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I. Total Synthesis of Acortatarin a Using a Palladium-Catalyzed Spiroketalization Methodology II. Tandem Gold-Catalyzed ...

Permanent Link: http://ufdc.ufl.edu/UFE0044863/00001

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Title: I. Total Synthesis of Acortatarin a Using a Palladium-Catalyzed Spiroketalization Methodology II. Tandem Gold-Catalyzed Cyclization/Diels-Alder Reactions
Physical Description: 1 online resource (165 p.)
Language: english
Creator: Borrero, Nicholas V
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2012

Subjects

Subjects / Keywords: acortatarin -- alder -- diels -- gold -- palladium -- spiroketal
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Palladium and goldcomplexes have been shown to provide an efficient method for theformation of C-O and C-N bonds via activation of alkenes and alkynes towardsnucleophilic attack.  Ofparticular interest is the intramolecular cyclization of monoallylic andmonopropargylic diols to afford saturated and unsaturated heterocyclesrespectively.  The work presented in thisthesis is aimed at applying these methodologies to the total synthesis of abiologically active natural product, and expanding them to a mild synthesis ofdiene heterocycles for Diels-Alder reactions. Monoallylic keto-diols initially equilibrate to form ahemiketal between the non-allylic alcohol and carbonyl.  The newly formed hydroxy group has been shownto attack the double bond of the allylic alcohol forming anomeric spiroketalsunder transition metal catalysis.  Thiscyclization method was used to generate the spiroketal core of the naturalalkaloid acortatarin A.  The keyhemiketal intermediate was prepared in 15 total steps, and the cyclizationevent proceeded under palladium(II)-catalysis to deliver the desired spiroketalin high yield.  A concise end-gamestrategy successfully completed the natural product. The Diels-Alder reaction is a powerful C-C bond formingtechnique to effect the formation of unsaturated 6-membered rings from dienesand appropriate dienophiles. Monopropargylic diols cyclize under gold-catalyzedconditions to form cyclic dienol ethers, which may further react in thecapacity of dienes in the Diels-Alder reaction.  Likewise, the corresponding nitrogenheterocycles may be formed from substrates containing amine derivatives.  Systems comprised of 5- and 6-memberedunsaturated heterocycles with pendant vinyl groups forming the dienes wereprepared from propargyl alcohols using gold(I)-catalysis.  These dienes were trapped as theirDiels-Alder adducts with several dienophiles including N-methylmaleimide and tetracyanoethylene. Herein we demonstrate the utility of a novel palladium-catalyzedspiroketalization in the total synthesis of the natural product acortatarin A,and report novel methods of preparing fused-ring heterocyclic systems employinga tandem gold-catalyzed cyclization / Diels-Alder methodology.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Nicholas V Borrero.
Thesis: Thesis (Ph.D.)--University of Florida, 2012.
Local: Adviser: Aponick, Aaron Steven.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2012
System ID: UFE0044863:00001

Permanent Link: http://ufdc.ufl.edu/UFE0044863/00001

Material Information

Title: I. Total Synthesis of Acortatarin a Using a Palladium-Catalyzed Spiroketalization Methodology II. Tandem Gold-Catalyzed Cyclization/Diels-Alder Reactions
Physical Description: 1 online resource (165 p.)
Language: english
Creator: Borrero, Nicholas V
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2012

Subjects

Subjects / Keywords: acortatarin -- alder -- diels -- gold -- palladium -- spiroketal
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Palladium and goldcomplexes have been shown to provide an efficient method for theformation of C-O and C-N bonds via activation of alkenes and alkynes towardsnucleophilic attack.  Ofparticular interest is the intramolecular cyclization of monoallylic andmonopropargylic diols to afford saturated and unsaturated heterocyclesrespectively.  The work presented in thisthesis is aimed at applying these methodologies to the total synthesis of abiologically active natural product, and expanding them to a mild synthesis ofdiene heterocycles for Diels-Alder reactions. Monoallylic keto-diols initially equilibrate to form ahemiketal between the non-allylic alcohol and carbonyl.  The newly formed hydroxy group has been shownto attack the double bond of the allylic alcohol forming anomeric spiroketalsunder transition metal catalysis.  Thiscyclization method was used to generate the spiroketal core of the naturalalkaloid acortatarin A.  The keyhemiketal intermediate was prepared in 15 total steps, and the cyclizationevent proceeded under palladium(II)-catalysis to deliver the desired spiroketalin high yield.  A concise end-gamestrategy successfully completed the natural product. The Diels-Alder reaction is a powerful C-C bond formingtechnique to effect the formation of unsaturated 6-membered rings from dienesand appropriate dienophiles. Monopropargylic diols cyclize under gold-catalyzedconditions to form cyclic dienol ethers, which may further react in thecapacity of dienes in the Diels-Alder reaction.  Likewise, the corresponding nitrogenheterocycles may be formed from substrates containing amine derivatives.  Systems comprised of 5- and 6-memberedunsaturated heterocycles with pendant vinyl groups forming the dienes wereprepared from propargyl alcohols using gold(I)-catalysis.  These dienes were trapped as theirDiels-Alder adducts with several dienophiles including N-methylmaleimide and tetracyanoethylene. Herein we demonstrate the utility of a novel palladium-catalyzedspiroketalization in the total synthesis of the natural product acortatarin A,and report novel methods of preparing fused-ring heterocyclic systems employinga tandem gold-catalyzed cyclization / Diels-Alder methodology.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Nicholas V Borrero.
Thesis: Thesis (Ph.D.)--University of Florida, 2012.
Local: Adviser: Aponick, Aaron Steven.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2012
System ID: UFE0044863:00001


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1 I. TOTAL SYNTHESIS OF ACORTATARIN A USING A PALLADIUM CATALYZED SPIROKETALIZATION METHODOLOGY II. TANDEM GOLD CATALYZED CYCLIZATION/DIELS ALDER REACTIONS By NICHOLAS V. BORRERO A DISSERTATION PRESENTED TO THE GRADUATE SCH OOL 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 Nicholas V. Borrero

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3 To my parents

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4 ACKNOWLEDGMENTS The graduate chemistry program at the University of Florida has been instrumental in my instruction as a student of science, as well as shaping my education and providing the tools necessary to accomplish my future goals and endeavors. First and foremost I would like to thank my advisor Dr. A aron Aponick for the direction and support he has granted me during my tenancy as a graduate student. The past five years under his guidance have been a period of significant growth in breadth of knowledge and insight due to inspiring discussions and the freedom to pursue avenues of particular interest to me. I would like to give sincere gratitude for his efforts to prepare me for my aspirations as a chemist. Additionally, I would like to thank the members of my supervisory committee for their continued su pport throughout my years at the University of Florida: Dr. Ronald Castellano, Dr. Lisa McElwee White, Dr. Benjamin Smith, Dr. Daniel Talham, and Dr. Zhonglin Mou. Science, by its very nature, benefits from collaborative efforts. I have had the opportuni ty to work in a research group with talented individuals in a type of collaborative capacity, despite its tendency to place emphasis on individual research. In particular I would like to thank Dr. Berenger Biannic for his seminal work on the gold catalyze d cyclization of monoallylic diols, which laid foundation for the tandem gold catalyzed cyclization / Diels Alder methodology discussed in this thesis. I thank Lais Barbosa, an undergraduate exchange student from the University of Campinas (Brazil) who ai ded me on this project, and allowed me the opportunity to mentor a student in a laboratory setting. I also acknowledge the work of Dr. Jean Palmes, who established

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5 the novel palladium catalyzed spiroketalization method I used in the construction of a nat ural alkaloid. Apart from the scientists with whom I have worked on related projects, I would like to thank the former and present group members for stimulating discussions, including John Ketcham, Flavio Cardoso, Paulo Paioti, Thomas Ghebreghiorgis, Barry Butler, Carl Ballesteros, Jeremy Malinge, Romain Miotto, Justin Goodwin and Lucas Beagle. I would like to thank Judit Kovacs for the support, motivation and encouragement she has given me during my last two years, as well as the engaging conversations an d time we have spent together. In closing, I would like to express genuine appreciation for my family, and their never ending faith in my ability to succeed.

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6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LIST OF FIGURES ................................ ................................ ................................ .......... 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 13 ABSTRACT ................................ ................................ ................................ ................... 18 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 20 1.1 General Considerations in Pd and Au Systems Towards Attack by Heteroatom Nucleophiles ................................ ...................... 20 1.2 Gold Catalyzed Dehydrative/Dealkoxylative Cyclization ................................ ... 23 1.3 Spiroketalization: Fundamentals and Classical Approaches ............................. 29 1.4 Examples of Gold and Palladium Catalyzed Spiroketalization in Total Synthesis ................................ ................................ ................................ ............. 32 1.5 Conclusion and Outlook ................................ ................................ .................... 35 2 TOTAL SYNTHESIS OF ACORTATARIN A ................................ ........................... 37 2.1 5 Hydroxymethyl 2 formylpyrrole Compounds in Nature and Medicine ............ 37 2.2 Reactive Oxyg en Species and their Role in Diabetic Neuropathy .................... 40 2.3 Proposed Biosynthesis of Acortatarin A and Related Spiroketals ..................... 41 2.4 Pr evious Syntheses ................................ ................................ .......................... 43 2.4.1 Sudhakar Synthesis ................................ ................................ ................. 43 2.4.2 Brimble Synthesis ................................ ................................ .................... 48 2.4.3 Tan Synthesis ................................ ................................ .......................... 51 2.5 Total Synthesis of Acortatarin A Using a Pd(II) Catalyzed Spiroketalization Strategy ................................ ................................ ................................ ............... 53 2. 5.1 Initial Considerations ................................ ................................ ............... 54 2.5.2 Initial Retrosynthetic Analysis ................................ ................................ .. 56 2.5.3 Stereochemical Considerations ................................ ............................... 57 hydroxy group ................................ .............. 57 2.5.3.2 Stereocenter 2: anomeric equilibration at the spiro carbon ............ 58 2.5.3.3 Ste reocenter 3: the spiroketalization step ................................ ...... 59 2.5.4 Forward Synthesis 1 ................................ ................................ ................ 61 2.5.5 Revised Retrosynthesis ................................ ................................ ........... 67 2.5.6 Forward Synthesis 2 ................................ ................................ ................ 68 2.5.7 Final Retrosynthesis and Forward Synthesis to Acortatarin A ................. 72 2.5.8 Electrochemical Studies of Acortatarin A by Cyclic Voltammetry ............ 80

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7 2.6 Outcome ................................ ................................ ................................ ........... 83 3 TANDEM GOLD CATALYZED CYCLIZA TION / DIELS ALDER REACTIONS ...... 84 3.1 Background and Significance ................................ ................................ ........... 84 3.1.1 Synthetic Routes to Diene Heterocycles for DA Reactions ..................... 84 3.1.2 DA reactions of Dienol Ethers: Applications to Total Synthesis .............. 89 3.1.3 Examples of Oxa and Azadecalin Containing Na tural Products ............. 93 3.2 Synthesis of the Diels Alder Adducts ................................ ................................ 93 3.2.1 General Considerations ................................ ................................ ........... 94 3.2.2 Initial Study and Optimization of Dienophile Scope ................................ 96 3.2.3 Synthesis of Nitrogen Analogues ................................ ............................ 98 3.2.4 Alkyne Scope ................................ ................................ .......................... 99 3.2.5 Failed Attempts at Expansion of Dienophile Scope ............................... 100 3.3 Outcome and Future Plans ................................ ................................ ............. 102 3.3.1 Indolocarbazole Natural Products ................................ ......................... 102 3.3.2 Staurosporine Background and Synthetic Plan ................................ ..... 103 4 CONCLUSION AND OUTLOOK ................................ ................................ ........... 105 5 EXPERIMENTAL SECTION ................................ ................................ ................. 107 5.1 General Remarks ................................ ................................ ............................ 107 5.2 Chemical Procedures ................................ ................................ ...................... 108 5.2.1 Synthesis of Acortatarin A and Precursors ................................ ............ 108 5.2.2 Synt hesis of Diels Alder Precursors ................................ ...................... 141 5.2.3 General Synthetic Procedure and Characterization for Diels Alder Adducts ................................ ................................ ................................ ....... 150 LIST OF R EFERENCES ................................ ................................ ............................. 156 BIOGRAPHICAL SKETCH .......................................................................................... 165

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8 LIST OF TABLES Table page 2 1 Optimization of metal catalyzed spiroketalization of monoallylic keto diols ........ 55 2 2 N alkylation of pyrrole Weinreb amides ................................ .............................. 63 2 3 Spiroketalizati on conditions ................................ ................................ ................ 77 3 1 ................................ ................................ .............. 87 3 2 Conditions and Initial Results for Au catalyzed cyclization / DA Reacti ons of Monopropargylic diol 3 71 ................................ ................................ .................. 97 3 3 Diene Scope ................................ ................................ ................................ ..... 100

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9 LIST OF FIGURES Figure page 1 1 Transition metal activation of unsaturated systems ................................ ............ 21 1 2 Palladium catalyzed hydroamination of alkynes ................................ ................. 22 1 3 Gold catalyz ed hydroamination of alkynes ................................ ......................... 22 1 4 Gold catalyzed hydroxylation of alkynes ................................ ............................ 23 1 5 Examples of THP containing natural products ................................ .................... 24 1 6 Au catalyzed cycloetherification of monoallylic diols ................................ .......... 24 1 7 Chirality transfer in Au catalyzed cycloetherification ................................ ........... 25 1 8 Proposed catalytic cycle ................................ ................................ ..................... 25 1 9 Au catalyzed spiroketalization of monoallylic triols ................................ ............. 26 1 10 Spiroketalization pathway A ................................ ................................ ............... 27 1 11 Spiroketalization pathway B ................................ ................................ ............... 27 1 12 Synthesis of furans, pyrro les and thiophenes from propargyl alcohols ............... 28 1 13 Representative spiroketal containing natural products ................................ ....... 29 1 14 Physical origin s of the anomeric effect and spiroketal conformations ................. 3 0 1 15 Acid catalyzed spiroketalization of keto diols ................................ ..................... 31 1 16 yclization of alkyne diols ................................ ................................ ... 31 1 17 ................................ ....... 33 1 18 ) us hikulide A spiroketal moiety ................................ .. 34 1 19 F ................................ ................... 35 2 1 5 Hydroxymethyl 2 formylpyrrole family p ortrait ................................ ................. 37 2 2 Proposed biosynthesis of pollenopyrrosides ................................ ...................... 42 2 3 Possible biosynthesis of acortatarin B ................................ ................................ 42 2 4 Proposed and revised structures for acortatarins A B ................................ ........ 44

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10 2 5 ................................ ................................ 44 2 6 Pyrrole fragment 2 20 synthesis ................................ ................................ ......... 45 2 7 Synthesis of epoxide fragments 2 18 and 2 19 ................................ .................. 46 2 8 p TsOH cataly zed spiroketalization and deprotection ................................ ........ 46 2 9 ................................ ................................ .... 48 2 10 ................................ ................................ 49 2 11 Synthesis of amino alcohol fragment 3 42 ................................ .......................... 50 2 12 Dihydropyranone fragment 2 43 synthesis ................................ ......................... 50 2 13 Maillard condensation of amine and dihydropyranone fragments ....................... 50 2 14 End game sequence of acortatarin A and epimer ................................ ............... 51 2 15 ................................ ................................ ...... 52 2 16 Synthesis of intermediate 2 58 ................................ ................................ .......... 52 2 17 A mercury mediated synthesis of acortatarin A ................................ .................. 53 2 18 Spiroketalization of monoallylic keto diols and catalysts employed .................... 55 2 19 Acortata rin A retrosynthesis 1 ................................ ................................ ............. 56 2 20 Use of a chira hydroxy stereocenter .............................. 58 2 21 Possible stereoisomers accessible from keto diol / hemiketal equilibration ........ 59 2 22 Initial predictions for metal catalyzed spiroketalization ................................ ....... 60 2 23 ORTEP X ray crystal structure of acortatarin A ................................ .................. 61 2 2 4 Routes to pyrrole Weinreb amide 2 67 ................................ ............................... 62 2 25 Formylation of 2 67 and conversion to 2 82 ................................ ....................... 62 2 26 Pyrrole alkylation, formylatio n, and protection ................................ .................... 64 2 27 Oxidative cleavage of N methallyl pyrroles ................................ ......................... 65 2 28 Synthesis of aldol reaction components ................................ ............................. 66 2 29 Failed attempts at aldol reactions ................................ ................................ ....... 66

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11 2 30 Revised Retrosynthesis ................................ ................................ ...................... 67 2 31 Attempted propargyl alcohol synthesis ................................ ............................... 68 2 32 Synthesis of alkynylating reagent ................................ ................................ ....... 69 2 33 Attempted formylation of pyrrole 2 100 ................................ ............................... 69 2 34 Propargyl alcohol 2 104 synthesis ................................ ................................ ...... 70 2 35 Attempts at alkyne hydrosilylation using the Trost protocol ................................ 71 2 36 Unsuccessful hydrosilylation to acyclic vinylsilane ................................ ............. 71 2 37 Final retrosynthesis ................................ ................................ ............................ 72 2 38 Preparation of starting materials ................................ ................................ ......... 73 2 39 Bromoketone fragment 2 120 synthesis ................................ ............................. 74 2 40 Unifying fragments an d chemoselective aldehyde reduction .............................. 75 2 41 Elaboration of 2 124 to acortatarin A ................................ ................................ .. 79 2 42 Elaboration of 2 125 to acortatarin A ................................ ................................ .. 80 2 43 Blank CV measurement ................................ ................................ ...................... 82 2 44 CV of 1,2 diphenylanthracene ................................ ................................ ............ 82 2 45 CV of acortatarin A ................................ ................................ ............................. 83 3 1 General strategies towards vinyl DHP substrates ................................ .............. 85 3 2 catalyzed alkylation of a llylic acetate 3 2 ................................ ........... 85 3 3 Synthesis of cyclic dienol ether sugar derivative 3 11 ................................ ........ 86 3 4 Pd(0) catalyzed allylation of ketene ace tal phosphate 3 18 ............................... 88 3 5 Hiyama type coupling of vinyl silane 3 20 and vinyl iodide 3 21 ......................... 88 3 6 Ene ynamide RCM and DA reaction s ................................ ................................ 89 3 7 ................................ ..................... 90 3 8 ................................ ................... 91 3 9 ................................ .............................. 92

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12 3 10 Examples of biologically significant heteroatomic decalins ................................ 93 3 11 Au catalyzed cyclization of monopropargylic triols ................................ ............. 94 3 12 Au catalyzed cyclization of monoprotected triols control experiments ............. 95 3 13 Probable allene intermediate in the synthesis of vinyl DHP 3 58 ........................ 95 3 14 Possible structures arising from the Au catalyzed cyclization / DA me thodology ................................ ................................ ................................ ....... 96 3 15 Synthesis of diol substrates ................................ ................................ ................ 96 3 16 General synthesis of tosylamine substrates ................................ ....................... 98 3 17 Synthesis of N Boc substrate 3 81 ................................ ................................ .... 99 3 18 ORTEP X ray structure of 3 83. ................................ ................................ .......... 99 3 19 Oxaz oborolidine catalyst assisted DA cycloaddition ................................ ......... 101 3 20 Attempted dienophile activation using organocatalysis ................................ .... 101 3 21 Represent ative ICZ natural products ................................ ................................ 103 3 22 Retrosynthetic plan for staurosporine aglycone ................................ ................ 104

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13 LIST OF ABBREVIATION S Ac Acetyl Anhyd Anhydrous Ar Aromatic Atm Atmosp here BBN Borabicyclo[3.3.1]nonane Bn Benzyl BSA N O Bis(trimethylsilyl)acetamide Bp Biphenyl BQ Benzoquinone Bz Benzoyl Calcd Calculated Cbz Benzyloxycarbonyl Cod 1,5 cyclooctadiene Cond Conditions Cp Cyclopentadienyl Cp* Pentamethylcyclopentadienyl CSA Ca mphorsulfonic acid Cy Cyclohexyl DCE Dichloroethane DCM Dichloromethane DEAD Diethylazodicarboxylate Decomp Decomposition DHP Dihydropyran DIAD Diisopropylazodicarboxylate

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14 DMA N N dimethylaniline DMAD Dimethyl acetylenedicarboxylate DMAP 4 dimethylaminopyr idine DMF Dimethylformamide DMP Dess Martin periodinane DMPU 1,3 Dimethyl 3,4,5,6 tetrahydro 2(1H) pyrimidinone dr Diastereomeric ratio E Electrophile ee Enantiomeric excess ESI Electrospray ionization Et Ethyl G2 Grubbs second generation catalyst GC Gas c hromatography h Hour/Hours n hex Normal/unbranched hexyl HMDS Hexamethyldisilazane HMPA Hexamethylphosphoramide HRMS High resolution mass spectroscopy IBX 2 Iodoxybenzoic acid ipc Isopinocampheyl i Pr I so propyl IR Infrared LA Lewis acid LAH Lithium alumi numhydride lit Literature

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15 M Metal Me Methyl min Minutes mol % Percent molar equivalents MS 4 Four ngstrom molecular sieves LDA Lithium diisopropylamide m CPBA meta chloroperoxybenzoic acid Ms Methanesulfonyl MTPA Methoxy(trifluoromethyl)phenylacetic acid NME N methylephedrine NMM N methylmaleimide NMO N methylmorpholine N oxide NMR Nuclear magnetic resonance NOE DIFF Nuclear Overhauser effect difference NPM N phenylmaleimide NR No reaction n pent Normal/unbranched pentyl Nu Nucleophile OTf Trifluoromethan esulfonate [O] Oxidation PCC Pyridinium chlorochromate PDC Pyridinium dichromate Piv Pivaloyl Ph Phenyl p TsOH para toluenesulfonic acid

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16 PMB para methoxybenzyl PPTS Pyridinium para toluenesulfonate psi Pounds per square inch PTAD 4 Phenyl 3H 1,2,4 triazole 3,5(4H) dione Pyr Pyridine R Group RCM Ring closing metathesis Red Al Sodium bis(2 methoxyethoxy)aluminumhydride Ref Reference R f Retention factor rxn Reaction Sat Saturated S N 2 Bimolecular nucleophilic substitution Std Standard TBAF Tetrabutylammonium fl uoride TBAI Tetrabutylammonium iodide TBDPS tert butyldiphenylsilyl TBS tert butyldimethylsilyl t Bu tert butyl t amyl 1,1 dimethylpropyl TCNE Tetracyanoethylene TEA Triethylamine temp Temperature TES Triethylsilyl TESH Triethylsilane

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17 Tf Trifluoromethane s ulfonyl THF Tetrahydrofuran THP Tetrahydropyran TLC Thin layer chromatography Tol Toluene TPAP Tetrapropylammonium perruthenate Tr Trityl Ts Tosyl vs Versus X Halogen

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18 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy I. TOTAL SYNTHESIS OF ACORTATARIN A USING A PALLADIUM CATALYZED SPIROKETALIZATION METHODOLOGY II. TANDEM GOLD CATALYZED CYCLIZATION/DIELS ALDER REACTIONS B y Nicholas V. Borrero December 2012 Chair: Aaron Aponick Major: Chemistry Palladium and gold complexes have been shown to provide an efficient method for the formation of C O and C N bonds via activation of alkenes and alkynes towards nucleophilic attac k. Of particular interest is the intramolecular cyclization of monoallylic and monopropargylic diols to afford saturated and unsaturated heterocycles respectively The work presented in this thesis is aimed at applying these methodologies to the total sy nthesis of a biologically active natural product, and expanding them to a mild synthesis of diene heterocycles for Diels Alder reactions. Monoallylic keto diols initially equilibrate to form a hemiketal between the non allylic alcohol and carbonyl. The ne wly formed hydroxy group has been shown to attack the double bond of the allylic alcohol forming anomeric spiroketals under transition metal catalysis This cyclization method was used to generate the spiroketal core of the natural alkaloid acortatarin A. The key hemiketal intermediate was prepared in 15 total steps, and the cyclization event proceeded under palladium(II) catalysis to deliver the desired spiroketal in high yield. A concise end game strategy successfully completed the natural product.

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19 The Diels Alder reaction is a powerful C C bond forming technique to effect the formation of unsaturated 6 membered rings from dienes and appropriate dienophiles. Monopropargylic diols cyclize under gold catalyzed conditions to form cyclic dienol ethers, whic h may further react in the capacity of dienes in the Diels Alder reaction. Likewise, the corresponding nitrogen heterocycles may be formed from substrates containing amine derivatives. Systems comprised of 5 and 6 membered unsaturated heterocycles with pendant vinyl groups forming the dienes were prepared from propargyl alcohols using gold(I) catalysis. These dienes were trapped as their Diels Alder adducts with several dienophiles including N methylmaleimide and tetracyanoethylene. Herein we demonstrat e the utility of a novel palladium catalyzed spiroketalization in the total sy nthesis of the natural product a cortatarin A and report novel method s of preparing fused ring heterocyclic systems employing a tandem gold catalyzed cyclization / Diels Alder me thodology

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20 CHAPTER 1 INTRODUCTION 1.1 General Cons iderations in Pd and Au Systems Towards Attack by Heteroatom Nucleophiles Nucleophilic addition of heteroatoms to transition metal activated double and triple bonds is well known and documented in the scientific literature. 1 a Me tal complexes acids to activate both unreactive and electron rich alkenes, alkynes, and allenes. Early examples of these reactions include the Wacker oxidation 1 b and the metal catalyzed hydroboration of olefins. 1 c Since the 1960s and 1970s, the most commonly employed catalysts for these processes are palladium(II) salts in the form of organic soluble (homogenous) co mplexes such as Pd(MeCN) 2 Cl 2 Pd(OAc) 2 and ( PPh 3 ) 2 PdCl 2 2 Pd(II) species form complexes readily and reversibly to alkenes, with terminal alkenes being the most strongly ligated, followed by internal olefins. gem Disubstituted olefins are the next most st rongly bound; tri and tetrasubstituted alkenes form only weak complexes, if ligation occurs at all. 1 a Alkynes are also complexed by metal salts in a similar manner. 1 a In contrast to this well kno wn palladium chemistry, the earliest examples of related reactions catalyzed by gold complexes were reported in the late 1980s. 3 Moreover, the field of gold catalyzed organic reactions has enjoyed significant attention only in the past two decades due to t he advent of phosphine and carbene ligated gold complexes. 4 system, the substrate and in some cases metal center itself, is activated towards nucleophilic attack. The addition occurs primarily at the m ore substituted carbon, or at the carbon more capable of stabilizing a positive charge. Attack can occur from the opposite face of the metal

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21 ( trans addition) or from the same face ( syn addition) to form the new heteroatom carbon and metal carbon bonds (Fi gure 1 alkylmetal complex allyl palladium complexes formed by activation of an allyl compound with a Pd(II) salt in the presence of a reducing agent, the ste ric environment plays a significant role in regioselectivity of nucleophilic addition. Usually, the less sterically encumbered allyl terminus is attacked by the nucleophile. 1 a This mode of activation is operative in the well known Tsuji Trost allylation. 1 d Figure 1 1. Transition metal activation of unsaturated systems In 2002, Yamamoto et al showed a representative example of nucleophilic addition of a heteroatom to an unsaturated system using palladium catalysis. 5 In this instance, alkyne 1 1 undergoes an intermolecular hydroamination reaction with o aminophenol 1 2 to produce enamine 1 3 Hydrolysis of the enamine produces regioisomeric ketones 1 4 and 1 5 (Figure 1 2). Use of this particula r amine substrate greatly enhances the reaction rate for addition to internal alkynes, which tend to be inefficient when using palladium complexes.

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22 Figure 1 2. Palladium catalyzed hydroamination of alkynes Similarly, gold catalysts, in particular cation ic complexes such as [( o biphenyl) t Bu 2 ]PAuOTf, and PPh 3 AuOTf, prepared by ligand exchange between gold chloride salts complexes with the C bonds. In these complexes, the electron density from C C double and tripl e bonds is donated into an empty metal d orbital. The metal donates electrons back from a different filled d orbital into the empty C antibonding orbital according to the Dewar Chatt Duncanson model. 6 Cationic gold complexes are renowned for their abi lity to efficiently activate unsaturated C C bonds, especially alkynes. In 1987, Utimoto et al 3 7 studied the gold catalyzed intramolecular hydroamination of alkynes (Figure 1 3). Under mild conditions using a Au(III) salt, amine 1 6 is efficiently added intramolecularly across a triple bond to form enamine intermediate 1 7 which rapidly tautomerized to the more thermodynamically stable endocyclic imine 1 8 Figure 1 3. Gold catalyzed hydroamination of alkynes

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23 The ability of gold catalysts to effect alcohol additions has also been demonstrated. In 2000, Hashmi et al 8 reported the gold catalyzed cycloetherification of ( Z ) ethynylallylic alcohols 1 9 to form furans 1 11 via intermediate 1 10 which gains aromaticity through tautomerization. This reaction proceeds at very low catalyst loadings with both Au(I) and Au(III) precatalysts in different solvents such as THF, DCM and acetonitrile (Figure 1 4). Figure 1 4. Gold catalyzed hydroxylation of alkynes Pioneering efforts i n the field of transition metal activation have paved the way for enormous advances in the field. Organic reactions involving gold in particular has become a highly active field. The majority of focus is on alkyne activation, with olefinic substrates c ontinually bridging the gap. 1.2 Gold Catalyzed Dehydrative/Dealkoxylative Cyclization One of the primary focuses of our research group in recent years has been Au catalyzed dehydrative cyclization of monoallylic diols and monopropargylic triols to form vi nyl tetrahydropyrans and mono unsaturated spiroketals respectively. Studies aimed at the formation of saturated oxygen heterocycles gained our attention due to their ubiquity as structural motifs in natural products (Figure 1 5). 9 10 11 The development of a synthetic strategy relying on homogenous gold catalysis seemed advantageous because of the functional group tolerance, high turnover numbers, and high reactivity associated with gold complexes when applied to olefin activation. 12

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24 Figure 1 5. Examples o f THP containing natural products In 2008, Aponick et al 13 published preliminary results in this area, which began with the treatment of simple monoallylic diols 1 15 with Ph 3 PAuCl / AgOTf under the conditions shown below (Figure 1 6). Under these circums tances, 2,6 disubstituted tetrahydropyrans 1 16 were generated with low catalyst loadings and fast reaction times. The reaction products also exhibited high diastereoselectivity (up to >25:1) for the cis products. Figure 1 6. Au catalyzed cycloetherifi cation of monoallylic diols Mechanistically, the pendant alcohol attacks the gold activated double bond to eject H 2 O in a stepwise formal S N Disconnection of the gold complex from the substrate via elimination furnishes the final product, containing an exo vinyl group. Later, it was reported that cyclization of non racemic allylic alcohols 1 17 and 1 19 results in a transfer of chirality to the newly formed stereocenter in 1 18 and 1 20 respectively (Figure 1 7). 14 It is also interesting to note that substrates that undergo this

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25 type of chirality transfer do so despite bias from other stereocenters in the molecule. The olefin geometry in combination with the absolute stereochemistry of the allylic alcohol override these effects. The observ ed stereochemical outcome of the cyclization can be explained by either a syn addition / syn elimination or an anti addition / anti elimination process. Both pathways eventually lead to the same stereochemistry in the Figure 1 7. Chirality transfer in A u catalyzed cycloetherification Figure 1 8. Proposed catalytic cycle

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26 product, however, the latter process is preferred due to anti attack of a nucleophile on a complex being the typical mode of action in gold catalysis. 15 A probable catalytic cycle is shown in Figure 1 8. 14 In 2009, Aponick reported an extremely facile synthesis of unsaturated spir oketals 1 28 from monopropargylic triols 1 27 utilizing similar conditions (Figure 1 9). 16 Also a commonly noted core structure in natural products, it was hypothesized that spiroketal construction would take place by forming a C O bond between the pendant alcohol and the sp carbon distal to the propargyl hydroxy group to form an allene intermediate concurrent with a loss of water. The remaining hydroxy group should attack the allene, followed by elimination of the gold complex to generate the monounsaturat ed vinyl spiroketal. After having established the optimized reaction conditions, the substrate scope was explored, and the results indicate that the reaction performs well for a variety of differently substituted spiroketalization precursors. Figure 1 9. Au catalyzed spiroketalization of monoallylic triols Two tentative mechanistic pathways are proposed for the course of this reaction depending on which pendant alcohol cyclizes first. For an allene intermediate 1 32 to be involved, the C9 alcohol of 1 30 would attack initially, followed by nucleophilic attack by the C1 hydroxy group and loss of water (Figure 1 10). 16 In the case that C1 alcohol should attack first, loss of water forms oxocarbenium ion 1 37 which undergoes subsequent attack of the C9 alcohol (Figure 1 11). 16 Control experiments do not entirely

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27 rule out either possible mechanism, and data suggests that the reaction may operate by either pathway A or B. Figure 1 10. Spiroketali zation pathway A Figure 1 11. Spiroketalization pathway B

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28 In the same year, the synthesis of 5 membered ring heterocycles via dehydrative cyclization of propargyl alcohols was reported. 17 According to the preceding studies, two tentative mechanisms for spiroketalization were proposed, with neither pathway clearly prevailing over the other. Based on this assumption, the idea that unsaturated 5 membered rings could be created via endo cyclization of a propargyl alcohol 1 40 containing a pendant amine, thi ol, or alcohol to produce pyrroles, thiophenes, or furans respectively was explored. Remarkably, it was possible to synthesize these heteroaromatics 1 41 in high yields using mild conditions, with very fast reaction times and extremely low catalyst loadin gs (Figure 1 12). Figure 1 12. Synthesis of furans, pyrroles and thiophenes from propargyl alcohols More recently, in 2011, research conducted in our group demonstrated that leaving groups other than alcohols can be employed, 18 with ethers exhibiting sim ilar reaction times and percent conversion of starting materials to their hydroxyl group counterparts. Methyl and benzyl ethers have a similar reactivity profile to hydroxyl groups during Au catalyzed cyclization of allylic manifolds. Reactions involving silyl and tetrahydropyranyl ethers tend to be more sluggish, or do not go to completion. The progress made involving Au activation and cyclization of unsaturated alcohols and ethers sets the stage for significant expansion and application of the methodo logies presented here.

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29 1.3 Spiroketalization: Fundamentals and Classical Approaches The vast occurrence of spiroketals in natural products (Figure 1 13) 19 20 21 22 from sources such as fungi, marine organisms, insects, and plants portrays them as appealing tar gets for the development of new methodologies for their construction. 23 Spiroketals with [5,5], [5,6], [6,6] and [6,7] ring systems are commonly found in nature, and as such, have found themselves the center of attention for many research programs. 19 20 21 22 Figure 1 13. Representative spiroketal containing natural products Aside from ring size, conformational aspects are prerequisite to the description of spiroketal architectures. The stereochemistry of the spiro carbon is primarily influenced by the anomeric effect. 24 On the other hand, intramolecular interactions due to steric

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30 demands or hydrogen bonding are known to play a role as w ell. The anomeric effect is a stereoelectronic phenomenon observed in ring systems containing heteroatoms, which describes the tendency for an electronegative substituent geminal to the heteroatom within the ring to adopt an axial orientation. Several ph ysical origins for the anomeric effect have been proposed, 25 the simplest being that the partially aligned dipoles of the heteroatoms in the equatorial orientation oppose each other, whereas dipoles in the axial orientation interfere destructively, reducing the net dipole moment (Figure 1 14). Figure 1 14. Physical origins of the anomeric effect and spiroketal conformations A more widely accepted explanation is that hyperconjugation between a lone pair of the axial C heteroatom bond lowers the overall energy of the structure. In terms of spiroketals, the effects are compounded by more than one possible anomeric effect. 24 In the interest of avoiding confusion, doubly anomeri

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31 The most often exploited strategy for the preparation of spiroketals ( 1 47 ) utilizes an acid promoted cyclodehydration of keto di ols ( 1 46 ) (Figure 1 15). In the event, thermodynamic equilibrium is governed by the anomeric effect, and the product is driven towards the more energetically conservative anomeric spiroketal. 26 This stereochemical preference is auspicious in the sense that naturally occurring spiroketals are most often anomeric, but suffers drawbacks if acid labile groups are present in the substrate or the target molecule is indeed nonanomeric. Preparation of nonanomeric spiroketals has not been as widely explored, perhap s due to a combination of their scarcity in nature, and challenging synthesis. 23 b However, tactics for their syntheses have been developed with varying degrees of success. 27 Figure 1 15. Acid catalyzed spiroketalization of ke to diols In addition to the traditional acid promoted spiroketalization strategy, metal catalysts are known to produce spiroketals from acetylenic substrates. Alkynes are long known to undergo metal catalyzed hydration rendering them useful as ketone surr ogates. 28 Not surprisingly, alkyne diols may serve as keto diol equivalents, and their utility as such is revealed during metal catalyzed alkyne dihydroxylation reactions. Pioneering efforts by Utimoto 29 in 1983 demonstrated that Figure 1 yclization of alkyne diols

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32 Pd(II) catalyzed alkyne hydroalkoxylation of 1 48 effectively produced spiroketals 1 49 (Figure 1 16). Similar work and improvements have been accomplished by DeBrabander using Pt(II), Pd(II), Au(III) catalysis. 30 In a complement ary aspect, Messerle utilized alkyne diols as spiroketal precursors arising from reactions under dual Ir(I) and Rh(I) catalysis. 31 Additionally, Deslongchamps explored spiroketal synthesis from alkyne diols as well as monopropargylic triols with Hg(II) sal ts. 32 Seminal work by these chemists has allowed this type of spiroketalization strategy to be applied to complex molecule synthesis, of particular interest to this thesis, the total syntheses of bioactive natural products 1.4 Examples of Gold and Palladiu m Catalyzed Spiroketalization in Total Synthesis Numerous instances of metal catalyzed spiroketalization in total synthesis can be found in the chemical literature. 26 27 33 This section, however, w ill be restricted to several selected examples of gold and palladium dependent methodologies. The bisspiroketal containing natural product azaspiracid 1 is a marine toxin isolated from Irish blue mussels ( Mytilus edulis ) responsible for a toxic syndrome first reported in the Netherlands in 1995. 34 The true structure of this intriguing molecule was degradation studies and the synthesis of multiple diastereomers. 35 In 2 007, the Forsyth group reported the synthesis of the ABCD ring system using Au(I) catalyzed spiroketalization as their key step (Figure 1 17). 36 In their case, the ABCD domain precursor was subjected to a variety of metal salts, with AuCl and PPTS giving t he best results after careful screening.

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33 Figure 1 The process is envisioned to proceed through a syn addition of the hydroxyl group across the Au system 1 51 to form enol ether ring A 1 52 Protodeauration liberates the catalyst, and protonation at the distal enol carbon enables subsequent attack by the nearby methoxy oxygen of 1 53 Methyl transfer from 1 54 to a solvent molecule then neutralizes the resulting oxonium species to furnish trioxadispiroketal rings A D 1 55 In 2009, Trost et al published the total synthesis of ( ) ushikulide A, a previously stereochemically undefined member of the oligomycin rutamycin family. 37 In one of the key steps of the synthesis, a spiroketa l is formed through a hydroxyl group attack in a 6 endo dig pathway (Figure 1 18). Prior coordination of the hydroxy group to the metal cation is followed by a syn addition across the alkyne 1 57 work, 16 the benzoyl functional group would be expected to eliminate to form an allene.

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34 Figure 1 ) ushikulide A spiroketal moiety This is a thermodynamically more favorable process than alcohol or alkoxide elimination, however, counterintuitively, it does not take place. This observation can be rationalized by the formation of a 6 membered chelate 1 58 which diminishes the propensity towards elimination of the benzoyl group. In the following step, protodeauration and protonati on of the enol ether results in oxocarbenium ion 1 59 which undergoes ring closure with the pendant alcohol to form spiroketal 1 60 In 2009, Ramana and co workers developed a concise assembly of the [5,5] spiroketal cores of cephalosporolides E 1 66 and F 1 67 using a Pd(II) catalyzed cycloisomerization of alkyne diol 1 61 38 The relationship between the two cephalosporolides is epimeric at the spiro carbon, and since the cyclization reaction produces a 1:1 inseparable mixture of anomers, which can be resol ved after several subsequent steps, allowing access to both natural products. The key spiroketalization activation of the alkyne 1 61 to form complex 1 62 Next, a 5 exo dig mode of cyclization affords vinylpalladium intermediate 1 63 w hich undergoes

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35 protodepalladation to form the oxonium species 1 64 (Figure 1 19). Attack by the free alcohol and subsequent deprotonation yields spiro intermediates 1 65 The lack of diastereoselectivity observed here suggests rapid equilibration due to conformational flexibility in [5,5] systems. Figure 1 F 1.5 Conclusion and Outlook It has been demonstrated that Au(I) salts can effectively catalyze the dehydrative and dealkoxylative cyclization of unsatura ted alcohols. The work that has been accomplished in this field allows for expansion of the methodologies and their applications. Approaches to the metal catalyzed spiroketalization of propargylic alcohols is also a field that has enjoyed significant at tention over the past decades, and has found its place as a powerful means for the generation of spiro architectures in complex natural products.

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36 The following chapters of this document will describe in detail a synthetic application of a novel Pd catalyze d spiroketalization method, and the expansion of the Au catalyzed dehydrative cyclization technique as well as its utility in natural product synthesis.

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3 7 CHAPTER 2 TOTAL SYNTHESIS OF A CORTATARIN A 2.1 5 Hydroxymethyl 2 formylpyrrole Compounds in Nature and Medicine The 5 hydroxymethyl 2 formylpyrrole moiety is unique and uncommon in natural products. This small family of structurally related molecules is comprised of a handful of molecules including funebral, 39 magnolamide, 40 and the recently discovered poll enopyrrosides A B 41 and acortatarins A B 42 (Figure 2 1). The natural sources of these compounds have long found use in traditional medicine to treat a variety of ailments. 41 42 Figure 2 1. 5 Hydr oxymethyl 2 formylpyrrole family portrait Funebral 2 3 was first isolated from the potently aromatic flowers born of the Quarariebea funebris (Llave) Vischer (Bombacaceae), a large tree native to southeastern Mexico and Guatemala, owing its name to the fun eral rites performed under its branches by the Zapotec people of Oaxaca, Mexico. 43 The flower found traditional use as a flavoring agent for chocolate drinks, dating from pre Columbian

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38 times. In modern day folk medicine, it earns its place as an antitussi ve, antipyretic, and a treatment for menstrual disorders. Additionally, its biological profile extends further, towards the psychotropic. 44 Magnolamide 2 4 an alkaloid from the leaves of the Magnolia coco was isolated, along with eleven known compound s, in 1998 by Shieh and co workers. 45 The leaves, stems, and bark of the Magnolia plant are used as an herbal remedy for liver impairment and cancer in Chinese medicine. 46 The chemical constituents of the plant also include aporphine alkaloids. Although th e bioactivity of magnolamide has not been specifically investigated or determined, the Magnolia genus in general has historically found use in both Chinese and Japanese medicine. 46 Known bioactive constituents of the plant mat erial include the polyphenolic compounds honiokol and magnolol, both of which demonstrate anti anxiety, and anti angiogenic properties. 47 Furthermore, the aromatic bark has demonstrated an ability to reduce allergic and asthmatic reactions, 48 as well as pro tect against death of neuronal cells in vitro 49 The first total synthesis of this compound was reported in 2002 by Dong, in which a titanium isopropoxide mediated Paal Knorr synthesis was employed as the key step constructing the pyrrole core. 50 In 2010, t wo separate research groups simultaneously and independently isolated the spiroalkaloids acortatarin A 42 (Hou and Cheng) and pollenopyrroside B 41 (Zhang) from the rhizome of the Acorus tatarinowii Schott, and bee collected Brassica campestris pollen respectively. In the original isolation papers, the relationship between proposed structures of acortatarin A and pollenopyrroside B is enantiomeric. However, a total synthesis and stereochemical revi sion of acortatarin A by Sudhakar et al

PAGE 39

39 revealed the absolute stereochemistry by drawing starting materials from the chiral pool. 51 the identical relationship between acortatari n A and pollenopyrroside B. In addition to these same compounds, which will be termed solely as acortatarin A forthwith to avoid redundancy, two additional compounds were isolated, one from each source. The roots of the Acorus tatarinowii known as the c alamus of the orient, also contained a more highly oxidized derivative of acortatarin A 2 1 named acortatarin B 2 2 Interestingly, the bee collected pollen also contained pollenopyrroside A 2 5 which is a ring expanded analogue of acortatarin A 2 1 Bo th the plant material and the pollen have found use in Chinese medicine. The Acorus tatarinowii rhizome is known for treating central nervous system (CNS) disorders, 52 while the Brassica campestris pollen is used in China as a healthy food and herbal medic ine. The pollen has been found to possess antioxidant 53 and antitumor 54 properties. Moreover, it has application to regulation of serum lipids 55 and treatment of prostatitis. 56 After isolating acortatarins A and B by extensive chromatographic means, the two compounds were assayed by Hou, Cheng, and co workers for their ability to inhibit reactive oxygen species (ROS) induced by high glucose stimulated renal mesangial cells. ROS is believed to be a significant contributor to the pathogenesis of diabetic neuro pathy (DN), a major complication of diabetes. 57 Acortatarin A, and to a lesser extent, acortatarin B were shown to significantly reduce high glucose induced ROS production in renal cells. 42 It is worthy to note as well that the pyrrole fused spiroketal core of the molecule essentially forms a morpholine substructure, a common pharmacophore structural motif

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40 present in many enzyme inhibitors. Some examples of these inhibitors include phosphoinositide 3 kinases, 58 and tumor necrosi s factor inhibitors. 59 2.2 Reactive Oxygen Species and their Role in Diabetic Neuropathy ROS are highly reactive oxygen containing molecules generated as by products of cellular metabolism. 60 Their reactivity stems from the presence of unpaired electrons in tasks such as cell signaling and homeostasis, ROS may contribute to damaging effects to the cells of an organism. 60 During periods of enviro nmental stress such as high temperatures or UV exposure, a dramatic increase in the levels of ROS can be observed which can lead to the destruction of cellular structures. 61 When mitochondrial production of ROS exceeds the antioxidant capacity of a cell, a state of oxidative stress ensues. 61 Cells deal with oxidative stress using enzymes such as superoxide dismutase 62 and glutathione peroxidase 63 as intracellular antioxidants. Small molecule nutrients such as vitamin C (ascorbic acid), 64 vitamin E (tocopherol), 65 and glutathione 66 also serve the same purpose in cell defense against ROS. In addition to ROS induced oxidative stress being implicated in a large number of human diseases, evidence suggesting that ROS may play a role in dia betic neuropathy continues to grow. 57 a Among the medical community, there appears to be an agreement that there is an increase of ROS in diabetics. 57 b Several clinical studies show that the number of ROS markers in the kidneys of patients with type 1 and type 2 diabetes are elevated as compared to those of healthy, age matched subjects. 57 Diabetic neuropathies, collectively, are nerve disorders that result from micr ovascular injuries involving small blood vessels that supply nerve cells. 67 ROS in

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41 diabetes resulting from hyperglycemia is believed to be a key contributor to the development and progression of DN. 57 Various cell types includ ing endothelial, tubular epithelial, and mesangial (renal) cells are capable of producing ROS in a high glucose stimulated environment. In addition to being able to oxidize DNA, proteins, lipids, and carbohydrates, ROS can act as signaling molecules, to a ctivate stress sensitive pathways within the cell resulting in damage. 68 Inflammatory genes such as protein kinase C and t ransforming growth factor complications of diabetes, are activated by ROS. 69 Furthermore, these genes themselves signal through ROS, invoking its activity as a signal amplifier. At this point, clinical and e xperimental evidence suggests that high glucose induced ROS in vascular cells plays a significant role in DN. Strategies that could be effective in reversing the effects of ROS overproduction may include preventing their formation through gene inhibition, or removal of ROS with antioxidant therapy. 57 2.3 Proposed Biosynthesis of Acortatarin A and Related Spiroketals Zhang and co workers proposed a possible biosynthetic pathway to acortatarin A 2 1 and its ring expanded analog ue pollenopyrroside A 2 5 in the same publication describing the isolation of these two compounds. 41 Both molecules were envisioned to originate from a condensation reaction between 5 hydroxymethyl 2 formylpyrrole 2 6 and 3 de oxy D fructose 2 7 (Figure 2 2). However, no natural sources of this D sugar are known, and only a small number of reports for its synthesis have been published. 70 Regardless, from a biosynthetic standpoint, acortatarin A and pollenopyrroside A may arise from a series of reactions between the pyrrole and sugar.

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42 On the other hand, acortatarin B can be imagined to arise from the same series of reactions starting from D fructose 2 10 (Figure 2 anomer and pyrrole 2 6 would account for the stereochemistry observed in the natural product. Figure 2 2. Proposed biosynthesis of pollenopyrrosides Figure 2 3. Possible biosynthesis of acortatarin B

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43 Alternatively, it could be proposed that acortatarin A is derived from acortatarin B th rough a deoxygenation pathway. 2.4 Previous Syntheses As mentioned before, acortatarin A 2 1 has been identified and isolated from two unrelated sources. From 15 kg of the bee collected B. campestris pollen, 5 mg of the natural product was obtained by Zha ng et al Likewise, from 50 kg of the air dried powders of the A. tatarinowii 7.3 mg of the product was found. Both methods, of course, required extensive extraction and chromatographic protocols. Considering the bioactivity of this compound, and its m inute concentrations in natural media, acortatarin A makes an attractive target for the synthetic organic chemist. To date, three total syntheses 51 71 72 of acortatarin A have been completed aside from the synthesis described h erein. The goal of each was to produce an amount of the natural product for further biological testing and to develop a practical synthesis of acortatarin A as a template for drug discovery. 2.4.1 Sudhakar Synthesis During the course of our work in 2011, Sudhakar and co workers report the first total synthesis of acortatarin A 2 1 along with its hydroxy analogue acortatarin B 2 2 and the enantiomer of acortatarin B. 51 In their efforts to synthesize the enantiomers of the acor tatarin natural products from readily available D sugars, it was revealed that the originally proposed structures from the isolation article were incorrect. Beginning the synthesis of acortatarins A and B from 2 deoxy D ribose 2 16 (Figure 2 5) and D arab inose 2 34 (Figure 2 9) respectively resulted in end products with identical NMR spectra and optical rotations with similar magnitudes and the same signs as those reported by Cheng, Hou et al 42 Additionally, a diastereomer of acortatarin B was

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44 prepared from D ribose 2 17 With all stereocenters of the ring substituents available from the chiral pool, the misassigned stereochemistry of the acortatarins was proven and revised (Figure 2 4). Figure 2 4. Proposed and revised s tructures for acortatarins A B the acid promoted deprotection and spiroketalization of ketone intermediates 2 14 and Figure 2

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45 2 15 which should come from N alkylation of common precursor 2 20 with epoxides 2 18 and 2 19 respectively. Precursor 2 20 is prepared from pyrrole 2 21 and epoxides 2 18 and 2 19 are generated from their respective D sugars 2 deoxy D ribose 2 16 and D ribose 2 17 (Figure 2 5). The synthesis began with efforts towards the 2,5 disubstituted pyrrole fragment 2 20 The bis (hydroxymethyl)pyrrole was prepared by reacting pyrrole with formalin in an 73 (Figur e 2 6). Figure 2 6. Pyrrole fragment 2 20 synthesis Oxidation of pyrrole 2 22 with activated MnO 2 afforded mono and dialdehydes 2 6 and 2 23. Dialdehyde 2 23 was recycled via reduction with one hydride equivalent to monoaldehyde 2 6 Protection of the resulting alcohol as the THP ether completed the pyrrole fragment 2 20 The synthesis of protected epoxide fragments 2 18 and 2 19 started from the known benzylated D sugars 2 24 and 2 25 which were prepared in 3 steps following a reported procedure. 74 Lac tols 2 24 and 2 25 were subjected to Wittig reactions with methylenetriphenylphosphonium bromide to give terminal alkenes 2 26 and 2 27 Hydroxyl group protection with TBSOTf and alkene epoxidation with m CPBA yielded epoxide fragments 2 18 and 2 19 (Figu re 2 7).

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46 Figure 2 7. Synthesis of epoxide fragments 2 18 and 2 19 Treatment of pyrrole 2 20 with NaH in DMF followed by addition of the epoxide gave the best results, providing secondary alcohols (Figure 2 8), which after Dess Martin oxidation generated the spiroketalization precursors 2 30 and 2 31 Treatment of these substrates with acid ( p TsOH) deprotected the TBS and THP ethers to unmask Figure 2 8. p TsOH catalyzed spiroketalization and deprotection

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47 the ketodiol, as well as effected the spiroketa lization to produce a mixture of anomers in the ratio of 1.4:1 in the case of 2 32 and 1:1.3 for 2 33 The simultaneous deprotection / spiroketalization reaction gave the anomeric mixtures in 75% combined yield for 2 32 and 70% combined yield for 2 33 The final step in the synthesis was benzyl group deprotection, which under conventional hydrogenolysis over Pd/C, resulted in no reaction or complex mixtures at higher catalyst loadings. Deprotection using 1M TiCl 4 in DCM of each anomer of 2 32 separat ely gave, interestingly, anomeric mixtures of 2 1 again in the ratio of 9:1 in 80% combined yield for both cases. The 1 H and 13 C NMR spectra showed that the major product represented the natural product acortatarin A. The specific rotation of the compou 27 D +191.4 ( c 0.27, MeOH), had the same sign and similar magnitude to 27 D +178.4 ( c 0.4, MeOH). It was at this point, since the synthesis was designed for the enantiomer of the proposed structure, that the original ly proposed stereochemistry was revealed to be incorrect. Comparison of NMR spectra of MTPA esters prepared from 2 1 confirmed that the compound synthesized was indeed acortatarin A, and the absolute configuration of acortatarin A was revised. Similarly, anomeric mixture 2 33 was subjected to the same debenzylation reaction to yield 2 13 Unfortunately, the spectral data for these synthesized compounds did not match the reported NMR data for acortata rin B, which indicated this structure was misassigned as well. The correct stereochemistry for acortatarin B was obtained using D ( ) arabinose 2 34 as the chiral starting material, and the synthesis was completed in a similar manner as outlined below (Fig ure 2 9).

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48 Figure 2 2.4.2 Brimble Synthesis In 2012, the Brimble group developed a second synthesis of acortatarin A using a Maillard type condensation of a D mannitol derived amine 2 42 with a dihydropyranone 2 43 as the key step. 71 Retrosynthetically, the natural product should be accessed by an acid catalyzed deprotection / cyclization sequence of compound 2 41 followed by silyl group deprotection (Figure 2 10). Amino alcohol 2 42 res ults from diastereoselective allylation of the glyceraldehyde derivative 2 44 and carbohydrate surrogate 2 43 is prepared from an Achmatowicz ring expansion of protected furfuryl alcohol 2 45 to form the Maillard reaction components. This approach was ta ken due to the difficulty with N alkylation of 2 formylpyrrole compounds. 75

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49 Figure 2 The synthesis commences with building amino alcohol 2 42 starting from the D mannitol derived glyceraldehyde equivalent 2 44 (F igure 2 11). Allylation with allyl bromide in the presence of Zn dust afforded homoallylic alcohol 2 46 in good yield with excellent diastereoselectivity. The reaction was found to proceed better with the cyclohexylidene protecting group rather than the more commonly used acetonide, and proved more convenient for multi gram scale preparation. Hydrolysis of the ketal with methanolic HCl, and subsequent protection of the primary hydroxyl group as the TBDPS ether afforded 2 47 in 2 steps. The isopropyliden e functionality was installed by treatment of the diol 2 47 with dimethoxypropane under acidic conditions, and the terminal olefin was epoxidized with m CPBA to generate epoxide 2 48 Epoxide ring opening with sodium azide followed by the Staudinger proto col ended the synthesis of amine fragment 2 42

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50 Figure 2 11. Synthesis of amino alcohol fragment 3 42 The next segment of the synthesis was aimed at the construction of the dihydropyranone fragment. Here, furfuryl alcohol TBS ether 2 49 was lithiated th en formylated with DMF, and the resulting aldehyde was reduced by sodium borohydride to generate monoprotected diol 2 45 (Figure 2 12). Achmatowicz oxidation rearrangement using m CPBA delivered 2 43 posed for coupling with amine fragment 2 42 Figure 2 12. Dihydropyranone fragment 2 43 synthesis The Maillard coupling between fragments 2 42 and 2 43 was performed using the optimized conditions shown below (Figure 2 13). A two fold excess of amine to dihydropyranone in the presence of 3 equivalents of T EA in anhydrous 1,4 dioxane Figure 2 13. Maillard condensation of amine and dihydropyranone fragments

PAGE 51

51 gave the desired pyrrole 2 50 After exploring a handful of oxidants (PCC, PDC, IBX, DMP), Ley oxidation with TPAP and NMO cleanly oxidized 2 50 to k etone 2 41 Mild acid (PPTS, CSA, dilute HCl) cleaved the TBS ether of 2 41 but left the acetonide intact. More strongly acidic conditions (4N HCl) succeeded in removing all but the TBDPS protecting group, as well as forming the required spiroketal 2 51 in good yield as a 3:2 anomeric mixture. The final step involved deprotection of the remaining silyl ether with TBAF, to yield acortatarin A 2 1 and epi acortatarin A 2 52 which were separated at this stage by careful column chromatography (Figure 2 14). Figure 2 14. End game sequence of acortatarin A and epimer 2.4.3 Tan Synthesis In the same year, Tan and coworkers developed a third synthesis of acortatarin A, relying on a mercury(II) mediated stereoselective glycal cyclization. 72 According to the retrosynthesis, key intermediate 2 58 was accessed by alkylation of pyrrole dicarboxaldheyde 2 23 with ribal derivative 2 57 Compound 2 57 in turn was obtained in several steps from D thymidine 2 53 (Figure 2 15).

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52 Figure 2 15 thymidine 2 53 as the corresponding TIPS ethers to generate compound 2 54 which underwent nucleobase elimination to furnish diprotected ribal 2 55 Lit hiation of this intermediate with t BuLi, then formylation with DMF followed by reduction of the resulting aldehyde Figure 2 16. Synthesis of intermediate 2 58

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53 formed the hydroxymethyl derivative 2 56 which was then converted to iodide 2 57 Alkylati on of pyrrole 2 23 with iodide 2 57 completed key intermediate 2 58 The end game sequence commenced with by monoreduction of dialdehyde 2 58 with sodium borohydride to form cyclization precursor 2 59 Oxidative cyclization conditions with Hg(OAc) 2 led to an anomeric mixture mercurial spiroketals which were then demurcurated with sodium borohydride to give TIPS protected acortatarin A and its epimer at the spiro carbon. Cleavage of the Si O bond with fluoride ion afforded the natural product acortatarin A 2 1 and epi acortatarin A 2 52 in a 69% yield over 3 steps with a 9:1 dr favoring the desired product. Figure 2 17. A mercury mediated synthesis of acortatarin A 2.5 Total Synthesis of Acortatarin A Using a Pd(II) Catalyzed Spiroketalization Strategy Th e three preceding approaches to acortatarin A, while successful, derive two of the three stereocenters of acortatarin A from sugar derivatives. In our case, it was sought to showcase a novel methodology that at the outset should efficiently access the ste reochemistry of the natural product from a single stereocenter. Additionally, a mild palladium catalyzed synthetic strategy should be advantageous; obviating the need for

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54 the traditional acidic spiroketalization conditions and highly toxic metals associa ted with the previously established routes. Given the biologically active nature of this compound and the unusual architecture, a cortatarin A poses as an attractive target for total synthesis. Synthesis of the spiroketal core of this molecule is in line w ith our research interests and could be accomplished by exploiting our currently developing spiroketalization methodologies. 2.5.1 Initial Considerations Our previous experience with Au catalyzed dehydrative/dealkoxylative cyclization of monoallylic diols led to a subset of an ongoing research program in our group. These particular studies are aimed at a stereoselective method for forming spiroketals from monoallylic keto diols using metal catalysis. 76 As mentioned before, the classic method of spiroketali zation is the acid catalyzed dehydrative cyclization of keto diols, where both alcohols act as nucleophiles attacking the corresponding carbonyl electrophile with a loss of water. The predictable stereochemical outcome is exhibited in the anomeric product In an effort to access both anomeric and nonanomeric products, a strategy to the stereochemical information of the attacking alcohol is transferred down the chain to the carbonyl carbon and newly formed carbon stereocenter at the exo vinyl group (Figure 2 18 ). Mechanistically, attack of the non allylic alcohol on the carbonyl forms a hemiketal. The newly formed hydroxyl group of the hemiketal then performs an allylic transposition of the metal activated double bond to eject H 2 O. With this idea in mind, conditions to generate spiroketal 2 61 from ketoallylic diol 2 60 were investigated. Initial tetrahydropyrans.

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55 Figure 2 1 8 Spiroketalization of monoallylic keto diols and catalysts employed Table 2 1. Optimization of metal catalyzed spiroketalization of monoallylic keto diols Entry Catalyst Loading (mol %) Solvent Time (h) Yield a (%) 1 A /AgOTf 5 DCM r.t. 1.3 45 2 A /AgBF 4 5 DCM r.t. 1 32 3 B /AgOTf 5 DCM r.t. 24 55 4 C 2 DCM reflux 48 93 b 5 AuCl 5 THF r.t. 24 0 6 PdCl 2 (MeCN) 2 5 DCM r.t. 48 4 7 PdCl 2 (MeCN) 2 2 PhH r.t. 2 18 8 PdCl 2 (MeCN) 2 2 THF r.t. 1 64 9 PdCl 2 (MeCN) 2 5 THF 0 1. 5 83 c 10 PtCl 2 5 PhMe 40 24 83 11 PPTS 10 DCM r.t. 1 0 d a Isolated yield of pure diastereomer. b Complex diastereomeric mixture. c MS 4 omitted. d Starting material decomposed. Relevant preliminary results and optimization by Jean Palmes 76 is presented in Table 2 1. Entries 1 4 utilize gold catalysts to effect the spiroketalization of keto diol 2 60 Extensive studies proved that although only moderate yields could be obtained using Au catalysis, the reactions were highly diastereoselective and formed only traces of minor diastereomers. Entry 4 uses catalyst C to catalyze the reaction, but despite excellent yield, a complex mixture of diastereomers resulted. To deal with the viability of this methodology, other metal cata lysts were explored. In entries 6 9, the Pd(II) salt gave encouraging results and indicated the dependency of catalyst efficiency on the

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56 more coordinating solvent, THF. Platinum(II) chloride gave results similar to the Pd(II) complex, but with longer rea ction times and higher temperatures necessary to drive the reaction to completion. A control experiment was conducted with PPTS, an acid catalyst suitable for use in the classic spiroketalization strategy. This led only to rapid decomposition of the star ting material. The optimized conditions are outlined in entry 9. This methodology was then applied as the key step in the total synthesis of acortatarin A. The spiroketal core of the natural product would be formed from a monoallylic keto diol equivale nt based on the conditions shown in the above table. Since methyl ethers behave similarly to alcohols as leaving groups in the cyclization of monoallylic diols, 18 it was hypothesized the same would be true for the spiroketali zation. It would prove advantageous to use allylic methyl ethers to obviate the need for hydroxyl protecting group manipulation during the synthesis. 2.5.2 Initial Retrosynthetic Analysis Figure 2 1 9 Acortatarin A retrosynthesis 1

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57 The initial retrosynt hetic plan for acortatarin A is shown in Figure 2 1 9 It is worthy to note at this point that all of the routes explored during the total synthesis rely on the format hydroxy type ketone moiety embedded in spiroketalization precursor 2 63. The initial route attempted to address the synthesis of this required functionality via an asymmetric aldol reaction. In the end game, we would convert the terminal olefin handle of 2 62 to the alcohol, and access the aldehyde via metal hydride reduction of the Weinreb amide We envisioned the key step as forming spiroketal 2 62 by Au or Pd catalyzed dealkoxylative cyclization of allylic ether 2 63 This can occur initially by equilibration of keto diol 2 64 to the 6 membered hemiketal ring 2 63 followed by nucleophilic addition of the newly formed alcohol to the transition metal activated double bond to eject alcohol in a formal S N 2 64 sho uld be formed through an asymmetric aldol reaction between unsaturated aldehyde 2 66 and methyl ketone 2 65 The trisubstituted pyrrole 2 65 would be derived from pyrrole 2 21 by formylation at the 5 position then N alkylation. 2.5.3 Stereochemical Co nsiderations The stereoselective formation of the three chiral centers of acortatarin A at the position, the spiro carbon, and the to be formed stereogenic center of the exo vinyl group after spiroketalization, would require consideration. 2.5.3 hydroxy group Acortatarin A has three stereocenters, the first of which we plan ned to approach by using boron hydroxy unit shown below (Figure 2 20 ). The aldol reaction ma y be performed by generating the

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58 boron enolate of ketone 2 65 with a chiral dialkylboron halide 2 68 followed by addition to aldehyde 2 66 Figure 2 20 Use of a chiral boron enolate to set hydroxy stereocenter 2.5.3.2 Stereocenter 2: anomeric equil ibration at the spiro carbon Studies in our group have shown that metal catalyzed cyclization of monoallylic keto diols afford predominately anomeric product s Influenced by the anomeric effect, the second stereocenter should arise from equilibration of 2 64 at the hemiketal forming step to the thermodynamic products 2 70 or 2 72 ( Figure 2 21 ) Conformers 2 71 and 2 73 would be produced by an energetically unfavorable ring flip to the non anomeric hemiketals. At the outset, t he preference between 2 70 and 2 72 was unclear, and complicated by the role that H bonding interactions may have Setting the stereochemistry of the spiro carbon may also rely on differences in the rate of the metal catalyzed cyclization step for each conformer. In the case of the u ndesired stereochemistry, spiroketals would be epimerized under acidic conditions to the more stable product, which is often the naturally occurring compound.

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59 Figure 2 21 Possible stereoisomers accessible from keto diol / hemiketal equilibration 2.5.3.3 Stereocenter 3: the spiroketalization step The stereochemical outcome of the spiroketalization step can be predicted by the facial selectivity of nucleophilic attack on the activated olefin. The transition state s shown in Figure 2 22 for the metal cataly zed cyclization of anomeric hemiacetals 2 70 and 2 72 suggest that a trans relationship between the alcohol and the newly formed vinyl group in 2 62 should be preferred This preference may originate from the energ etic penalty associated with 1,2 allylic strain in the transition states of the cis products. 77 The cyclization favors the formation of 2 62 or 2 76 and the diastereomeric excess of the reaction depends on the relative populations of 2 70 and 2 72 respectively. As is the case for Acortatarin A, it exhibits a 5,6 anomeric system. From the X ray crystal structure 51 of this compound, the C 8 O3 bond of the 5 membered is axial to the parent 6 membered ring ( Figure 2 2 3 ) for anomeric stabilization The bond lengths

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60 Fig ure 2 2 2 Initial predictions for metal catalyzed spiroketalization measured via X ray crystallography in the isolation paper support this claim. The C8 O3 bond measures 1.403 which is significantly shorter than the 1.421 C8 O2 distance. Differences in bond lengths of heteroatoms to the anomeric center are associated with the anomeric effect. 78 For example, in sugars, the exocyclic C O bond is shortened and the ring C O bond from the anomeric center is lengthened in the anomeric vs nonanomeric confor mers. The exocyclic C O bond length in anomeric

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61 spiroketal, the C O distance of the 6 membered ring is greater than the C O distance of the 5 me mbered ring. The anomeric relationship between 5 membered rings and an exocyclic oxygen is less clear, with the C O bond outside of the ring tending to adopt a pseudo axial orientation. These data indicate that acortatarin A features an anomeric spiroke tal, and t he predicted outcomes of the stereochemical induction models in dicate that the spiroketalization should provide the anomeric product. Figure 2 2 3 ORTEP X ray crystal structure of acortatarin A Armed with this retrosynthetic plan and models fo r stereochemical induction, procedures for the initial synthetic route towards acortatarin A were planned and executed. 2.5.4 Forward Synthesis 1 We began the synthesis starting with conversion of pyrrole 2 21 to the Weinreb amide 2 67 as an aldehyde synt hon allowing for a stable starting material tolerant to future transformations. This was accomplished using either the acylation / hydrolysis / amidation route or a triphosgene / amidation route 79 (Figure 2 2 4 ).

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62 Figure 2 2 4 Routes to pyrrole Weinreb a mide 2 67 With Weinreb amide 2 67 in hand, we prepared the 2,5 disubstituted pyrrole 2 82 in three additional steps. Vilsmeier Haack formylation 80 furnished the disubstituted pyrroles 2 79 and 2 80 as two regioisomeric products with the desired 5 for myl p yrrole in excess over the N formyl isomer (Figure 2 2 5 ). Aldehyde reduction and hydroxyl group protection gave pyrrole 2 82. Figure 2 2 5 Formylation of 2 67 and conversion to 2 82

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63 The next step in the synthesis, N alkylation, proved to be more challen ging than anticipated. For substrate 2 82 where R is CH 2 OTBS, all of the attempts to alkylate with chloroacetone gave no reaction or decomposition (Table 2 2) Refluxing the reagents in dioxane or THF with potassium carbonate or KO t Bu failed to facili tate reaction (entries 1 and 2) Harsher conditions with NaH in DMF at reflux only led to decomposition (entry 3) It was then decided to use a superior alkylating agent that we could later convert to the methyl ketone However, t reating pyrrole 2 82 wi th methallyl chloride in the presence of KO t Bu in refluxing THF resulted in decomposition of the starting material (entry 4) Table 2 2. N alkylation of pyrrole Weinreb amides Entry Substrate Base Halide Solvent Temp Time (h) Yield (%) 1 2 82 K 2 CO 3 MeCOCH 2 Cl dioxane reflux 24 0 2 2 82 KO t Bu MeCOCH 2 Cl THF reflux 16 0 3 2 82 NaH MeCOCH 2 Cl DMF reflux 24 Decomp. 4 2 82 KO t Bu methallyl Cl THF reflux 48 Decomp. 5 2 67 K 2 CO 3 MeCOCH 2 Cl dioxane reflux 16 0 6 2 67 KO t Bu MeCOCH 2 Cl THF r.t. 72 0 7 2 67 KOH methallyl Br DMSO r.t. 5 99 8 2 82 KOH methallyl Br DMSO r.t. 5 Decomp. It was concluded that two factors might prevent the alkylation from proceeding : the steric bulk of the amide and CH 2 OTBS groups flanking the nitrogen, or the possibility that b y forming the pyrrole anion, OTBS is eliminated. Because of the difficulty to alkylate the 2,5 disubstituted pyrrole, we turned our attention to alkylation of monosubstituted pyrrole 2 67. A ttempts to alkylate with chloroacetone again were not

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64 met with success (entries 5 and 6), however, allylation with methallyl halides using a KOH/DMSO system 81 at ambient temperature (entry 7) provided the desired N methallyl pyrrole 2 83 in quantitative yield. Using the same KOH/DMSO system that worked so well for pyr role 2 67 failed to effect the same allylation of disubstituted pyrrole 2 82 (entry 8). Carrying the synthesis forward with 1,2 substituted pyrrole 2 83 Vilsmeier Haack formylation 80 and subsequent reduction with sodium boroh ydride provided olefin 2 85 TES protection of the free alcohol produced ketone precursor 2 86 (Figure 2 2 6 ). Figure 2 2 6 Pyrrole alkylation, formylation, and protection Oxidative cleavage reactions of the olefin were then explored with mainly unsatisf actory results. The first and simplest procedure tested was ozonolysis (Figure 2 2 7 ). However, this reaction failed to deliver the desired product, leading only to complex mixtures. Ozone is known to react with unsubstituted pyrrole via a 1,4 addition p rocess 82 The next attempt was the Lemieux Johnson oxidation protocol with OsO 4 and sodium meta periodate in water/dioxane. 83 The free alcohol 2 87 along with a minor inseparable impurity in 28 % yield was isolated Cleavage of the silyl group by NaIO 4 is most likely attributed to an oxidative mechanism rather than periodic acid

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65 under the buffered conditions 84 Low yields l ed us to try the reaction in a two stage process : Upjohn dihydroxylation 85 with OsO 4 and NMO to afford the vicinal diol, then glycol clea vage furnished ketone 2 87 as a mixture of keto alcohol (open chain) and hemiketal (cyclic) forms with no improvement in overall yield The synthesis was continued by re protection of the hydroxy group to yield aldol substrate 2 65 Figure 2 2 7 Oxid ative cleavage of N methallyl pyrroles Aldol coupling partners 2 66 86 or 2 90 could be accessed by monomethylation of cis 1,4 butenediol and oxidative isomerization with PCC, or allylic oxidation with activated MnO 2 (not attempted) (Figure 2 2 8 ). Both isom ers were considered due to uncertainty regarding how the olefin geometry would affect the stereochemical outcome during the spiroketalization step.

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66 Figure 2 2 8 Synthesis of aldol reaction components Unfortunately, all attempts at aldol reactions between methyl ketone 2 65 and aldehyde 2 66 failed. The test reactions were performed to generate racemic compound 2 69 through boron chemistry, the Mukaiyama protocol 87 or LDA (Figure 2 2 9 ) The first attempt involved forming the boron enolate of 2 65 with n Bu 2 BOTf in the presence of TEA, followed by introduction of the aldehyde. After several hours of reaction time, only starting materials were recovered. Generating the silyl enol ether by reacting 2 65 with TBSOTf and TEA was also unsuccessful no enol e ther was ever observed to have formed by 1 H NMR. With the strong base LDA, fragmentation of the methoxide moiety from the Weinreb amide was the only observed product. 88 As aldol reactions were problematic, it was decided to focus on finding an alternativ hydroxy ketone subunit Figure 2 2 9 Failed attempts at aldol reactions

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67 2.5.5 Revised Retrosynthesis A revised retrosynthesis employing a propargyl alcohol as an aldol synthon was then considered (Figure 2 30 hydroxy k etone 2 64 was envisioned to arise from a hydrosilylation/oxidation sequence of the alkyne component in compound 2 91 Work by Trost and Ball has shown that ruthenium catalyzed regioselective trans hydrosilylation of propargyl alcohols and subsequent Flem ing Tamao oxidation serves hydroxy ketones via an aldol surrogate 89 Alternatively, the alkyne could be converted to the ketone using an alkyne hydration procedure. Hydrosilylation was considered first due to chemo and re gioselectivity issues propargyl alcohols were found to direct silanes groups to the distal sp carbon, and prefer addition to alkynes over alkenes under ruthenium catalysis. 89 Compound 2 91 would be prepared by alkylation o f pyrrole 2 67 with propargyl chloride, then asymmetric alkynylation of aldehyde 2 66 followed by formylation of the resulting disubstituted pyrrole. Additionally, compound 2 91 could be derived from alkylation of pyrrole 2 67 with alkyne 2 90. Figure 2 30 Revised Retrosynthesis

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68 2.5.6 Forward Synthesis 2 Figure 2 31 Attempted propargyl alcohol synthesis Following a similar route as before, alkylation with propargyl bromide yields disubstituted pyrrole 2 92 in nearly quantitative yield. Formylation under Vilsmeier conditions, 80 reduction of the aldehyde, and protection of the resulting alcohol then afforded alkynylation precursor 2 95 Achiral test reactions to add alkyne 2 95 to aldehyde 2 66 were not met with success however. Alkyne metalation with diethylzinc or n butyllithium followed by addition of 2 66 gave little to no conversion of the starting material (Figure 2 31 ) No further trials to optimize this reaction were made. Due to limited success in alky nylation under these conditions we planned to avoid this problem by constructing an alkylating agent that would incorporate the propargyl alcohol functionality, and concurrently result in a more convergent synthesis. Racemic p ropargyl chloride 2 97 was generated via alkynylation of unsaturated aldehyde 2 66

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69 followed by protection of the newly formed alcohol as the base stable triisopropysilyl ether 2 99 or the TBS ether 2 98 (Figure 2 3 2 ) Alkylation with the KOH/DMSO system as before furnished adduct 2 100 in modest yield. With this compound in hand, the formylation step r esulted in a complex mixture and the desired product was not identified in the crude mixture (Figure 2 3 3 ) This is likely due to the ability of the Vilsmeier reagent to react with non arom bonds through several different mechanisms. 90 Figure 2 3 2 Synthesis of alkynylating reagent Figure 2 3 3 Attempted formylation of pyrrole 2 100 The only conceivable way of avoiding the problematic Vilsmeier side reactions was to revisit the N a lkylation protocols, in particular, a procedure to alkylate 2,5 disubstituted pyrrole 2 79 which should be facile due to the presence of two electron withdrawing substituents. In the previous pyrrole N alkylation studies, pyrrole 2 79 was not considered b ecause of potential difficulties performing a chemoselective reduction of the pyrrole 2 formyl group in the presence of a ketone functionality in the spiroketalization precursor. In the revised retrosynthesis, however, the formyl group

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70 could be reduced pr ior to the alkyne ketone transformation. To our delight, alkylation of pyrrole 2 79 with propargyl chloride 2 98 was readily accomplished by applying conditions from a known procedure wherein a similar pyrrole was alkylated with aliphatic halides. 91 Pyrrol e 2 79 was heated in acetonitrile with potassium carbonate and compound 2 98 in the presence of a phase transfer catalyst to form trisubstituted pyrrole 2 102 Aldehyde reduction and removal of the silyl group furnished hydrosilylation precursor 2 104 Figure 2 3 4 Propargyl alcohol 2 104 synthesis With propargyl alcohol 2 104 established, a series of experiments were conducted to regioselectively transform the internal alkyne into ketone 2 105 method 89 (Figure 2 3 5 ). Formation of the siloxacyclic ring of intermediates 2 106 or 2 107 would be carried out via Ru catalyzed hydrosilylation with trimethoxy or ethoxydimethylsilane, and subsequent intramolecular transalkoxylation of the resulting vinyl silane to for m the 5 membered ring.

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71 Figure 2 3 5 Attempts at alkyne hydrosilylation using the Trost protocol Testing the reaction, formation of the unstable siloxacycle could not be verified, and thus it was subjected directly to the Tamao Fleming oxidation condition s used by Trost and Ball. 89 Unfortunately, spectroscopic analysis of the crude product revealed significant decomposition of the starting material. Attempts to test the hydrosilylation portion of the reaction by forming a sta ble acyclic vinylsilane 2 108 using the Trost catalyst with TESH met with failure no reaction was observed (Figure 2 3 6 ). 92 Figure 2 3 6 Unsuccessful hydrosilylation to acyclic vinylsilane To our dismay, alternative approaches to alkyne ketone function al group interconversion via alkyne hydration with Au(I) salts, 93 Hg(OTf) 2 94 or through hydroboration / oxidation also failed to deliver the ketone 2 105 Under all of these conditions, no desired product was found, with little or no conversion of the star ting

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72 material. At this point, the synthetic plan would require further revision to access the necessary spiroketalization precursor. 2.5.7 Final Retrosynthesis and Forward Synthesis to Acortatarin A The final retrosynthetic analysis would derive acortatar in A from vinyl spiroketal 2 125 as shown before, which in turn should be obtained from benzylated keto alcohol 2 123 through a metal catalyzed spiroketalization event (Figure 2 3 7 ). With the synthesis of pyrrole fragment 2 79 secured previously, our atte ntion was turned toward the synthesis of the bromoketone component 2 120 We envisioned making use of a dithiane to install the ketone functionality the umpolung strategy 95 would allow easy access to both substituents on the ketone from dithiane 2 114 an d bromide 2 116 Combination of pyrrole 2 79 and bromoketone fragment 2 120 followed by a chemoselective aldehyde reduction would form the cyclization precursor. Bromoketone 2 120 would be constructed in several steps from known hydroxyester 2 113 Figure 2 3 7 Final retrosynthesis Armed with a new synthetic strategy, we embarked on the plan by preparing multigram quantities of starting materials. Guided by a known 4 step procedure, 96 L

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73 Figure 2 3 8 Preparation of startin g materials diethyl tartrate benzylidene acetal 2 109 was prepared from the tartrate diester and benzaldehyde in acidic media with Dean Stark trap assisted azeotropic removal of water (Figure 2 3 8 ). LAH / AlCl 3 reduction of the acetal and ester functional ities afforded O benzyl threitol 2 110 Glycol cleavage of this compound with periodate gave the unstable glyceraldehyde 2 111 which was immediately subjected to the Horner Wadsworth Emmons reaction with triethyl phosphonoacetate 2 112 in a sodium hydrid e suspension to deliver 2 113 Dithiane 2 114 was prepared via transthioacetalization of ethyl diethoxyacetate and propane dithiol. 97 With hydroxyester 2 113 in hand, the synthesis commenced with a one pot Appel bromination / DIBAL H ester reduction 98 to ge nerate bromo alcohol 2 115 (Figure 2 3 9 ). 99 was used to form allyl methyl ether 2 116 reaction times and lower yields due to dif ficulties during workup. Iodomethane and

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74 Figure 2 3 9 Bromoketone fragment 2 120 synthesis sodium hydride, although faster and higher yielding, produced significant amounts of benzyl enol ether corresponding to E2 elimination of HBr. Dithiane 2 117 wa s synthesized using optimized conditions shown above. In this step, all of the conditions illustrated were crucial to the success of the dithiane alkylation and suppressing the competing E2 process of bromide substrate 2 116 Use of n butyllithium as a b ase did not effect the desired substitution reaction, and starting materials were recovered. Without a catalytic amount of t butanol, mostly the E2 enol ether product was observed in the crude mixture. The optimized synthesis of 2 117 required 2.0 equiva lents of NaH, 2.0 equivalents of the dithiane, a catalytic amount of t butanol in THF at 0 to effect the desired transformation in good yield. The resulting ester 2 117 was cleanly reduced with an excess of LAH in THF to form hydroxymethyl dithiane 2 118 The oxidative dithiane deprotection 100 of 2 118 was initially performed in a MeOH H 2 O THF 9:1:5 solvent system. With methanolic solvent, varying amounts of the corresponding

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75 dimethyl acetal were formed. This was easily remedied by shaking the crude mixture with dilute aqueous HCl, or by modifying the solvent system oxidative cl eavage of the dithiane moiety in MeCN revealed the latent ketone, cleanly rendering acyloin 2 119 Halogenation of 2 119 using conventional Appel conditions as before completed bromoketone fragment 2 120 Compound 2 121 was prepared by joining fragments 2 120 and 2 79 in hot ace tonitrile with base (Figure 2 40 ). In order to avoid a competing elimination reaction with a strong base, the first reagents employed to drive the reaction were potassium carbonate and 18 crown 6, as used in the alkylation of the 2,5 disubstituted pyrrole with propargyl chloride 2 98 Unfortunately, these conditions failed to give satisfactory conversion of the starting materials with only 30 43% isolated yields, possibly due to lower nucleophilicity of the bromoketone as compared to the propargylic halides. The more basic and soluble cesium carbonate was effective at delivering the desired product 2 121 in 79% yield after 8 hours reaction time as indicated by TLC analysis. Figure 2 40 Unifying fragments and chemoselective alde hyde reduction The resulting substrate 2 121 contains several functionalities (amide, ketone, aldehyde) that are all capable of being reduced by hydride reducing agents. It is known

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76 that some aldehydes may be chemoselectively reduced in the presence of ke tones using careful control of hydride stoichiometry, solvent, and low temperature ( when using sodium borohydride. 101 Of several conditions tried, little selectivity was observed with this reagent. With sodium borohydride, the best results were obt ained in DCM EtOH at triacetoxyborohydride has been reported to achieve selectivity even at higher temperatures (refluxing benzene), 102 but in our hands, no conversion of the starting material even with exc ess hydride over prolonged reaction times was observed. This is likely due to the reduced reactivity of aromatic aldehydes as compared to their aliphatic counterparts. With this in mind, it was decided to exploit steric rather than electronic differences Krishnamurthy showed that bulky LAH derivatives with the formula Li(RO) 3 AlH, where R = t Bu, t amyl, Et 2 MeC, and Et 3 C (LTEPA), exhibit high selectivity for the reduction of unreactive aldehydes even in the presence of more reactive ketones such as cyclo hexanone. 103 Of the reducing agents that were tested, LTEPA gave the most promising results. Nearly complete selectivity was shown for aldehydes in the LTEPA reduction of several aldehyde/ketone combinations at 103 The reagent was conveniently prepared as outlined by Krishnamurthy by adding 3.1 equivalents of triethylcarbinol to LAH in THF followed by 1 hour of reflux to give a mixture of known molar concentration. This was then added in 0.5 molar equivalent port ion the 2.0 equivalent mark, and the reaction was quenched to give a high yield of the desired substrate. The resulting acyclic compound 2 122 was found to exist with its cyclic isomer 2 123 by 1 H NMR. Observing the closed chain form was encouraging,

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77 since the first step in the spiroketalization mechanism is ring closure of the keto alcohol to form a hemiketal. Table 2 3. Spiroketalization conditions Entry Catalyst Additive Solvent Temp Time(h) Comments 1 5% PPh 3 AuCl / AgOTf DCM r.t. 24 Trace pdt. 2 10% Au[( o Bp) t Bu 2 P]MeCN SbF 6 4 MS DCM 16 No rxn. 3 10% Pd(MeCN) 2 Cl 2 THF r.t. 48 50% d.r. 3:1 4 20% Pd(MeCN) 2 Cl 2 DCM r.t. 3 50% d.r. 3:1 5 20% Pd(MeCN) 2 Cl 2 10% MeCN DCM r.t. 16 No rxn. 6 20% Pd(MeCN) 2 Cl 2 PPTS DCM r.t. 16 No rxn. 7 10% Pd(PhCN) 2 Cl 2 4 MS THF r.t. 16 50% d.r. 1:1 8 10% Pd(PhCN) 2 Cl 2 4 MS DCM 24 87% d.r. 1:1 9 10% Pd(PhCN) 2 Cl 2 4 MS DCM 48 No rxn. 10 10% PtCl 2 PhH 48 50% d.r. 1:1 11 10% PtCl 2 PhH 16 Decomp. With the spiroketalization precursor in hand, we set forth to investigate conditions for the metal 3). Of the first metal catalysts tested, the two cationic gold complexes gave trace amounts of product at best (entries 1 and 2), a compelling reason to exami ne Pd(II) salts. Pd(MeCN) 2 Cl 2 in THF gave encouraging results, with 50% conversion of the starting material and a 3:1 dr (entry 3). With the Pd catalyst, the solvent effects were opposite to those indicated by the results in Table 2 1, where high reactio n yields depended on the more coordinating solvent THF. Running the reaction in the less coordinating solvent, DCM, required significantly reduced reaction times, and attained the same end result as with THF. In both cases however, only half of the start ing

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78 material was converted to product. It could be suggested that some factor is contributing to deactivation of the catalyst. We hypothesized that during the course of the reaction, the acetonitrile ligands may dissociate from the metal, facilitating ca talyst decomposition. Another possibility for the low conversion could be sluggish formation of the hemiketal from the keto alcohol. We set out to address both problems by incorporating acetonitrile (entry 5) or PPTS (entry 6) to the reaction mixtures. Acetonitrile proved inhibitory, and the attempt at acid promoted hemiketal formation resulted in no reaction as well. With promising initial results from Pd(MeCN) 2 Cl 2 we looked towards the more robust Pd(PhCN) 2 Cl 2 complex. Gratifyingly, we were able to obtain good and clean conversion of the starting material to products 2 124 and 2 125 however with no diastereoselectivity. Attempts at lowering the temperature to improve ted any reaction from occurring. As we know from prior results that PtCl 2 can catalyze this type mirrored those from entry 7. Increasing the temperature of the reac decomposition of the starting material. Optimization was deemed successful with the conditions shown in entry 8, but the lack of selectivity would still need to be addressed. It is worthy to note that at this point, without having don e extensive spectroscopic studies, that the absolute stereochemical assignment of spiro compounds 2 124 and 2 125 was unknown. Since few transformations were left to complete the synthesis, both diastereomers were taken forward separately through the fina l stages. Trials to interconvert the compounds 2 124 and 2 125 under acidic conditions (PPTS, p TsOH, 1N HCl) were unsuccessful.

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79 Transformation of the terminal olefin to primary alcohol 2 126 was accomplished by treating 2 124 with catalytic OsO 4 and NMO, followed by glycol cleavage with NaIO 4 and sodium borohydride reduction of the resulting aldehyde (Figure 2 41 ). Weinreb amide reduction with LAH cleanly provided the aldehyde 2 127 synthesis, 51 the dibenzyla ted acortatarin A 2 32 was deprotected using 20.0 eq. TiCl 4 in DCM when conventional hydrogenation over Pd/C failed. To avoid any epimerization of an enantiopure substrate, we decided to subject the monobenzylated compound 2 127 to high pressure hydrogena tion at 100 psi over 24 h. Not surprisingly, no conversion of protocol. With minor adjustments, similar results were achieved using the Lewis acid TiCl 4 Compounds 2 1 and 2 52 were obtained in 70% and 8% yield respectively, which corresponds to a 9:1 diastereomeric ratio in the product mixture. Separation of the two anomers and characterization by NMR and optical rotation revealed their identities as acortatarin A and epi acortatarin A with the ratio in favor of the natural product. Figure 2 41 Elaboration of 2 124 to acortatarin A

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80 Anomer 2 125 was taken through the same course of reactions to yield acortatarin A 2 1 and epi acortatarin A 2 52 in 84% combined yield with an 83:17 dr in favor of the natural product (Figure 2 4 2 ). Figure 2 4 2 Elaboration of 2 125 to acortatarin A Completion of the synthesis and verification of the final structures by spectroscopic means verified that the key Pd(II) catalyzed spirok etalization event succeeded in setting the non epimerizable stereocenter with complete selectivity for the desired 1,2 trans relationship to the existing benzyloxy group. Moreover, the major product in both end game syntheses was acortatarin A. 1 H and 1 3 C NMR spectra were taken in acetone d 6 to compare to the chemical shifts reported by Zhang for pollenopyrroside B. 41 The spectra are identical in all respects; confirming that acortatarin A and pollenopyrroside B are indeed t he same compounds. 2.5.8 Electrochemical Studies of Acortatarin A by Cyclic Voltammetry Having completed the synthesis of acortatarin A, we became interested in quantifying the antioxidant activity, if any, possessed by the natural product. It has been sh own that acortatarins A and B reduce ROS in mesangial cells, and their mode of

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81 action suggested to be due to antioxidant properties. 42 Common antioxidants usually contain more electron rich heterocycles such as phenols with on e or more resonance donors. 104 Pyrrole itself is an electron rich heteroaromatic, however, the pyrrole substructure in acortatarin A is deactivated by one electron withdrawing group. In other words, the attenuated electron density of this pyrrole diminishe s its susceptibility toward oxidation. Testing antioxidant activity can be accomplished by several means. While oxygen radical absorbance capacity (ORAC) 105 has become the industry standard for testing foods, juices, and food additives, it is not suitabl e to be applied to a single organic compound. The Trolox equivalent antioxidant capacity (TEAC) 106 assay and Folin Ciocalteu reagent 107 are appropriate for this type of analyte, but both are operationally difficult and measurements are reported as values rela tive to Trolox (a vitamin E derivative) and gallic acid respectively. To obtain a measurement with an associated physical dimension, cyclic voltammetry (CV) may be used. CV has been employed extensively as a method for characterizing the antioxidant capa city of organic molecules via a 1e oxidation of the substrate. 108 CV experiments began by measurement of a blank sample (Figure 2 4 3 ), then a control experiment with 1,2 diphenylanthracene (Figure 2 4 4 ), and lastly a cortatarin A (Figure 2 4 5 ) in acetonitril e. Water as solvent would have better mimicked a physiological environment, but was not chosen due to lack of solubility of the substrates. In the literature, oxidation potentials for certain known antioxidants are recorded in acetonitrile, and the numbe rs match well to those reported for the same compounds in water. U nder these conditions acortatarin A was found to undergo irreversible oxidation, with two oxidation potentials at + 1.74 and + 1.90 V. According to Penketh,

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82 compounds with oxidation potenti als greater than +0.70 V are not considered to be of any appreciable value as antioxidants. 109 All CV measurements were carried out in acetonitrile, using glassy carbon working electrodes in conjunction with a Pt flag auxiliary electrode and a Ag/AgNO 3 wir e reference electrode connected to the test solution via a salt bridge containing 0.1 M Bu 4 NPF 6 in acetonitrile. Accurate potentials were obtained using ferrocene as an internal standard. Figure 2 4 3 Blank CV measurement Figure 2 4 4 CV of 1,2 diphen ylanthracene

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83 Figure 2 4 5 CV of acortatarin A 2.6 Outcome Acortatarin A and its epimer have been synthesized using a novel Pd(II) catalyzed spiroketalization as the key step. Electrochemical studies conducted on acortatarin A suggest that it is not redu cing ROS species, but instead operating by an alternative avenue. I f acortatarin A is not working as an antioxidant, it probably operates under a different manifold which could be by preventing ROS overproduction This may be accomplished by glycemic co ntrol and/or inhibition of cytokines and growth factors The acortatarins may potentially be used to treat DN, a major complication of diabetes.

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84 CHAPTER 3 TANDEM GOLD CATALYZED CYCLIZATIO N / DIELS ALDER REACTIONS 3.1 Background and Significance The Diels Alder (DA) reaction has been a powerful tool to generate molecular complexity since its first documentation by Otto Diels and Kurt Alder in 1928. 110 This organic reaction, more specifically a [4+2] cycloaddition between an electron rich conjugated diene an d an electron deficient alkene (dienophile), forms a cyclohexene ring system. The DA reaction has been extensively studied, applied, and modified over the years to find its place as one of the more useful and general reactions in the organic enal. 111 Beginning in the early 1980s, vinyl dihydropyrans emerged as diene substrates in DA reactions used to prepare fused ring heterocycles. 112 However, only a limited number of reaction protocols for the preparation of unsaturated heterocycles containing a vinyl group forming the diene are known in the literature. Herein, we report a novel method for their synthesis, and explore their utility in the DA reaction. The nitrogen containing analogues can be prepared in the same way, and undergo DA cycloadditi on. 3.1.1 Synthetic Routes to Diene Heterocycles for DA Reactions The requisite 5 and 6 membered ring dienol ether functionalities (termed vinyl dihydrofuran and vinyl dihydropyran respectively) are typically prepared using somewhat complex synthetic sche mes. Strategies have usually revolved around three synthetic routes: oxidation/Wittig olefination of sugar derivatives, cross coupling reactions, or a vinylation / dehydration sequence from lactones (Figure 3 1). These major approaches, as well as their use in DA cycloaddition reactions will be discussed further in detail.

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85 One of the first examples was shown by Trost, who used a palladium catalyzed alkylation / DA strategy to rapidly generate polycyclic systems (Figure 3 2). 113 Figure 3 1. General strateg ies towards vinyl DHP substrates The lithiated dihydropyran 3 1 is condensed with acrolein, then acetylated to give diallylic acetate 3 2 allyl palladium complex with Pd(0) and 3 2 followed by alkylation with acrylate 3 3 smoothly generated cyclic dienol ether 3 4 as a single regioisomeric product. Heating the resulting diene in toluene sufficed to provide the intramolec ular DA adduct 3 5 in 75% yield. Figure 3 catalyzed alkylation of allylic acetate 3 2 synthesis and DA reactions of dieno pyranosides. 112 a A later publication detailed the synthetic schemes and scope of the methodology, and investigated the diastereofacial selectivity of the cycloaddition step. 112 b One sugar dienol ether was prepared starting

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86 with benzyli denation of D glucopyranose derivative 3 6 followed by methylation, hydrogenolysis, and hydroxyl group activation to yield 3 9 (Figure 3 3). Conversion of 3 9 to enal 3 10 was accomplished by trityl group deprotection and mesyl group elimination under ac idic conditions, then oxidation of the resulting hydroxyl group. Wittig olefination provided the DA substrate 3 11 in 17% overall yield. Figure 3 3. Synthesis of cyclic dienol ether sugar derivative 3 11 The first DA reactions were carried out on diene 3 12 with N phenylmaleimide (NPM) in refluxing benzene (Table 3 1, entry 1). Under these conditions, the best yields were obtained, however, in some cases a migration of the double bond from the expected position to the ring junction was observed. Attrib uting the isomerization to trace amounts of acid, the cycloadditions were re examined with 1 equivalent of formed without the double bond shift. Cycloadditions of 3 12 w ere also conducted with DMAD (entry 2), PTAD (entry 3), and DEAD (entry 4). Although quinonoid dienophiles (benzo and naphthoquinone) did not afford significant yields, the varied functionalities of the adducts that were obtained demonstrate the versatil ity of cycloadditions with sugar derived dienes. In all cases, the predicted endo products were observed, with facial selectivity for the addition anti to the side containing the ring methoxy group.

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87 Table 3 Entry Dienophi le Product Yield (%) 1 76 2 46 3 80 4 48 All reactions carried out in refluxing benzene. In 1997, Nicolaou and co workers developed a palladium catalyzed functionalization of lactones via their cyclic ketene acetal phosphates as an efficient strategy towards the construction of cyclic ethers. 114 In one application, bis(lactone) 3 17 is converted to the ketene acetal phosphate 3 18 through treatment of its potassium enolate with phosphoryl chloride (Figure 3 4). Reaction with a vinyls tannane in the presence of catalytic Pd(PPh 3 ) 4 in refluxing THF resulted in the formation of bis(dienolether) 3 19 This strategy and compound were later used by Nicolaou et al in the total synthesis of brevetoxin A. 115 A host of dienol ethers from ketene acetal phosphates were prepared with excellent yields. Aside from the usefulness of this Stille

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88 coupling methodology to construct polyethers, the products may also find use for other synthetic transformations, namely DA reactions. Figure 3 4. Pd(0) cata lyzed allylation of ketene acetal phosphate 3 18 In 2000, Denmark and Neuville demonstrated another cross coupling alkoxyvinyl)silanols and silyl hydrides. 116 While the majority of the work involved aryl iodide electrophiles, an alkenyl e lectrophile was briefly examined. Following the works of Hiayama, 117 organosilicon compound 3 20 behaves effectively as the nucleophilic partner in this coupling reaction. The rate and yield of the reaction in Figure 3 5 is comparable to those obtained usi ng aryl iodides. Figure 3 5. Hiyama type coupling of vinyl silane 3 20 and vinyl iodide 3 21 In 2002, Mori et al used a ruthenium catalyzed ring closing ene ynamide metathesis for the synthesis of dienamines (Figure 3 6). 118 In this case, RCM with Gru afforded bi and tricyclic compounds 3 25 and 3 26 Interestingly, when 3 24 was

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89 purified and subjected to the DA conditions with NPM, the same type of double bond isomerization observed by Guiliano was found here, with cycloadduct 3 26 forming as an inseparable 1.3:1 mixture favoring the expected adduct. Isomerically pure cycloadducts (shown) were obtained by using the crude reaction mixture from the RCM procedure directly in t he next step. Figure 3 6. Ene ynamide RCM and DA reactions 3.1.2 DA reactions of Dienol Ethers: Applications to Total Synthesis In addition to the development of methodologies aimed at the construction of vinyl dihydro furans, pyrans and their nitrogen ous analogues, some applications of these methods are found in the realm of total synthesis. In the following examples, the dienes are formed by a vinylation/dehydration of lactones protocol. Some recent examples statin F 119 and vinigrol core architectures, 120 relatives. 121 Penostatin F is a metabolite from the Penicillium sp., OPUS 79 fungal strain, separated from the marine alga Enteromorp hia intestinalis The compound has been found to be cytotoxic to P388 Leukemia cell cultures. 122 In 2004, Barriault demonstrated a rapid assembly of the penostatin F core via a hydroxyl directed Diels Alder/Claisen sequence (Figure 3 7). 119 The final steps of the synthesis of the

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90 Danishefsky type diene 3 28 commenced with addition of lithiated ethyl vinyl ether to lactone 3 27 followed by dehydration with thionyl chloride, and lastly deprotection of the silyl ether to produce 3 28 The diene was then treated with vinylmagnesium bromide to form the corresponding magnesium alkoxide, which served to coordinate to the maleimide carbonyl oxygen and direct the facial selectivity of the DA reaction to form adduct 3 29 Heating compo und 3 29 in toluene with trace triethylamine effected the Claisen reaction to form the penostatin F core 3 30 The completion of penostatin F 3 31 by the Barriault group is currently underway. Figure 3 re A short time later, Barriault and Morency published a synthesis of the octalin ring of the natural product vinigrol. 120 A highly sought after target for total synthesis, this diterpene bears a cis decalin subunit surmounted by a cyclooctane ring. It was first isolated in 1987 from a culture of the Virgaria nigra fungal strain. 123 Similar to the DA/Claisen rearrangement of diene 3 33

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91 The diene was prepared by treatment of lactone 3 32 with vinyl Grignard, followed by dehydration and TMS group deprotection with fluoride ion (Figure 3 8). Formation of magnesium bridged chelate between 3 33 and N benzylmaleimide was accomplished with magnesi um dibromide diethyl etherate in the presence of triethylamine. Subsequent [4+2] cycloaddition furnished DA adduct 3 34 which upon heating in toluene with the amine base underwent the Claisen rearrangement to yield cyclooctenone 3 35 Since the time thi s article was published in the literature, several strategies to construct the vinigrol 3 36 core by Barriault et al have appeared, the most recent effort culminating in a 2012 formal synthesis of the natural product. 124 Figure 3 of the vinigrol octalin ring Research in the Corey laboratory resulted in the 2006 synthesis of the woody fragrances georgyone, arborone and related compounds. 1 21 a Their work determined the active principles of the commercial indicated the importance of absolute stereochemical configuration to olfactory perception, and served as a model template for the synthesis of other potential

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92 fragrances. In one example, synthesis of the wood fra grance analogue 3 43 starts with a vinylation / dehydration sequence of valerolactone 3 37 (Figure 3 9). 121 b The acid sensitive diene 3 38 was subjected to an ( S ) oxazoborolidine 3 39 mediated DA reaction with ( E ) 2 methyl 2 b utenal 3 40 Acid catalyzed olefin transposition followed by Grignard addition and Ley oxidation of the resulting alcohol furnishes the intensely aromatic compound 3 43 This is perhaps the only instance of a Diels Alder reaction between a vinyl dihydrop yran and a dienophile of inherently lesser reactivity in the published literature. Examples of this type of DA reaction have only been demonstrated to work with highly reactive/electron poor alkenes such as maleic anhydride, N substituted maleimides, and PTAD. 112 Interestingly, the reaction was unable to be carried out using any of the standard achiral Lewis acids: Me 2 AlCl, BF 3 OEt 2 MgBr 2 OEt 2 Yb(OTf) 3 Sc(OTf) 3 or ZnCl 2 Furthermore, the reaction was unsuccessful using th e ( R ) enantiomer of the oxazoborolidine catalyst. This is an intriguing example of a special case where a complex chiral catalyst accesses an otherwise impossible reaction pathway. Figure 3

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93 3.1.3 Examples of Oxa and Azadecalin Containing Natural Products Aside from the molecules presented in the previous section, there are a variety of other biologically active compounds containing oxa and azadecalin skeletons. Some clear examples are depicted below (Figure 3 10 ). Figure 3 10. Examples of biologically significant heteroatomic decalins Pumiliotoxin C 3 44 one of the main alkaloids from the poison dart frog Dendrobates pumilio is a potent neurotoxin that acts as a noncompetitive acetylcholine blocker, and thus has attracted considerable attention from a pharmaceutical standpoint. 125 The decahydroquinoline structure would be formed via DA reaction with a vinyl dihydropiperidine The diterpene p homactin A 3 46 is an antagonis t of platelet activating factor and its oxadecalin core structure may be ac c essed using the methods presented herein 126 The final example is the t ricothecenes 3 45 which belong to the sesquiterpene class of compounds are mycotoxins and powerful inhibitors of protein synthesis once used on occas ion by the Soviet Union as chemical warfare agents 127 3.2 Synthesis of the Diels Alder Adducts Our interest in this type of diene was inspired by results of a control experiment aimed at investigating the mechanism of gold catalyzed dehydrative cyclization of monopropargylic triols. As mentioned in an earlier section, two modes of cyclization are

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94 possible, depending on which of the pendant alcohols attacks first (Figures 1 10 and 1 11). 3.2.1 General Considerations We have previously shown that monoproparg ylic triols can undergo gold catalyzed cyclization to form unsaturated spiroketals ( Figure 3 11 ). 16 Figure 3 11. Au catalyzed cyclization of monopropargylic triols As part of a mechanistic study, C1 monoprotected triol 3 49 was subjected to the same reaction conditions, and cyclization afforded vinyl dihydropyran (DHP) 3 50 and unsaturated ketone 3 51 in a combined yield of 91% ( Figure 3 12 ). When the C9 alcohol is not available for cyclization, C1 attacks to form diene 3 53 although in only 21% yield. Deprotection of 3 53 and re exposure to the Au catalyzed cyclization conditions furnishes expected spiroketal 3 55 in 82% yield. According to the se results, we believe that two cyclization pathways are possible. Of inte rest to this project is the path involving formation of the diene through an allene intermediate, which is allowed to isomerize in the absence of a suitable pendant nucleophile to a vinyl DHP (Figure 3 13) This dienol ether may exist in equilibrium with its open chain form as a result of hydration of the ring double bond, or hydrolysis on silica gel during workup (removal of the inorganics was accomplished by passing the crude mixture over a plug of silica gel). This method constitutes a mild and effecti ve procedure to build dienes from simple and easily modifiable substrates.

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95 Figure 3 12. Au catalyzed cyclization of monoprotected triols control experiments Figure 3 13. Probable allene intermediate in the synthesis of vinyl DHP 3 58 We quickly reali zed the advantage of arriving at an electron rich diene it is prone to undergo DA cycloaddition to potentially construct a variety of substrates. Intermolecular DA reactions could create oxadecali ns and intramolecular DA reactions may form fused 3 ring systems ( Figure 3 14 ). It should be noted that in some cases, as was described by Corey and Guiliano isomerization of the newly formed bond is observed and can be attributed to trace amounts of acid, or thermodynamic stabilization by forming the lower energy tetrasubstituted olefin.

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96 Figure 3 14. Possible structures arising from the Au catalyzed cyclization / DA methodology 3.2.2 Initi al Study and Optimization of Dienophile Scope Substrates for the oxadecalin Diels Alder adducts were prepared from commercially available alkynyl alcohols beginning with protection of the alcohol as the TBS ether. Following addition to an aliphatic aldehy de, and deprotection of the silyl ether with TBAF the final products were obtained in 3 steps ( Figure 3 15 ) Ini tial Au catalyzed cyclization/ DA reactions were carried out using diol 3 71 as a test substrate, and the initial results are summarized in the following table ( Table 3 2 ) Figure 3 15. Synthesis of diol substrates Cycloaddition of the vinyl DHP 3 72 generated through Au catalyzed cyclization of monopropargylic diol 3 71 was attempted using several dienophiles The first candidate, methyl acry late, did not undergo cycloaddition with the pre formed diene (Entry 1), which led us to test a more electron deficient dienophile, N methyl maleimide

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97 (Entries 2 4) This reaction proceeded smoothly under reflux conditions in benzene, with the optimal r ea ction time being 48 hours. T he adduct underwent double bond isomerization to tetrasubstituted olefin type structure 3 73 In an effort to increase the reaction scope, several other dienophiles were tested, but with disappointing results (Entries 5 9) Ta ble 3 2. Conditions and Initial Results for Au catalyzed cyclization / DA Reactions of Monopropargylic diol 3 71 Entry Dienophile Solvent Temp. Additive Time (h) Yield (%) 1 methyl acrylate THF r.t. 18 No rxn 2 NMM PhH reflux 72 76 3 NMM PhH refl ux 24 64 4 NMM PhH reflux 48 82 5 DMAD PhH reflux 24 No rxn 6 dimethyl fumarate DCM r.t. 6 decomp 7 benzoquinone PhH reflux 48 trace 8 maleic anhydride PhH reflux 48 46 9 N,N dimethylacrylamide PhH reflux 48 decomp 10 NMM PhH reflux PP h 3 12 25 11 methyl acrylate THF reflux ZnCl 2 96 No rxn The lack of reactivity led us to believe that the silver and gold salts, although Lewis acids that could potentially promote the DA reaction, may have been inhibiting the process in some way. Triph enylphosphine was used as an additive to occupy the metal complexes (Entry 10 ), however yields decreased as compared to entry 4. Zinc chloride was employed next to aid in activating the dienophile (Entry 11 ), but no Diels Alder adduct was observed after t he initial formation of the diene during 96 hours reaction

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98 time. In the cases where no adduct was formed, 1 H NMR of the crude material showed a mixture of vinyl DHP and open chain keto diol suggesting that the two exist in equilibrium. Inclusion of 4 m olecular sieves in the reaction media to remove water and force formation of the vinyl DHP did not seem to help the cycloaddition step. 3.2.3 Synthesis of Nitrogen Analogues Given the limited scope of dienophiles found to undergo cycloaddition with our die ne, the focus was shifted towards investigating the scope of dienes that could react with powerful dienophiles. Nitrogen analogues were prepared and explored for their reactivity under the optimized conditions. Tosylamine derivatives 3 74 128 and 3 75 128 were generated beginning with a Mitsunobu reaction between alcohol s 3 65 or 3 66 and TsNHBoc 129 (prepared from TsNCO and t BuOH) A lkynylation of an aldehyde and cleavage of the carbamate afforded tosylamino alcohols 3 76 and 3 77 ( Figure 3 16 ). Figure 3 16. General synthesis of tosylamine substrates The N Boc derivative 3 81 was constructed from tosylate 3 78 130 starting by nucleophilic substitution with bis Boc amine. Monodeprotection of the bis Boc amine according to a known pr ocedure 131 yielded carbamate 3 80 Double deprotonation and a ddition of the lithium acetylide to acetaldehyde provide d N Boc amino alcohol 3 81 132 in 4 steps (Figure 3 17) With the diol substrates as well as the nitrogen analogues in hand, additional Au cycl ization / DA reactions were performed and summarized in the following section.

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99 Figure 3 17 Synthesis of N Boc substrate 3 81 3.2.4 Alkyne Scope The compounds in Table 3 3 entries 2 and 5 exhibited an isomerization of the double bond from the expected p osition The stereochemistry of all compounds has been extrapolated by analogy to the X ray crystal structure of entry 2 ( Figure 3 18 ) as the predicted endo trans product s Entries 1,3,4 and 6 8 do not show the double bond shift, suggesting that the NMM dienophile may cause their adducts to adopt a lower energy structure due to minimized steric interactions. Most of the compounds listed were isolated as single d iastereomers, with the exception of 3 88 and 3 99 which were found as inseparable distereome ric mixtures with dr (3 : 2) and dr (4 : 1 ) respectively. Figure 3 18. ORTEP X ray structure of 3 83.

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100 Table 3 3. Diene Scope Entry Alkyne Dienophile Product Yield (%) 1 a NMM 78 2 b NMM 79 3 b PTAD 54 4 a TCNE 91 5 a TCNE 82 6 b TCNE 75 7 b TCNE 69 dr 3:2 8 b TCNE 80 dr 4:1 Reactions carried out in benzene/THF, 1.0 1.5 eq. dienophile and 2 mol % Au[P( t Bu) 2 ( o biphenyl)]Cl / AgOTf, 4 MS a Room temperature overnight. b Reflux 24 h. 3.2.5 Failed Attempts at Expansion of Die nophile Scope The unexpected low reactivity of the dienol ethers prompted us to explore methods to increase the reactivity of standard acyclic dienophiles commonly used in DA

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101 the chiral oxazoborolidine catalyst to effect similar reactions, 121 we used this approach to drive the DA reaction between 3 71 and methyl acrylate (Figure 3 19). Our efforts were largely ineffective, with the best result be ing formation of the cycloadduct 3 90 in 11% yield based on consumption of the starting material in the crude NMR. Figure 3 19. Oxazoborolidine catalyst assisted DA cycloaddition on to activation via iminium catalysis using conditions similar to those developed by the MacMillan group for the activation of simple unsaturated aldehydes enantioselective catalytic DA reactions. 133 Activation of cinnamaldehyde with a proline derivative 3 91 towards cycloaddition resulted in a complex mixture in our hands, containing mostly the diene hydrolysis product 3 93 (Figure 3 20). Figure 3 20. Attempted dienophile activation using organocatalysis

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102 3.3 Outcome and Future Plans From the monopropargylic alcohols generated through Au catalyzed cyclization, several dienophiles were tested under several alternative conditions in an effort to increase the dienophile scope. From the results it was apparent that the Diels Alder reactions promoted by Lewis acids or otherwise were unsuccessful. The reactions of these dienol ethers have previously been shown only to work with the most p owerful dienophiles and under neutral conditions. The focus was shifted from varying dienophiles to varying the dienes that could possibly undergo the reaction sequence. Thus far, it has been shown that 5 and 6 membered rings containing O, NTs, and NBoc can be formed under Au catalysis of the corresponding propargylic alcohols. Furthermore, the dienes can undergo [ 4+2 ] cycloaddition with N methyl maleimide (NMM), tetracyanoethylene (TCNE), and 4 phenyl 1,2,4 triazoline 3,5 dione (PTAD) in good yields at room tem perature or reflux in benzene or THF. At this juncture, we are exploring the feasibility of applying the Au catalyzed cyclization/DA methodology to total synthesis. Of the potential targets that should be accessed using the method, the indolocar bazole (ICZ) natural products appear particularly attractive, as many of them contain maleimide type functionalities fused to a 6 membered ring. 3.3.1 Indolocarbazole Natural Products The ICZ family of natural products (Figure 3 21) is comprised of over 100 different compounds isolated from a variety of different sources including slime molds, microorganisms, and marine invertebrates. 134 Since the discovery of the first ICZ natural alkaloid staurosporine 3 94 (AM 2282 or STS) in 1977 by Omura, 135 this family

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103 of compounds has garnered significant attention from the chemical, biological, medical, and pharmaceutical communities due to their wide range of biological activity. Figure 3 21. Representative ICZ natural products 3.3.2 Staurosporine Background and S ynthetic Plan The first report of an ICZ from a natural source was by Omura and co workers, 135 who isolated STA from the cultured broth of Streptomyces staurosporeus (now known as Lentzea albida ). The producing organism was f ound in a soil sample in the Iwate Prefecture, Japan. Omura also reported a preliminary characterization of the compound, as well as initial biological tests. Throughout the years, STA was found to have properties ranging from anti microbial to anti hype rtensive, 136 prompting further investigation into its potential for clinical use. More importantly, STA has been shown to be one of the most potent protein kinase inhibitors to date, operating by blocking the binding site of ATP to the kinase due to its hig her affinity. 137 This mode of inhibition, however, suffers the drawback of being promiscuous with respect to kinase binding selectivity. From a synthetic standpoint, the staurosporine aglycone should be accessible from the Au catalyzed cyclization/DA method ology. Shown below is a tentative

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104 retrosynthetic plan, where the key diene intermediate 3 99 is obtained from cyclization substrate 3 100 (Figure 3 22). The Diels Alder reaction between maleimide 3 98 and diene 3 99 would finish the core of staurosporine aglycone 3 97 Progress towards this end and initial investigations are currently underway. Figure 3 22. Retrosynthetic plan for staurosporine aglycone

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105 CHAPTER 4 CONCLUSION AND OUTLO OK In recent years, palladium and gold complexes have emerged as pow erful tools for the activation of unsaturated C C bonds towards attack by heteroatom nucleophiles. This mild and efficient method of forming carbon heteroatom bonds has attracted many research programs aimed at the development of methodologies that take a dvantage of this concept. Through transition metal catalysis, otherwise difficult transformations are achieved using operationally simple techniques. This has often been shown to result in high yielding reactions under mild conditions The work described here expands upon methodologies utilizing both monoallylic and monopropargylic diols (and their ethers) to form oxygen and nitrogen containing heterocycles with palladium and gold catalysis respectively. Our preliminary results demonstrated that hemiketa ls attack pendant allylic alcohols to form saturated spiroketals. The relevance of this approach was showcased in the synthesis of a spiroalkaloid natural product. Acortatarin A was successfully prepared using a novel palladium catalyzed spiroketalizatio n as the key step. A methodology developed in our group involving spiroketalization of m onopropargylic diols was extended to the synthesis of diene heterocycles. These dienes, which can be produced using mild conditions and a minimal number of synthetic s teps, were used as components in the Diels Alder reaction Despite only a moderately favorable outcome, the methodology exhibits a case wherein high molecular complexity can arise from simple starting materials Additionally, these dienes may serve as te mplates for the synthesis of ladder polyethers. In both examples, this protocol currently being applied to natural product synthesis by our group.

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106 The developments presented in this thesis help to exemplify the importance of transition metal catalysis in organic synthesis. Although many challenges remain in this area of chemistry, significant progress has been made towards understanding and applying some of the concepts described herein. Meanwhile, new methodologies are continuing to emerge.

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107 CHAPT ER 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 n itrogen. Anhydrous tetrahydrofuran (THF), acetonitrile, ether, dichloromethane (DCM), pentane, toluene were dried using a mBraun solvent purification system. Analytical t 60 F254 pre coated plates (EMD Chemicals Inc.). Flash column chromatography was performed using 230 400 Mesh 60 Silica Gel (Whatman Inc.). The eluents employed are reported as volume:volu me percentages. Melting points were recorded on a MEL TEMP capillary melting point apparatus. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using Varian Unity Inova 500 MHz and Varian Mercury s reported in parts per million (ppm) downfield relative to tetramethylsilane (TMS, 0.0 ppm) or CDCl 3 (7.26 ppm) CD 3 OD (3.31 ppm) and acetone d 6 (2.05) Coupling constants ( J ) are reported in Hz. Multiplicities are reported using the following abbreviatio ns: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; Carbon 13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded using a Varian Unity Inova 500 MHz spectrometer at 125 MHz. Chemical shift is reported in ppm relative to the carbon resonance of CDCl 3 (77.20 ppm) CD 3 OD (49.20 ppm) and acetone d 6 (29.8) Specific Optical ro tations were obtained on a JASCO P 2000 Series Polarimeter (wavelength = 589 nm). Infrared spectra were obtained on a Perkin Elmer Spectrum RX 1 at 0.5 cm 1 resolution and are

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108 repo rted in wave numbers. Cyclic voltammograms were obtained on a EG&G PAR model 263A potentiostat. High resolution mass spectra (HRMS) were obtained by The Mass Spectrometry Core Laboratory of University of Florida, and are reported as m/e (relative ratio). Accurate masses are reported for the molecular ion (M+) or a suitable fragment ion. 5.2 Chemical Procedures 5.2.1 Synthesis of Acortatarin A and Precursors 2,2,2 trichloro 1 (1 H pyrrol 2 yl)ethanone (2 77). To a solution of trichl oroacetyl chloride (9.80 mL, 88.0 mmol) in 13 mL of Et 2 O was added freshly distilled pyrrole (5.25 g, 78.0 mmol) in 39 mL Et 2 O via addition funnel over 1 h at r.t. The violet colored reaction was stirred for 3 h, then slowly neutralized with a saturated a queous solution of Na 2 CO 3 to reveal a red biphasic mixture. The resulting phases were separated, and the organics treated with activated carbon, filtered, and dried over MgSO 4 Filtration and concentrated revealed essentially pure title compound as a whi te solid (10.8 g, 65%) that satisfactorily matched all previously reported characterization data. 138 1 H pyrrole 2 carboxylic acid (2 78). Compound 2 77 (10.8 g, 50.9 mmol) was refluxed in 100 mL of EtOH H 2 O 1:1 with KOH (14.3 g, 254 mmol) on an oil bath at

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109 approximately half volume and made acidic with 1N HCl. The resulting mixture was extracted with Et 2 O (5x100 mL), dried over MgSO 4 and concentrated to yield a light brown solid (4.97 g, 88%) with spectral data in ag reement with the published literature. 139 N methoxy N methyl 1 H pyrrole 2 carboxamide (2 67). Method 1: A suspension of 2 78 (3.44 g, 31.0 mmol) in 45 mL of toluene was treated with SOCl 2 (5.67 mL, 78.2 mmol) and heated to reflux for 3 h. After the reflux period, the reaction was cooled then concentrated. The crude i ntermediate was then N O dimethylhydroxylamine hydrochloride (3.66 g, 37.5 mmol) followed by TEA (10.5 mL, 75.1 mmol) were added, and the reaction allowed warm to r.t. overnight. The reaction was quenched with 50 mL H 2 O and extracted with DCM (3x100 mL). The pooled organics were dried over Na 2 SO 4 filtered, then concentrated. Subjecting the residue to flash chromatography (40% EtOAc/hexanes) gave the Weinreb amide as an orange oil (3.81 g, 78%). Method 2: A solution of triphosgene (7.52 g, 25.3 mmol) in 35 mL toluene was added via dropping funnel to a stirred solution of N,N dimethylaniline (9.63 mL, 76 .0 mmol) and pyrrole (5.27 mL, 76 .0 mmol) in 75 allowed to stir at room temperature for 2 hours. In a separate flask was added triethylamine (25.4 mL, 182 mmol) to a suspension of N,O dimethylhydro xylamine hydrochloride (15) (8.89 g, 91.2 mmol) in 70 mL DCM, and the mixture stirred at room temperature for 30 minutes. The contents of this flask was filtered into a clean dropping

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110 funnel, the filter cake washed with DCM, and the solution added to the pyrrole mixture d to reach room temperature overnight. The crude mixture was concentrated, taken up in 150 mL EtOAc, and washed with a saturated aqueous solution of NaHCO 3 followed by H 2 O, then dried over Na 2 SO 4 and concentrated. The residue was purified by column chro matography (50% EtOAc/hexanes) to furnish th e product as a gray solid (11.4 g, 97%). R f = 0.47 (50% EtOAc/hexanes); MP 112 1 H NMR (500 MHz, CDCl 3 6.94 (m, 1H), 6.92 (ddd, J = 3.8, 2.4, 1.4 Hz, 1H), 6.45 6.13 (m, 1H), 3.78 (s, 3H), 3.35 (s, 3H); 13 C NMR (125 MHz, CDCl 3 7, 61.3, 33.2; IR (film): max 3269, 2974, 2937, 1755, 1690, 1597, 1547, 1438, 1296, 1178, 1104, 1045, 749; HRMS (ESI) calcd for C 7 H 10 N 2 O 2 Na [M+Na]+ 177.0642, found 177.0632. 5 formyl N methoxy N methyl 1 H pyrrole 2 carboxamide (2 79) and 1 formyl N methoxy N methyl 1 H pyrrole 2 carboxamide (2 80). To p yrrole 2 67 (1.0 0 g, 6.49 mmol) in DMF (4.3 0 of the Vilsmeier reagent (prepared by dropwise addition of 0.65 mL POCl 3 to 0.65 mL of the flask were cooled to room temperature, poured into 10 g crushed ice, and quenched by slowly adding 15 mL of saturated aqueous K 2 CO 3 followed by stirring for 15 minutes. The mixture was extracted with EtOAc, dried over N a 2 SO 4 and concentrated. Column chromatography (3 0% EtOAc/hexanes ) afforded compound 2 79 as a crystalline white

PAGE 111

111 solid (591 mg, 50 %). R f = 0.34 (50% EtOAc/hexanes) ; MP 118 1 H NMR (500 MHz, CDCl 3 6.95 (m, 1H), 6.94 6.92 (m, 1H), 3.79 (s, 3H), 3.39 (s, 3 H) ; 13 C NMR ( 125 MHz, CDCl 3 180.3, 160.1, 133.6, 129.4, 120.2, 115.6, 61.7, 33.3 ; IR (film): max 3240, 1677, 1612, 1391, 1216, 1193, 811, 751; HRMS (ESI) calcd for C 8 H 10 N 2 O 3 Na [M+Na] + 205.0584, found 2 05.0582. Compound 2 80 was isolated as a crystalline yellow solid (212 mg, 18%). R f = 0.40 (50% EtOAc/hexanes); MP 116 1 H NMR (500 MHz, CDCl 3 ) 9.81 (s, 1H), 7.68 (m, 1H), 7.08 (m, 1H), 6.31 (m, 1H), 3.65 (s, 3H), 3.32 (s, 3H). 5 (hydroxymethyl) N methoxy N methyl 1 H pyrrole 2 carboxamide (2 81). Pyrrole 2 79 (950 mg, 5.20 mmol) was dissolved in 26 mL EtOH and cooled to 0 4 (393 mg, 10.4 mmol) was added to the reaction vessel portionwise over 5 min, and the suspension was stirred for 2 h Quenching with 1 volume H 2 O, removal of EtOH under reduced pressure and extraction with EtOAc yielded the title compound as a pink solid (772 mg, 83%). R f = 0.60 (100% EtOAc); MP 140 1 H NMR (3 00 MHz, CDCl 3 J = 3.7 2.5 Hz, 1H), 6.16 (dd, J = 3.7, 2.5 Hz, 1H), 4.67 (d, J = 6.3 Hz, 2H), 3.78 (s, 3H), 3.51 (t, J = 6.5 Hz, 1H), 3.39 (s, 3H).

PAGE 112

112 5 (((tert butyldimethylsilyl)oxy)methyl) N methoxy N methyl 1H pyrrole 2 carboxamide (2 82). The alcohol 2 81 (583 mg, 4.77 mmol) was immediately taken up in 24 mL DCM and treated with imidazole (649 mg, 9.54 mmol) then TBSCl (1.07 g, 7.12 mmol). After stirring at r.t. for 16 h, the reaction was quenched with 10 mL of a saturated aqueous solution of NH 4 Cl and 25 mL H 2 O. The m ixture was extracted with EtOAc (3x75 mL), washed with brine, dried over MgSO 4 and concentrated to yield essentially pure title compound (1.10 g, 77%). R f = 0.55 (50% EtOAc/hexanes); MP 80 1 H NMR (500 MHz, CDCl 3 J = 3.8 2.5 Hz, 1H), 6.06 (dd, J = 3.7, 2.9 Hz, 1H), 4.72 (s, 2H), 3.77 (s, 3H), 3.34 (s, 3H), 0.92 (s, 9H). N methoxy N methyl 1 (2 methylallyl) 1 H pyrrole 2 carboxamide (2 83). Pyrrole 2 67 (8.58 g, 55.7 mmol) was added to a suspension of powdered KOH (12.5 g, 222 mmol) in 280 mL DMSO, and stirred at room temperature for 2 hours, after which time the solution took on a purple color. Me thallyl chloride (10.9 mL, 111 mmol) was added at the same temperature, and stirred an additional 3 hours. The reaction was quenched by addition of 200 mL ice H 2 O, and extracted with DCM 5x175 mL. The combined organic phases were washed with 3x100 mL brine, and dried over Na 2 SO 4 Concentration in vacuo and column chromatography (25% EtOAc/hexanes) of the crude oil yielded the product as an orange oil (11.6 g, 99%). R f = 0.70 (50% EtOAc/hexanes); 1 H NMR (300 MHz, CDCl 3

PAGE 113

113 4.79 (m, 2H), 3.64 (s, 3H), 3.30 (s, 3H), 1.68 (s, 3H) ; 13 C NMR (75 MHz, CDCl 3 162.9, 143.5, 127.9, 116.6, 110.9, 107.7, 61.2, 54.4, 34.2, 21.2, 20.3. 5 formyl N methoxy N methyl 1 (2 methyl allyl) 1 H pyrrole 2 carboxamide (2 84). POCl 3 (10.2 mL, 111 mmol) was added dropwise to 21.5 mL DMF with stirring at 5 added to pyrrole 2 83 (11.6 g, 55.7 mmol) in 280 mL D CM at bath, and allowed to reach room temperature overnight. The flask was then fit with a reflux condenser, and 60 mL of a saturated aqueous solution of NaHCO 3 was added slowly at first, then as fast as possible. The biphasic solu tion was refluxed for 30 minutes on the water bath, filtered, washed with brine 2x25 mL then concentrated under reduced pressure. The residue was subjected to column chromatography (25% EtOAc/hexanes) to provide the product as a yellow oil (6.15 g, 47 %). R f = 0.55 (50% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 J = 4.2 Hz 1H ), 6.73 (d, J = 4.6 Hz 1H ), 5.30 (s, 2H), 4.76 (s, 1H), 4.24 (s, 1H), 3.63 (s, 3H), 3.33 (s, 3H), 1.71 (s, 3H); 13 C NMR (125 MHz, CDCl 3 122.4, 114.4, 110.0, 61.3, 51.0, 33.8, 2 0.2.

PAGE 114

114 5 (hydroxymethyl) N methoxy N methyl 1 (2 methylallyl) 1 H pyrrole 2 carboxamide (2 85). Pyrrole 2 84 (5.91 g, 25.0 mmol) was dissolved in absolute ethanol and cooled to 4 (946 mg, 25.0 mmol) was added to the reaction vessel in several por tions, and the contents stirred for 1 hour. The reaction was quenched by the addition of 75 mL H 2 O and the mixture was stripped of ethanol under reduced pressure. The remaining slurry was taken up in EtOAc, separated, and the aqueous phase extracted wit h 3x25 mL EtOAc. The pooled organics were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo The concentrate was subjected to column chromatography (50% EtOAc/hexanes) to furnish the alcohol as a colorless oil (5.14 g, 86%). R f = 0.30 (50% EtOAc/hexanes); 1 H NMR (300 MHz, CDCl 3 (s, 2H), 4.75 (m, 1H), 4.56 (s, 2H), 4.13 (s, 1H), 3.64 (s, 3H), 3.30 (s, 3H), 1.74 (s, 3H), 1.64 (br s, 1H); 13 C NMR: 162.8, 144.4, 115.5, 109.2, 109.3, 109.0, 108.8, 61.3, 57.2, 5 0.4, 34.3, 20.6. 5 (triethylsilyloxymethyl) N methoxy N methyl 1 (2 methylallyl) 1 H pyrrole 2 carboxamide (2 86). Pyrrole 2 85 (186 mg, 0.78 mmol) and imidazole (106 mg, 1.56 mmol) were dissolved in 4.0 mL DMF then treated by dropwise addition of TESCl ( 0.20 mL, 1.17 mmol). After stirring overnight, the reaction was diluted with 4.0 mL H 2 O and extracted with Et 2 O (3x25 mL). The extracts were washed twice with brine, dried over Na 2 SO 4

PAGE 115

115 and concentrated. Purification of the crude material with flash chrom atography (35% EtOAc/hexanes) furnished the product as a colorless oil (221 mg, 81%). R f = 0.75 (50% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 ) 6.81 (d, J = 3.9 Hz, 1H), 6.08 (d, J = 3.9 Hz, 1H), 4.97 (s, 2H), 4.72 (m, 1H), 4.58 (s, 1H), 4.10 (m, 1H), 3.63 (2, 3H), 3.30 (2, 3H), 1.72 (dd, J = 1.4, 0.8 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9 H), 0.60 (q, J = 7.9 Hz, 6 H); 13 C NMR (125 MHz, CDCl 3 ) 162.9, 143. 6 137.7, 124.3, 115. 5 115.5, 109.2, 109.1, 108. 3 108.1, 61. 2 61. 1 57. 6 57. 5 57.4, 50.5, 34.4, 34. 4 20. 6 20.5 7 0 6.9, 6.7, 4. 7 5 (hydroxymethyl) N methoxy N methyl 1 (2 oxopropyl) 1 H pyrrole 2 carboxamide (2 87 ). To pyrrole 2 8 6 (35 mg, 0.10 mmol) in H 2 O dioxane (2:1, 2.4 mL) was added OsO 4 (45 L, 4 % aq. solution) followed by NaIO 4 (128 m g 0.60 m mol ) portionwise over 30 minutes. Stirring was continued overnight, and the OsO 4 destroyed by adding 2 mL of a saturated aqueous solution of Na 2 SO 3 After stirring for 1 h at room temperature, the slurry was filtered, extracted with EtOAc, washed with br ine and dried over Na 2 SO 4 The organic extracts were concentrated then chromatographed (75% EtOAc / hexanes) to afford the title compound as a 2.5:1 mixture of keto alcohol to the corresponding hemiketal ( 7.0 m g, 28 %). R f = 0.12 (50% EtOAc/hexanes); 1 H NM R (300 MHz, CDCl 3 major: 6.91 (d, J = 4.0 Hz 1H ), 6.16 (d, J = 4.0 Hz 1H ), 5.18 (s, 2H), 4.53 (s, 2H), 3.66 (s, 3H), 3.27 (s, 3H), 2.23 (s, 3H); minor: 6.97 (d, J = 4.1 Hz 1H ), 5.91 (d, J = 4.2 Hz

PAGE 116

116 1H ), 5.00 (d, J = 14.9 Hz 1H ), 4.86 (m, 1H), 4.79 ( d, J = 14.9 Hz 1H ), 4.60 (d, J = 14.3 Hz 1H ), 3.68 (s, 3H), 3.29 (s, 3H), 1.55 (s, 3H). 1 (2,3 dihydroxy 2 methylpropyl) N methoxy N methyl 5 (((triethylsilyl)oxy)methyl) 1 H pyrrole 2 carboxamide (2 88). To pyrrole 2 86 (98 mg, 0.28 mmol) in THF H 2 O (1 0:1, 3.0mL) at r.t. was added NMO (84 mg, 0.33 mmol) followed by OsO 4 ( 35 L, 4 % aq. solution) The reaction was stirred for 20 h, then quenched by the addition of solid Na 2 SO 3 followed by an additinoal 1 h of stirring. The slurry was diluted with H 2 O, extracted with EtOAc (3x20 mL), and the organics dried over Na 2 SO 3 The s olvent was stripped off in vacuo to yield essentially pure material (68 mg, 64%). R f = 0.10 (50% EtOAc/hexanes); 1 H NMR ( 5 00 MHz, CDCl 3 6.90 (d, J = 4.0 Hz, 1H), 6.13 (d, J = 4.0 Hz, 1H), 4.67 (s, 2H), 3.68 (s, 3H), 3.34 (s, 3H), 1.17 (s, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 7.7 Hz, 6H). 13 C NMR (125 MHz, CDCl 3 ) 163.8, 137.9, 124.5, 116.7, 116.6, 110.0, 109.8, 73.0, 68.0, 61.3, 61.2, 57.4, 57.3, 51.1, 34.5, 34.5, 23.9, 6.9, 6.9, 4.5, 4.5. N methoxy N methyl 1 (2 oxopropyl) 5 (((triethylsilyl)o xy)methyl) 1 H pyrrole 2 carboxamide (2 65).

PAGE 117

117 Pyrrole 2 87 (700 mg, 2.91 mmol) and imidazole (396 mg, 5.83 mmol) were dissolved in 15 mL DMF and treated with TESCl (0.73 mL, 4.37 mmol) via dropwise addition. After 16 h, the reaction was quenched with 10 mL H 2 O, diluted with 50 mL EtOAc and separated. The organic phase was dried over Na 2 SO 4 concentrated, then chromatographed (50% EtOAc/hexanes) to yield the title compound as a colorless oil (590 mg, 57%). R f = 0.50 (50% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 J = 4.0 Hz 1H ), 6.10 (d, J = 4.0 Hz 1H ), 4.57 (s, 2H), 3.67 (s, 3H), 3.20 (s, 3H), 2.14 (s, 3H), 0.91 (t, J = 8.0 Hz 9H ), 0.59 (q, J = 8.0 Hz 6H ); 13 C NMR (125 MHz, CDCl 3 204.1, 162.5, 137.2, 116.0, 108.9, 61.2, 57.4, 55.7, 33.9, 27.0, 21.3, 6.9, 4.6. ( E ) 4 methoxybut 2 enal (2 66). was added cis 1,4 butenediol (6.58 mL, 80.0 mmol) and the mixture stirred for 20 min. Iodomethane (2.49 mL, 40.0 mmol) was ad ded at the same temperature, and the reaction allowed to warm to room temperature overnight. The reaction was quenched by adding 50 mL H 2 O, and extracted with EtOAc followed by drying over Na 2 SO 4 The solvent was removed in vacuo and the residue purified by column chromatography (50% Et 2 O / hexanes) to furnish ( Z ) 4 methoxy 2 buten 1 ol (2.90 g, 71%). The alcohol was taken up in DCM (140 mL) and to the reaction vessel was sequentially added 6.70 g celite, 1.5 g 4 MS, and 6.70 g PCC (in several portions) The contents of the flask were stirred at room temperature for 1 h, then filtered over florisil and the filter cake washed with Et 2

PAGE 118

118 20 torr furnished the trans aldehyde (411 mg, 14%) with spectral data mat ching those previously reported. 86 N methoxy N methyl 1 (prop 2 yn 1 yl) 1 H pyrrole 2 carboxamide ( 2 92 ). Pyrrole 2 67 (2.25 g, 14.6 mmol) was added to a suspension of powdered KOH (3.27 g, 58.3 mmol) in 73 mL DMSO, and sti rred at room temperature for 2 hours. Propargyl bromide (3.14 mL, 29.1 mmol) was added at the same temperature, and stirred an additional 15 min. The reaction was quenched by addition of 50 mL ice H 2 O, and extracted with DCM 5x50 mL. The combined organi c phases were washed with 3x20 mL brine, and dried over Na 2 SO 4 Concentration under reduced pressure and purification (25% EtOAc/hexanes) of the crude oil by column chromatography yielded the product as an orange oil (2.4 0 g, 86%). R f = 0.40 (30% EtOAc/he xanes); 1 H NMR (500 MHz, CDCl 3 ) J = 2.5 2H ), 3.68 (s, 3H), 3.33 (s, 3H), 2.38 (t, J = 2.5 Hz 1H ); 13 C NMR (125 MHz, CDCl 3 127.0, 122.9, 117.5, 108.4, 79.2, 77.5, 61.3, 38.8, 33.9. 5 formyl N methoxy N methyl 1 (prop 2 yn 1 yl) 1 H pyrrole 2 carboxamide ( 2 93 ).

PAGE 119

119 POCl 3 (2.29 mL, 25.0 mmol) was added dropwise to 4.83 mL DMF with stirring at 5 added to pyrrole 2 92 (2.40 g, 12.5 mmol) in 62 mL DCM at and allowed to reach room temperature overnight. The flask was then fit with a reflux condenser, and 15 mL of a saturated aqueous solution of NaHCO 3 was added slowly at first, then as fast as possible. The biphasic sol ution was refluxed for 30 minutes on the water bath, filtered, washed with brine 2x10 mL then concentrated under vacuum The residue was subjected to column chromatography (30% EtOAc/hexanes) to provide the product as a colorless oil (1.03 g, 37 %). R f = 0.64 (50% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 J = 4.0 Hz 1H ), 6.77 (d, J = 4.2 Hz 1H ), 5.60 (d, J = 2.0 Hz 2H ), 3.64 (s, 3H), 3.38 (s, 3H), 2.25 (s, 1H); 13 C NMR (125 MHz, CDCl 3 180.8, 123.3, 115.2, 100.0, 79.5, 72.2, 61.9, 36.0 5 (hydroxymethyl) N methoxy N methyl 1 (prop 2 yn 1 yl) 1 H pyrrole 2 carboxamide ( 2 94 ). Pyrrole 2 93 (1.03 g, 4.68 mmol) was dissolved in absolute ethanol and cooled to 4 (177 mg, 4.68 mmol) was added to the reaction vessel in several portions, and the contents stirred for 1 hour The reaction was quenched by the addition of 10 mL H 2 O and the mixture was stripped of ethanol under reduced pressure. The remaining slurry was taken up in 150 mL EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to furnish the al cohol as an colorless oil (1.00 g, 96%) which

PAGE 120

120 was used without further purification and characterized as the silyl ether 2 95 R f = 0.18 (50% EtOAc/hexanes). N methoxy N methyl 1 (prop 2 yn 1 yl) 5 ((triethylsilyl)methyl) 1 H pyrrole 2 carboxamide ( 2 95 ) Imidazole (611 mg, 9.00 mmol) and pyrrole 2 94 (1.00 g, 4.49 mmol) were dissolved in 22 mL DCM, then treated with triethylsilyl chloride (1.13 mL, 6.74 mmol) via dropwise addition. The mixture was stirred at room temperature during 15 h, then quenched with 10 mL H 2 O and diluted with DCM and separated. Concentration of the organic phase under high vacuum afforded essentially pure title compound (1.19 g, 79%). R f = 0.82 (50% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 Hz 1H), 6.06 ( d, J = 3.6 Hz 1H ), 5.29 (d, J = 2.5 Hz 2H ), 4.74 (s, 2H), 3.66 (s, 3H), 3.34 (s, 3H), 2.23 (s, 1H), 0.94 (t, J = 7.5 Hz 9H ), 0.62 (q, J = 8.0 Hz 6H ); 13 C NMR (125 MHz, CDCl 3 71.7, 61.3, 57.3, 34.9, 34.0, 6.9, 4.6 ( E ) 7 chloro 1 methoxyhept 2 en 5 yn 4 ol ( 2 97 ). To a solut ion of propargyl chloride (0.35 mL, 4.8 mmol) in Et 2 O at added n BuLi (2.8 mL, 4.4 mmol, 1.6 M in hexanes) dropwise and the mixture stirred for

PAGE 121

121 0.5 h. A solution of aldehyde 2 66 (400 mg, 4.0 mmol) in 5 mL Et 2 O was then added at the same temperature. After stirring for 1 additional hour, the reaction was quenched via addition of 5 mL of a saturated aqueous solution of NH 4 Cl and then extract ed with EtOAc. The pooled organics were washed with brine and dried over Na 2 SO 4 to afford, after concentration, the crude product, which was of sufficient pur ity to use in the next step (610 mg, 87%). 1 H NMR (300 MHz, CDCl 3 1H), 4.18 (s, 2H), 3.80 (d, J = 3.0 Hz, 2H ), 3.37 (s, 3H). ( E ) tert butyl((7 chloro 1 methoxyhept 2 en 5 yn 4 yl)oxy)dimethylsilane (2 98). To propargyl alcohol 2 97 (367 mg, 2.10 mmol) and imidazole (286 mg, 4.20 mmol) in 10.5 mL THF was added TBSCl (411 mg, 2.73 mmol). After stirring overnight at r.t., the contents of the flask were quenched with H 2 O, diluted with EtOAc, separated, and the organics dried over Na 2 SO 4 Purification via column chromatography (5% E tOAc/hexanes) furnished the title compound as a colorless oil (623 mg, 99 %) R f = 0.69 (10% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 5.90 (dtd, J = 15.3, 5.5, 1.5 Hz, 1H), 5.76 (ddt, J = 15.3, 5.0, 1.4 Hz, 1H), 4.97 (d, J = 3.4 Hz, 1H), 4.17 (d, J = 2.1 Hz, 2H), 3.95 (d, J = 5.6 Hz, 2H), 3.34 (s, 3H), 0.93 (s, 9H), 0.20 (s, 6H); 13 C NMR (125 MHz, CDCl 3 131.8, 127.8, 86.4, 80.2, 7 2.2, 68.0, 63.0, 58.4, 30.7, 26.5, 26.0, 18.6.

PAGE 122

122 ( E ) ((7 chloro 1 methoxyhept 2 en 5 yn 4 yl)oxy)triisopropylsilane (2 99). To propargyl alcohol 2 97 (611 mg, 3.50 mmol) in 17.5 mL THF were sequentially added pyridine (0.57 mL, 7.00 mmol), DMAP (43 mg, 0.3 5 mmol), and TIPSOTf (1.03 with a saturated aqueous solution of NH 4 Cl, and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrat ed. The crude residue was subjected to flash chromatography (5% EtOAc/hexanes) to furnish the product as a colorless oil (627 mg, 54%). R f = 0.71 (10% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 5.92 (m, 1H), 5.79 (m, 1H), 5.05 (m, 1H), 4.16 (d, J = 2.0 Hz 2H), 3.96 (dt, J = 1.1, 6.0 Hz 2H ), 3.34 (s, 3H), 1.15 (m, 3H), 1.08 (m, 18H) ; 13 C NMR (125 MHz, CDCl 3 ) 132.1, 127.6, 86.6, 80.0, 72.3, 63.0, 58.3, 30.5, 18.0, 12.4. ( E ) N methoxy 1 (7 methoxy 4 ((triisopropylsilyl)oxy)hept 5 en 2 yn 1 yl) N methyl 1 H pyrrole 2 carboxamide (2 1 00 ). Pyrrole 2 67 (288 mg, 1.87 mmol) was added to a suspen sion of powdered KOH (210 mg, 3. 75 mmol) in 10 mL DMSO, and stirred at room temperature for 2 h. Propargyl chloride 20 (620 mg, 1.87 mmol) was added at the same temper ature, and stirred an additional 2 h. The reaction was quenched by addition of 5 mL ice H 2 O, diluted with DCM 75 mL and separated. The organic phase was dried over Na 2 SO 4 then concentrated. The crude material was subjected to column chromatography (25%

PAGE 123

123 EtOAc/hexanes) to afford the product as a yellow oil (263 mg, 31%). R f = 0.14 (10% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 7.08 (m, 1H), 6.94 (m, 1H), 6.15 (m, 1H), 5.90 (m, 1H), 5.78 (m, 1H), 5.21 (m, 2H), 5.03 (m, 1H), 3.94 (dt, 2H, J = 1.2, 5.6 Hz), 3.67 (s, 3H), 3.33 (s, 3H), 3.32 (s, 3H), 1.10 (m, 3H), 1.05 (t, J = 7.0 Hz 18H ) ; 13 C NMR (125 MHz, CDCl 3 132.5, 127.3, 126.9, 117.3, 108.1, 85.4, 80.5, 72.3, 63.3, 61.3, 58.2, 39.0, 33.9, 18.2, 12.4. ( E ) 1 (4 (( tert butyldimethylsilyl)oxy) 7 methoxy hept 5 en 2 yn 1 yl) 5 formyl N methoxy N methyl 1 H pyrrole 2 carboxamide (2 102). Pyrrole 2 79 (440 mg, 2.40 mmol), K 2 CO 3 (1.00 g, 7.20 mmol), propargyl chloride 2 98 (830 mg, 2.90 mmol), and a catalytic amount of 18 crown 6 were dissolved in 2.5 mL aceto nitrile and refluxed for 48 h. After this time, the reaction was diluted with EtOAc and washed once with H 2 O, then brine, and finally dried over Na 2 SO 4 and concentrated. Purification of the crude residue by flash chromatography (25% EtOAc/hexanes) produc ed the desired compound (705 mg, 68%), which was characterized after two subsequent steps as 2 104 R f = 0.63 (50% EtOAc/hexanes).

PAGE 124

124 ( E ) 1 (4 (( tert butyldimethylsilyl)oxy) 7 methoxyhept 5 en 2 yn 1 yl) 5 (hydroxymethyl) N methoxy N methyl 1 H pyrrole 2 ca rboxamide (2 103) To compound 2 102 (700 mg, 1.62 mmol) 4 (61.0 mg, 1.62 mmol) in two portions, and the mixture stirred for 1.5 h. The flask contents were quenched with 8 mL H 2 O, diluted with EtOAc, and the organic phase separated. The organics were washed with brine, dried over Na 2 SO 4 and concentrated to yield the crude title compound (500 mg, 71%), to be carried into the following step for characterization. R f = 0.32 (50% EtOAc/hexanes). ( E ) 1 (4 hydroxy 7 methoxyhept 5 en 2 yn 1 yl) 5 (hydroxymethyl) N methoxy N methyl 1 H pyrrole 2 carboxamide (2 104). Crude silyl ether 2 103 (500 mg, 1.15 mmol) was stirred in 6 mL THF and TBAF (1.72 mL, 1.0M in THF) overnight. Addition of H 2 O quenched the reaction, and the mixture was diluted with EtOAc, followed by separation, and con centration under reduced pressure. The resulting material was purified by column chromatography (100% EtOAc) to yield the title compound as a viscous orange syrup (242 mg, 65%). R f = 0.39 (100% EtOAc); 1 H NMR (500 MHz, CDCl 3 6.80 (d, J = 3.9 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H), 5.87 (dtd, J = 15.4, 5.5, 1.3 Hz, 1H), 5.75 (ddt, J = 15.4, 5.4, 1.4 Hz, 1H), 5.26 (dd, J = 1.8, 1.0 Hz, 2H), 4.81 (dd, J = 5.0, 1.5 Hz, 1H), 4.67 (s, 2H), 3.90 (dd, J = 5.4, 1.2 Hz, 2H), 3.64 (s, 3H), 3.31 (s, 3H), 3.30 (s, 3H); 13 C NMR (125 MHz, CDCl 3

PAGE 125

125 162.5, 137.2, 131.5, 128.8, 124.2, 116.0, 109.4, 83.0, 82.4, 72.1, 62.2, 61.4, 58.3, 56.7, 35.2, 34.0. d 2,3 O benzylidene L tartrate (2 109). According to a known procedure, diethyl L tartrate (42.8 mL, 250 mmol), benzaldehyde (25.4 mL, 25 0 mmol) and p TsOH monohydrate were combined with 400 mL cyclohexane in a 500 mL round bottom flask equipped with a Dean Stark apparatus. The biphasic mixture attained complete solubility at reflux temperature, which was maintained during 16 h until 9.0 m L (theoretical) of H 2 O was collected. The reaction vessel was then cooled and concentrated under reduced pressure. The crude syrup was dissolved in 200 mL Et 2 O, and washed successively with 100 mL saturated aqueous KHCO 3 and 2x100 mL H 2 O. The organic ph ase was separated, dried over MgSO 4 filtered, and concentrated on the hi vac. After trituration of the resulting wet solids with 75 mL hexanes, a yellow solid was able to be filtered off (39.1 g, 53%) with analytical data matching those reported previous ly. 96 ( +) 2 O benzyl L threitol (2 110). A 2 L 3 neck flask equipped with a mechanical stirrer, reflux condenser and addition funnel was charged with LAH (17.9 g, 472 mmol) and 182 mL of Et 2 O at 30 on the dry ice isopropanol bath. A solution of AlCl 3 (62.9 g, 472 mmol) in 146 mL Et 2 O was then added via addition funnel over 40 min. Immediately after the addition was

PAGE 126

126 complete, 146 mL of DCM was added quickly, followed by acetal 2 109 (70.8 g, 240 mmol) in 146 mL DCM over 30 min. The reaction was allowed to reach r.t. during 1 h, then refluxed for 2 h. The flask contents were cooled to 2 O, followed by 68 g KOH in 100 mL H 2 O were slowly added, and stirred until the flask con tents turned from gray to white. THF (200 mL) was then added, and the mixture brought to reflux again for 1 h. The solids were collected via vacuum filtration on the Bchner funnel, and extracted using the Soxhlet with 300 mL DCM for 3 days. The origina l filtrate and the Soxhlet washings were combined, and washed with 50 mL 1N HCl to provide 41.9 g, 82% of the desired benzylated threitol. The spectral data of this compound satisfactorily matched those reported in the literature, and the product was used without further purification. 96 ( ) 2 O benzyl L glyceraldehyde (2 111). To triol 2 110 (14.1 g, 68.3 mmol) in 155 mL H 2 O was added NaIO 4 (14.6 g, 68.3 mmol) over 45 min. in ca. 1 g portions at r.t., and the mixture stirred an additional 2 h at the same temperature. After this time, the pH of the solution was brought to 7.0 by adding solid K 2 CO 3 The mixture was then extracted with DCM 3x200 mL, dried over MgSO 4 and concentrated. The crude oil was purified by distillatio Hg to yield a colorless compound (6.67 g, 54%), which thickened upon standing due to oligomerization. The compound was dissolved in THF and used immediately in the following step.

PAGE 127

127 e [R ( E )] 4 O benzyl 4,5 dihydroxy 2 pentenoa te (2 113). triethy lphosphonoacetate (2 112) (12.4 mL, 62.6 mmol) over 20 min, ultimately resulting in a transparent solution. The reaction mixture was cooled down to al dehyde 2 111 (6.67 g, 36.8 mmol) in 45 mL THF was then added over a 20 min period. The reaction was stirred an additional 15 min at the same temperature, brought with 9 0 mL of a saturated aqueous solution of NH4Cl, then extracted with Et2O in 300, 120, and 120 mL portions. The pooled extracts were washed with 100 mL of a saturated solution of NaHCO3 brine 1:1, then dried over MgSO4. Filtration and concentration of the organic solution yielded a residue, which was purified by column chromatography (10 30% EtOAc/hexanes) to furnish the title compound as a pale yellow oil (7.93 g, 86%). Analytical data satisfactorily matched those reported previously. 96 ethyl 1,3 dithiane 2 carboxylate (2 114). According to a known procedure, a mixture of propanedithiol (5.02 mL, 50.0 mmol) and ethyl diethoxyacetate (9.00 mL, 50.0 mmol) in 10 mL CHCl 3 were added dropwise, over 15 min, to a solution of BF 3 OE t 2 (12.3 mL, 100.0 mmol) in 30 mL CHCl 3 The reaction mixture was boiled for 30 min more, then cooled and quenched with 40 mL

PAGE 128

128 H 2 O, then 40 mL aqueous 20% K 2 CO 3 The organic phase was separated, dried over MgSO 4 filtered, then concentrated. The resultin g orange oil was purified by distillation those in the published literature. 97 ( R E ) 4 (benzyloxy) 5 bromopent 2 en 1 ol ( 2 115) A s olution of ( R E ) ethyl 4 (benzyloxy) 5 hydroxypent 2 enoate ( 2 113 ) (250 mg, 1.0 mmol) and CBr 4 (660 mg, 2.0 mmol) in 6 mL of dichloromethane was treated with PPh 3 a dry ice / acetone bath. DIBAL H 1.0 M in toluene (5.0 mL, 5.0 mmol) was then added dropwise, and the mixture stirred for 30 min. The reaction was quenched and allow ed to rise to ambient temperature over 2 h. The biphasic system was separated, and the aqueous phase extracted with DCM (3 x 20 mL). The combined organics were dried over Na 2 SO 4 filtered, and concentrated in vacuo Purification of the crude material by flash chromatography (40 % EtOAc/hexanes) provided the allylic alcohol as a colorless oil (210 mg, 79 %). R f = 0.59 (60% EtOAc/hexanes); 25 D = 31.79 ( c 1, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.38 7.33 (m, 5 H), 5.95 (dtd, J = 15.6, 5.1, 0.9 Hz, 1H), 5.68 (ddt, J = 15.6, 7.4, 1.7 Hz, 1H), 4.56 (dd, J = 73.5, 11.9 Hz, 2H), 4.21 (d, J = 3.5 Hz, 2 H), 4.06 (dddd, J = 7.4 6.4, 5.2, 0.8 Hz, 1H), 3.53 3.34 (m, 2H), 1.44 ( br s, 1H) ; 13 C NMR ( 125 MHz, CDCl 3 138.1, 134.6, 128.7, 128.6, 128.1,

PAGE 129

129 128.0 78.7, 71.1, 62.9, 35.1 ; IR (film): max 3379, 3030, 2866, 1454, 1217, 1090, 739, 698 ; HRMS (ESI) calcd for C 12 H 15 BrO 2 Na 2 [M+2Na] + 317.0155, found 317.0699. ( R E ) (((1 bromo 5 methoxypent 3 en 2 yl)oxy)methyl)benzene (2 116). To a suspension of NaH (660 mg, allylic alcohol 2 115 (7.46 g, 27.5 mmol) in 69 mL THF over 10 min., and stirred an additional 5 min. To the reaction vessel was added iodomethane (4.28 mL, 68.8 mmol) dropwise, followed by stirring for 45 min. a t the same temperature. The reaction was quenched with a saturated aqueous solution of NH 4 Cl, and extracted with DCM (3 x 150 mL). The pooled organics were concentrated under reduced pressure and chromatographed on silica gel (7% EtOAc/hexanes) to afford the title compound as a colorless oil (4.82 g, 62 %). R f = 0.58 (25% EtOAc/hexanes) 25 D = 28.56 ( c 1.91, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.41 7.29 (m, 5H), 6.04 5.84 (m, 1 H), 5.69 (ddtd, J = 15.6, 7.4, 1.5, 0.5 Hz, 1 H), 4.58 (dd, J = 91.0, 11.9 Hz, 2 H), 4.07 (dddt, J = 7.2, 6.5, 5.1, 0.7 Hz, 1 H), 4.00 (ddd, J = 5.5, 1.5, 0.6 H z, 2H), 3.50 3.39 (m, 2 H), 3.39 ( s 3H ) ; 13 C NMR ( 125 MHz, CDCl 3 138.1, 132.2, 130.2, 128.7, 128.1, 128.1, 129.0, 78.8, 72.3, 71.1, 58.4, 35.2 ; IR (film): max 3030, 2927, 2870, 1452, 1383, 1102, 1066, 974, 738, 698 ; HRMS (ESI) calcd for C 13 H 17 BrO 2 Na [M MeOH +Na] + 275 .0 047 found 275 0901

PAGE 130

130 ( S E ) ethyl 2 (2 (benzyloxy) 5 methoxypent 3 en 1 yl) 1,3 dithiane 2 carboxylate ( 2 117 ). Ethyl 1,3 dithiane 2 carboxylate ( 2 114 ) (4.88 g, 25.2 mmol) in 35 mL DMF was added slowly to a stirred suspension of NaH (606 mg, 25.2 mmol) and cat. t BuOH in 35 Bromide 2 116 (3.60 g, 12.6 mmol) in 35 mL DMF was then added dropwise to the reaction mixture, and the temperature was maintained for 5 h. After the reacti on was complete by TLC analysis, the solution was diluted with Et 2 O and poured into a cold saturated aqueous solution of NH 4 Cl. The organic phase was separated, and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dri ed over Na 2 SO 4 and concentrated. Flash chromatography (5 10% EtOAc/hexanes) of the crude material afforded the title compound as a colorless oil (3.68 g, 73 %). R f = 0.41 (25% EtOAc/hexanes); 25 D = 9.91 ( c 0.76, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) 7.46 7.14 (m, 5H), 5.96 5.76 (m, 1H), 5.72 5.59 (m, 1 H), 4.42 (dd, J = 67.2, 11.0 Hz, 2 H), 4.25 (td, J = 8.3, 3.5 Hz, 1H), 4.13 3.84 (m, 4 H), 3.36 ( s, 3H), 3.31 ( ddd, J = 14.2, 11.6, 2.6 Hz,, 1 H), 3.12 (ddd, J = 14.2, 11.6, 2.6 Hz, 1 H), 2.71 (ddd, J = 14.3, 5.2, 3.1 Hz, 2 H), 2.58 (dd, J = 14.4, 9.0 Hz, 1 H), 2.23 (dd, J = 14.4, 3.7 Hz, 1 H), 2.13 (ddt, J = 13.7, 5.3, 2.6 Hz, 1H), 2.01 1.82 (m, 1 H), 1.18 (t, J = 7.1 Hz, 3 H) ; 13 C NMR ( 125 M Hz, CDCl 3 170.8, 138.5, 132.6, 130.0, 128.3, 127.6, 76.3, 72.5, 71.0, 62.0, 58.3, 52.7, 44.9, 28.1, 28.0, 25.1, 14.2 ; IR (film): max 2979, 2927, 1723, 1204, 1094, 1027, 737, 698 ; HRMS (ESI) calcd for C 20 H 28 O 4 S 2 Na [M+Na] + 419.1329, found 419.1326.

PAGE 131

131 ( S E ) (2 (2 (benzyloxy) 5 methoxypent 3 en 1 yl) 1,3 dithian 2 yl)methanol ( 2 118 ) To ester 2 117 mg, 22.8 mmol) in 3 portions over 5 min. After 2.5 h, the reaction was quenched at the same temperature v ia slow addition of 60 mL of a saturated aqueous solution of mL). The organic extracts were dried over Na 2 SO 4 filtered, and concentrated yieldi ng an essentially pure co mpound, which was used without further purification (3.23 g, 99 %). R f = 0.20 (25% EtOAc/hexanes) 25 D = 32.89 ( c 0.26, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.14 (m, 5H), 5.83 (dtd, J = 15.6, 5.5, 0.7 Hz, 1H), 5.68 (ddt, J = 15.6, 7.8, 1.4 Hz, 1H), 4.46 (dd, J = 92.7, 11.1 Hz, 2H), 4.30 4.19 (m, 2H), 3.96 (d, J = 6.2 Hz, 2H), 3.90 3.69 (m, 2H), 3.36 (s, 1H), 3.20 (t, J = 7.3 Hz, 1H), 2.87 (dddd, J = 29.0, 14.4, 10.2, 3.0 Hz, 2H), 2.75 2.57 (m, 2H), 2.25 (dd, J = 15.4, 9.1 Hz, 1H), 2.14 1.96 (m, 2H), 1.91 (dtt, J = 13.4, 10.1, 3.2 Hz, 1H). 13 C NMR ( 125 MHz, CDCl 3 137.6, 132.7, 130 .0, 128.7, 128.4, 128.1, 76.5, 72.4, 71.0, 65.6, 58.4, 53.5, 44.2, 26.4, 25.9, 25.4 ; IR (film): max 3454, 2930, 2360, 2341, 1063, 981, 909, 738, 699 ; HRMS (ESI) calcd for C 18 H 26 O 3 S 2 Na [M+Na] + 377.1223, found 377.1221. ( S E ) 4 (benzyloxy) 1 hydroxy 7 met hoxyhept 5 en 2 one ( 2 119 ). To dithiane 2 1 1 8 (78 mg, 0.22 mmol) in THF MeOH H 2 O 5:9:1 (1.5 mL) was added [bis(trifluoroacetoxy)iodo]benzene 100 The reaction mixture was quenched af ter 45 min. with a 1.0 mL saturated aqueous

PAGE 132

132 solution of NaHCO 3 and then extracted with Et 2 O. The crude product was purified by flash chromatography (40 % EtOAc/hexanes) to furnish the deprotected ketone (55 mg, 95 %). R f = 0.35 (50% EtOAc/hexanes) 25 D = 35.88 ( c 2.40, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.43 7.14 (m, 5 H), 5.85 (dtd, J = 15.8, 5.3, 0.7 Hz, 1 H), 5.65 (ddt, J = 15.6, 7.7, 1.4 Hz, 1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.41 4.28 (m, 2 H), 4.25 (t, J = 5.1 Hz, 2 H), 3.96 (dd, J = 5.3, 1.5 Hz, 2H ), 3.36 (s, 3 H), 3.10 (t, J = 5.0 Hz, 1 H), 2.79 (dd, J = 14.8, 8.8 Hz, 1 H), 2.52 (dd, J = 14.9, 4.3 Hz, 1 H) ; 13 C NMR ( 125 MHz, CDCl 3 208.0, 137.9, 131.2, 130.9, 128.6, 128.0, 100.1 75.9, 72.2, 70.9, 69.7, 58.4, 40.0 ; IR (film): max 3393, 2783, 1723, 1 090, 1070, 740, 699 ; HRMS ( ESI ) calcd for C 15 H 20 O 4 Na [M+Na] + 287.1254, found 287.1248. ( S E ) 4 (benzyloxy) 1 bromo 7 methoxyhept 5 en 2 one (2 120). To alcohol 2 119 (1.26 g, 4.77 mmol) and CBr 4 (1.90 g, 5.72 mmol) in 48 mL DCM was added PPh 3 (1.50 g, 5.72 mmol). The solution changed color from yellow to dark brown, then orange after stirring for 1 h. The reaction mixture was diluted with Et 2 O, then filtered over a pad of silica, and the filter cake washed with additional Et 2 O. The filtrate and washi ngs were concentrated, then chromatographed (20 % EtOAc/hexanes) to yield the title compound as a colorless oil (1.13 g, 72 %). R f = 0.32 (20% EtOAc/hexanes) 23 D = 6.06 ( c 1, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.41 7.20 (m, 5 H), 5.88 (dtd, J = 15.6 5.4, 0.9 Hz, 1 H), 5.68 (ddt, J = 15.6, 7.7, 1.5 Hz, 1 H), 4.59 (d, J = 11.3 Hz, 1 H), 4.43 4.31 (m, 2 H), 3.98 (dd, J = 5.5, 1.4 Hz, 2 H), 3.95 (d, J = 0.4 Hz, 2 H), 3.38 (s, 3 H), 3.02 (dd, J = 15.4, 8.7 Hz, 1 H), 2.75 (dd, J = 15.4, 4.3 Hz, 1 H) ;

PAGE 133

133 13 C NMR ( 12 5 MHz, CDCl 3 199.8, 138.1, 131.3, 130.8, 128.7, 128.1, 128.0, 76.3, 72.3, 71.0, 58.5, 46.2, 35.9 ; IR (film): max 2873, 2825, 1725, 1587, 1452, 1383, 1093, 1069, 739, 699 ; HRMS (ESI) calcd for C 15 H 19 BrO 3 Na [M+Na] + 349.0418, found 349.0400. ( S E ) 1 (4 (benzyloxy ) 7 methoxy 2 oxohept 5 en 1 yl) 5 formyl N methoxy N methyl 1 H pyrrole 2 carboxamide ( 2 121 ). To pyrrole 2 79 (128 mg, 0.70 mmol) and bromide 2 120 (229 mg, 0.70 mmol) in 5 mL MeCN was added Cs 2 CO 3 (228 mg, 0. The mixture was stirred for 8 h, then diluted with EtOAc (50 mL) and washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 concentrated, then chromatographed (33 50% EtOAc/hexanes) to yield 236 mg, 79 % of the aldehyde. R f = 0.51 (50% EtOAc 23 D = +11.53 ( c 0.1, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) 9.59 (s, 1H), 7.38 7.29 (m, 5H), 6.95 (d, J = 4.2 Hz, 1H), 6.86 (d, J = 4.2 Hz, 1H), 5.96 5.54 (m, 4H), 4.56 (d, J = 11.4 Hz, 1H), 4.42 (d, J = 11.4 Hz, 1H), 4.40 4.32 (m, 1H), 3.95 (dd, J = 5.6, 1.5 Hz, 2H), 3.63 (s, 3H), 3.34 (s, 3H), 3.26 (s, 3H), 2.92 (dd, J = 15.9, 8.0 Hz, 1H), 2.69 (dd, J = 15.9, 4.8 Hz, 1H) ; 13 C NMR (125 MHz, CDCl 3 ) 202.1, 181.1, 161.3, 138.4, 133.4, 131.9, 130.3, 128.5, 127.9, 127.7, 123.2, 115.2, 75.4, 72. 4, 70.8, 61.7, 58.2, 56.4, 46.6, 33.4, 29.9; IR (film): max 2926, 1732, 1668, 1634, 1522, 1447, 1374, 1261, 1211, 1098; HRMS (ESI) calcd for C 23 H 28 N 2 O 6 Na [M+Na ] + 451.1847, found 451.1825.

PAGE 134

134 (2 R ,4 S ,5 R ) 4 (benzyloxy) N methoxy N methyl 5 vinyl 1',4,4',5 tet rahydro 3 H spiro[furan 2,3' pyrrolo[2,1 c ][1,4]oxazine] 6' carboxamide ( 2 124 ) and (2 S ,4 S ,5 R ) 4 (benzyloxy) N methoxy N methyl 5 vinyl 1',4,4',5 tetrahydro 3 H spiro[furan 2,3' pyrrolo[2,1 c ][1,4]oxazine] 6' carboxamide ( 2 125 ). Aldehyde 2 121 (1.12 g, 2. 62 mmol) was taken u and was treated with 13.0 mL of LTEPA 103 (0.2 M / THF). After 2.5 h, TLC analysis indicated the reaction was complete, and the mixture was quenched via slow addition of 5 % AcOH until evoluti on of H 2 gas ceased. The resulting mixture was extracted with EtOAc, washed with a saturated aqueous solution of NaHCO 3 then brine, and dried over Na 2 SO 4 The extracts were concentrated under reduced pressure and subjected to flash chromatography (60 % EtOAc/hexanes) to yield the title compound as an equilibrating mixture of keto alcohol 2 122 and hemiketal 2 123 (1.05 g, 93 %). The mixture (20 mg, 0.046 mmol) was dissolved in 5.0 mL DCM with 4 MS and 2 Cl 2 (1.8 mg) and stirring was continued for 12 h. The reaction was filtered over a silica plug, the plug washed with EtOAc, and the pooled organics concentrated in vacuo The crude material was chromatographed to yield 2 124 (8.0 mg, 43 %) and 2 125 (8.0 mg, 43 %). Spiro compound 2 124 : R f 23 D = +66.57 ( c 0.15, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.42 7.27 (m, 5H), 6.98 (d, J = 4.1 Hz, 1H), 5.91 (d, J = 4.2 Hz, 1H) 5.82 (dddd, J = 17.2, 10.4, 6.7, 0.5 Hz, 1H), 5.34 (dt, J = 17.1, 1.1

PAGE 135

135 Hz, 1H), 5.17 (dt, J = 10.4, 1.1 Hz, 1H), 5.01 (d, J = 14.5 Hz, 1H), 4.84 (d, J = 14.8 Hz, 1H), 4.63 4.49 (m, 4H), 4.33 (d, J = 14.2 Hz, 1H), 3.92 (ddd, J = 7.9, 5.0, 3.4 Hz, 1H), 3. 69 (s, 3H), 3.29 (s, 3H), 2.30 (dd, J = 14.1, 3.2 Hz, 1H), 2.23 (dd, J = 14.1, 8.2 Hz, 1H) ; 13 C NMR (125 MHz, CDCl 3 ) 162.5, 138.0, 136.1, 131.0, 128.7, 128.0, 117.5, 117.1, 103.3, 103.0, 85.6, 82.0, 77.5, 77.2, 77.0, 72.2, 61.1, 58.5, 51.8, 42.7, 33.7, 29.9; IR (film): max 3445, 2925, 2361, 2343, 1622, 1496, 1456, 1351, 1098, 1053, 1026; HRMS (ESI) calcd for C 22 H 26 N 2 O 5 Na [M+Na] + 421.1742, found 421.1740. Spiro compound 2 125 : R f 23 D = 85.58 ( c 0.26, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.28 (m, 5H), 6.97 (d, J = 4.1 Hz, 1H), 5.93 (ddd, J = 17.4, 10.4, 7.9 Hz, 1H), 5.88 (d, J = 4.1 Hz 1H), 5.32 (ddd, J = 17.1, 1.0 Hz, 1H), 5.20 (ddd, J = 10.3, 1.4, 1.0 Hz, 1H), 5.02 (d, J = 14.7 Hz, 1H), 4.77 (d, J = 14.7 Hz, 1H), 4.63 (d, J = 14.1 Hz, 1H), 4.59 4.51 (m, 3H), 4.32 (d, J = 13.9 Hz, 1H), 4.22 (ddd, J = 7.2, 6.8, 5.1 Hz, 1H), 3.68 (s, 3H), 3.29 (s, 3H), 2.51 (dd, J = 13.1, 6.7 Hz, 1H), 2.13 (dd, J = 13.1, 6.7 Hz, 1H); 13 C NMR ( 125 MHz, CDCl 3 ) 4 137.9, 137.8, 130.5, 128. 7 128.0, 127. 9 122. 3 118.0, 116.9, 103. 6 102. 9 86. 8 82. 2 72.3, 61.1, 58. 9 52.1, 43. 1 33.7, 29.9. IR (film): max 3445, 2925, 2361, 2343, 1622, 1496, 1456, 1351, 1098, 1053, 1026; HRMS (ESI) calcd for C 22 H 26 N 2 O 5 Na [M+Na] + 421.1742, found 421.1740. (2 R ,4 S ,5 R ) 4 (benzyloxy) 5 (hydroxymethyl) N methoxy N methyl 1',4,4',5 tetrahydro 3 H spiro[furan 2,3' pyrrolo[2,1 c ][1,4]oxazine] 6' carboxamide ( 2 126)

PAGE 136

136 To spiro compound 2 124 (160 mg, 0.40 mmol) in THF H 2 O 10:1 (8.9 mL) was added NMO (117 mg, 1.00 mmol) then OsO 4 (4 wt. % in H 2 O) (50 L) and allowed to stir for 24 h. The remaining OsO 4 was destroyed with 100 mg of Na 2 SO 3 followed by stirring for 0.5 h. The resulting mixture was taken up in EtOAc (100 mL), washed wit h H 2 O, then brine, and concentrated. The crude diol was taken up in THF pH 7 buffer 5:1 4 (99 mg, 0.46 mmol). Stirring was continued for 12 h, then the reaction was quenched with 1 mL of phosphate buffer, d iluted with EtOAc, and separated. The organic phase was concentrated under reduced pressure to furnish the crude aldehyde. The aldehyde was dissolved in EtOH 4 (13 mg, 0.36 mmol). The reaction was stirred for 1 h, then quenched with 3 mL H 2 O, diluted with EtOAc, and separated. The organic phase was washed with brine and concentrated to give essentially pure title compound ( 70 mg, 70 % ) ; R f 23 D = +94.51 ( c 1.2, CHCl 3 ); 1 H NMR (5 00 MHz, CDCl 3 7.45 7.28 (m, 5H), 6.99 (d, J = 4.0 Hz, 1H), 5.92 (d, J = 4.1 Hz, 1H), 4.99 (d, J = 14.8 Hz, 1H), 4.85 (d, J = 14.8 Hz, 1H), 4.68 4.55 (m, 2H), 4.52 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 14.1 Hz, 1H), 4.26 4.20 (m, 2H), 4.19 4.04 (m, 1H), 3.76 (dd, J = 12.1, 3.1 Hz, 1H), 3.69 (s, 3H), 3.56 (dd, J = 12.2, 4.0 Hz, 1H), 3.28 (s, 3H), 2.31 (dd, J = 14.1, 2.4 Hz, 1H), 2.17 (dd, J = 14.1, 8.4 Hz, 1H) ; 13 C NMR ( 125 MHz, CDCl 3 162.4, 138.0, 131.0, 128.7, 128.0, 122.0, 117.2, 103.9, 103.0, 85.6, 78.2, 72.2, 62.7, 61.1, 58.6, 51.5, 43.0, 33.6, 29.9 ; IR (film): max 2926, 2855, 2363, 2346, 1719, 1686, 1654, 1560, 1508, 1458, 1350, 1260, 1106, 1042; HRMS (ESI) calcd for C 21 H 26 N 2 O 6 Na [M+Na] + 425.1691, found 425.1677.

PAGE 137

137 (2 R ,4 S ,5 R ) 4 (benzyloxy) 5 (hydroxymethyl) 1',4,4',5 tetrahydro 3 H spiro[furan 2,3' pyrrolo[2,1 c ][1,4]oxazine] 6' carbaldehyde (2 127 ). To spiro compound 2 126 (65 mg, 0.15 mmol) in 7.5 mL THF at LAH (11 mg, 0.42 mmol), and the temperature allowed to rise to 0 temperature was maintained an additional 1 h, then the reaction was quenched with KHSO 4 (65 mg) then 5 mL 1 N HCl. The reaction was diluted with 80 mL EtOAc, separated, then dried over Na 2 SO 4 The dry organics were concentrated to yie ld an essentially pure compound ( 50 mg, 89 % ). R f 23 D = +87. 77 ( c 0.68, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.28 (m, 5H), 6.92 (d, J = 4.1 Hz, 1H), 6.02 (d, J = 4.1 Hz, 1H), 5.01 (dd, J = 15.5, 1.1 Hz, 1H) 4.87 (d, J = 15.5 Hz, 1H), 4.68 4.56 (m, 2H), 4.53 (d, J = 12.1 Hz, 1H), 4.32 4.20 (m, 2H), 4.16 (ddd, J = 8.3, 4.7, 2.4 Hz, 1H), 3.78 (dd, J = 12.2, 3.1 Hz, 1H), 3.73 3.65 (m, 1H), 3.59 (dd, J = 12.0, 3.9 Hz, 1H), 2.33 (dd, J = 14.2, 2.4 Hz, 1H), 2.20 (dd, J = 14.2, 8.4 Hz, 1H); 13 C NMR ( 125 MHz, CDCl 3 9 135. 3 131. 2, 128. 1, 128.0, 124.5, 105. 1 103.4, 85. 9 78.1, 72. 3 62.6, 58.1, 51.0, 42.8, 30.0 ;IR (film): max 2920, 2852, 2360, 2342, 1716, 1652, 1558, 1507, 1465, 1260, 1185, 1042; HRMS (ESI) calcd for C 19 H 21 NO 5 Na [M+Na] + 366.1320, fo und 366.1299.

PAGE 138

138 (2 S ,4 S ,5 R ) 4 (benzyloxy) 5 (hydroxymethyl) N methoxy N methyl 1',4,4',5 tetrahydro 3 H spiro[furan 2,3' pyrrolo[2,1 c ][1,4]oxazine] 6' carboxamide ( 2 128 ). To spiro compound 2 125 (95 mg, 0.24 mmol) in THF H 2 O 10:1 (5.5 mL) was added NMO (7 0 mg, 0.60 mmol) then OsO 4 (4 wt. % in H 2 O) (45 L) and allowed to stir for 24 h. The remaining OsO 4 was destroyed with 100 mg of Na 2 SO 3 followed by stirring for 0.5 h. The resulting mixture was taken up in EtOAc (85 mL), washed with H 2 O, then brine, and concentrated. The crude diol was taken up in THF pH 7 buffer 5:1 4 (102 mg, 0.476 mmol). Stirring was continued for 12 h, then the reaction was quenched with 2 mL of phosphate buffer, diluted with EtOAc, an d separated. The organic phase was concentrated under reduced pressure to furnish the crude aldehyde. The aldehyde was dissolved in EtOH 4 (13 mg, 0.36 mmol). The reaction was stirred for 1 h, then quenched wi th 2 mL H 2 O, diluted with EtOAc, and separated. The organic phase was washed with brine and concentrated to give essentially pure title compound (92 mg, 89 %). R f 23 D = 19.11 ( c 0.65, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 7.27 (m, 5H), 6.98 (d, J = 4.1 Hz, 1H), 5.91 (d, J = 4.1 Hz, 1H), 5.00 (d, J = 14.7 Hz, 1H), 4.82 (d, J = 14.7 Hz, 1H), 4.69 (d, J = 14.2 Hz, 1H), 4.59 4.44 (m, 2H), 4.36 (d, J = 14.2 Hz, 1H), 4.33 4.25 (m, 2H), 3.69 (s, 3H), 3.30 (s, 3H), 2.55 (dd, J = 13.6, 6.4 Hz, 1H), 2.17 (dd, J = 13.5, 6.1 Hz, 1H); 13 C NMR ( 125 MHz, CDCl 3 1 137.6, 129. 8 128.5, 127.9, 127.7, 116.8, 104. 1 102.8, 86.5, 78. 4 7 2.0 64.2, 6 1.0 5 9 0 51.9, 43. 5 33. 5 29.7; IR (film): max 2926, 2855, 2363, 2346, 1719, 1686, 1654, 1560, 1508, 1458, 1350, 1260, 1106, 1042; HRMS (ESI) calcd for C 21 H 26 N 2 O 6 Na [M+Na] + 425.1691, found 425.1677.

PAGE 139

139 (2 S ,4 S ,5 R ) 4 (benzyloxy) 5 (hydroxymethyl) 1',4,4',5 tetrahydro 3 H spiro[furan 2,3' pyrrolo[2,1 c ][1,4]oxazine] 6' carbaldehyde (2 129) To spiro compound 2 128 (92 mg, 0.21 mmol) in 5 mL THF at LAH (16 mg, 0.42 temperature was maintained an additional 1 h, then the reaction was quenched with KHSO 4 (92 mg) then 5 mL 1 N HCl. The reaction was diluted with 70 mL EtOAc, separated, t hen dried over Na 2 SO 4 The dry organics were concentrated to yield an essentially pure compound (61 mg, 84 %) R f = 0.55 (66 23 D = 31.56 ( c 0.2, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 9.45 (s, 1H), 7.62 7.26 (m, 5H), 6.91 (d, J = 4.1 Hz, 1H), 6.00 (d, J = 4.1 Hz, 1H), 5.02 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.5 Hz, 1H), 4.77 (d, J = 14.3 Hz, 1H), 4.53 (d, J = 2.5 Hz, 2H), 4.37 4.22 (m, 3H), 3.76 (dd, J = 11.9, 3.4 Hz, 1H), 3.66 (dd, J = 11.9, 5.1 Hz, 2H), 2.55 (dd, J = 13.5, 6.3 Hz, 1H) 2.18 (dd, J = 13.6, 6.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) 179.0, 137.7, 134.3, 131.3, 128.7, 128.1, 127.9, 124.3, 105.0, 103.7, 86.7, 78.5, 72.2, 64.3, 58.7, 51.7, 43.4 ; IR (film): max 2920, 2852, 2360, 2342, 1716, 1652, 1558, 1507, 1465, 1260, 1185, 1042 ; HRMS (ESI) calcd for C 19 H 21 NO 5 Na [M+Na] + 366.1320, found 366.1299.

PAGE 140

140 Acortatarin A (2 1) and epi Acortatarin A (2 52) from 2 127. Similar to a known procedure, 51 spiro compound 2 127 (31 mg, 0.090 mmol) in DCM (3.0 mL) was treated with 0.9 mL of TiCl 4 the same temperature, the reaction was then quenched with a saturated aqueous solution of NaHCO 3 (3.0 mL), extracted with EtOAc (3 x 50 mL), and the combi ned extracts dried over Na 2 SO 4 Careful purification by column chromatography (100% EtOAc) separated the anomeric mixture yielding acortatarin A ( 2 1 ) (16 mg, 70 %) and ( epi 1 ) (1.5 mg, 7 %). Acortatarin A ( 2 1 ): R f = 0.2 9 (10 0 % EtOAc 23 D = +185.22 ( c 0.15, MeOH); 1 H NMR (500 MHz, CD 3 J = 4.1 Hz, 1H), 6.08 (d, J = 4.1 Hz, 1H), 5.02 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.59 (d, J = 14.0 Hz, 1H), 4.29 (ddd, J = 8.3, 4.5, 2.7 Hz, 1H), 4.23 (d, J = 14.0 Hz, 1H), 4 .07 (td, J = 4.8, 3.2 Hz, 1H), 3.71 (dd, J = 12.1, 3.3 Hz, 1H), 3.62 (dd, J = 12.1, 4.9 Hz, 1H), 2.35 (dd, J = 14.1, 8.3 Hz, 1H), 2.15 (dd, J = 14.0, 2.7 Hz, 1H); 13 C NMR ( 125 MHz, CD 3 OD) 180. 4 137. 8 132.6, 126.2, 106. 4 104.7, 89.4, 72.4, 63. 2 58.9, 52.2, 46. 1 ; HRMS (ESI) calcd for C 12 H 15 NO 5 Na [M+Na] + 276.0850 found 276.0851. 1 H NMR (500 MHz, Acetone J = 4.1 Hz, 1H), 6.07 (d, J = 3.8 Hz, 1H), 5.01 (d, J = 15.1 Hz, 1H), 4.85 (d, J = 15.5 Hz, 1H), 4.55 (d, J = 14.1 Hz, 1H), 4.36 (dt, J = 7.6, 3.5 Hz, 1H), 4.21 (d, J = 14.0 Hz, 1H), 4.11 (q, J = 4.3 Hz, 1H), 3.70 (dd, J = 12.0, 3.5 Hz, 1H), 3.63 (dd, J = 12.0, 4.4 Hz, 1H), 2.41 (dd, J = 13.9, 8.1 Hz, 1H), 2.15 (dd, J = 13.9, 2.7 Hz, 1H); 13 C NMR (125 MHz, Acetone d6) 179.0, 135.9, 132.2, 124.3, 105.4, 105.3, 104.0, 89.5, 62.7, 58.2, 51.7, 45.8; HRMS (ESI) calcd for C 12 H 15 NO 5 Na [M+Na] + 276.0850 found 276.0851.

PAGE 141

141 epi Acortatarin A ( 2 52 ): R f 23 D = 73.13 ( c 0.0 5 MeOH); 1 H NMR (500 MHz, CD 3 9.38 (s 1H), 7.03 (d, J = 4.1 Hz, 1H), 6.07 (d, J = 3.9 Hz, 1H), 5.10 (d, J = 15.9 Hz, 1H), 4.82 (d, J = 15.7 Hz, 1H), 4.68 (d, J = 13.9 Hz, 1H), 4.52 4.30 (m, 1H), 4.23 (d, J = 14.8 Hz, 1H), 4.09 3.87 (m, 1H), 3.71 (dd, J = 11.8, 4.5 Hz, 1H), 3.62 (dd, J = 11.6, 6.9 Hz, 1H), 2.51 (dd, J = 13.3, 6.9 Hz, 1H), 2.10 (dd, J = 13.3, 6.9 Hz, 1H). HRMS (ESI) calcd for C 12 H 15 NO 5 Na [M+Na] + 276.0850 found 276.0851. Acortatarin A (1) and epi Acortatarin A (2 52) from 2 129. Compounds ( 2 1 ) and ( 2 52 ) were prepared from spiro compound 2 129 as described for the preparation of the same compounds from spiro compound 2 127 5.2.2 Synthesis of Diels Alder Precursors Tert butyldim ethyl(pent 4 ynyloxy)silane (3 67 ). A stirred solution of pent 4 yn 1 ol (0.74 mL, 8.0 mmol ) and imidazole (816 mg, 12.0 mmol) in 30 mL of DCM was cooled on the ice bath to 0 C. A solution of tert butyldimethylsilyl chloride (1.18 g, 7.9 0 mmol) in 10 mL DCM was then added, and the mixture allowed to warm to room temperature while stirring over night. The reaction was diluted with DCM (30 mL), then quenched with 1 N HCl (5 mL) and H 2 O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over MgSO 4 and

PAGE 142

142 concentrated. Purification by flash chromatography (5% EtOAc/hexane) afforded the p roduct as a colorless oil (1.5 g, 93%) with spectral data matching those previously reported. 140 Tert butyldimeth ylsilyl hex 5 yn 1 yl ether (3 68 ). A stirred solution of hex 5 yn 1 ol (600 mg, 6.11 mmol) and imidazole (816 mg, 12.0 mmol) i n 15 mL of DCM was cooled on the ice bath to 0 C. A solution of tert butyldimethylsilyl chloride (900 mg, 6.0 0 mmol) in 15 mL DCM was then added, and the mixture allowed to warm to room temperature while stirring overnight. The reaction was quenched wit h 1 N HCl (20 mL) then H 2 O (20 mL). The aqueous layer was separated and extracted with DCM (3x15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO 4 and concentrated. Purification by flash chromatography (5% EtOAc/hexane) yielded the product as a colorless oil (1.12 g, 94%) with spectral data matching those previously reported. 141 7 Methyloct 4 yne 1,6 diol (3 69) A stirred solution of 3 67 (340 mg, 1.71 mmol) in 8.5 mL of dry THF cooled to 78 C on the dry ice/acetone bath was treated with n BuLi (0.75 mL, 2.5 M in hexane) over 10 minutes, and stirred for 0.5 h. At the same temperature, isobutyraldehyde (0.47 mL, 5.13 mmol) was added neat over 5 minutes. The mixture was stirred for an additional 0.5 h at 78 C, then allowed to warm to room temperature. The reaction was quenched with H 2 O (10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted

PAGE 143

14 3 with EtOAc (3x15 mL), and the combined extracts were dried over MgSO 4 and evaporated in vacuo The crude mixt ure was taken up in 10 mL dry THF, treated with a solution of TBAF (3.42 mL, 1.0 M in THF) and stirred at room temperature overnight. The reaction was diluted with 10 mL H 2 O, and extracted with EtOAc (3x20 mL). The organics were washed with brine (10 mL) then dried over MgSO 4 The residue was subjected to flash chromatography (50% EtOAc/hexane) to furnish the product as a colorless oil (208 mg, 78% over 2 steps) with spectral data matching those previously reported. 142 8 Methylnon 5 yne 1,7 diol (3 70 ) A stirred solution of 3 68 (1.58 g, 7.44 mmol) in 37 mL of dry THF cooled to 78 C on the dry ice/acetone bath was treated with n BuLi (3.12 mL, 2.5 M in hexane) over 10 minutes, and stirred for 0.5 h. At the same temperature, isobutyraldehyd e (3.4 mL, 37 mmol) was added neat over 5 minutes. The mixture was stirred for an additional 0.5 h at 78 C, then allowed to warm to room temperature. The reaction was quenched with H 2 O (20 mL) and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3x25 mL), and the combined extracts were dried over MgSO 4 and evaporated in vacuo The crude mixture was taken up in 40 mL dry THF, treated with a solution of TBAF (16.0 mL, 1.0 M in THF) and stirred at room temperature overnight. The reaction wa s diluted with 20 mL H 2 O, and extracted with EtOAc (3x30 mL). The organics were washed with brine (20 mL) then dried over MgSO 4 The residue was subjected to flash chromatography (50% EtOAc/hexane) to furnish the product as a colorless oil (1.14 g,

PAGE 144

144 90% over 2 steps) R f = 0.27 (50% EtOAc/hexanes); 1 H NMR (500 MHz, CDCl 3 ) 4.12 (dt, J = 5.6, 2.0 Hz, 1H), 3.72 3.57 (m, 2H), 2.61 ( br s, 2 H), 2.25 (td, J = 6.9, 2.0 Hz, 2H), 1.81 (m, 1H), 1.73 1.62 (m, 2H), 1.63 1.49 (m, 2H), 0.97 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H) ; 13 C NMR (125 MHz, CDCl 3 85.6, 80. 4 68.0, 62. 2 34. 7 31.7, 25.0, 18. 5, 18.2, 17.5; IR (film): max 3399, 2960, 2211, 1468, 1385, 1193, 1154, 1029, 735. 1 cyclohexylhept 2 yne 1,7 diol ( 3 71 ). A stirred solution of 3 6 8 (500 mg, 2.36 mmol) in 6 mL of dry THF cooled to 78 C on the dry ice/acetone bath was treated with n BuLi (1.04 mL, 2.5 M in hexane) over 10 minutes, and stirred for 0.5 h. At the same temperature, a solution of cyclohexanecarboxaldehyde (264 mg, 2.36 mmol) in dry THF (2 mL) was added over 5 min. The mixture was stirred for an additional 0.5 h at 78 C, then warmed to room temperature and stirred for 0.5 h. The reaction was diluted with diethyl ether (10 mL) and quenched with H 2 O (5 mL). The aqueou s layer was extracted with ether (2x10 mL), and the combined extracts were dried over MgSO 4 and evaporated in vacuo The crude mixture was taken up in 8 mL dry THF, treated with a solution of TBAF (7.0 mL, 1.0 M in THF) and stirred at room temperature ov ernight. The reaction was diluted with 10 mL H 2 O, and extracted with ethyl acetate (3x20 mL). The organics were washed with brine (10 mL) then dried over MgSO 4 The residue was subjected to flash chromatography (50% EtOAc/hexane) to furnish the product as a viscous yellow oil (415 mg, 84% over 2 steps) R f = 0.30 (50% EtOAc/hexanes); 1 H NMR (300 MHz, CDCl 3 )

PAGE 145

145 4. 12 (m, 1H), 3.68 (t, J = 6.2 Hz, 2 H), 2.26 (td, J = 6.8, 2.0 Hz, 2H), 2.01 1.39 (m, 11H), 1.39 0.91 (m, 6H) ; 13 C NMR (75 MHz, CDCl 3 ) 86.0 80.8, 67.6, 62. 6 44.6, 32.0, 28.8, 28. 4 26. 7 26.1, 25.2, 18. 8; IR (film): max 3468, 2936, 2214, 1266, 1167, 1035, 733; HRMS (ESI) calcd for C 13 H 22 O 2 Na 2 [M+ 2 Na] + 256.1420 found 256.1326. N tert butoxycarbonyl N tosyl 4 pentynyl 1 amine (3 74 ) In a round bottom flask were combined pent 4 yn 1 ol (0.5 0 mL, 5.40 mmol), triphenylphosphine (2.22 g, 8.47 mmol), tert butyl tosylcarbamate 129 (2.09 g, 7.70 mmol) and benzene (27 mL) at room temperature. To the stirred solution was added DIAD (1.59 mL, 8.09 mmol) dropwise, and the mixture stirred during 24 h. The volatile compounds were stripped off under vacuum, and the residue dissolved in DCM. Purification by flash chromatography provides the amine as a colorless oil which c rystallizes upon standing (2.23 g, 91 %), having spectral data matching those reported previously. 128 N tert butoxycarbony l N tosyl 5 hexynyl 1 amine (3 75 ). In a round bottom flask were combined hex 5 yn 1 ol (0.76 mL, 7. 0 mmol), triphenylphosphine (2.89 g, 11.0 mmol), tert butyl tosylcarbamate 129 (2.71 g, 10.0 mmol) and benzene (35 mL) at room temperature. To the stirred solution was slowly added DIA D (2.07 mL, 10.5 mmol) via dropwise additi on and the mixture stirred during 40 h. The volatile compounds were stripped off under vacuum, and the residue dissolved in DCM then purified by flash chromatography to give the amine as a colorless oil which

PAGE 146

146 crystallizes upon standing (2.3 g, 92 %) ha ving spectral data matching those reported previously. 128 N (7 Hydroxy 8 methylnon 5 ynyl) 4 methylbenzenesulfonamide (3 76 ). To a stirred solution of 3 74 (1.66 g, 4.93 mmol) in 25 mL of dry THF cooled to 78 C on the dr y ice/acetone bath was added n BuLi (2.07 mL, 2.5 M in hexane) over 10 minutes, and the solution stirred for 20 min. At the same temperature, isobutyraldehyde (0.90 mL, 9.86 mmol) was added dropwise. The mixture was stirred for an additional 0.5 h at 78 C, then warmed to room temperature and stirred for 0.5 h. The reaction was quenched with H 2 O (10 mL), then diluted with EtOAc (15 mL) and the biphasic mixture separated. The aqueous layer was extracted with EtOAc (3x20 mL), and the combined extracts we re dried over MgSO 4 and evaporated in vacuo The crude mixture was taken up in 25 mL MeOH, and added to a flask containing K 2 CO 3 (3.41 g, 24.7 mmol) and the suspension refluxed overnight at 75 C. Following aqueous workup and extraction with EtOAc, the organics were concentrated then subjected to flash chromatography (30% EtOAc/hexane) to furnish the product as a yellow oil (816 mg, 53% over 2 steps) R f = 0.49 (50% EtOAc/hexanes); 1 H NMR (300 MHz, CDCl 3 ) 7.75 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.3 Hz, 2 H), 4. 79 (t J = 6.7 Hz, 1H), 4. 10 (m, 1H), 3.06 (q, J = 6.6 Hz, 2H), 2.42 (s, 3 H), 2.26 (td, J = 6.8, 2.0 Hz, 2H), 1.80 (pd, J = 6.7, 5.5 Hz, 1H), 1.67 (p, J = 6.8 Hz, 2H), 0.95 (d, J = 3.8 Hz, 3H), 0.93 (d, J = 3.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) 14 3.7 137.1, 129.9, 127.3, 84. 6 81. 6 68.2, 42.5, 34. 8 28 .5, 21.7,

PAGE 147

147 18.3, 17.7, 16.3; IR (film): max 3281, 2968, 1715, 1598, 1322, 1153, 1092, 813; HRMS (ESI) calcd for C 16 H 23 NO 3 S Na [M+Na] + 332.1291 found 332.1305. N (7 hydroxy 7 phenylhept 5 yn 1 yl) 4 methylbenzenesulfonamide (3 77 ). To a stirred solution of 3 75 (0.50 g, 1.42 mmol) in 7.1 mL of dry THF cooled to 78 C on the dry ice/acetone bath was added n BuLi (0.62 mL, 2.5 M in hexane) over 10 minutes, and the solution stirred for 20 min. At t he same temperature, benzaldehyde (0.22 mL, 2.13 mmol) was added dropwise. The mixture was stirred for an additional 0.5 h at 78 C, then warmed to room temperature and stirred for 0.5 h. The reaction was quenched with H 2 O (10 mL), then diluted with Et OAc (15 mL) and the biphasic mixture separated. The aqueous layer was extracted with EtOAc (3x20 mL), and the combined extracts were dried over MgSO 4 and evaporated in vacuo The crude mixture was taken up in 7.1 mL MeOH, and added to a flask containing K 2 CO 3 (0.98 g, 7.1 mmol) and the suspension refluxed overnight at 75 C. Following aqueous workup and extraction with EtOAc, the organics were concentrated then subjected to flash chromatography (40% EtOAc/hexane) to furnish the product as a yellow oil (0 .47 g, 71% over 2 steps) R f = 0.32 (50% EtOAc/hexanes); 1 H NMR (300 MHz, CDCl 3 7.75 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.38 7.29 (m, 3H), 5.45 (d, J = 5.8 Hz, 1H), 4.50 (br s, 1H), 2.99 (q, J = 6.6 Hz, 2H), 2.44 (s, 3H), 2.33 (d, J = 6.0 Hz, 1H), 2.28 (td, J = 6.7, 2.0 Hz, 2H), 1.73 1.50 (m, 4H); 13 C NMR (125 MHz, CDCl 3 143.7, 141.4, 137.1, 130.0, 128.8, 128.5, 127.3, 126.8, 86.9, 81.1, 65. 0, 42.9,

PAGE 148

148 29.0, 25.5, 21.8, 18.6; IR (film): max 3270, 2938, 2203, 17 17, 1639, 1314, 1264, 1153, 1091, 813; HRMS (ESI) calcd for C 2 0 H 23 NO 3 S Na [M+Na] + 380.1202 found 380.1216. Hex 5 yn 1 yl 4 methylbenzenesulfonate (3 7 8). To a solution of hex 5 yn 1 ol (0.87 mL, 8.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in 20 mL DCM was added p toluenesulfonylchloride (1.5 g, 8.0 mmol) in 20 mL DCM at 0 C. The mixture was stirred overnight and allowed to slowly warm to room temperature. The reaction was quenched with 10 mL NaHCO 3 saturated aqueous solution, extracted with DCM, washed with brine, and dried over MgSO 4 The crude product was concentrated in vacuo and the residue subjected to flash column chromatography (15 30% EtOAc/hexanes) to yield the product as a colorless oi l (1.3 g, 67%) with spectral data in agreement with the published literature. 130 N,N bis Boc 1 amino 5 hexyne (3 7 9). To a suspension of NaH (0.19 g, 6.63 mmol) in DMF (23 mL) was added a solution of bis Boc amine in a minimum amount of THF dropwise. The reaction was stir red for 1 h at room temperature, then cooled on the ice bath to 0 C. T osylate 3 78 was added in 3 mL DMF dropwise, and stirring continued overnight. The reaction as quenched with NH 4 Cl saturated aqueous solution, extracted with Et 2 O, washed with H 2 O the n brine, and dried over MgSO 4 The resulting organic phases were concentrated under reduced pressure, and chromatographed (10 % EtOAc/hexanes) to furnish the produc t as a viscous yellow oil (0.93 g, 71 %) R f = 0.78 (25% EtOAc/hexanes); 1 H NMR ( 5 00 MHz,

PAGE 149

149 CDCl 3 9 (t, J = 7.4 Hz, 2 H), 2.22 (td, J = 7.1, 2.7 Hz, 2H ), 1.9 4 ( t J = 2.6 Hz, 1H), 1. 79 1.64 (m, 2H), 1.62 1.52 (m, 2 H) 1.51 (s, 18H) ; 13 C NMR (12 5 MHz, CDCl 3 ) 152.9, 84.4, 82.4 68. 7 46.1, 28. 4 28. 3, 26 0 18. 4; IR (film): max 3310, 29 80, 1739, 1694, 1367, 1251, 1135, 1111, 855; HRMS (DART ) calcd for C 12 H 28 NO 4 [M+H ] + 298.2013 found 298.2009. tert butyl hex 5 yn 1 ylcarbamate ( 3 8 0). To a solution of carbamate 3 79 (930 mg, 3.13 mmol) in 31 mL acetonitrile was added LiBr (816 mg, 9. 131 The reaction was then cooled, concentrated under reduced pressure, and taken up in DCM. The organic phase was washed with H 2 O, brine, then concentrated. Purification by flash chromatography (15 % EtOAc/hexanes) furnished the title compound as a yellow oil (0.372 g, 60 %). R f = 0.74 (25% EtOAc/hexanes); 1 H NMR (5 00 MHz, CDCl 3 4.53 (s, 1H), 3.22 3.03 (m, 2H), 2.21 (td, J = 6.8, 2.7 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H) 1.64 1.49 (m, 4H), 1.43 (s, 9 H) ; 13 C NMR (12 5 MHz, CDCl 3 ) .3, 29.4, 28.7, 25.9, 18.4; IR (film): max 3310, 2978, 2936, 1688, 1514, 1366, 1247, 1166; HRMS (DART ) calcd for C 22 H 39 N 2 O 4 [2M+H ] + 395.2904 found 395.2916. ter t butyl (7 hydroxyoct 5 yn 1 yl)carbamate ( 3 8 1). T o compound 3 80 (372 mg, 1.88 mmol) in 9.4 mL THF cooled to added n BuLi (1.65 mL, 2.5 M in hexanes) over 1 h. Acetaldehyde (0.53 mL, 9.4 mmol) was added to the mixture at the same temperatur e, and the solution gradually brought

PAGE 150

150 to r.t. After 2 h, the reaction was quenched with a saturated aqueous solution of NH 4 Cl, diluted with Et 2 O, separated, and the aqueous phase extracted again with Et 2 O. The pooled organics were washed with brine, drie d over MgSO 4 and concentrated. Purification of the residue by column chromatography produced the title compound as a yellow oil (230 mg, 70%), with spectral data in agreement with the published reference 132 5.2.3 General Sy nthetic Procedure and Characterization for Diels Alder Adducts 4 Cyclohexyl 2 methyl 4,5,7,8,9,9b hexahydropyrano[3,2 e ]isoindole 1,3(2 H ,3a H ) dione (typical procedure) ( 3 86 ) In a round bottom flask at room temperature were combined Au[P( t Bu) 2 ( o b iphenyl)]Cl (2.6 mg, 0.005 0 mmol), AgOTf (1.3 mg, 0.005 0 mmol), benzene (0.25 mL), and 4 MS (50 mg). The solution was stirred for 10 minutes, after which time a solution of diol 3 71 (50 mg, 0.237 mmol) and N methylmaleimide (53 mg, 0.474 mmol) were add ed in 1.0 mL benzene. After 0.5 h, TLC analysis indicated that the Au catalyzed cyclization was complete. The reaction vessel was fitted with a cold finger condenser and placed on a preheated oil bath to reflux at 90 C during 48 h. The crude mixture wa s allowed to cool to room temperature, filtered over silica, and the plug washed with EtOAc (15 mL). The crude solids were purified by flash chromatography (12.5 % EtOAc/hexanes) to give the cycloadduct as a white solid (72 mg, 82 %) R f = 0.31 (12.5% Et OAc/hexanes); MP 92 95 C ; 1 H NMR (300 MHz, CDCl 3 ) 4.03 (dtd, J =

PAGE 151

151 10.3, 3.8, 1.7 Hz, 1H), 3.77 (ddd, J = 10.5, 7.5, 5.4 Hz, 1H), 3.31 (ddd, J = 7.8, 4.2, 1.7 Hz, 1H), 3.21 (dd, J = 7.8, 1.3 Hz, 1H), 2.91 (s, 3H), 2.42 (dtd, J = 15.5, 8.1, 3.3 Hz, 1H), 2. 16 1.99 (m, 3H), 1.97 1.58 (m, 7H), 1.50 (ddt, J = 12.3, 9.9, 4.3 Hz, 1H), 1.41 1.04 (m, 4H), 1.04 0.65 (m, 2H). 13 C NMR (75 MHz, CDCl 3 ) 178.0, 177.7, 150.3, 99.6, 66.0, 46.8, 40.9, 40.6, 37.7, 32.0, 31.2, 28.7, 26.7, 26.3, 24.6, 23.1, 22.6 ; IR (neat) : max 2928, 2846, 1764, 1696, 1433, 1380, 1154, 982 ; HRMS (ESI) calcd for C 18 H 26 NO 3 [ M +H] + 304.1907, found 304.1908. 6 Isopropyl 3,3a dihydrobenzofuran 4,4,5,5(2 H ,6 H ) tetracarbonitrile ( 3 82 ). The typical procedure was followed with 3 69 (39 mg 0 .25 mmol) and tetracyanoethylene (48 mg, 0.3 8 mmol) to give the title compound (52 mg, 78 %) R f = 0.47 (25% EtOAc/hexanes); MP 158 160 C ; 1 H NMR (300 MHz, CDCl 3 5.05 (t, J = 3.0 Hz, 1H), 4.46 (t, J = 8.8 Hz, 1H), 4.20 (ddd, J = 11.3, 8.9, 5.3 Hz, 1H) 3.43 (ddt, J = 12.1, 7.5, 2.5 Hz, 1H), 3.02 (ddd, J = 5.3, 3.5, 2.4 Hz, 1H), 2.64 (ddd, J = 12.5, 7.4, 5.2 Hz, 1H), 2.53 2.20 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ) 152.2 115.5, 111. 9 111. 3 110. 7 109. 3 91. 3 69. 4 48. 2 42. 4 31.6, 29. 2 23. 8 18.9; IR (neat) : max 3854, 3746, 3672, 3649, 2970, 2913, 2361, 1700, 1471, 145 6, 1381, 1195, 1171, 990, 938; HRMS (CI) calcd for C 15 H 1 5 N 4 O [ M +H] + 267.1201, found 267.1245.

PAGE 152

152 4 Isopropyl 2 methyl 4,5,7,8,9,9b he xahydropyrano[3,2 e]isoindole 1,3(2 H ,3a H ) dione ( 3 83 ). The typical procedure was followed with 3 70 (53 mg, 0.31 mmol) and N methylmaleimide (33 mg, 0.31 mmol) to give t he title compound (63 mg, 77 %). R f = 0.66 (25% EtOAc/hexanes); MP 106 1 H NMR (300 MHz, CDCl 3 4.04 (dtd, J = 9.5, 3.7, 1.7 Hz, 1H), 3.78 (ddd, J = 10.4, 7.4, 5.3 Hz, 1H), 3.30 (m, 1H), 3.23 (dd, J = 8.2, 2 .2 Hz, 1H), 2.92 (s, 3H), 2.56 2.28 (m, 2H), 2.13 (d, J = 3.9 Hz, 1H), 2.00 1.69 (m, 4H), 1.42 (ddt, J = 12.2, 10.2, 4.2 Hz, 1H), 1.07 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) 1, 47 0 42.3, 41.6, 29.3, 28.9, 24.7, 23.2, 22. 7 2 2 0 21.4; IR (film): max 2951, 1597, 1456, 1349, 1162, 1090, 711; HRMS (CI ) calcd for C 15 H 22 NO 3 [M+ H ] + 264.1621 found 264.1596. 5 Isopropyl 2 phenyl 8,9,10,10a tetrahydropyrano[3,2 c ][1,2,4]triazolo[1,2 a]pyridazine 1,3(2 H ,5 H ) dione ( 3 84 ). The typical procedure was followed with 3 70 (43 mg, 0.25 mmol) and 4 phenyl 1,2,4 t riazoline 3,5 dione (66 m g, 0.38 mmol) to give the title compound (44.3 mg, 54 %) R f = 0.81 (50% EtOAc/hexanes); MP 108 111 C ; 1 H NMR (300 MHz, CDCl 3 7.57 7.27 (m, 5 H), 5.39 (dd, J = 5.0, 1.7 Hz, 1 H), 4.54 (td, J = 4.7, 2.2 Hz, 1H), 4.22 (m, 1H), 4.10 (m, 1 H), 3.66 (td, J = 11.7, 11.0, 2.5 Hz, 1H), 3.14 (m, 1 H), 2.46 (pd, J = 6.9, 4.5 Hz, 1H), 2.04 (m, 1H), 1.93 1.65 (m, 2 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H). 13 C NMR (75 MHz, CDCl 3 ) 153.9, 150.6, 149.3, 131. 5 129.3, 129. 2

PAGE 153

153 128.3, 126.0, 125.8, 100.7, 7 1. 4 56. 2 55. 1 31.4, 28. 9, 24 0 19. 5 17. 3 ; IR (neat) : max 3855, 3752, 3630, 3464, 3067, 2964, 2874, 2362, 2251, 1772, 1715, 1600, 1504, 1418, 1274, 1216, 1165 ; HRMS (DART) calcd for C 18 H 22 N 3 O 3 [ M +H] + 328.1656, found 328.1663. 7 Isopropyl 4,4a dihyd ro 2 H chromene 5,5,6,6(3 H ,7 H ) tetracarbonitrile ( 3 85 ) The typical procedure was followed with 3 70 (43 mg, 0.25 mmol) and tetracyanoethylene (48 mg, 0.3 8 mmol) to give the title compound (64 mg, 91 %) as an amorphous yellow solid. R f = 0.82 (50% EtOAc /hexanes); MP 139 1 H NMR (300 MHz, CDCl 3 5.33 (t, J = 2.4 Hz, 1H), 4.23 (m, 1H), 3.68 (m, 1H), 3.05 (ddt, J = 12.8, 5.0, 2.1 Hz, 1H), 2.92 (dt, J = 5.0, 2.4 Hz, 1H), 2.42 1.89 (m, 5 H), 1.26 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6. 8 Hz, 3H) ; 13 C NM R (75 MHz, CDCl 3 150.1, 111.8, 111. 4 110. 8 109. 5 103. 4 70.5, 45.8, 44. 7 41.6, 40.7, 30.8, 27.6, 25. 6 23.0, 18.7; IR (neat) : max 3856, 3753, 3631, 3569, 2977, 2878, 2363, 1685, 1654, 1560, 1473, 1438, 1381, 1276, 1162; HRMS (C I) calcd for C 16 H 17 N 4 O [ M +H] + 281.1358, found 281.1402 6 isopropyl 1 tosyl 3,3a dihydro 1 H indole 4,4,5,5(2 H ,6 H ) tetracarbonitrile ( 3 8 7). The typical procedure was followed with 3 76 (77 mg, 0.25 mmol) and tetracyanoethylene (48 mg, 0.38 mmol) to give the title compound as an amorphous

PAGE 154

154 yellow solid (79 mg, 76 %) R f = 0.33 (25% EtOAc/hexanes); MP 49 1 H NMR (300 MHz, CDCl 3 7.68 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 5. 96 (m, 1 H), 4.00 (dd, J = 10.3, 8.1 Hz, 1H), 3.45 (ddd, J = 11.3, 10.3, 5.9 Hz, 1H), 3. 13 2.83 (m, 2H), 2.44 (m, 5 H), 2.08 (qd, J = 11.9, 8.5 Hz, 1H), 1.29 (d, J = 6. 8 Hz, 3 H), 1.09 (d, J = 6.8 Hz, 3 H) ; 13 C NMR (75 MHz, CDCl 3 ) 145.6, 134.7, 133. 6 130.4, 127. 2 111. 5 110. 8 110.3, 108.7, 101.7, 48. 4 48.2, 43.2, 43. 2 42. 1 31. 8 26.5, 24. 1 21.7, 19.2; IR (neat) : max 3855, 3748, 3673, 3578, 2972, 2341, 2256, 1684, 1457, 1360, 1165 ; HRMS (DART) calcd for C 22 H 22 N 5 O 2 S [ M +H] + 420.1489, found 420.1486. 7 phenyl 1 tosyl 2,3,4,4a tetrahydroquinoline 5,5, 6,6(1 H ,7 H ) tetracarbonitrile (3 88 ). The typical procedure was followed with 3 77 (89 mg, 0.25 mmol) and tetracyanoethylene (48 mg, 0.38 mmol) to give the title compound an inseparable diastereomeric mixture, as a yellow gum (81 mg, 69 %) dr 3:2. R f = 0.30 (25% EtOAc/hexanes); 1 H NMR (30 0 MHz, CDCl 3 J = 8. 3 Hz, 2H), 7.6 8 7. 43 (m, 5 H), 7.40 7.35 (m, 2H), 6.19 (t, J = 2.2 Hz, 1H), 4.47 (dd, J = 3.7, 1.2 Hz, 1H), 4.29 (m, 1H), 3.20 (ddd, J = 14.4, 13.0, 2.6 Hz, 1H), 2.87 (m, 1H), 2.47 (s, 3H), 2.35 2.16 (m, 2H), 1.9 8 1.71 (m, 2H); (minor) 7.74 (d, J = 8.3 Hz, 2H), 7.68 7.43 (m, 5H), 7.40 7.35 (m, 2H), 6.34 (t, J = 2.2 Hz, 1H), 4.41 (t, J = 2.4 Hz, 1H), 4.24 (m, 1H), 3.33 (ddd, J = 13.9, 12.3, 3.0 Hz, 1H), 2.91 (m, 1H), 2.48 (s, 3H), 2.35 2.16 (m, 2H) 1.98 1 .71 (m, 2H); IR (neat) : max 3067, 2954, 2871, 2256, 166 5, 1598, 1494,

PAGE 155

155 1454, 1349, 1163; HRMS (ESI) calcd for C 26 H 21 N 5 O 2 S Na [M+Na] + 490.1316 found 490.1205. Tert butyl 5,5,6,6 tetracyano 7 methyl 3,4,4a,5,6,7 hexahydroquinoline 1(2 H ) carboxylate ( 3 89 ) The typical procedure was followed with 3 8 1 (60 mg, 0.25 mmol) and tetracyanoethylene (48 mg, 0.3 8 mmol) to give the title compound an inseparable diastereomeric mixture, as a yellow gum (70 mg, 80 %) dr 4:1. R f = 0.50 (25% EtOAc/hexanes); 1 H NMR ( 300 MHz, CDCl 3 5.69 (t, J = 2.5 Hz, 1H), 4.25 (dt, J = 13.2, 3.8 Hz, 1H), 3.38 (m, 1H), 3.22 2.67 (m, 2H), 2.39 (m, 1H), 2.16 (m, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.64 (d, J = 7.3 Hz, 3H), 1.46 (s, 9H); (minor) 5.48 (t, J = 2.5 Hz, 1H), 4.37 ( dt, J = 13.2, 3.8 Hz, 1H), 3.38 (m, 1H), 3.22 2.67 (m, 2H), 2.39 (m, 1H), 2.16 (m, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.60 (d, J = 7.1 Hz, 3H) 1.46 (s, 9H); IR (neat) : max 2980, 2939, 2880, 2256, 1705, 1453, 1385, 1369, 1284, 1253, 1158 ; HRMS (DART ) calcd for C 19 H 2 5 N 6 O 2 [M+NH 4 ] + 369.2034 found 369.2043.

PAGE 156

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165 BIOGRAPHICAL SKETCH Nicholas Borrero was born in San Juan, Puerto Rico in 1984, where he stayed for two years until moving to the D.C. Metro area. The following years were spent traveling between Virginia and the Republi c of Panama, where he graduated in 2002 from the International School. He returned to the United States to begin studying engineering and chemistry at Virginia Polytechnic Institute and State University, and received his same year he started his doctoral research at the University of Florida under the guidance of Dr. Aaron Aponick, where he worked on novel gold and palladium catalyzed cyclization methodologies and their application towards the synthesis of biologically a ctive natural products.