17 (m, 5H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H). 13 C NMR (126 MHz, CDCl 3 210.3 147. 5 142. 6 128. 3, 126.4, 125.6, 71.6 51. 4, 42.9 42.4 42. 1 40. 3 38.8, 36. 4, 31.6, 28.8 28. 5, 28.3 25. 9, 25. 8 25. 7, 23.5, 23.3, 23.1 19. 7 19. 6, 18.1 4. 4.

PAGE 182

182 (1 S ,11 S,Z ) 11 (tert butyldimethylsilyloxy) 1 cyclohexyl 1 hydroxy 13 phenyltridec 2 en 7 one (3 68). A solution of TBAF (1.0M in THF, 4.0 mL) was added dropwise at 0 C to a solution of the protected diol obtained above in dry THF (5 mL). The reaction was stirred 16h, and the mixture was concentrated in vacuo. Flash chromatography (40% EtOAc/Hexanes) afforded the product as colorless oil (293 mg, 81%). 1 H NMR (500 MHz, CDCl 3 7.23 (m, 2H), 7.22 7.14 (m, 2H), 5.50 5.38 (m, 2H), 4.10 4.06 (m, 1H), 3.61 3.55 (m, 1H), 2.78 (ddd, J = 13.7, 9.1, 6.4 Hz, 1H), 2.67 (ddd, J = 13.8, 9.1, 7.0 Hz, 1H), 2.49 2.32 (m, 4H), 2.22 2.07 (m, 1H), 2.04 (s, 2H), 1.97 1.88 ( m, 1H), 1.80 1.57 (m, 6H), 1.52 1.41 (m, 1H), 1.37 1.30 (m, 1H), 1.24 1.09 (m, 3H), 1.03 0.84 (m, 2H). 13 C NMR (126 MHz, CDCl 3 3, 142.0 132. 1 131. 6 128. 4 128.2 125. 8 71. 8, 70.7 44.0 42. 5, 41.8, 39.0 37.0 32.0 28.8, 28.5, 27.0, 2 6.5 26. 1 26.0, 23.5, 19.6 HRMS (ESI) calculated for C 25 H 3 8 O 3 [M+Na ] + = 409.2713 found 409.2723 (2 S ,6 S ,8 S ) 2 (( E ) 2 cyclohexylvinyl) 8 phenethyl 1,7 dioxaspiro[5.5]undecane (3 70) To a stirred solution of monoallylic ketodiol 3 68 (74 mg, 0.19 mmol) in THF (3.8 ml) at 0 C was added PdCl 2 (MeCN) 2 (2.5 mg, 0.0095 mmol). The reaction was monitored by TLC, and after 16 h the reaction mixture was filtered through a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (hexanes to 2% ether i n hexanes) to yield 39.5 mg of the spiroketals (56 %). 1 H NMR (500 MHz, CDCl 3 7.24 (m, 2H), 7.22 (ddd, J = 7.8, 1.4, 0.7 Hz,

PAGE 183

183 2H), 7.19 7.13 (m, 1H), 5.47 (ddd, J = 15.6, 6.2, 1.0 Hz, 1H), 5.37 (ddd, J = 15.6, 6.2, 1.2 Hz, 1H), 3.99 3.95 (ddd, 11.5, 6.1, 2.3 Hz 1H), 3.62 (dddd, J = 11.0, 8.6, 4.3, 2.2 Hz, 1H), 2.90 (ddd, J = 14.0, 10.0, 5.8 Hz, 1H), 2.65 (ddd, J = 14.0, 9.8, 6.4 Hz, 1H), 1.99 1.88 (m, 3H), 1.86 1.69 (m, 4H), 1.67 1.51 (m, 5H), 1.45 1.34 (m, 2H), 1.33 1.13 (m, 4H), 1.1 1 1.01 (m, 2H). 13 C NMR (126 MHz, CDCl 3 7 137. 6, 128.9, 128.5, 128.4, 125.8 96. 3 70. 1 68. 6 40. 5 38. 1, 35.6 35. 5 33.0, 32.9, 32.3 31. 5 31. 4, 26.4 26. 3 26.2 18.95. HRMS (ESI) calculated for C 25 H 36 O 2 [M+K] + = 391.2608, found 391.2606. Scheme 5 14. Synthesis of 3 69 (1 R ,11 S ) 11 (tert butyldimethylsilyloxy) 1 cyclohexyl 1 hydroxy 13 phenyltridec 2 yn 7 one (S24) A 50 mL flask was charged with Zn(OTf) 2 (180 mg, 0.48 mmol) and (+) N methylephedrine (96 mg, 0.53 mmol) was added. To the flask was added toluene (1.5 mL) and triethylamine (0.074 mL, 0.53 mmol,). The resulting mixture was stirred for 2 h at r.t. before the alkyne 3 66 (184 mg, 0.48 mmol) in t oluene (1 mL) was added in one portion. After stirring for 0.25 h at r.t. cyclohexane carboxaldehyde (0.053 mL, 0.44 mmol) was added in one portion. The reaction mixture was stirred at r.t. for 20 hours. The reaction was quenched by addition of NH 4 Cl (sat. ) (3

PAGE 184

184 mL). The reaction mixture was poured into a separatory funnel containing diethyl ether (10 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined ethereal portion was washed with NaCl (sat.) (10 mL), dried over anhydrous MgSO 4 filtered and concentrated in vacuo The crude material was purified by flash chromatography (gradient; 5,10% EtOAc/hexanes) to give the product as a colorless oil (210 mg, 99%); Rf = 0.5 (10% EtOAc/hexanes ) (1 R ,11 S ,Z) 1 cy clohexyl 1,11 dihydroxy 13 phenyltridec 2 en 7 one (S25) Lindlar catalyst (5% palladium on calcium carbonate, poisoned with lead, 17.6 mg) was added to a solution of S24 (176 mg, 0.35mmol ) and quinoline (17.6 mg) in dry EtOH (1 mL). The reaction mixture w as stirred 8 h under H 2 (1 atm). After filtration over celite and removal of the solvent, crude product was purified by flash column chromatography and obtained the product contaminated with quinoline. The quinoline was distilled by Kuhgelhror. A colorles s oil S25 (106 mg, 56%) was obtained and used in the next step. 1 H NMR (500 MHz, CDCl 3 7.24 (m, 3H), 7.21 7.14 (m, 2H), 5.51 5.45 (m, 1H), 5.44 5.38 (m, 1H), 4.13 4.04 (m, 1H), 3.71 (p, J = 5.7 Hz, 1H), 2.67 (ddd, J = 13.7, 9.8, 7.0 Hz, 1H), 2.59 (ddd, J = 13.7, 9.8, 6.6 Hz, 1H), 2.40 (m, 5H), 2.17 2.01 (m, 3H), 1.91 (ddd, J = 12.8, 3.4, 1.7 Hz, 1H), 1.80 1.69 (m, 2H), 1.69 1.57 (m, 4H), 1.50 1.43 (m, 2H), 1.35 (ddd, J = 11.7, 7.0, 3.5 Hz, 1H), 1.28 1.08 (m 3H), 1 .04 0.85 (m, 13H), 0.06 (s, 3H), 0.05 (s, 3H). 13 C NMR (126 MHz, CDCl 3 9 142. 6 132. 1 131.7 128.3, 128.3, 125.7 71. 8, 71.6, 43.9 42. 9, 41.9 38. 9, 36.4, 31.6 28. 8 28. 6, 27.1, 26.5, 26.1 2 6.0 25.9 23.6 19.6, 18.1, 14.2, 4.4. (1 R ,11 S Z ) 1 cyclohexyl 1,11 dihydroxy 13 phenyltridec 2 en 7 one (3 69). A solution of TBAF (1.0M in THF, 0.4 mL) was added dropwise at 0 C to a solution of the

PAGE 185

185 protected diol S25 obtained above in dry THF (5 mL). The reaction was stirred 16h, and the mixtu re was concentrated in vacuo. Flash chromatography (40% EtOAc/Hexanes) afforded the product as colorless oil (46 mg, 63%). 1 H NMR (500 MHz, CDCl 3 7.24 (m, 4H), 7.22 7.16 (m, 2H), 5.50 5.36 (m, 2H), 4.08 (dd J = 7.9 7.9 Hz, 1H), 3.58 (s, m H ), 2.79 (ddd, J = 13.8, 9.1, 6.3 Hz, 1H), 2.67 (ddd, J = 13.8, 9.2, 7.1 Hz, 1H), 2.50 2.36 (m, 4H), 2.21 1.98 (m, 2H), 1.94 1.86 (m, 1H), 1.79 1.59 (m, 5H), 1.50 1.41 (m, 1H), 1.38 1.29 (m, 1H), 1.27 1.08 (m, 2H), 1.04 0.85 (m, 2H). 13 C NMR (126 MHz, CDCl 3 2, 132.1, 131.6 128. 4 128. 4 128. 3, 125.8 77. 3 71. 8 70. 7 44.0 42.4, 41. 8, 39.0 36. 9, 32.0 28. 8 28. 6, 27.0, 26.5, 26.1 26.0, 23.5 19. 6 14. 2 (2 R ,6 R ,8 S ) 2 (( E ) 2 cyclohexylvinyl) 8 phenethyl 1,7 dioxaspiro[5.5]undecane (3 72 ) and (2 R ,6 S ,8 S ) 2 (( E ) 2 cyclohexylvinyl) 8 phenethyl 1,7 dioxaspiro[5.5]undecane (3 73 To a stirred solution of monoallylic ketodiol 3 69 (46 mg, 0.11 mmol) in THF (1.1 ml) at 0 C was added PdCl 2 (MeCN) 2 (1.5 mg, 0.0059 mmol). The reaction was monitored by TLC. After 2.5 h at 0 C, the mixture was allowed to warm to room temperature and after 14 h, it was filtered t hrough a short plug of silica. The solution of crude product was concentrated in vacuo, and purified by flash chromatography (hexanes to 2% ether in hexanes) to yield spiroketals 3 72 (14.6 mg, 33%) and 3 73 (8.5 mg, 19%).

PAGE 186

186 3 72 : Rf = 0.7 (10% EtOAc in hexa nes ); 1 H NMR (500 MHz, CDCl 3 7.26 7.15 (m, 2H), 5.64 (ddd, J = 15.6, 6.5, 1.1 Hz, 1H), 5.44 (ddd, J = 15.6, 6.6, 1.3 Hz, 1H), 4.55 (ddd, J = 11.5, 6.5, 2.3 Hz, 1H), 3.51 (dddd, J = 12.9, 8.4, 3.7, 2.3 Hz, 1H), 2.96 (ddd, J = 13.8, 10.7, 5.4 Hz, 1H), 2.64 (ddd, J = 13.8, 10.5, 6.0 Hz, 1H), 2.26 (d, J = 13.7 Hz, 1H), 2.02 1.87 (m, 2H), 1.84 1.69 (m, 5H), 1.68 1.61 (m, 3H), 1.55 1.49 (m, 1H), 1.36 1.23 (m, 5H), 0.99 (d, J = 6.7 Hz, 1H), 0.93 0.88 (m,6). 13 C NMR (126 MHz, CDCl 3 142. 6, 137.5, 128.7 1 28.3 128. 3, 125.6 97. 7, 72.3, 71.2 40. 4 38. 2, 36.6 36. 4 34. 7 32. 8, 32.7 32. 5 31. 8 31. 6, 31.0, 28.1, 26.2 26. 1 24. 7, 22.6, 20.0 18. 2, 14.1 3 73 : Rf = 0.75; 1 H NMR (500 MHz, CDCl 3 J = 15.6, 6.8, 1.1 Hz, 1H) 5.56 (ddd, J = 15.5, 6.4, 0.8 Hz, 1H), 4.08 3.94 (m, 2H), 2.75 2.59 (m, 3H), 2.05 (d, J = 13.7 Hz, 1H), 2.00 1.81 (m, 2H), 1.77 1.67 (m, 3H), 1.67 1.52 (m, 7H), 1.31 1.17 (m, 5H), 1.14 0.99 (m, 2H), 0.97 0.83 (m, 3H). 13 C NMR (126 MHz, CDCl 3 142.6 137.1, 129.0 128. 4, 128.3 128. 3, 128.2, 125.5 97. 1, 73.8, 69.3 38. 2, 36.6 36. 1, 32.9 32. 9, 31.7 31. 2, 30.9, 26.2 26.1, 26.0 18. 4 18.3.

PAGE 187

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193 BIOGRAPHICAL SKETCH Jean Palmes received her b c hemistry from the University of the Phillipines Los Baos in 1998. After working in the industry for a few years, she moved to the University of Florida to pursue graduate studies. She joined the research group of Dr. Aaron Aponick in 2006 where she starte d her work on the development of metal catalyzed organic transformations. Her PhD thesis focused on the metal catalyzed spiroketalization of monoallylic ketodiols.