Diastereoselective Gold (I) and Bismuth (III) Catalyzed Cyclizations of 1,4 and 1,5-Diols in the Formation of Substitute...

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Title:
Diastereoselective Gold (I) and Bismuth (III) Catalyzed Cyclizations of 1,4 and 1,5-Diols in the Formation of Substituted 1,3-Dioxolanes, 1,3-Dioxanes, and 3,6-Dihydro-2H-pyrans.
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english
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Ballesteros, Carl F
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University of Florida
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Gainesville, Fla.
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Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Aponick, Aaron
Committee Members:
Castellano, Ronald K
Enholm, Jonathan E
Smith, Ben W
Sloan, Kenneth B

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Subjects / Keywords:
bismuth -- dioxanes -- dioxolanes -- gold -- pyrans
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

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Abstract:
Gold (I) catalyzed reactions are of growing importance in the synthetic community. They have been shown to be widely applicable in the nucleophillic addition of C, N, O, P, and S species to a variety of unsaturated C-C bonds. This is due in large part to the electronic tuning and steric impedance of ligands among other factors. Surprisingly, few reports on the effects of various ligands are reported. Moreover, there are no known reports of the effects of electron withdrawing ligands in gold catalysis. In this work,the effects of ligands in gold (I) catalysis are discussed, while ligands with electron withdrawing capability are given special attention. In addition, two new methodologies are reported based on the application of electron deficient gold (I) catalyst systems. Diastereoselective gold (I) and bisthmuth (III) catalyzed tandem hemiacetalization and ketalization/dehydrative cyclization was developed. In this method, easily prepared 1,4 and 1,5-monoallyic diols are transformed into cis-1,3-dioxolanesand dioxanes. This transformation may have practical use in the synthesis of protected syn-1,2 and 1,3 diols in natural products. This method is the first to show a cooperative nature between bismuth and gold which are both capable of catalyzing the transformation, but only when the other catalyst cannot. It also represent the first known use of a phosphite ligand in gold (I) catalysis to be able to activate both a C-C double bond and a C-O double bond towards nucleophillic attack.
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In the series University of Florida Digital Collections.
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Includes vita.
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Statement of Responsibility:
by Carl F Ballesteros.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Aponick, Aaron.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-11-30

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1 DIASTEREOSELECTIVE GOLD (I) AND BISMUTH (III) CATALYZED CYCLIZATIONS OF 1,4 AND 1,5 DIOLS IN THE FORMATION OF SUBSTITUTED 1,3 DIOXOLANES, 1,3 DIOXANES AND 3,6 DIHYDRO 2H PYRANS By CARL FRANCIS BALLESTEROS A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2013

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2 2013 Carl Francis Ballesteros

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3 To my beautiful wife Elin and my wonderful children Carl Junior, Brielle, and Carolynn

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4 ACKNOWLEDGMENTS I thank my wife Elin for all of her love, support, and encouragement over the entirety of my gradua te career. She has been my greatest source of strength and support. She amazes me each day in her undertaking of raising our two living children Carl Junior and Carolynn on top of working a full time job. I am most grateful for her perseverance and faith in me I th ank my parents for all of their help in getting to this point of my life. Without their love and support, I would have never even thought to pursue a graduate level degree. To this day I rely upon their advice and loving support. I thank Dr. Aaron Aponick f or building an organic synthetic driven research group here at the University of Florida thus giving me the opportunity of a lifetime in studying chemistry in my field of choice. Not only has he built a group that daily works to expand the state of the art, but he has made this research group a powerhouse of learning synthetic chemistry. It is my humble opinion that this research group is the most knowledgeable in the construction of complex molecules in the entire division of organic chemistry at the U niversity of Florida The group Dr. Aponick has built has even attracted many other like minded very talented, and smart students whom I also thank for their constant positivity. Everyone of these students, past and present, has made this endeavor one of one of joy shared learning, and great fun.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF ABBREVIATIONS ................................ ................................ ........................... 11 ABSTRA CT ................................ ................................ ................................ ................... 16 CHAPTER 1 ELECTRON DEFICIENT LIGANDS IN HOMOGENEOUS GOLD (I) CATALYSIS ................................ ................................ ................................ ............ 18 1.1 Ubiquity of Gold Catalysis ................................ ................................ ............. 18 1.2 The Nature of Gold (I) Catalysis ................................ ................................ ....... 19 1.2.1 Relativistic Effects of Gold. ................................ ............................... 20 1.2.3 Electronic and Steric Effects of the Ligand ................................ ........ 23 1.2.4 Silver Cocatalyst ................................ ................................ ............... 29 1.3 Applications of Electron Deficient Ligands in Gold Catalysis ............................ 30 1.3.1 C, N, and O nucleophilic attack of non activated olefins .......................... 31 1.3.2 C and O nucleophilic a ttack of alkynes. ................................ ................... 34 1.3.3 Cycloadditions and C, O nucleophilic attack of allenes. .......................... 36 1.4 Conclusions ................................ ................................ ................................ ...... 41 2 DIASTEREOSELECTIVE GOLD (I) AND BISMUTH (III) TANDEM HEMIACETAL FORMATION/HYDROALKOXYLATION REACTIONS OF 1,4 AND 1,5 MONOALLYLIC DIOLS TO FURNISH 1,2 DIOXOL ANES AND 1,3 DIOXANES ................................ ................................ ................................ ............. 43 2.1 Introduction ................................ ................................ ................................ ....... 43 2.2. Results ................................ ................................ ................................ ............. 52 2.2.1 Catalyst Screening ................................ ................................ .................. 52 2.2.2 1,3 Dioxolane Conditions Optimization ................................ .................... 53 2.2.3 Aldehyde Scope ................................ ................................ ...................... 54 2.2.4 Synthesis of 1,5 Monoallylic Diols ................................ ........................... 56 2.2.5 Diol Scope ................................ ................................ ............................... 57 2.2.6 Proposed Mechanism and Origin of Selectivity ................................ ....... 64 2.2.7 Application to Natural Product Synthesis ................................ ................. 66 2.2.8 Investigation of Other Substrates ................................ ............................ 69 2.2.9 Investig ation of Other Electrophiles ................................ ......................... 75 2.2.10 Investigation of 1,3 Dioxane De protection ................................ ............ 80 2.3 Future work ................................ ................................ ................................ ....... 81

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6 2.4 Conclusions ................................ ................................ ................................ ...... 83 3 DIASTEREOS ELECTIVE GOLD (I) CATALYZED SYNTHESIS OF 3,6 DIHYDRO 2H PYRANS FROM SYN 1,5 MONOALLYLIC DIOLS ......................... 84 3.1 Introduction ................................ ................................ ................................ ....... 84 3.2 Results ................................ ................................ ................................ .............. 93 3.3 Future Work ................................ ................................ ................................ ...... 96 3.4 Conclusions ................................ ................................ ................................ ...... 97 4 EXPERIMENTAL ................................ ................................ ................................ .... 98 4.1 Catalyst Screening ................................ ................................ ............................ 9 9 4.2 Aldehyde Scope ................................ ................................ .............................. 101 4.3 Substrate Syntheses ................................ ................................ ....................... 104 4.4 Acetals from Diol Scope and Other Studies ................................ .................... 128 4.5 Ketals ................................ ................................ ................................ .............. 135 4.6 De protection of Acetal 2 152 ................................ ................................ ......... 137 4.7 3,6 Dihydro 2H pyran Syntheses ................................ ................................ .... 137 LIST OF REFERENCES ................................ ................................ ............................. 139 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 145

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7 LIST OF TABLES Table page 1 1 M P bond lengths in gold (I) and silver (I) Tp salts. ................................ ............ 22 1 2 Gold (I) catalyzed hydroalkoxylation of non activated olefins. ............................ 32 1 3 ................................ ......................... 33 1 4 ............................... 35 1 5 Synthesis of indenyl ethers from alkynes. ................................ .......................... 36 2 1 Catalyst screening of various catalysts. ................................ .............................. 53 2 2 1,3 dioxolane conditions optimization ................................ ................................ 54 2 3 Aldehyde scope. ................................ ................................ ................................ 55 2 4 Initial diol scope. ................................ ................................ ................................ 58 2 5 Optimization of 1,3 dioxane formation. ................................ ............................... 60 2 6 Optimization of E 1,5 monoallylic diols. ................................ .............................. 61 2 7 Diol scope. ................................ ................................ ................................ ......... 63 2 8 Trial of proposed strategy in natural product synthesis. ................................ ..... 71 2 9 Re optimization of methodology for Roush type Z 1,5 monoallylic diols. ........... 73 2 10 Re optimization of methodology for Roush type E 1,5 monoallylic diols. ........... 74 2 11 Investigation of tandem hemiketalization/dehydrative cyclization. ...................... 75 2 12 Investigation of tandem hemiketalization/dehydrative cyclization. ...................... 76 2 13 Investigation of vinyl ketal 2 166 formation. ................................ ........................ 77 2 14 Investigation of 1,3 dioxane de protection methods. ................................ .......... 80 3 1 dihydro 2H pyrans. .......................... 92 3 2 Investigation of required additives and catalysts. ................................ ............... 94 3 3 Investigation of diastereoselectivity. ................................ ................................ ... 94 3 4 Investigation of gold/silver catalyst system. ................................ ........................ 95

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8 LIST OF FIGURES Figure page 1 1 ............... 18 1 2 Contraction of 6s orbital and expansion of 5d orbitals. ................................ ....... 21 1 3 Common mechanism for gold (I) catalyzed nucleophilic attack of an alkyne.. .... 23 1 4 Rates of protodeauration of common ligands in gold (I) catalysis. ...................... 25 1 5 Rates of C C unsaturated bond activation of common ligands in gold (I) catalysis. ................................ ................................ ................................ ............ 26 1 6 Catalyst lifetimes of common ligands in gold (I) catalysis. ................................ .. 27 1 7 Optimized structures (B3 LYP/SDD) of the complexes of (Ph 3 P)AuOTf. ............. 28 1 8 Sterics and electron deficiency of various phosphorous ligands. ........................ 31 1 9 activated olefins by various catalysts and catalyst loadings. ................................ ................................ ................................ 32 1 10 ................................ 33 1 11 Proposed mechanism for the tandem enyne cyclization/nucleophilic attack. ..... 35 1 12 intramolecular hydroarylation of allenes. ................................ .............. 36 1 13 Intermolecular [2 + 2] cycloaddition of N allenylsulfonamides with enol ethers. ................................ ................................ ................................ ................ 37 1 14 ................................ ................ 37 1 15 Ligand controlled access to [4 + 2] or [4 + 3] cycloadditions of allenyldienes. .... 38 1 16 Proposed common intermediate between products 1 56 and 1 57 resulting from arrow a or b. ................................ ................................ ............................... 39 1 17 Enantioselective [4 + 2] cycloaddition of allenyl diene malonates. ..................... 40 1 18 Enantioselective [4 + 2] cycloaddition of allenyl diene sulfonamides. ................. 41 2 1 Diastereoselective dehydrative cyclizations of 1,7 monoallylic diols. ................. 43 2 2 First investigation of and proposed mechanism of dehydrative cyclization. ........ 44 2 3 Chirality transfer study of dehydrative cyclization methodology. ......................... 45

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9 2 4 Proposed mechanism for the dehydrative cyclization methodology. .................. 45 2 5 Rates of dehydrative cyclization of various allylic ethers. ................................ ... 46 2 6 The complete enthalpy/free energy reaction coordinate profile gold (I) catalyzed dehydrative cyclization of 2 24 by Me 3 PAu + cation. ............................ 47 2 7 Other gold (I) catalyzed dehydrative methodologies from Aponick group. .......... 48 2 8 Original hypothesis for the formation of protected diols. ................................ ..... 49 2 9 sphate extension methodology. ................................ ..................... 50 2 10 ................................ ...................... 50 2 11 Evans diastereoselective synthesis of protected 1,3 diols and carbamates. ...... 51 2 12 monoallylic diols to produce protected syn 1,3 diols. ................................ ................................ ................................ ............. 52 2 13 First attempt at proposed methodology ................................ .............................. 52 2 14 General synthesis of 1,5 monoallylic diols. ................................ ......................... 56 2 15 Synthesis of 1,5 monoallylic diols. ................................ ................................ ...... 57 2 16 ..... 59 2 17 ...... 59 2 18 Complem entary system for the formation of 1,3 dioxanes. ................................ 61 2 19 Synthesis of diols 2 96 2 98 2 100 and 2 102 ................................ ................ 62 2 20 Proposed mechanism for the gold (I) catalyzed tandem hemiacetalization/dehydrative cyclization ................................ ........................... 65 2 21 Proposed origin of diastereoselectivity. ................................ .............................. 66 2 22 Com parison of competing 1,3 diol syntheses. ................................ .................... 67 2 23 Possible natural product targets. ................................ ................................ ........ 67 2 24 Synthesis of isomeric 1,5 monoallylic diol 2 128 and allylic ethers 2 131 and 2 134 ................................ ................................ ................................ ................ 68 2 25 Synthesis of diols 2 137 and allylic ether 2 142 ................................ ................. 69 2 26 Synthesis of diols 2 152 and 2 153 ................................ ................................ ... 72

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10 2 27 Synthesis of diols 2 158 and 2 159 ................................ ................................ ... 74 2 28 Investigation of imines and paraformaldehyde as electrophiles. ......................... 79 2 29 Investigation of epoxides as electrophiles. ................................ ......................... 79 2 30 Chirality transfer investigation. ................................ ................................ ............ 82 3 1 Three examples of natural products containing 3,6 dihydro 2H pyran moieties. ................................ ................................ ................................ ............. 85 3 2 Swinholide A mode of binding two actin molecules.. ................................ .......... 86 3 3 3 4 B: Synthesis of 3 9 and 3 12 ...... 87 3 4 3 4 B: Synthesis of 3 18 and 3 20 ................................ ................................ ................................ ................ 89 3 5 ) apicularen A. B: Synthesis of 3 24 ................... 90 3 6 3 30 and 3 32 ........ 91 3 7 First attempt at tandem hemiketalization/dehydrative cyclization of 3 36 and acetone. ................................ ................................ ................................ .............. 93 4 1 Calibration plot between molar ratio of decane to acetal versus peak area ratios. ................................ ................................ ................................ .............. 100 4 2 Calibration plot of molar ratio between aldehyde to decane versus peak area ratios. ................................ ................................ ................................ .............. 100

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11 LIST OF ABBREVIATION S Ac Acetyl Anhyd Anhydrous aq Aqueous Ar Aromatic Atm Atmosphere BBN (9 BBN) 9 Borabicyclo[3.3.1]nonane (9 BBN) Bn Benzyl Boc t Butyloxycarbonyl BOM Benzyloxymethyl bp Boiling Point BQ Benzoquinone Bz Benzoyl Bu (nBu) n Butyl c speed of light ca Circa (approximately) CAN Cerium (IV) Ammonium Nitrate Calcd Calculated cat. Catalytic Cbz Benzyloxycarbonyl conc. Concentrated Cond Conditions COD 1,5 Cyclooc tadiene Cp Cyclopentadienyl Cp* Pentamethylcyclopentadienyl

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12 CSA Camphorsulfonic Acid Cy Cyclohexyl Heat d Days (length of reaction time) DBU 1,8 diazabicclo[5.4.0]undec 7 ene DCC dicyclohexylcarbodiimide DCD Dewar Chatt Duncanson model DCE 1,1 Dicycloethane DDQ 2,3 Dichloro 5,6 Dicyano 1,4 Benzoquinone DHP 3,4 Dihydro 2H Pyran DIAD Diisopropyl Azodicarboxylate DIBAL H Diisobutylaluminum Hydride DMAP N,N 4 Dimethylamineopyridine DMF N,N Dimethylformamide DMS Dimethylsulfide DMSO Dimethylsulfoxide dr Diastereomeric Ratio E + Electrophile E2 Bimolecular Elimination ee Enantiomeric Excess Et Ethyl EWG Electron Withdrawing Group g Gas GC Gas Chromatography h Hours (length of reaction time)

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13 Het Heterocycle HMDS 1,1,1,3,3,3 Hexamethyldisilazane HOMO High est Occupied Molecular Orbital HPLC High Pressure Liquid Chromatography HWE Horner Wadworth Emmons i Iso IPA Isopropyl Alcohol Ipc Isopinocamphenyl IR infrared spectroscopy L ligand LA Lewis Acid LAH Lithium Aluminim Hydride liq. Liquid LUMO Lowest Unoccupied Molecular Orbital m Meta m CPBA 3 Chloroperbenzoic Acid Me Methyl MOM Methyoxymethyl mp Melting Point MS Molecular Sieve n Normal (e.g. unbranched alkyl chain) NMR Nuclear Magnetic Resonance NR No Reaction Nuc Nucleophile o Ortho

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14 Oxone Potassium Peroxymonosulfate p Para PCC Pyridinium Chlorochromate Ph Pheynyl Piv Pivaloyl PMB 4 Methoxybenzyl PPTS Pyridinium p Toluenesulfonate psi Pounds Per Square Inch P.T. Proton Transfer PTSA (or TsOH) p Toluenesulfonic Acid Py Pyridine rt Room Temperature rac Racemic RDS Rate Determining Step Red Al Sodium Bis(2 methoxyethoxy) Aluminium Hydride R f Retention Factor s Solid Sia 1,2 Dimethylpropyl Sec Secondary TBAF Tetra n Butylammonium Floride TBS t Butyldimethlsilyl TBDPS t Butyldiphenylsilyl TEA Triethylamine TES Triethylsilyl TFA Trifluoroacetic Acid

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15 THF Tetrahydrofuran THP 2 Tetrahydropyranyl TMS Trimethylsilyl TP bis[2 (diphenylphosphino) phenyl]phosphine TS Transition State Tos p Toluenesulfonyl TOF turn over frequency

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16 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 DIASTEREOSELECTIVE GOLD (I) AND BISMUTH (III) CATALYZED CYCLIZATIONS OF 1,4 AND 1,5 DIOLS IN THE FORMATIO N OF SUBSTITUTED 1,3 DIOXOLANES, 1,3 DIOXANES, AND 3,6 DIHYDRO 2H PYRANS By Carl Francis Ballesteros May 2013 Chair: Aaron Aponick Major: Chemistry Gold (I) catalyzed reactions are of growing importance in the synthetic community. They have been shown to be wid ely applicable in the nucleophi lic addition of C, N, O, P, and S species to a variety of unsaturated C C bonds. This is due in large part to the role of ligands among other factors. Surprisingly, few reports on the effects of various ligands are r eported Moreover, there are no known reports of the effects of electron withdrawing ligands in gold catalysis. In this work, the effects of ligands in gold (I) catalysis are discussed, while ligands with electron withdrawing capability are given special a ttention. In addition, two new methodologies are reported based on the application of electron deficient gold (I) catalyst systems. Diastereoselective gold (I) and bisthmuth (III) catalyzed tandem hemiacetalization and ketalization/dehydrative cyclization was developed. In this method, easily prepared 1,4 and 1,5 monoallyi c diols are transformed into cis 1,3 dioxolanes and dioxanes This transformation may have practical use in the synthesis of protected syn 1,2 and 1,3 diols in natural products. This meth od is the first to show a cooperative nature between bismuth and gold which are both capable of catalyzing the transformation, but only

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17 when the other catalyst cannot. It also represent the first kno wn use of a phosphite ligand in gold (I) catalysis to be able to activate both a C C double bond and a C O double bond towards nucleophilic attack. Diastereoselective gold (I) catalyzed synthesis of 3,6 dihydro 2H pyrans was also developed. This methodology has the potential to becoming a new strategy in natural product synthesis for the facile production of these interesting dihydropyran moieties which are found in many marine natural products. Most of which have been shown to posses important biological activity and are currently the subject of great interest a s potential new antifungals, antibiotics, and even anticancer treatments. These important biological functions are believed to stem from the structural shape and rigidity of the dihydro 2H pyranyl moiety.

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18 CHAPTER 1 ELECTRON DEFICIENT LIGANDS IN HOMOGENEOUS GOLD (I) CATALYSIS 1.1 Ubiquity of Gold Catalysis Gold catalyzed reactions are an increasingly powerful tool in the synthesis of a wide variety o f compounds. Over the past two decades there has been an exp losion of reports that exemplify this phenomenon in 1991 wh ile in 2011 there were 800 (Figur e 1 1). 1 Figure 1 1. Number of publications found on Web of Science for gold catalysis. The reasons for this growth in the utility of gold are four fold: 1) Gold is a carbophil ic Lewis acid and thus can activate all manner o f C C nucleophil ic attack. 2) Gold is air and water stable and does not need stringent measures for handling. 3 ) Gold has been shown to be a mild catalyst, tolerant to a wide va riety of functional groups. 4) Gold can be coordinated to a variety o f ligands; which 0 100 200 300 400 500 600 700 800 900 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

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19 allows for increased catalyst lifetime the possibility of stereochemical induction, and also electronic tuning of the catalyst system. Because of the exponential growth in the field of gold catalysis, a large number of reviews are publish ed annually in order to keep up with the state of the art. The se are in large part an appendix of new transformations 2 7 and only a few reviews address the fundamental questions that drive innovation in the field. 8 10 One such review from Toste 11 is the la t est review on ligand effects in homoge nous gold catalysis. Since its publication in 2008, there have been over 3,000 new reports in the field. It therefore seems that a n updated review is needed as the role of ligands is now more clearly defined and better understood. This is especially true f or electron deficient ligands, which have promising reactivity, but are scarcely reported in the literature while electron rich ligands are ubiquitous In fact, there are already a large number of reviews on electron rich ligands in gold (I) catalysis Thi s chapter will therefore strive to not only i nclude examples of electron deficient ligands in various transformations, but also to give clear insight into the ligand s effect on the reactivity of gold (I) catalysis 1.2 The Nature of Gold (I) Catalysis As previously d escrib ed, gold has been shown to catalyze a large number of transformations. These include, but are not limited to: oxidations, condensations, cyc lizations, ring openings, cross couplings, pericyclic transformations, and even tandem processes w hich combine these transformations. All of these are the result of nucleophi lic attack on a given system that is activated by coord ination to the gold catalyst The nucleophile can be C, N, O, S, or even P. The following subsections will discuss four major pillars for understanding gold (I) catalysis, and the impact ligands

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20 contribute to this reactivity. These are relativistic effects, common mechanistic steps, electronic and steric effects of the ligand, and lastly the silver cocatalysts. 1.2.1 Relativistic Effect s of Gold Relativistic effects are an important facet to gold (I) catalysis. They have been evoked to explain the preference of gold (I) complexes interaction with substrates to be orbitally contro lled rather than charge controlled. 12 These effects are also used to explai n why gold forms strong er gold ligand (Au L) bonds than the other group 11 and period 6 metals 13 and also explains the linear coordination geometry of gold (I) complexes Below is a brief explanation of what these effects are, and the consequences they incur on gold (I) catalysis. Group 11 metals all have completely filled f orbitals. As a result electrons in the 1s orbital are traveling at such great veloc ity that they are mov ing at a significant fraction of the speed of light (c) and therefore subject to the special th eory of relativity. This theory stated simply, means that mass increases towards infinity as velocity approaches c. Because the Bohr radius of an electron orbital is inversely proportional to its mass; electrons in 1s orbital are pulled clo ser towards the nucleus of the atom contract ing this and all other s and p orbitals Since gold (0) has the electron configuration [Xe] 4f14 5d10 6s1, electrons in the d and f orbitals are shielded from the nucleus by el ectrons in the s and p orbitals, they are not contracted as much Practically this means that overall gold, regar d less of oxidation state, experience s a contraction of its 6s orbital an d relative expansion of its 5d orbitals compared to the other group 11 elements copper and silver (Figure 1 2 ) 14,15 The consequence of t his relative change in s ize of orbitals is that gold can form very strong bonds with ligands and interacts preferentially with C C unsaturated bonds due to the improved orbital ove rlap

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21 F igure 1 2 Contraction of 6s orbital and expansion of 5d orbitals. According to the Dewar Chatt Duncanson (DCD) model 16 substrates systems (S) share electrons with Lewis acidic m etals (M) in two important ways, donation) as well as metal to substrate back back bonding). It was previously believed that when gold (I) donation is the largest contributing factor to the bo nd. 17 However, a recent theoretical study by Tarantelli and coworkers show ed that the nature of this int eraction is ba back donation for gold (I) chloride 18 This is directly due to relativistic effects. The result of equally sized contribution between donation and back donation is t hat the interaction does not cause a build u p of charge nor does it cause significant distortion of the C C unsaturated bond typically seen with other metals such as platinum or palladium. It is for this reason that gold (I) catalysis is orbi t all y controll ed rather than charge controlled. It is also important to note that the degree in which donation and back donation plays a role in bonding depends also upon the electronic and structural nature of the ligand. This was demonstrated when the contributio back bonding was measured for a carbene ligand and was found to be one half less than that of a chloride

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22 ligand Electron deficient ligands such as phosphites, fluorine en riched phosphines, and phosphoramidi tes were not examined. The tu nability of back donation was also shown in a report from Toste, 19 who showed that NHC ligated gold complexes were better at stabilizing the carboca tion that arises from the metal catalyzed ring opening of cyclopropenes. The bond gold (I) makes with ligands has been shown to be markedly strong. In a report from Zank et a l 20 dimethylsulfide gold (I) chloride (DMSAuCl) is treated with an equivalent of bis[2 (diphenylphosphino) phenyl]phosphine (TP) to generate the p hosphine gold (I) c omplex (TPAuCl, 1 1 ) (Table 1 1 ). The phosphin e to gold bond is 2.32 which is significantly short er than the silver phosphine bond (2.46) shown in the corresponding silver complex (TpAgCl 1 2 ). This is also du e to the change in orbi tal size caused by relativisti c effects. Because the 6s orbital is smaller, it can better overlap with carbene and phosphorous containing ligands in addition to other non metal elements of the p block elements 8 A consequence of this tight bond between gol d (I) and phosphine is that gold (I) salts are primarily dicoordinate, linear molecules. 21 Table 1 1. M P bond lengths in g old (I) and s ilver (I) Tp salts. 1.2. 2 Common Mechanistic Steps in Homogenous Gold (I) Catalysis. Commonly, gold (I) is used to ca talyze a nucleophilic attack on a system. Most gold (I) catalyzed reactions share the same four common mechanistic steps (Figure 1 3 a d ). The first step, activation of catalyst ( a ) is usu ally accomplished through counterion

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23 exchange with a silver cocatalyst. This presumably makes the gold (I) catalyst more cationic sin ce the new counterion is non coordinating or less coordinating than chloride The next step is usually coordination to and a ctivation of the system ( b ) T h is is the n followed by nucleophilic attack on the system ( c ) in an anti fashion Lastly, regeneration of the cationic catalyst ( d ) a llows the catalytic cycle to begin again This last step is most commonly accomplished by protodeauration but can also occur in other ways Each of these steps is greatly affected by ligand effects which will be discussed at length in the followi ng two section s Figure 1 3 Common mechanism for gold (I) catalyzed nucleophilic attack of an alkyne. a) Activation of gold (I) complex. b) Coordination and activation of C C unsaturated bond. c) Nucleophilic attack o f complex 1 8 d) Protodeauration of complex 1 9 1.2.3 Electronic and Steric Effects of the Ligand It is well known that the reactivity of transition metals is g reatly altered by ligands In a recent report from Wang 22 common phosphorous and NHC ligands in gold (I) catalysis were categorized into one of four groups depending upon their effect on protodeauration, ac tivation of unsaturated C C bonds, and catalyst lifetime. This was

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24 accomplished by measuring the rates of these three steps through 31 P NMR. The results were then compared by ligand. To measure the rate of protodeauration, a series of complex es (Figure 1 4 1 11 a f ) were first made between a gold (I) catalyst and a substrate beforehand The complex was then treated with trifluoroacetic acid to promote protodeauration The percent conversion was measured over time by NMR. To measure the rate of activation o f a C C unsaturated bond, the same NMR technique was used to observe the formation of a gold (I) cation substrate complex over time This was done with a series of gold (I) cations (Figure 1 5 1 13 a f ) that varied by ligand Catalyst lifetime was also m easured similarly by treating a series of catalyst s (Figure 1 6 1 13 a f ) with 10 eq u ivalents of an alkyne ( 1 17 ) and observing the formation of twice ligated gold (I) complex (Ln 2 Au + 1 19 ) which comes about by transmetallation between two of the same catalyst species. The byproduct of this reaction is gold (0), which precipitates out of solution. It was observed that the rate of protodeauration is favor ed when the ligand is electron donatin g (Figure 1 4 ) The fastest results came from an NHC ligand ( I ) while the slowest by a wide margin came from an electron deficient fluorinated phosphine ( (p CF 3 C 6 H 4 ) 3 P) Sterics were also shown to play a role in t his as bulky Buch wald type ligands also s howed higher rates of reactivity ( II, and III ) These ligands ty pically feature a biphenyl phosphine which has been shown to interact with the gold metal center remotely at the biphenyl moiety This interaction changes the P Au C bond angle from 23 Howeve r, bulky ligands that di d not have a biphenyl phosphine were slower than their counterpart s

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25 The rate of C C unsaturated bond activation was favored by ligands that are electron withdrawing al though by a much smaller extent than what is see n in protodeauration (Figure 1 5 II vs. (p CF 3 C 6 H 4 ) 3 P). This is probably due to the fact that all gold (I) species can activate C C unsaturated bonds due to relativistic effects, regardless of electron donating or withdrawing ability of the ligand Figure 1 4 Rates of protodeauration of common ligands in gold (I) catalysis. Reprinted with permission f rom Wang W.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2012 134 5697 5705. Copyright 2012 American Chemical Society.

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26 Catalyst lifetimes were found to be prolonged by increasing bulk ab out the metal center (Figure 1 6 ). Particularly ligand II which features a biphenyl moiety was shown to have very little decomposition over 250 hours. This compares favorably to the other tested symmetric triarylphosphines, which were shown to lose active catalyst ( 1 13 ) within 24 hours. Figure 1 5 Rates of C C unsaturated bond activation of common ligands in gold (I) catalysis Reprinted with permission from Wang W.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2012 134 5697 5705. Copyright 2012 American Chemical Society. In addition, the electronic nature of the ligand is also responsible for affecting the Lewis acidity of transit ion metal complexes This is due to the polarization of metal ligand bond orbitals 24 This is especially true in gold (I) catalysis where the ligand metal

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27 substrate bond is linear. W hen a given transition metal is ligated to an electron withdrawing ligand its Lewis acidity is increased. 25 However, d ue to relativi stic effects of gold, it is (or soft Lewis acid) b ut when an electron withdrawing ligand is present on a gold (I) catalyst then it becomes a hard Lewis Figure 1 6 Catalyst lifetimes of common ligands in gold (I) catalysis. Reprinted with permission from Wan g W.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2012 134 5697 5705. Copyright 2012 American Chemical Society. It is somewhat novel for a Lewis acid to be both hard and soft Lewis acidic. 26 Classical Lewis acids ar e typically hard acids favoring coordination with a lone pair ra complexes however, are among a relatively new class o f Lewis acids that can be both hard and soft Lewis acidic. Other examples include platinum, palladium, copper, mercury, and silver c omplexes For example, gold (I) chloride has been shown to be both hard and soft Lewis acidic but triphenylphosphine gol d (I) trifluromethanesulfonate [ (Ph 3 P)AuOTf] is shown

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28 to be only soft Lewis acidic 26 When the latter catalyst system was mixed with a stoichiometric amount of benzaldehyde, benzamine, p henylacetylene, and styrene, the resulting complexes formed crystals and were subjected to x ray analysis. These x ray data are shown in F igure 1 7. When mixed with benzaldehyde, this gold catalyst is shown not to coordinate with the oxygen atom of the ald ehyde. Instead, it only coordinates with the nitrogen of the benzamine, and the C C triple bond of phenylacetylene. This example demonstrates the dichotomy in the Lewis acidity of gold complexes They can be either soft Lewis acidic or both hard and soft L ewis acidic by selecting the appropriate ligands and counter anion. Figure 1 7 Optimized structures (B3LYP/SDD) of the complexes of (Ph 3 P)AuOTf with benzaldehyde (upper left), benzamine (upper right), phenylacetylene (lower left), and styrene (lower right). Gold (orange), phosphorous (violet), oxygen (red), nitrogen (blue), fluorine (green), sulfur (yellow). Reprinted with

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29 permission from Yamamot o Y. J. Org. Chem. 2007 72 7817 7831. Copyright 2007 American Chemical Society. 1.2.4 Silver Cocatalyst Activation of a gold (I) catalyst is not always needed, but is widely used for the purpose of increasing the cationic nature of the gold center. This is typi cally accomplished by mixing a gold (I) chloride species with a silver salt as a cocatalyst because silver is a known chloride scavenger. The end result is the presumed precipitation of silver chloride, and exchange of the counter anion to the gold (I) catalyst. Usually, the new counter anion is selected to be non coordinating. Examples include triflu o romethansulfonate (triflate, TfO ), tetrafluoroborate (BF 4 ), hexafluorophosph on ate (PF 6 ), and hexafluoroantimonate (SbF 6 ). Although the silver is u sually presumed not to be involved in a gi ven gold (I) catalyzed reaction a recent report has shown it can play a crucial role. 27 In the report from Shi it was the reaction, it could actually be one of three types: true gold catalysis, gold and silver bimetallic catalysis, or silver assisted catalysis. Wang then classified a number of known g old (I) catalyzed reactions by screening them with only gold, only silver and with both metals present in solution The yields for all three tests were subsequently compared. Reactions where gold only yields matched the yields of gold and silver were deemed to be true gold catalysis. When reaction yields did not match, then one of two scenarios had to be determined. If the yield was less than combined two metals yield, then the react ion was deemed to be silver assisted. If however the gold only and silver only e t together they gave moderate to good yields; then these were deemed bimetallic. It should be noted that no ne of the reactions tested were ever observ ed to be promoted

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30 by silver alone. The author s were able to find multiple working examples of all three reaction classifications thus demonstrating that the role of the silver cocatalysts is inherently more complex than previously thought. 1.3 Application s of Electron Deficient Ligands in Gold Catalysis In homogeneous gold (I) catalysis, the use of electron withdrawing ligands is much less common than the use of electron donating ligands. This may be somewhat expected considering the above discussion regar ding the effect of electron donating ligands on protodeauration. However, by using an electron poor ligand, a change in Lewis acidit y occurs which opens the door for the possibilit y of expanding the reactivity of gold (I) catalysis Typically, electron poo r ligands in homogeneous gold (I) catalysis are fluorinated phosphines however phosphites are known to be more electron deficient than phosphines when coordinated to a metal. In a review from Tolman, presented (Figure 1 8). 28 In the figure, phosphorous ligands are plotted parameter also known as ligand cone angle) versus ligand cone angle is determined from x ray crystal structures to be the apex angle of a cylindrical cone 2.28 from the center of the P atom to the van der Waals radii of the outermost atoms. If the ligand is not symmetric then the ligand cone angle is determined by an equation which minimizes the sum of half angles. The electronic from the absorbed IR frequency th at corresponds to the C O triple bond mode of vibration that is observed in Ni(CO) 3 L dissolved in methylene chloride. When the ligand (L) is electron poor, the observed IR frequency increases while the reverse is true for electron rich ligands. If one compares the plots of

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31 triphenylphosphine versus triphenylphosphite, the phosphite is les s bulky, but more electron def icient. This trend holds for most phosphites in comparison to phosphines. Figure 1 8. Sterics and electron deficiency of various phosphorous ligands. Reprinted with permission from Tolman, C. A. Chem. Rev. 1977, 77 313 348 Copyright 1977 American Chemical Society. Below are some examples where electron poor gold (I) complexes were found to better catalyze the transformation th an a more electron rich complexe s in homogeneous gold (I) catalysis 1.3.1 C, N, and O n ucleophil ic attack of non activated olefins A report from Tokunaga showed how electron deficient ligands were better able to activate a hydroalkoxylation of a non activated olefin ( 1 20 Table 1 2 ). 29 The authors speculated that the electro n withdrawing ability of the fluorinated aryl phosphine was the reason for the increased r e activity compared to the non fluorinated triphenylphosphine (e ntry 1) or even the tri (4 fluoromethylphenyl) phosphine ( (p CF 3 C 6 H 4 ) 3 P, entry 2)

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32 However, it was unclear to the authors why the addition of extra phosphine made such an improvement on reactio n yield (entry 4) This improvement may be due to the extra by pr event ing the formation of gold (0). Table 1 2. Gold (I) catalyzed hydroalkoxylation of non activated olefins. In another report on non activat ed olefins, a hydro amination is reported by Njera using very low catalyst loadings (Figure 1 9 ) 30 Triphenylphosphite was shown to give vastly improved results compared to triphenylphosphin e (entries 1 and 2). Because the reactivity was so high in this method, the authors were able to r educe the catalyst loading to as little as 0.01 mol %. When these same conditions were used on non activated dienes, the reaction did not require heating F igure 1 9 ydroamination of non activated olefins by various catalysts and catalyst loadings. In analogous fashion, Che used triphenylphosphine as a ligand in an earlier report of gold (I) catalyzed hydroamination of non activated olefins The n itrogen compounds

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33 were also sulfonamides (Figure 1 10 ) 31 The triphenylphosphine gold (I) chloride /silver triflate catalyst system ha d to be run at a significantly higher catalyst loading (100 times as much) higher temperature, and longer reaction time to get similar yields method. Fi gure 1 10 hydroamination of terminal olefins by sulfonamides Phosphite ligands were also able to show efficacy towards the hydroarylation of allylic alcohols in a report by Bandini and coworkers (Table 1 3 ) 32 In this example, other ligands were not compared to the phosphite ligand but interesting reactivity was observed nonetheless. The methodology only works for the Z olefin as t he E olefin led mostly to decomposi tion Allylic ethers were shown not to work at all. The authors Table 1 3. ydroar ylation of allylic alcohols

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34 propose that the free hydroxyl group is hydrogen bonded to the sulfonyl moiety of the sulfonamide which facilitates the dehydrative cyclization on the Z olefin. This is in spite the fact that the hydrogen would have to interact with an oxygen nine atoms away. For a more detailed understanding of leaving groups in gold (I) catalyzed dehydrative cyclizations see selected works from Aponick and coworkers. 33,34 1.3.2 C an d O nucleophilic attack of alkynes Echavarren and coworkers found a phosphite ligand (Table 1 4 entry 2) was found to be optimal rather than a Buch wald type biphenyl phosphine or even an NHC carbene (entries 1 and 6) in the reaction of a tandem en yne cycl ization/electron rich aromatic addition methodology. 35 The reason why an electron withdrawing ligand is favored is unclea r. In the mechanism (Figure 1 11 ), it is believed that the gold cation first activat es the alkyne towards nucleophi lic attack by the olefin thus cyclizing the substrate to a five membered ring intermediate 1 40 The authors then postulate the formation of a fused cyclopropane ring by d onatin g electrons from the gold atom to form a carben oid 1 41 However, this step must be reversible which se ts u p an interesting equilibrium If the gold (I) catalyst has an electron donating group attached, then the forward direction must be favored and thus giving rise to the cyclopropane gold carben o i d 1 41 When the nucleophile attacks, it attacks the carben oid giving rise to product 1 38 b On the other hand, if the ligand is electron withdrawing and the R group is electron rich then the reverse dire ction must be favored. This gives rise to a secondary carbocation (Figure 1 11 1 40 ) that can then be subsequently attacked by the nucleophile giving rise to product 1 38a This would seem to indicate that electron deficient ligands do not favor formatio n of gold carben oids thus pushing the equilibrium

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35 towards the carbocation 1 40 However, it has been shown that these ligands do in fact form stronger Au C carbenoid bonds than electron rich ligands. 23 This pos es an interesting question and should be examined more thoroughly. Table 1. andem cyclization/nucleophi lic ring opening. Figure 1 11 Proposed mechanism for the tand em enyne cyclization/nucleophil ic attack. In a report from Toste, a f luorinated arylphosphine ligand was found to be superior to triphenylphosphine in the synthesis of indenyl ethers from alkynes. 36 In fact, Ph 3 PAuCl gave no reaction, while ( p CF 3 C 6 H 4 ) 3 PAu Cl/ Ag BF 4 was shown to give 81%

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36 yield. Interestingly, the methodology was even shown to transfer chirality with lit tle loss of ee (Table 1 5 1 42 into 1 42 ). Table 1 5 Synthesis of indenyl ethers from alkynes. 1.3.3 Cycloadditions and C, O nucleophilic attack of allenes. Phosphites have also been shown by Gagne and coworkers to activate allenes towards intramolecular hydroarylation by electron rich aryl groups (Figure 1 12 ). 37 Initially, the authors used an el ectron rich BINAP type phosphine ligand which was shown to achieve full conversion after 16 hours. The phosphite ligand was shown to work in 6 hours for near full conversion. This methodology was later extended to an intermolecular variant using the same c atalyst system. 38 Figure 1 12 ntramolecular hydroarylation of allenes. In another example phosphites were again shown to be more reactive than electron rich NHC li gand. Gonz lez and coworkers 39 were able to furnish the intermolecular [2 +2] cycloaddition of N allenylsulfonamids with enol ethers and

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37 styrenes with as little as 0.5 mol% catalyst loadings at ro om temperature in just 5 minutes (Figure 1 1 3 ). The methodology also applied to allenylsilylethers with enol ethers. In the same report, the authors were even able to dimerize the N allenylsulfonamides by adding a c atalytic amount of norbornene Figure 1 13 Intermolecular [2 + 2] cycloaddition of N allenylsulfonamid e s with enol ethers. A phosphite ligand was also shown to work best in the cascade cyclization of allenylepoxides from Gagn (Figure 1 13). 40 In this example, the authors believe that gold first coordinates to the allene which activates it towards nucleophilic attack by a pendant epoxide. But because the epoxide is also an electrophile, the ring opening was made into a cascade by attack by another epoxide. Howe ver, another plausible mechanism would have the gold (I) catalyst first coordinating to an epoxide, which is Figure 1 14. ascade cyclization of allenylepoxides.

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38 then attacked by a pendant alcohol to make the first tetrahydrofuran. The resulting intermediate can then continue to cascade down the backbone to lastly cyclize with the pendant allene resulting in 1 54 In an extremely rare instance in gold (I) catalysis th e choice of the ligand was shown to actually change the outcome o f a gold (I) catalyzed reaction as reported by Toste (Figure 1 15 ). 41 It was found that when 5 mol% Ph 3 PAuCl/AgSbF 6 catalyst was used, a mixture of both cycloadducts ( 1 56 and 1 57 ) were formed in 2:1 ratio in favor of the [4 + 2] product 1 56 However, when a phosphite ligand ( VIII ) was used, only the [4 + 2] product is observed. In addition, if an electron r ich ligand such as a Buch wald type ( IX ) ligand is used then the [4 + 3] product 1 57 is almost exclusively formed over the [4 + 2] in ratio of 96:4 Figure 1 15 Ligand controlled access to [4 + 2] or [4 + 3] cycloadditions of allenyldienes. The reason for this difference in products is believed to stem from a single inter mediate 1 58 (Figure 1 16 ) This intermediate comes about from a [4 + 3]

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39 cy cloaddition that can then either undergo a 1,2 hydride shift or a 1,2 alkyl shift depending upon the nature of the ligand bound to gold. Figure 1 16 Proposed common interme diate between products 1 56 and 1 57 resulting from arrow a or b In a study, 23 it was found that this bifurcation of mechanism comes from both the electronic and steric nature of the ligand. In the study, Toste and Goddard compared three ligands; PPh 3 P(OPh) 3 and P(t Bu) 2 (o biPh) to find that all three were shown to have about the same activation barrier for an alkyl shift of 6.1, 6.0, and 5.7 kcal/mol respectively for [AuP(t Bu) 2 (o biPh)] + [AuP(OPh) 3 ] + and [AuPPh 3 ] + cations Therefore, all three of these ligands should be capable of undergoing [4 + 2] cycloaddition The key to the bifurcation of mechanism therefore lies in the difference of each hydride shift. The bond angle between P Au C is Bu) 2 (o biPh)] + This is due to a remote steric interaction of the biphenyl moiety with the gold metal center. Because this angle is significantly different 5 d orbital electrons have less overlap with t he C sp 2 orbitals and thus the gold carbenoid has more carbene character than a carbenoid stabilized by a gol d cation with a symmetric ligand (i.e. P Ph 3 or P (OPh) 3 ). This then favors a 1,2 hydride shift over an alkyl shift and is in agreement with the calculated activation barriers. The hydride shift of a free carbene was found to be 1.3 kcal/mol, while the [AuP( t Bu) 2 (o biPh)] + was 2.6 kcal/mol, and the [AuP(OPh) 3 ] + was 6.9 kcal/mol.

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40 The [AuP(OPh) 3 ] + seems to only favor the 1,2 alkyl shift as no [4 + 3] product is ever observed This appears to be due to the carbene. It has a snap bond energy (which is a type of calculated bond energy) of 92 kcal/mol versus the 78 kcal/mol of the [AuP(t Bu) 2 (o biPh)] + This increased stabilization polarizes the Au C bond, thus fav oring the 1,2 alkyl shift completely. Toste followed this work by using electron deficient ligands to do an enantioselective intramolecular [4 + 2] cycloaddition of allenes. 42 After a thorough catalyst screening and conditions opti mization, high yields and selectivity were observed at room temperature for cyclization of the dimethylmalonate (Figure 1 1 7 ). Even more impressive ly the authors report that they were able to recover and reuse the catalyst without degradation to ee. In t he same report, Toste was also able to show that allenyldiene sulfonamides could also work but required the use of another electron deficient, phosphoramidite ligand in higher loading (Figure 1 18 ). The higher catalyst loading was needed because of the coo rdinating ability of the nitrogen moiety. Figure 1 1 7 Enantioselective [4 + 2] cycloaddition of allenyl diene malonates.

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41 Figure 1 18 Enantioselective [4 + 2] cycloaddition of allenyl diene sulfonamides. 1.4 Conclusions From these examples, one can conclude that C, O, and N nucleophilic attack on non activated alkenes and alkynes can be accomplished by electron rich or poor gold (I) catalysts, but that electron poor catalysts can do so more efficiently in all the above ca ses. This results in lower cataly st loadings, reaction times, temperatures and sometimes higher yields Presumably, this is because of the increased Lewis acidity of the electron poor catalyst, which can better activate the alkene or alkyne towards nucleo philic attack. Use of e lectron deficie nt ligands in gold (I) catalysis r emain s relatively un der explored. However from the examples above, these ligands have been shown to be advantageous and have even led to the development of highly enantioselective cata lyst systems. Even more promising is the effect that electron withdrawing ligands have on the Lewis acidity of the gold cat ion. This phenomenon seems well suited for allowing a Lewis acid, and may be able to catalyze

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42 multiple bond forming events in a given reaction thus harnessing the potential dual activity of the catalyst. This could be a new and unexplored frontier in the vast expanse of reactivity in gold (I) catalysis. In the following chapters, the du al Lewis acidity of electron deficient ligands in homogeneous gold (I) catalysis is utilized in the tandem hemiacetalization and hemiketalization/dehydrative cyclization of 1,4 and 1,5 monoallylic diols as well as in the cyclization of these same diols int o 3,6 dihydro 2H pyrans.

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43 CHAPTER 2 DIASTEREOSELECTIVE G OLD (I) AND BISMUTH (III) TANDEM HEMIACE TAL FORMATION/HYDROALKOX YLATION REACTIONS OF 1,4 AND 1,5 MONOALLYLIC DIOLS TO FURNISH 1,2 DIOXOLANES AND 1,3 DIOXANES 2.1 Introduction In 2008, Aponick and coworkers reported gold (I) catalyzed dehydrative cyclization of 1,7 monoallylic diols (Figure 2 1, 2 1 ) to produce substitu ted tetrahydropyrans ( 2 2 ). 43 The method wa s shown to have tolerance to a wide varie ty of functional groups and catalyst loadings as low as 0. 1 mol% to promote the reaction at room temperature. Inte restingly, the catalyst does not appear to be working through a cationic mechanism. When two isomeric substrates (Figure 2 2, 2 3 and 2 4 ) were subjected to the same con ditions only 2 3 produced tetrahydropyran 2 5 Even when diol 2 4 was treated with higher catalyst loading and heating, no reaction was observed. I nstead the reaction appears to undergo the proposed stepwise S N addition and elimination of the gold (I) cation (Figure 2 2 ) After coordination of the gold (I) cation to the olefin, nucleophilic attack by the pendant alcohol produces intermediate 2 7 Thereafter, water and gold are eliminated producing product 2 8 At the time of this report, it was not yet clear how the elimination of water or gold (I) cation took place. Figure 2 1. Diastereoselective dehydrative cyclizations of 1,7 monoallylic diols.

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44 Figure 2 2. First investigation of and proposed mechanism of dehydrative cyclization. In a subsequent report, Aponick show ed that this methodology was also applicable in the transfer of chirality. 44 In fact, it was observed that when the geometry of the allylic alcohol moiety is changed; so too is the stereochemical outcome (Figure 2 3). The transfer of chirality was shown to work on a number of substrates showing little to no loss of enantiomeric excess (ee) The most plausible way for chirality to transfer fr om the allylic alcohol moiety to the newly formed tetrahydropyran wit hout loss of ee is if the gold (I) cation were adding and eliminating in anti fashion to the incoming hydroxyl group. Thus, the proposed mechanism for the method ology was first proposed i n greater detail (Figure 2 4). After coordination with the gold (I) cation, the substrate then undergoes nucleophilic attack of the pendant alcohol moiety to the olefin in an anti or syn fashion to produce intermediate 2 14 or 2 15 Presumably, this is act ually occurring as an anti addition due to the incoming nucleophile encumbering a syn addition pathway. It was also proposed that in either of these intermediates, 2 14 or 2 15 that formation of 2 16 might be facilitated by a hydrogen bond between the prot onated ether and free alcohol moieties. These intermediates then under go elimination of gold (I) cation and water to furnish the Z olefin product 2 1 7 Again, if the addition is presumed

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45 to be anti, then the elimination would occur in anti fashion. If this i s the true mechan ism at work, then it represents a rare e xample of gold (I) catalysis that does not require protodeauration for the regeneration of catalytic gold (I) cation. 45 Figure 2 3. Chirality tran sfer study of dehydrative cyclization methodology. Figure 2 4. Proposed mechanism for the dehydrative cyclization methodology. To investigate the possibility of hydrogen bonding in the above proposed mechanism, a study was undertaken to investigate the types of leaving groups that this methodology could tolerate. 33 Va rious allylic ethe rs were subjected to standard

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46 conditions (Figure 2 5 ) The rate of the reaction was monitored by gas chromatography (GC) as follows. Aliquots were removed from the reaction and treated with Reaxa Quadrapure TM MPA resin beads. These serve to irreversibly bi nd the active gold (I) cation catalyst and thereby stop any further reaction progress. The sample was then diluted and chromatographed via GC. Peak area ratios were then used to calculate reaction progress and thus rates of conversion. This was the first r eport to show this utility of the resin beads. Figure 2 5. Rates of dehydrative cyclization of various allylic ethers. 33 It was found that a traditional leaving group, such as benzoyl (Figure 2 5, 2 23 ) showed very little conversion while poor leaving groups such as hydroxyl, methoxy, and even benzyl ( 2 18 2 19 and 2 20 ) gave highest conversions. Furthermore, tert butyldiphenylsilyl (TBDPS) ether and tetrahydropyranyl (THP) ether ( 2 21 and 2 22 )

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47 also gave good conversion but took longer to reach moderate to good yields. These results give further support for a hydrogen b onded motif described in the proposed mech anism for this transformation, a s the most reactive leaving groups tend to be the best hydrogen bond acceptors. Finally, full elucidation of the proposed mechanism was achieved through a calculations study. 34 In this last report of the dehydrative cyclization methodology, DFT calculations were performed in collaboration with Ess group These calculations not only corroborate t he stepwise anti addition/elimination of gold (I) cation, but also show the importance of hydrogen bonding in the dehy drative cyclization Figure 2 6. The complete enthalpy/free energy reaction coordinate profile gold (I) catalyzed dehydrative cyclizatio n of 2 24 by Me 3 P Au + cation. Bond lengths are written above each structure while relative energies are given below. 34 A hydrogen bond was found to occur even before nucleophilic attack of the alcohol on the activated olefin (Figure 2 6, 2 25 ). Furthermore, once this hydrogen bond is established, it is very unlikely to break throughout the course of the reaction. This adds rigidity to the complex, thus acting as a tran s decalin like template for the next steps in the reaction mechanism. After hydrogen bond formation, the mechanism proceeds

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48 through the anti addition nucleophilic attack of the olefin ( 2 26 ), followed by proton transfer ( 2 27 ), then subsequent anti elimina tion of gold (I) cation and concomitant elimination of water ( 2 28 to 2 29 ). The above dehydrative cyclization methodology was extended into several other methodologies. Aponick and cow orkers were able to show a gold (I) catalyzed dehydrative spiroketaliza tion methodology (Figure 2 7 A). 46 Additionally, a gold catalyzed tandem dehydrative cyclization/aromatization (B), 47 and also a gold (I) catalyzed dehydrative cyclizati on of monoallylic alcohol containing phenols to furnish chromenes (C) 48 methodologies were developed. Figure 2 7. Other gold (I) catalyzed dehydrative methodologies from Aponick group. More recently, Aponick reports a gold (I) catalyzed tandem intermolecular hydroalkoxylation/Claisen rearrangement (Figure 2 7, D) 49 This is the first report from Aponick that shows a gold (I) catalyzed intermolecular reaction, in this case for the

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49 formatio n of an enol ether However, the impetus for studying a tandem hemiacetalization/hydroalkoxylation (this work) was to address this ve ry issue. The original hypothesis was to see if it would be possible to extend the dehydrative cyclization to an intermolecular variant such that the gold (I) catalyst not only served to activate a C C unsaturated bond, but also to catalyze further bond forming events. In this way, the new methodology would serve to add increasingly complex molecules from very simple ones. The original hypothes is stemmed from the idea th at a monoallylic di ol (Figure 2 8, 2 39 ) could first attack an electrophile with such functionality as to create a pendant nucleophile that could then undergo subsequent dehydrative cyclization. It was thought that this could best be accomplished by using aldehydes ( 2 40 ) as these are known to undergo facile hydration to form hemiacetals ( 2 41 ). 50 Overall, the transformation would produce a protected diol in the form of an acetal. Figure 2 8. Original hypothesis for the formation of protected diols To date, no gold (I) catalyzed transformation s of this kind have yet been reported. However similar reaction mechanisms or products have been reported as early as 19 77 In a report from Bartlett, homoallylic alcohols are functionalized by a process referred to as 51 In the method, the homoallyl ic alcohol is first converted to a phosphate and then subsequently treated with elemental iodine (Figure 2 9, 2 43 to 2 44 ) This new cyclic phosphate ( 2 43 ) can then be treated with sodium ethoxide to produce epoxide 2 44

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50 Figure 2 9. Bartlett Unfortunately, the phosphate extension methodology suffers from one drawback. It is very difficult to remove the phosphate via hydrolysis. Instead, Bartlett later found that carbonates were able to undergo the same type of reactivity, yet easily furnish the desired 1,3 diol. 52 Much like before (Figure 2 10) a homoallylic alcohol is converted to the tert butylcarbonate 2 46 then subsequently treated with elemental iodine to produce the cyclic carbonate 2 47 The selectivity for the new methodology is not as good as the previous method, but can be easily converted into an array of compounds ranging from various substitut ed diols to epoxides. Figure 2 10. In 1993, Evans was also interested in the synthesis of protected 1,3 diols for use in macrolide antibiotics. 53 In analogous fashion, homoallylic alcohols were subjected to basic c onditions in order to prepare benzylidene acetals 2 49 (and cyclic carbamates 2 51 ) via conjugate addition. The method was shown to work in good yields and diastereo Inter estingly, when p anisaldehyde was used, the reaction w as sluggish, but w hen p nitrobenzaldyde was used, the reaction proceeded smoothly to give multiple products.

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51 Aliphatic aldehydes were shown to work, but not with any diastereosel ectivity. These observat ions implicate hemiacetalization may be the rate determining step. Figure 2 11. Evans diastereoselective synthesis of protected 1,3 diols and carbamates The above methodology has since become the standard protocol for formation of syn 1,3 diols in natu ral product synthesis As such, the methodology was employed in the formation of many natural products including (+) rox aticin, leucascandrolid e A, cochleamycin A, and ( ) apiclaren A 54 57 expanded to similar methodologies that differ in substrate and in catalyst but still undergo the same hemiacetal formation followed by conjugate addition motif 58 61 In an entirely different approach Zakarian reports formation of protect ed syn 1,3 diols by way of a rhenium catalyzed transposition of allylic alcohols. 62 In the method, 1 5 monoallyli c diols (Figure 2 12, 2 52 ) are treated with Re 2 O 7 and dimethoxy acetals or ketals to furnish the desired acetonide 2 53 or PMP acetal 2 54 Th ough th e mechanism is not yet known, the method shows tolerance f o r a variety of functional groups, however is su fficiently Lewis acidic to deprotect silyl protected alcohols and preexisting acetals or ketals present in the substrate.

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52 Figure 2 12. monoallylic diols to produce protected syn 1,3 diols 2.2. Results To test our hypothesis, the commercially available reagents cis 1,4 butenediol ( Figure 2 13, 2 55 ), benzaldehyde ( 2 56 ), and cyclohexane carboxaldehyde ( 2 5 8 ) were treated with 5 mol% of I /AgOTf. After 36 hours, acetal s 2 57 and 2 5 9 were found on the firs t attempt of our proposed methodology. Figure 2 13. First attempt at proposed methodology 2.2.1 Catalyst S creening We next so ught to d etermine which catalyst was optimal for the transformation (Table 2 1). The best yielding catalysts were found to be go ld salt I /AgOTf (entry 10) and also the tri meric gold (I) oxonium catalyst (entry 9, [(Ph 3 P)Au] 3 BF 4 ). However, the best diastereoselectivity came from gold salt V /AgSbF 6 (entry 12)

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53 Table 2 1. Catalyst screening of various catalysts. 2.2.2 1,3 D ioxolane C onditions O ptimization Before an examination of reaction scope could be condu cted, we sought to first determine the best reaction conditions (Table 2 2). For the formation of 2 59 the best conditions were found in entry 10. Interestingly, increa sing the num ber of aldehyde equivalents decreased the reaction time, thus suggesting that formation of the hemiacetal is the rate determining step. The cis diastereomer was found to be the major diastereomer as confirmed by nOe.

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54 Table 2 2. 1,3 dioxolan e conditions optimization 2.2.3 Aldehyde Scope Using the conditions found above, various aldehydes were screened Our resu lts turned out to be exactly opposite of Evans methodology 53 In fact, branched aliphatic aldehydes not only gave the best yields, but also the highest sele ctivity ( Table 2 3, entries 1 4 ). Oddly, aromatic a ldehydes show little to no reactivity despite the presence of electron donating or electron withdrawing moieties (entries 7 9 ). Chloral hydrate was found to be the most reactive, but also gave the lowest selectivity (entry 6 ).

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55 Table 2 3. Aldehyde scope

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56 2.2.4 Synthesis of 1,5 Monoallylic D iols In order to determine the substrate scope, diols were pr e pared in one of two general methods (Figure 2 14). The first method involves an alkynylation of an aldehyde to produce propargylic diols 2 71 This is usually done without protecting the alkynyl alcohol s 2 70 The propargylic diols are then reduced to 1,5 monoallylic diols by either LAH or Lindlar reduction to afford the corresponding E or Z olefin 2 72 Alternatively, isomeric 1,5 diols that have a prim ary allylic alcohol moiety 2 75 were made via allylation with a G rignard reagent to produce homoallylic alcohol s 2 74 This was followed by metat hesis with crotonaldehyde and subsequent reduction with sodium borohydride (NaBH 4 ) Figure 2 14. General s y nthesis of 1,5 monoallylic diols. The first s et of diols were prepared as described above D iol E 2 55 was made via the lithium aluminum hydride (LAH) reduction of diol 2 76 which was furnished in 70% (Figure 2 15). 1,5 monoallylic diols E 2 79 and Z 2 79 were prepared over two steps in

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57 69% and 58% respectively. Isomeric 1,5 monoallylic diol 2 8 2 was produced in 9% over three steps. Figure 2 15. Synthesis of 1,5 monoallylic diols. 2.2.5 Diol S cope Application of the standard conditions found above on an i nitial diol scope found no reactivity (Table 2 4 ). It seemed that the conditions optimized for the formation of 1,3 dioxolanes from cis butene 1,4 diol z 2 55 would need to be completely changed to furni sh the desired reactivity on other substrates It wa s thought that investigating

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58 Brnsted acid additives such as camphor sulfonic acid (CSA) or p toluene sulfonic acid (pTSA) could help Also, an entirel y new catalyst perhaps needed to be considered Table 2 4. Initial diol scope. Other metal salts are k nown to catalyze dehydrative substitution reactions. Two examples were recently reported. Shibasaki foun d bismuth (III) triflate to catalyze an allylic or propargylic alcohol substitution in good yields on a va riety of substrates (Figure 2 16 ). 63 In a different report, Kitamura found that ruthenium catalyst 2 91 was also able to catalyze the allylic alco hol substitution rea ction on allylic alcohols dehydratively (Figure 2 17 ).

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59 Figure 2 16 substitution. Figure 2 17 titution. Looking back at the catalyst screening results from Table 2 1 entry 12, catalyst V was shown to catalyze our tandem hemiacetalization/dehydrative cyclization methodology with high selectivity. It was thought that perhaps this catalyst, if optimized, might yield better results than the phosphine I because phosphites are known to be more electron deficient than phosphines. 28 This might increase the Lewis acidity of the gold (I) cation, which might facilitate formation of the hemiacetal which is believed to be the rate limiting step The methodology was then re optimized using diol Z 2 79 (Table 2 5) This time, isobutyraldehyde was used because it had previously been shown to give good yields and selectivity in the aldehyde scope (Tabl e 2 3). In addition, excess aldehyde could be easily removed via rotary evaporation of the crude sample. This meant that excess aldehyde did not have to be first reduced with sodium borohydride (NaBH 4 ) then separated from product via flash column chromatog raphy. Because this excess

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60 aldehyde was no longer problematic, the number of equivalents used was raised from 3 to 5 in order to facilitate formation of the hemiacetal. During the optimization, the addition of pTSA was first investi gated (entries 1 and 2). This showed no increase in yield or reactivity, but did sharply decrease diastereoselectivity. Next, temperature and concentration were examined (entries 3 7) only to show no favorable change from entry 1. Finally, phosphite catalyst V was tested (entry 8 ). Because phosphites are known to be more electron poor than pho s phines, 28 it was theorized that catalyst V might facilitate the formation of the hemiacetal by c oordinating to the aldehyde in addition to the substrate. Table 2 5. O ptimization of 1,3 dioxane formation.

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61 In fact, catalyst V was shown to give the highest yields and selectivity without the need for heating. Comparing entries 7 and 8 of Table 2 5, pho sphine catalyst I was not able to provide nearly the same reactivity as phosphite V Unfortunately, when the E diol E 2 79 was treated with these same conditions (Table 2 6, entry 1) the reaction Table 2 6. Optimization of E 1,5 monoallylic diols. Figure 2 18 Comple mentary system for the formation of 1,3 dioxanes.

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62 Figure 2 19. Synthesis of diols 2 96 2 9 8 2 100 and 2 102

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63 Table 2 7. Diol scope. was very sluggish. Moreover, the diastereoselectivity was found to be low compared to the results found with Z 2 79 Interestingly, bismuth (III) triflate was found to cyclize E 2 79 yet it was unable to cyclize Z 2 79 to produce 2 92 Thus a complementary s ystem was found for the formation of 1,3 dioxanes (Figure 2 18) between the bismuth (III) triflate and gold (I) phosphite catalyst V /AgSbF 6

PAGE 64

64 Additional 1,5 monoallylic diols were prepared (Figure 2 19) in order to determine the role of the R group attach ed to the internal allylic alcohol moiety. These were prepared in analogous fashion to the general method described previously in Figure 2 14. Thus diols 2 96 2 98 2 100 and 2 102 were prepared below. It was found that when the moiety attached to the in ternal allylic alcohol was electron rich, complete decomposition was observed. However, when this was an electron withdrawing group or alkane, high yields and diastereoselectivities are observed. Interestingly, the olefin geometry of the starting material did not change the product geometry. Both the E and Z olefin starting materials gave rise to the same cis 1,3 dioxolane or 1,3 dioxane of E olefin geometry. This was confirmed by NMR and nOe observations. The diol scope is given in Table 2 7. 2.2.6 Propos ed Mechanism and Origin of Selectivity By analogy to our previously reported gold (I) catalyzed dehydrative cyclization methodology, we propose the following mechanism (Figure 2 20 ). First, the gold (I) cation is believed to activate the carbonyl of the al dehyde towards nucleophilic attack ( 2 108 ) by an incoming diol ( 2 107 ) to form hemiacetal 2 109 after proton transfer The gold (I) cation then coordinates to the olefin to make complex 2 110 which can then cyclize to form intermediate 2 111 After rotation of the C C bon d, a hydrogen bound conformer 2 112 is formed. It is from this last intermediate that the concomitant loss of gold (I) catalyst and water takes place to produce the cis 1,3 dioxane 2 113 T he formation of the hemiacetal is believed t o be the ra te determining step, and it has been shown that gold (I) precatalyst V is much more reactive than precatalyst I ; it is believed that the elect ron deficient gold (I) cation derived from precatalyst V is

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65 Figure 2 20 Proposed mechanism for the g old (I) catalyzed tandem hemiacetalization/de hydrative cyclization of Z monoallylic 1,5 diols to for m cis 1,3 dioxanes. working to activate the aldehyde in the formation of hemiacetal The importance of hydrogen bonding in gold (I) catalyzed dehydrative c yclizations has been previously shown and is therefore thought to also occur in this transformation. 34 This may also be attributed to the formation of E olefin in th e 1,3 dioxane product. Lastly, the major diastereomer formed was shown to be the cis acetal as observed by nOe. This last piece of evidence suggests the following orig in of diastereoselectivity (2 21 ). Because previous studies have shown that gold (I) activates nucleophilic addition in anti fashion, 34 it is thought that for the Z olefin the chair like conformation that puts the al lylic alcohol in pseudo equatorial position 2 110 a is favored over the pseudo axial conformation 2 110 b In the E olefin case, the same argument is made for bismuth as it

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66 is also able to afford a single diastereomer It is believed that bismuth might also work for the cis, however it instead follows another path. Gold can also be used for the E olefin case, though lower selectivity is observed. Figure 2 21. Proposed origin of diastereoselectivity. 2.2.7 Application to Natural Product Synthesis It was orig inally thought that this new methodology would have utility as a new strategy in the synthesis of natural products c ontaining 1,3 diols One way of producing syn 1,3 diols 2 118 would be to use an iterative approach (Figure 2 22 ) In this approach, an asym metric alkylation can be used to produce homoallylic alcohol 2 116 After protecting the alcohol and then treating with ozone to produce aldehyde 2 117 steps 1 and 2 can be repeat ed to finally yield the protected 1,3 diol after a total of five steps. H owe ver, if instead one were to use Rous double allylboration methodology 64 in tandem with our proposed methodology, then an analogously protected 1,3 diol 2 121 can be produced in only two steps.

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67 Figure 2 22 Comparison of competing 1,3 diol syntheses. 1) Asymmetric alkylation, 2) alcohol protection, 3) ozone oxidation, 4) Tandem hemiacetalization/dehydrative cyclization methodology. This new synthetic strategy could be employed for the synthesis of the following natural products which all feature one or more syn 1,3 diols (Figure 2 23). RK 397 2 12 4 features three sets of these moieties which serve as nearly half of the natural product backbone As such, this represents an interesting synthetic target that would serve as a great medium for the application of our new methodology. Figure 2 2 3 Possible natural product targets.

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68 Figure 2 24. Synthesis of isomeric 1,5 monoallylic diol 2 128 and allylic ethers 2 131 and 2 134

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69 Figure 2 25. Synthesis of diols 2 137 and allylic ether 2 142 2.2.8 Investigati on of Other S ubstrates In order to apply the tandem hemiacetal/dehydrative cyclization methodology towards natural product syntheses, simple experiments served first as a proof of concept (Table 2 8). It was initially thought that a simple trans positioning of the olefin in the previous1, 5 monoallyic diols would not affect the reactivity of the methodology. Because the previous method for forming these diols (by way of cross metathesis) had proven low yielding, a styrene oxide opening strategy was instead employed. Thus,

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70 isomeric 1,5 monoa llylic diol 2 128 and its analogous allylic ethers 2 131 and 2 134 were prepared (Figure 2 24). Unfortunately, the styrene oxide opening reaction did not work well for methyl or benzyl ethers which were produced in 27% and 18% overall. Therefore, the met athesis strategy was again employed for the synthesis of diol E 2 137 which also was produced in 27% overall (Figure 2 25). This strategy was also employed in the synthesis of allylic ether 2 142 Thus, the isomeric 1,5 monoallylic diols 2 128 and 2 137 w ere subjected to various conditions (Table 2 8) No reaction or decomposition was largely observed. It was then thought that hemiacetalization was occurring predominantly at the terminal alcohol but not at the internal alcohol T his would decrease the amou nt of activated aldehyde available for t he internal alcohol to attack, thus t he overall result would be the slower formation of the hemiacetal at the secondary alcohol position if it is even occurring at all To test this theory, the primary allylic alcohol was protected as various ethers since these had previously been shown to be effective leaving groups in other gold (I) catalyzed dehydrative cy clizations. 33 Unfortunately, little to no reactivity was observed except in entries 6 and 14 w hich were not optimized further as entry 6 gave only 20% yield and entry 14 gave only 40% yiel d. Although the reactivity and selectivity is low, it is hoped that upon deprotection of the acetal that only a single diastereomer of the 1,3 diol will be found. If this is the case then the formation of these tri substituted dioxanes needs only an optimi zation of

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71 reaction conditions to try and improve the yield. Though the relative stereochemistry of the diol backbone has not yet been determined. Tab le 2 8. Trial of proposed strategy in natural product synthesis. In a new trial, it was then hoped that substituted 1,5 diols made from the Roush double allylboration methodology might be able to undergo the tandem hemiacetalization/dehydrative cyclization ; if only the conditions could be optimized for the transformation. These were prepared from commercial ly available propargyl bromide 2 14 5 and ( ) alpha pinene 2 15 0 (Figure 2 26). Bromide 2 14 5 was converted

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72 into boronate ester 2 149 which was hydroborated by borane 2 15 1 that had been prepared from the alpha pinene 2 150 The Roush one pot double allylb oration proceeded smoothly to afford both diols 2 15 2 and 2 15 3 Figure 2 26. Synthesis of diols 2 15 2 and 2 15 3 Z 1,5 monoallylic diol s 2 1 5 2 and 2 153 (Table 2 9) were screened at various solvents and temperatures. Unfortunately, no conditions were found to give moderate yields and selectivity. Entry 6 was shown not to even produce a protected 1,3 diol but a 2,3 dihydropyran instead in low yield. Entry 7 used chloral hydrate instead of

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73 isobutyraldehyde which was shown t o give good reactivity furnis hing 85% product in a 1 : 1 ratio of diastereomers. Bismuth triflate was also screened as the catalyst but did not undergo dehydrative cyclization; instead it quantitatively furnished the 8 membered acetal. Table 2 9. Re optimization of methodology for Ro ush type Z 1,5 monoallylic diols. Re optimization was also undertaken for the Roush type E 1,5 monoallylic diols 2 158 and 2 159 These were synthesized in analogous fashion to diols 2 152 and 2 153 but used a different borolane 2 157 (Figure 2 27). These diols showed a marked improvement in reactivity as nearly each entry gave some amount of product (Table 2 10) Entry 6 was shown to give the highest yield in only 5 minutes. Unfortunately no diastereoselectivity was observed in entries 1 3, 5, and 7; which instead gave a complex mixture of four diastere omers. Entries 4 and 6 gave only two diastereomers, but in equal amounts.

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74 Figure 2 27. Synthesis of diols 2 158 and 2 159 Table 2 10. Re optimization of methodology for Roush type E 1,5 monoallyli c diols.

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75 2.2.9 Investigation of Other E lectrophiles Because the previously investigated tandem hemiacetalization/dehydrative cyclization was producing decidedly complex mixtures of diastereomers the elect rophile was changed from isobut y r aldehyde 2 62 to acetone. In this way, only two stereocenters would be found in the product. In addition, acetone was used as a solvent instead of a whole number equivalent in methylene chloride By doing so, it was thought that the relative concentration of electrophile would be increased significantly and thus f acilitate the formation of hemiketal Roush type E 1,5 monoallylic diols 2 158 and 2 159 were tested (Table 2 11) since these two substrates showed modest reactivity with the isobutyraldehyde stud y (Table 2 10) Table 2 11. Investigation of tandem hemiketalization/dehydrative cyclization. From these results, it was theorized that the Roush type E 1,5 monoallylic diols 2 158 and 2 159 were actually in the wrong configuration to undergo dehydrative cyclization. In other words, we needed to experiment on E syn 1,5 monoallylic di ols rather than the anti diols 2 158 and 2 159 furnished by the Roush methodology. Unfortunately, to date, there does not exist a method to synthesize these diols. Instead, we continued to o ptimize the acetonide variant of the tandem hemiacetalization/

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76 dehydrative cyclization methodology (Table 2 12) using Z 1,5 monoallylic diols 2 83 and 2 106 This would not only bypass any issues that might exist with relative stereochemistry, but also the number of products formed as there are no diastereomers formed. Table 2 12. Investigation of tandem hemiketalization/dehydrative cyclization. Upon the results of entry 1, Table 2 12; it was thought that an additive would be required to further facilitat e formation of hemiketal. However, entry 11 gave the best reactivity and yield, thus proving that the acetonide variation of our methodology does indeed work but only with E 1,5 monoallylic diols as catalyzed by bismuth (III) triflate. Interestingly, when Z 1,5 monoallylic diol 2 106 was treated with gold catalyst V and

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77 silver co catalyst AgSbF 6 the acetonide product 2 165 was not observed. Instead, a 3,6 dihydro 2H pyran was instead observed in 66% yield and will be discussed in Table 2 13. Invest igation of vinyl ketal 2 166 formation.

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78 greater detail in chapter 3. Because this new variation was shown to work, we next decided to investigate the tandem hemiketalization/dehydrative cyclization of isomeric 1,5 monoallylic diols 2 137 and 2 142 to affo rd vinyl acetonide 2 166 (Table 2 13). Entry 5 of table 2 13 showed the most promise yie lding product in 73 % with modest diastereomeric ratio of 1 : 3 This entry was heated in a sealed tube T hus it was thought that this high temperature and pressure was the cause for the poor selectivity. Entry 8 did in fact give bet ter selectivity, yet the yield was only 44% All other conditions gave no b etter results than these two entries It was then thought to switch leaving groups from OH to OMe because methyl et her derivatives have previously been shown to undergo tandem hemiacetalization/dehydrative cyclization (see Table 2 8, entry 8) in low yield but high diastereose lectivity. However no improvement was observed even upon treatment with a variety of different microwave irradiation conditions Finally, other electrophiles were investigated to see if other variants of the methodology could work. Because aldehydes had been shown t o undergo the transformation, it was decided to test im ines a nd para formaldehyde (Figure 2 28 ). Interestingly, para formaldehyde did not produce the predicted 1,3 dioxolane product but instead produced divinyl 1,4 dioxane 2 173 This 1,4 dioxane was thought to come about by a dehydrative dimerization of Z 1,4 butenediol 2 55 However, when 2 55 is treated with no electrophile and subjected to standard conditions, no reaction is observed. The electrophile must play some role in the formation of the 1,4 dioxane 2 173

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79 Figure 2 28 Investigation of imines and para formaldehyde as electrophiles. Figure 2 29 Investigation of epoxides as electrophiles. Tandem ring opening/dehydrative cyclization of epoxides using our standard conditions to furnish substituted 1,4 dioxanes (Figure 2 29) was also considered.

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80 Unfortunately, these failed to produced the desired compound but did interestingly furnish the same divinyl 1,4 dioxane 2 173 This seems to suggest that the nature of the electrophile does not matter in the formation of byproduct 2 173 The formation of this byproduct was not further studied. 2.2.10 Investigation of 1,3 Dioxane D e protection In order to determine the diastereomeric ratio of dioxane 2 151 or 2 152 and to demo nstrate the applicability of the tandem hemiacetalization/dehydrative cyclization methodology; a method of de protection needed to be found to yield the 1,3 diol. Table 2 14. Investigation of 1,3 dioxane de protection methods. Thus, various Brnsted acids were screened (Table 2 14). Entry 6 was found to give the best yield of 1,3 diol 2 181 Better still, it did not destroy the starting material,

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81 which was also found in 47%. Unfortunately, this result was not reproducible using different workup solvents to quench the excess base (see entries 8, 9, and 11 which did not use pyridine to quenc h reaction). Alternatively, we should examine Lewis acids such as antimony trichloride, or even bismuth (III) triflate. 2.3 Future work In order to complete the first phase of this project, more complexity should be added to the current diol scop e. As it s tands, the effect, if any, is not known for a nitrogen containing substrate on the tandem hemiacetalization/dehydrative cyclization methodology. Other heteroatoms should also be shown to be compatible with the standard conditions, which should work conside ring how facile the methodology is to use. Additionally, a chirality transfer study needs to be conducted to gather further evidence of the mechanism at work and further add utility to the new method. Currently, both of the above are underway. In conjunct ion with a fellow graduate student, Justin Goodwin, n ew substrates featuring heteroatoms are under construction while the first attempt at a chirality transfer experiment has shown great promise (Figure 2 30 ). When a 1 : 1 mixture of diastereomers 2 182 wa s treated with standard conditions, only one diastereomer was shown to cyclize to give 2 183 while the other diastereomer was left mostly unreacted. This experiment should be repeated with each of the separated diastereomers 2 1 8 2 to confirm this observat ion and also try to find where the missing amount of starting material is going. Lastly, we need to confirm the absolute configuration of 2 183 in order to conclusively show that a transfer of chirality has taken place. To do this, we need to de protect th e acetal moiety, and esterify with

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82 alcohol will be established. Further corroboration can come from HPLC analysis of both starting materials and products. In order to impleme nt our new strategy for natural product synthesis, we must still show that the formation of 1,3 dioxolanes containing a terminal vinyl moiety 2 99 is possible. Low yield but high diastereoselectivity was obtained in Table 2 8, entry 8 when gold (I) phosphi te catalyst V was used in standard conditions. Perhaps if the reaction were heated, reactivity would be increased while maintaining good to moderate diastereoselectivity. If not, then a different electron deficient gold (I) catalyst should be investigated. Chapter one prominently featured phosphoramidate gold (I) catalysts that have shown great results. A new catalyst would not need to be chiral, but it would need to maintain steric bulk about the phosphorus in order to maintain high diastereoselectivity. Figure 2 30 Chirality transfer investigation. In addition to this, the potential new strategy in natural product synthesis must be realized by the clean deprotection of 1,3 dioxolanes. Currently, we have investigated

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83 only Brnsted acids and should also c onsider various Lewis acids as well. A literature search has indicated that these acetals are difficult to deprotect, but if the right conditions can be found, then it would provide grea t utility to the synthetic community. Finally, the ultimate test for a new methodology is its application in natural product synthesis. Once all the above has been addressed, then we can then try to synthesize any of the above natur al products shown in Figure 2 23 2.4 Conclusions A new intermolecular gold (I) catalyzed tan dem hemiacetal and hemiketal/dehydrative cyclization methodology has been developed. To our knowledge, it is the first example to show a gold (I) phosphite cation capable of activating both C C double bonds and carbonyls in the same pot. This new methodolo gy may yet have practical applications as a new strategy in the synthesis of natural products.

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84 CHAPTER 3 DIASTEREOSELECTIVE GOLD (I) CATALYZED SYNTHESIS OF 3,6 DIHYDRO 2H PYRANS FROM SYN 1,5 MONOALLYLIC DIOLS 3.1 Introduction The synthesis of 3,6 d ihydro 2H pyrans remains a challenge for the syntheti c community. There are only a small handful of synthetic strategies available to the synthesis of these compounds. Traditional ly, the synt hetic chemist has relied on the following three strategies for th e formation of these interesting moieties. These strategies are olefin metathesis, hetero Diels Alder and Ferrier type rearra ngements These compounds are a principle component to many marine natural products. This moiety is thought to be a major contrib utor to the three dimensional shape of many of these compounds, and thus might also play a significant rol e in the biological activity demonstrated by these marine natural products There are many examples of marine natural products containing 3,6 dihydro 2H pyrans. A few examples include swinholides, 65 sorangici n A, 66 scytophycins, 67,68 laulimalide, 69 and isolaulimalide 70 Three selected examples are shown below ( Figure 3 1), a ll of which are known cytotoxins and are effective compounds that could be developed into new treatments as antifungals, antibiotics and even anticancer drug s. A recent report from Rayment shows a structural basis for the cytotoxicity of sw inholide A 71 This macrolid e is actually one of the better known membrane permeable compounds that is known to specifically inhibit actin filaments. As such, it is commonly used in cell biology studies, and represents a promising new class of anticancer

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85 Figure 3 1. Three examples of natural products cont aining 3,6 dihydro 2H pyran moieties.

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86 Figure 3 2. Swinholide A mode of binding two actin molecules. A: Bottom and side view of swinholide A actin complex. B: Ornit electron density map of swinholide A. C: Map of swinholide A interactions with actin. Rep rinted from Chemistry & Biology, 12, Klenchin, V. A.; King, R.; Tanaka, J; Marriott, G.; Rayment, I., Structural Basis of Swinholide A Binding to Actin, 287 291, Copyright (2005), with permission from Elsevier. compounds. Its cytotoxicity is believed to st em from its ability to sever and sequester actin filaments, however the exact mechanism is still not known. In the report, swinholide A is shown to be capable of binding to two actin molecules at the same binding site used by known toxins of the trisoxazol e family as well as numerous actin binding proteins. Crucial to this mode of binding is the structural framework provided by

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87 the two 3,6 dihydro 2H pyran moieties which serve to position the binding units of swinholide A towards and within two actin molecu les (Figure 3 2). Synthesis of t his important heterocycle is common ly reported using the traditional methods mention ed above All four of these are exemplified in natural product syntheses. In a report from Mulzer 72 the synthesis of laulimalide was accomplished via an olefin metathesis to produce both of t he 3,6 dihydro 2H pyranyl moieties This strategy had been previously investigated by the Mulzer group where they found that this transformation occurred smoothly with only 1 2% G rubbs first generation catalyst in either substrate 3 8 or 3 9 (Figure 3 3.) 73 Figure 3 3. 3 4 B: Synthesis of 3 9 and 3 12

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88 Although thi s strategy produces the desired dihydropyran in high yield, it requires many steps from commercially available starting materials to get to the desired substrate. As a consequence, the overall yield of the dihydropyran is quite small compared to another st rategy, which might be more direct. In addition, this strategy must rely on other methods to establish the correct stereochemistry of either the subs trate or the product, which only adds to the tota l number of steps required In another synthesis of laulim alide, Pa terson used a hetero Diels Alder strategy for the synthesis of the terminal 3,6 dihydro 2H pyran yl moiety 3 13 (Figure 3 4) 74 This was accomplished using a chiral chromium complex 3 17 which was originally developed by Jacobse n. 75 The authors were able to afford the required stereochemistry of 3 18 Unfortunately, one of these stereocenters is obliterated in the synthesis of 3 13 This strategy is much more direct than the metathesis route as it can accommodate commercially available substrates. Moreover, the ca talyst used in the method is the source of stereochemical information, thus it does not rely on other methods to install the correct stereochemistry upon the desired dihydropyran. However, this method does not directly produce the 3,6 dihydro 2H pyran. Ins tead, this method produces an acetal that can then be r educed into the dihydropyran, which means that multiple reactions are still required to furnish the desired compound Ferrier rearrangements have long been known, and were first reported in 1914 by Fi scher. 76 However, the synthetic utility of the method was first recognized by Ferrier in ed in the synthesis of glycosyl compounds. 77,78 This method is recognized as a Lewis acid catalyzed tandem elimination/alkylation to produce 3,6 dihydro 2H pyrans or other glycosyl compounds. In the Pa terson synthesis

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89 of laulimalide, internal dihydropyran 3 14 was produced by way of a Ferrier type I rearrangement when 3 19 was treated with titanium tetra chloride (TiCl 4 ) and trimethylallylsilane 79,80 Figure 3 4. A: Pa retro synthesis of laulimamide 3 4 B: Synthesis of 3 18 and 3 20 Three more modern methods for producing 3,6 dihydro 2H pyrans have recently been reported. The first of which is a [4 + 2] cycloaddition reported by Panek in the

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90 synthesis of ( ) a picularen A. 81 In this method, an aldehyde is treated with silane 3 26 and a stoichiometric amount of trimethylsilyltrifulouromethane sulfonate (TMSOTf) to produce 3,6 dihydro 2H pyran 3 24 as a single diastereomer in good yield (Figure 3 5). This method works well to produce the desired stereochemistry, however is highly substrate dependent. In most examples shown in the report, low to moderate yields and selectivities plague this method. In addition, the synthesis of silane 3 26 requires 5 st eps from commercially available materials Figure 3 5. A: retro synthesis of ( ) a picularen A. B: Synthesis of 3 24 In a report from Uenishi, palladium (II) complexes were shown to stereospecifically cyclize 1,3 monoallylic diols into 3,6 diydro 2H pyrans. 82 This met hodology was then applied to the synthesis of laulimalide (Figure 3 6) 83,84 Diol 3 29 was first made i n 21 steps before being treated with bis ( acetonitrile ) palladium (II) chloride to dehydratively

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91 cyclize to 3 30 in an enantio specific manner. D ihydropyran 3 28 was also formed through the palladium (II) catalyzed diastereoselective dehydrative cyclization of diol 3 31 to produce 3 32 Although this methodology works quite well, and can even be used to generate the opposite epime r, high catalyst loading and sometimes very long reaction times are required Figure 3 6. A: retro synthesis of laulimalide. B: Syntheses of 3 30 and 3 32 In one last example of 3,6 dihydro 2H pyran synth esis, Roush also reports a dehydrative cyclization based upon his earlier work in the synthesis of substituted 1,5 monoallylic diols discussed previously in chapter 2. 64 In the ir report, 1,5 monoallylic diols that were made from the Roush double ally l boration methodology were treated with various catalysts and were found to give 3,6 dihydro 2H pyrans in moderate

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92 yie lds. 85 Unfortunately, the method could not furnish good diastereomeric nor enantiomeric selectivities Therefore, other reagents and substrates were investigated. The best results came from the sta n nyl ether catalyzed cyclization of hydroxyl mesylate 3 33 which occurred with a small amount of mesylate elimination to form the diene by product 3 35 (Table 3 1 ) This method has the potential to be widely us ed in natural product synthesis, however the formation of the hydroxymesylate is a lengthy and challenging synthesis. After the one step synthesis 1,5 monoallylic diol, one diol must be first selectively protected. This is done by TBS protection o f the allylic alcohol moiety which occurs in low selectivity and yield. This is then follow ed by formation of the mesylate and deprotection of the silyl ether to furnish the hydroxymesylate 3 33 In addition, the method is substrate dependent giving only o ne product in entry 1, but both products in the remaining entries. Therefore the method has not been used in natural product syntheses possibly due to these problems. Table 3 1 dihydro 2H pyrans.

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93 3.2 Results While conducting experiments in the tandem hemiketalization/dehydrative cyclization of 1,5 monoall ylic diols with acetone, the Z 1,5 monoallyic diol 3 36 was subjected to standard conditions with 30 mol% of pTSA and instead of forming the desired acetal 3 37 3,6 dihydro 2H pyran 3 38 was found in a 66% yield (Figure 3 7). This was a completely unexpected outcome, and one that merited further investigation. Figure 3 7. First attempt at tandem hemiketalization/dehydrative cyclization of 3 36 and acetone. This serendipitous finding led to a screening of a variety of conditions to determine what reagents we re needed to furnish this observation and also to gain insight into how the transformation may be occurring (Table 3 2). Inter esting ly, it was found that the initial co nditions used the gave the best results. Entry 2 suggests t hat pTSA was required for the transformation, in addition to the catalyst system V /AgSbF 6 Entry 6 shows that acetone was not required to produce dihydropyran, however this yields on ly half as much product compared to the initial conditions (entries 1 and 6). Further investigation was conducted to determine the effect of temperature and catalyst loading on the diastereoselectivity (Table 3 3) It was theorized that by lowering tempera ture, or by decreasing the amount of catalyst, that the diastereomeric ratio

PAGE 94

94 between the cis and trans 3,6 dihydro 2H pyrans would increase. It was found that catalyst loading had little effect on the dr, however when the temperature was lowered Table 3 2. Investigation of required additives and catalysts. Table 3 3. Investigation of diastereoselectivity to diastereomer 3 40 was observed (entry 5). However, this greatly decreased the reactivity giving nearly one third product and one third unreacted starting material. It is not yet known what happens to the missing third of material, though it may

PAGE 95

95 be that some of the starting material decomposes and is then caught within the plug of silica used to quench the reaction. In cooperation with fellow group member, Thomas Ghebreghiorgis, t he gold/silver catalyst system was investigated to determine if V or AgSbF 6 were required for the transformation to occur (Table 3 4). Interestingly, Thomas found that under the original Table 3 4. Investigation of gold/silver catalyst system.

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96 conditions with prolonged reaction times, the yield and dr were greatly improved (compare Table 3 4 entry 2 and Table 3 3 entry 1). However, when AgOTf was used instead of AgSbF 6 the reaction occu rred more rapidly and gave the highest yield (Table 3 4 entry 3). Thomas demonstrated that the reaction does not need each of the three catalysts pTSA, V and AgOTf. The reaction was shown to proceed without gold, using only pTSA and AgOTf as catalysts (Ta ble 3 4, entry 6), while in entry 5 neither gold nor silver were required to yield 51%. In addition, the role of pTSA is critical. In entries 8 11 no reaction is observed. These data show that protic acidic conditions are needed to furnish the desired dih ydropyran, which is expected since the overall transformation is a substitution reaction of a one hydroxyl moiety for another. Presumably one hydroxyl group must be protonated before the other can substitute (S N 2) or that the allyl hydroxyl group leaves t o form an allyl cation (S N 1). In either case, the role of pTSA is likely to protonate the leaving hydroxyl group, thus favoring its substitution. Unfortun ately, the role of acetone, gold, and silver remains in question. 3.3 Future Work Optimization of the reaction conditions appears to be complete. It i s known that pTSA is the only catalyst required to make the reaction work, but that gold catalyst V silver catalyst AgOTf, and 5 equivalents acetone allow the reaction to proceed more smoothly and give high er yield. The role of these auxiliary catalysts should be further investigated. In addition, the method should be tested to see if it can retain stereochemical information Lastly, a determination of what functional groups can be tolerated must be made.

PAGE 97

97 In answering these questions, the applicability of the methodology will be demonstrated as well as providing invaluable insight into a possible mechanism for the transformation. Once this level of understanding has been reached, the methodology should be app lied to a natural product synthesis in order to showcase its utility 3.4 Conclusions To conclude, a new method for the formation of 3,6 dihydropyrans has been developed. It has the potential to be of great use in natural product synthesis. When used in co can be converted into elaborate dihydro 2H pyrans in only two steps. Hopefully, this process will be shown to conserve chirality and thus become the new sta ndard in the state of the art in the synthesis of natural products containing 3,6 dihydro 2H pyrans

PAGE 98

98 CHAPTER 4 EXPERIMENTAL All reactions were carried out under an atmosphere of dry nitrogen unless otherwise specified. Anhydrous solvents were transferred via syringe to flame dried (or oven dried) glassware, which had been cooled under a stream of dry nitrogen. Anhydrous methylene chloride (CH 2 Cl 2 ), tetrahydrofuran (THF), acetonitrile, ether, benzene and toluene were dried and degassed using an mBraun solvent purification system equipped with argon. 60 fluorescence dye pre coated plates (Whatman Inc.). TLC analysis was primarily conduct ed using UV short wave light, iodine to s tain 2,4 dinitrophenylhydrazine (DNP), potassium permanganate (KMnO 4 ), and ceric ammonium molybdonate (CAM) stains. Flash column chromatography (FCC) was performed using 230 400 mesh 60 silica gel (Whatman Inc.). The eluents employed are reported as v olume:volume percentages. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded using Varian Unity Inova 500 MHz and Varian Mercury 300 MHz spectrometers. tetramet hylsila ne (TMS, 0.0 ppm) or chloroform (CH Cl 3 7.26 ppm). Coupling constants ( J ) are reported in Hz. Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Carbon 13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded on the same spectrometers that reported in ppm relative to the carbon resonance of CDCl 3 (77.26 ppm). Infrared spectra were obtained on a PerkinElmer Spectrum RX1 FTIR spectrometer at 1.0 cm 1

PAGE 99

99 resolution and are reported in wave numbers. High resolution mass spectra (HRMS) were obtained by the Mass Spectrometry Core Laboratory of the 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. Gas chromatography (GC) traces were measured on a Hewlett Packard 5890 Series II instrument equipped with a Restek 5 capillary column (30m, Packard 3396a integrator. 4 .1 Catalyst Screening Note: all transition metal catalysts, cocatalysts, and activated molecular sieves were weighed out in a glovebox under a dry argon atmosphere except for diacetonitrile palladium (II) chloride and tris[triphenylphosphine gold(I)]oxonium tetrafluoroborate ca talysts which are considered to be air stable. General Procedure: Catalysts (0.01 mmol) were dissolved in solvent (1 mL) and at room temperature for a few minutes befor monitored by TLC and GC. GC measurements were made by removing a small aliquot of reaction mixture, which was then adsorbed onto s ilica gel (0.05 0.10 mL), diluted in CH 2 Cl 2 (0.5 mL), and then 1 yields from the calibration plots below. Reaction s were quenched by filtering crude mixture over a short plug of silica and then concentrated by rotary evaporation before purifying by FCC.

PAGE 100

100 In order to determine yield as well as conversion using GC two calibration plots were made. Known quantities of cy clohexylcarboxaldehyde 2 58 (t R = 7.2 min) to decane (t R = 8.3 min) or acetal 2 59 (t R = 17.5 and 17.7 min) to decane were combined Figure 4 1. Calibration plot between molar rat io of decane to acetal versus peak area ratios. Figure 4 2. Calibration plot of molar ratio betwe en aldehyde to decane versus peak area ratios. respectively in CH 2 Cl 2 concentrations were run in order to make each calibra tion plot. From these plots, an equation wa s found to relate peak area ratio to concentration of the individual

PAGE 101

101 constituents of the mixture with respect to decane. These plots and equations are given abo ve. 4 .2 Aldehyde Scope Note: All aldehydes were freshly distilled before each reaction was run. General Procedure: I (0.01 mmol, 5.3 mg) and AgOTf (0.01 mmol, 2.7 mg) were combined with molecular sieves (4 ) in a test tube under argon in a glove box. The reaction vessel was wrapped in aluminum foil before being taken out of the glove box and the mixture of solids was dissolved in CH 2 Cl 2 (1 mL) at room temperature and allowed one minute to five minutes to stir in order to form the gold(I) cationic complex before the addition of aldehyde (0.30 mmol ). Z but 2 en 1,4 diol 2 55 (0.20 mmol, 16.4 reaction was quenched by filtering crude mixture over a plug of silica which was th en concentrated by rotary evaporation and purified by flash column chromatography. If the aldehyde was not volatile, then the excess aldehyde was reduced to alcohol by NaBH 4 then purified by flash column chromatography. 2 Cycl ohexyl 4 vinyl 1,3 dioxolane (2 59 ): Reaction of 2 55 and cyclohexylcarboxaldehyde ( 2 58 ) afford ed acetal as a colorless oil (93%yield, 1:8 d.r.). t R = 17.5 and 17.6 min. R f (CH 2 Cl 2 /pentanes 20%): 0.23. Proton and carbon NMR spectra were found to match reported data. 86 1 H NMR (300 MHz, CDCl 3 2 (ddd, J = 17.2, 10.3, 7.0 Hz, 1H), 5.42 5.27 (m, 1H), 5.21 (ddd, J = 10.3, 1.5, 1.0 Hz, 1H), 4.77 (d, J = 4.9 Hz, 1H), 4.50 4.35 (m, 1H), 4.14 (ddd, J = 8.2, 6.2, 0.4 Hz, 1H), 3.51

PAGE 102

102 (dd, J = 8.2, 7.6 Hz, 1H), 1.85 0.85 (m, 11H). 13 C NMR (CDCl 3 75 MH z 27.34, 27.5, 42.2, 68.4, 70.4, 108.0, 118.0, 133.2, 135.9. 2 Cyclohexyl 4,7 dihydro1,3 dioxepine (2 60): Reaction of 2 55 and cyclohexylcarboxaldehyde ( 2 58 ) without molecular sieves at 0.8 M affor ded acetal as a colorless oil (8 3%yield). R f (CH 2 Cl 2 /pentanes 20%): 0.23. 1 H NMR (300 MHz, CDCl 3 5.75 5.67 (m, 2H), 4.49 4.31 (m, 4H), 4.22 4.06 (m, 1 H), 1.93 1.47 (m, 1H), 1.39 0.93 (m, 10H). 13 C NMR (CDCl 3 75 MHz 118.0, 135.9 2 Isopropyl 4 vinyl 1,3 dioxolane (2 61a): Reaction of 2 55 and isobutyraldehyde ( 2 62 ) afforded acetal as a colorless oil (80 % yield, 1:8 dr ). R f (CH 2 Cl 2 /hexane 4 0%): 0.23. Proton and carbon NMR spectra were found to match reported data. 87 1 H NMR (500 MHz, CDCl 3 5.76 (m, 1H), 5.34 (dq, J = 17.1, 1.5 Hz, 1H), 5.22 (dq, J = 10.6, 1.5 Hz, 1H), 4.79 (d, J = 4.6 Hz, 1H), 4.53 4.40 (m, 3H), 4.16 (ddd, J = 8.8, 6.3, 2.2 Hz, 1H), 3.53 (ddd, J = 9.8, 7.7, 2.3 Hz, 1H), 1.94 1.76 (m, 3H), 1.02 0.87 (d, 6H). 13 C NMR (126 MHz, CDCl 3 118.1 108 .7, 105.0, 70.5, 32.6, 32.4, 30.7, 30.4 17.0, 16.9 2 Tert butyl 4 vinyl 1,3 dioxolane (2 61b): Reaction of 2 55 and piv aldehyde ( 2 6 3 ) afforded acetal as a colorless oil (70 % yield, 1: 1 8 dr). R f (EtOAc/hexane 5%): 0.50 1 H NMR (500 MHz, CDCl 3 major diastereomer J = 14.4, 10.3 7.1 Hz, 1H),

PAGE 103

103 5.40 5.26 (m, 1H), 5.22 (ddd, J = 9.9, 2.2, 1.1 Hz, 1H), 4.68 (s, 1H), 4.42 (q, J = 6.9 Hz, 1H), 4.15 (ddd, J = 8.3, 5.7, 2.2 Hz, 1H), 3.53 (dd, J = 9.1, 6.8 Hz, 1H), 0.93 (s, 9H). 13 C NMR (126 MHz, CDCl 3 135.9, 118.1, 110.7, 77.8, 77.5, 77.2, 77.0, 70.7, 34.9, 24.5, 24.4 2 Heptyl 4 vinyl 1,3 dioxolane (2 61c ): Reaction of 2 55 and octanal ( 2 64 ) afford ed acetal as a colorless oil (81 % yield, 1:3 dr ). 1 H NMR (300 MHz, CDCl 3 5.74 (m, 1H), 5.40 5.28 (m, 1H), 5.22 (dt, J = 10.3, 1.2 Hz, 1H), 5.02 (t, J = 4.8 Hz, 1H), 4.53 4.39 (m, 1H), 4.17 (dd, J = 8.3, 6.3 Hz, 1H), 3.52 (dd, J = 8.3, 7.5 Hz, 1H), 1.75 1.58 (m, 2H), 1.49 1.12 (m, 10H), 0.95 0.78 (m, 3H). 13 C NMR (75 MHz, CDCl 3 2 Pheny let hyl 4 vinyl 1,3 dioxolane (2 61d ): Reaction of 2 55 and hydrocinnamaldehyde ( 2 65 ) afforded acetal as a clear and colorless oil (68 % yield, 1:5 dr). R f (2 runs CH 2 Cl 2 /pentane 10%): 0.30. 1 H NMR (300 MHz, Chloroform 7.13 (m, 5H), 5.92 5.75 (m, 1H), 5.36 (dq, J = 17.2, 1.5 Hz, 1H), 5.28 5.19 (m, 1H), 5.07 (t, J = 4.7 Hz, 1H), 4.58 4.42 (m, 1H), 4.21 (dd, J = 8.3, 6.3 Hz, 1H), 3.54 (dd, J = 8.3, 7.5 Hz, 1H), 2.84 2.67 (m, 2H), 2.12 1.89 (m, 2H). 13 C NMR (75 MHz, CDCl 3 30.0, 30.3, 35.9, 36.0, 70.5, 100.0, 104.2, 104.6, 118.1, 126.1, 128.6, 135.8, 141.8.

PAGE 104

104 2 Trychloromethyl 4 vinyl 1,3 dioxolane (2 62e ) : Reaction of 2 55 and chloral hydrate ( 2 6 1 c ) afforded acetal as a clear and colorless oil (98 % y ield, 2:3 dr ). R f (EtOAc/hexanes 20%): 0.60. 1 H NMR (5 00 MHz, CDCl 3 both diastereomers) (ddd, J = 14.4, 10.3, 7.1 Hz, 1H), 5.40 5.26 (m, 1H), 5.22 (ddd, J = 9.9, 2.2, 1.1 Hz, 1H), 5.02 (s, 1H), 4.42 (q, J = 6.9 Hz, 1H), 4.15 (ddd, J = 8.3, 5.7, 2.2 Hz, 1H), 3.53 (dd, J = 9.1, 6.8 Hz, 1H) 13 C NMR (126 MHz, CDCl 3 2 phenyl 4 vinyl 1,3 dioxolane (2 62f) : Reaction of 2 55 and benzaldehyde ( 2 67 ) afforded acetal as an oil (55% yield, 1:2 dr). R f (CH 2 Cl 2 :hexanes 20%): 0.40. Proton and carbon NMR spectra were found to match re ported data. 88 1 H NMR (500 MHz, CDCl 3 both diastereomers 7.59 (m, 1H), 7.54 7.46 (m, 2H), 7.45 7.32 (m, 2H), 5.99 5.88 (m, 1H), 5.41 (ddt, J = 17.2, 2.0, 1.2 Hz, 1H), 5.27 (ddt, J = 11.1, 6.7, 1.2 Hz, 1H), 4.71 4.60 (m, 1H), 4.32 (dd, J = 8.3, 6.4 Hz, 1H), 3.82 3.75 (m, 1 H), 3.72 (ddd, J = 8.1, 7.3, 0.6 Hz, 1 H). 13 C NMR (126 MHz, CDCl 3 ) 127.8, 126.3 119.4, 109.6 95.4, 72.9 4 .3 Substrate Syntheses (E) 2 butene 1,4 diol (E 2 55 ) : To a stirred solution of LAH (24 mmol, 0.9108 g) in THF (100 mL) at 0 butyn 1,4 diol 2 76 (20 mmol, 1.7218 g) in THF (8 mL) in a dropwise fashion. Mixture was allowed to reach room temperature while reaction progress was monitored by TLC. After 4.5 h full reduction was observed, and

PAGE 105

105 crude mixture was quenched via the Fieser and Fieser ( n:n:3n ) method whereby 1 mL/g of wa ter/LAH is added very slowly and with great care to 0 allowed at least fifteen minutes to stir before doubling the volume of the reaction with ether. Addition of 1 mL/g 10% NaOH solution is added very slowly in a dropwise manner an d then allowed an additional fifteen minutes before adding 3 mL/g of water. This mixture is then allowed at least one hour to reach room temperature or until white precipitate has formed. The slurry is filtered, dried over magnesium sulfate, and concentr ated by vacuum before purification by flash column chromatography to yield a clear, colorless oil (65 %). R f (ethyl acetate 100%): 0.22. 1 H NMR (300 MHz, CDCl 3 1.30 1.43 (bs, 2H), 4.20 (s, 2H), 5.90 (s, 2H). 13 C NMR (126 MHz, CDCl 3 130.9. 1 Phenylbut 2 yne 1,4 diol (2 95) : To a stirred solution of propargylic alcohol 2 94 (20 mmol, 1.18 mL) in THF (82 mL) was added n butyl lithium (17.6 mL, 2.5 M) dropwise over a period of 30 minutes at 78 35 a ddition of benzaldehyde 2 67 (24 mmol, 2.44 mL). Mixture was allowed to reach room temperature over 6 hours. Crude was obtained by washing the mixture with a saturated solution of ammonium chloride and brine with ethyl acetate, dried over magnesium sulfa t e, and concentrated in vaccuo. Product was obtained as a yellow solid by flash column chromatography (63% yield, mp 82 84 f (ethyl acetate/hexanes 60%): 0.52. Melting point and NMR data matches previously reported data. 89 1 H NMR (500

PAGE 106

106 MHz, CDCl 3 2.80 (bs, 2H), 4.35 (s, 2H), 5.55 (s, 1H), 7.30 7.56 (m, 5H). 13 C NMR (126 MHz, CDCl 3 (E ) 1 p henylbut 2 ene 1,4 diol (E 2 96 ) : To a stirred solution of LAH (6 mmol, ed 2 95 (3 mmol, 0.4865 g) with THF (5 mL) and allowed to stir until disappearance of starting material by TLC (22 h). Reaction was quenched via the n:n:3n method as previously described and purified via flash column chromatography to yield t he yellow solid (87% yield, mp 76 78 matches previously reported data. 90 R f (ethyl acetate/hexanes 50%): 0.22. 1 H NMR (500 MHz, CDCl 3 3.10 (bs, 2H), 4.18 4.22 (d, 1H), 4.38 4.44 (d, 1H), 5.30 (s, 1H), 5.75 5.80 (s, 2H), 7.30 7.56 (m, 5H). 13 C NMR (126 MHz, CDCl 3 58.8, 70.1, 126.3, 127.9, 128.9, 130.2, 134.8, 143.2. (Z ) 1 p henylbut 2 ene 1,4 diol (Z 2 96 ): To a stirred solution of 2 95 (3 mmol, 0.4865 g) in ethyl acetate at room temperature was added quinoline (2.1 mmol, 0.25 s catalyst (15% wt., 73 mg). This mixture was put under an atmosphere of hydrogen and allowed to stir until the disappearance of starting material could be observed by NMR (17 h). Crude was filtered over celite, concentrated in vaccuo and purified by fla sh column chromatography to yield a yellow solid (86% yield, mp 71 73 f (ethyl acetate/hexane 50%): 0.24. Melting point and NMR data match previously reported data. 89 1 H NMR (500 MHz, CDCl 3 3.30 (bs, 2H), 4.18

PAGE 107

107 4.20 (d, 2H), 5.25 (s, 1H), 5.92 (s, 2H), 7.30 7.56 (m, 5H). 13 C NMR (126 MHz, CDCl 3 1 Phenylpent 2 yne 1,5 diol (2 78) : To a stirred solu tion of 3 butyn 1 ol 2 77 (20 mmol, 1.52 mL) in THF (100 mL) at 78 n butyl lithium (19.2 mL, 2.5 M) dropwise over a period of 15 minutes. Reaction mixture was warmed to 45 addition of benzaldehyde 2 67 (24 mmol, 2.44 mL) and allo wed to reach room temperature over 20 hours. Crude mixture was washed with ammonium chloride and brine with ethyl acetate and was dried over magnesium sulfate, concentrated in vaccuo before purification by flash column chromatography to yield a colored so lid (81% yield, mp 66 69 f (ethyl acetate/hexanes 50%): 0.20. IR: 3347, 2945, 2887, 1452, 1279, and 1043 cm 1 1 H NMR (300 MHz, CDCl 3 2.24 (bs, 1 H), 2.40 2.45 (m, 2 H), 2.50 2.65 (bs, 1 H), 3.60 3.65 (t, 2 H), 5.40 (s, 1 H), 7.2 0 7.50 (m, 5 H). 13 C NMR (75 MHz, CDCl 3 (E) 1 ph enylpent 2 ene 1,5 diol (E 2 79 ): To a stirred solution of LAH (2.4 mmol, 0.0911 g) in THF (4 mL) at 0 2 78 (1 mmol, 0.1762 g) with THF (1 mL ) and allowed to stir until disappearance of starting material by TLC (22 h). Reaction was quenched via the n:n:3n method as previously described and purified via flash column chromatography to yield a clear and colorless oil (85% yield). R f (ethyl aceta te/hexanes 50%): 0.20. 1 H N MR (500 MHz, CDCl 3 2.00 (bs, 1 H), 2.20 2.58 (bs, 1H),

PAGE 108

108 2.32 (q, J = 6.18 Hz, 2 H), 3.65 3.70 (m, 2 H), 5.19 (d, J = 5.77 Hz, 1 H), 5.71 5.83 (m, 2 H), 7.25 7.39 (m, 5 H) 13 C NMR (126 MHz, CDCl 3 61.9, 75.2, 126.4, 127.9, 128.4, 128.8, 135.6, 143.2. (Z) 1 phenylpent 2 ene 1,5 diol ( Z 2 79 ): To a stirred solution of 2 78 (2 mmol, 0.3524 g) in ethyl acetate (10 mL) was added quinoline (1.4 mmol, 0.17 mL) and is mixture was put under an atmosphere of hydrogen and allowed to stir 16 hours. Reaction progress was monitored by NMR, product was afforded as a clear, red colored oil upon filtration over celite followed by flash column chromatography (91% yield). R f (ethyl acetate/hexanes 50%): 0.39. 1 H NMR (300 MHz, CDCl 3 2.42 (bs, 2H), d 2.50 2.73 (m, 2 H), 3.65 (td, J = 9.21, 4.62 Hz, 2 H), 3.70 3.8 5 (m, 1 H), 5.52 (d, J = 8.60 Hz, 1 H), 5 .62 (dd, J = 17.11, 10.10 Hz, 1 H), 5.76 5.93 (m, 1 H), 7.23 7.53 (m, 5 H). 13 C NMR (75 MHz, CDCl 3 61.5, 69.3, 126.1, 126.2, 126.4, 127.7, 128.7, 128.8, 135.7, 143.7. 1 Phenylbut 3 ene 1 ol (2 80) : To a stirred solution of benzaldehyde 2 67 (20 mmol, 2.0 mL) in THF (100 mL) at 35 1.0 M) over five minutes and allowed to reach room temperature over one hour. Mixture was washed with 0.1 N HCl and brine with ethyl acetate, dried over magnesium sulfate, and concentrated in vaccuo before purif ication by flash column chromatography. Alcohol was afforded as a clear yellow oil (86% yield). R f (ethyl acetate/hexanes 10%):

PAGE 109

109 0.30. 1 H NMR (300 MHz, CDCl 3 2.04 (bs, 1 H), 2.42 2.60 (m, 2 H), 4.65 4.78 (m, 1 H), 5.05 5.21 (dd, 2 H), 5.75 5.91 (m, 1 H), 7.21 7.42 (m, 5 H). 13 C NMR (75 MHz, CDCl 3 172.9, 181.9. (E) 1 phenylpent 3 ene 1,5 diol (2 82 ): In a round bottom flask equipped with an immersion condenser, a stirred solution of Grubbs second generation catalyst (0.02 mmol, 17.0 mg) in CH 2 Cl 2 (5 mL) at 45 s added a premixed solution of 2 80 (2 mmol, 0.2964 g) and crotonaldehyde (predominantly trans, 10 mmol, 0.83 mL) in CH 2 Cl 2 (5 mL) and allowed to stir f or 8 hours but starting material was never observed to disappear. Flash chromatography silica gel (10 mL) was added to refluxing solution and left open to air without condenser for at least 20 minutes to reach room temperature. Solvent was removed from s lurry by rotary evaporation, and colored silica gel was filtered over a bed of clean silica gel with ethyl acetate to afford crude aldehyde 2 81 About 20% conversion was observed and kept crude. R f (ethyl acetate 20%): 0.15. 1 H NMR (300 MHz, CDCl 3 6 2.83 (q, 2 H), 4.84 4.90 (m, 1 H), 6.12 6.22 (ddd, J = 15.7 Hz, 8.0 Hz, 1.2 Hz, 1 H), 6.80 6.90 (dd, J = 15.7 Hz, 7.2 Hz, 1 H), 7.20 7.40 (m, 5 H), 9.48 9.52 (d, J = 1.2 Hz, 1 H). Crude aldehyde 2 81 was then taken into MeOH (2.8 mL) and cooled to 0 before addition of sodium borohydride (0.68 mmol, 25.7 mg); temperature was allowed to reach room temperature. After 3 hours, aldehyde was still present and so 1.2 more equivalents of sodium borohydrid e was added. Reaction was allowed to proceed until the disappearance of starting material via TLC, at which time mixture was reduced in

PAGE 110

110 volume by 2/3 via rotary evaporation. This mixture was then dissolved in ethyl acetate, washed with brine and concentr ated in vaccuo before purification by flash column chromatography to yield a colored oil (9.5% yield over two steps). R f (ethyl acetate/hexanes 50%): 0.20. 1 H NMR (300 MHz, CDCl 3 2.04 (bs, 1 H), 2.42 2.60 (m, 2 H), 4.65 4.78 (m, 1 H), 5.05 5.21 (dd, 2 H), 5.75 5.91 (m, 1 H), 7.21 7.42 (m, 5 H). 13 C NMR (75 MHz, CDCl 3 ) 22.2, 32.6,38.9, 42.4, 62.8, 63.6, 73.8, 74.8, 126.0, 126.1, 127.8, 127.9, 128. 6, 128.7, 133.0, 144.1, 145.0. 1 (4 Methoxyphenyl)pent 2 yne 1,5 diol (2 97) : To a cooled s olution of 2 77 ( 15 mmol, 1.13 mL) in THF ( 50 mL), 50 butyllithium ( 36 mmol, 15 mL) and allowed 30 minutes to stir. Then anisaldehyde 2 69 ( 22.5 mmol, 2.74 mL) in THF ( 10 mL) was added, and the mixture was allowed to warm to ambient temperat ure over 18 hours. Ice cold ammonium chloride was added to the mixture, and extracted three times with ethyl acetate. The layers were separated, dried with magnesium sulfate, and concentrated to yield crude viscous oil. This was purified by flash column ch romatography to yield an orange oil (43%). R f (EtOAc/hexanes 50%): 0.12. 1 H NMR (500 MHz, CDCl 3 7.37 (m, 2H), 6.99 6.77 (m, 2 H), 5.40 (t, J = 2.1 Hz, 1 H), 3.80 (d, J = 1.1 Hz, 3H), 2.58 2.47 (m, 2 H ), 1.5 (bs, 2H ). 13 C N MR (126 MHz, CDCl 3 159.8, 133.4 128.2 114.1, 84.0, 82.3, 77.4, 77.2, 76.9, 64.5, 61.1, 55.5, 23.4

PAGE 111

111 (E) 1 (4 methoxyphen yl)pent 2 ene 1,5 diol (E 2 98): To a cooled solution of 2 97 (1.21 mmol, 250 mg) in THF (6 mL) at 0 portion wise over a few minutes. This mixture was allowed to stir for 18 hours and was quenched via n:n:3 method previously described above. This slurry was filtered over a bed of celite to remove all solids, and was concentrated to yield crude oil. This oil was purif ied by flash column chromatography to yield E 2 98 as a clear colorless oil (94%). R f (EtOAc/hexanes 50%): 0.12. 1 H NMR (500 MHz, CDCl 3 7.28 (m, 2H), 6.95 6.85 (m, 2H), 5.86 5.70 (m, 2H), 5.16 (d, J = 6.0 Hz, 1H), 3.81 (d, J = 0.7 Hz, 3H), 3. 70 (q, J = 5.9 Hz, 2H), 2.39 2.30 (m, 2H), 2.00 (bs, 1H), 1.59 (bs, 1H). 13 C NMR (126 MHz, CDCl 3 (Z) 1 (4 methoxyphenyl)pent 2 ene 1,5 diol (Z 2 98) : To a solution of 2 97 (1.21 mmol, 250 mg EtOAc (9 mL) was added hydrogen gas. This mixture was allowed to stir for 15 hours, afterwards this mixture was filtered over celite to remove catalyst. The filtrate was concentrated to yiel d yellow crude oil, which was purified via flash column chromatography to yield a clear orange colored oil (88%). R f (EtOAc/hexanes 50%): 0.12. 1 H NMR (500 MHz, CDCl 3 J = 8.9, 2.6 Hz, 2H), 6.88 (dd, J = 8.8, 2.7 Hz, 2H), 5.85 (ddt, J = 13.3, 7.9, 1.8 Hz, 1H), 5.66 5.54 (m, 1H), 5.48 (d, J = 8.6 Hz, 1H), 3.84 3.70 (m, 4H), 3.69 3.58 (m, 1H), 2.67 2.53 (m, 1H), 2.44 2.29 (m, 1H),

PAGE 112

112 1.5 (bs, 2H). 13 C NMR (126 MHz, CDCl 3 114.1, 69.0, 61 .5, 55.4, 38.7, 31.0 1 (4 Fluoroph enyl)pent 2 yne 1,5 diol (2 99): To a cooled solution of 2 77 ( 10 mmol, 0.76 mL) in THF (20 mL) 0 mL) slowly. The mixture was then heated to reflux for 1 hour, before cool ing the solution back down to 0 fluorobenzaldehyde (10 mmol, 1.07 mL) in THF (5 mL). This mixture was allowed to stir for 16 hours. After this, the reaction was quenched with ice cold ammonium chloride, separated, and extracted wit h EtOAc before being dried with magnesium sulfate and concentrated to furnish crude oil. This was purified by flash column chromatography to yield a clear colorless oil (37%). R f (EtOAc/Hexanes 50%):0.35. 1 H NMR (500 MHz, CDCl 3 7.26 (m, 2H), 7.23 7.19 (m, 2 H), 5.40 (t, J = 2.1 Hz, 1 H), 3.80 (d, J = 1.1 Hz, 3H), 2.58 2.47 (m, 2 H) 1.5 (bs, 2H) 13 C N MR (126 MHz, CDCl 3 128.7 114.1 8 4.0, 82.3, 64.5, 61.1, 55.5, 23.4 (E) 1 (4 fluorophenyl)pent 2 ene 1,5 diol ( E 2 100): To a cooled solution of 2 99 (1.87 mmol, 364.1 mg) in THF (9.35 mL) at 0 mg) in small portions over a few minutes, and allowed to stir for 18 hours. After this time had elapsed, the reaction was quenched by way of the n: n:3 method previously described above. Solids were removed by filtering over a bed of celite, and

PAGE 113

113 concentrating the filtrate to yield a crude oil, which was purified by flash column chromatography to yield a clear colorless oil (63%). R f (EtOAc/Hexanes 50% ): 0.24. 1 H NMR (300 MHz, CDCl 3 7.30 (m, 2H), 7.09 6.96 (m, 2H), 5.85 5.56 (m, 2H), 5.51 (d, J = 8.5 Hz, 1H), 3.79 (dt, J = 10.4, 5.2 Hz, 1H), 3.73 3.59 (m, 1H), 2.87 (s, 1H), 2.74 2.53 (m, 1H), 2.46 2.27 (m, 1H). 13 C N MR (126 MHz, CDCl 3 133.4, 129. 6 128.7 128.0 114.1 64.5, 61.1, 55.5, 23.4 (Z) 1(4 fluorophenyl)pent 2 ene 1,5 diol (Z 2 100) : To a solution of 2 99 (1.87 (9.35 mL) was a dded hydrogen gas. This mixture was allowed to stir for 15 hours, afterwards this mixture was filtered over celite to remove catalyst. The filtrate was concentrated to yield yellow crude oil, which was purified via flash column chromatography to yield a cl ear colorless oil (77%). R f (EtOAc/hexanes 50%): 0.24. 1 H NMR (300 MHz, CDCl 3 7.30 (m, 2H), 7.09 6.96 (m, 2H), 5.82 (ddt, J = 11.0, 8.5, 1.3 Hz, 1H), 5.72 5.56 (m, 1H), 5.51 (d, J = 8.5 Hz, 1H), 3.79 (dt, J = 10.4, 5.2 Hz, 1H), 3.73 3.59 (m 1H), 2.87 (s, 1H), 2.74 2.53 (m, 1H), 2.46 2.27 (m, 1H). 13 C NMR (126 MHz, CDCl 3 23.4

PAGE 114

114 7 Ph enylhept 3 yne 1,5 diol (2 101): To a cooled solution of 2 77 (10 mmol, 0.76 mL) in THF (20 mL) 0 The mixture was then heated to reflux for 1 hour, before cooling the solution back down 2 65 (10 mmol, 1.32 mL) in THF (5 mL). This mixture wa s allowed to stir for 16 hours. After this, the reaction was quenched with ice cold ammonium chloride, separated, and extracted with EtOAc before being dried with magnesium sulfate and concentrated to furnish crude oil. This was purified by flash column ch romatography to yield a clear colorless oil (66%). R f (EtOAc/Hexanes 50%):0.27. Proton NMR spectrum was found to match reported data 91 1 H NMR (500 MHz, CDCl 3 7.12 (m, 5H), 4.37 (s, 1H), 3.73 (q, J = 5.7 Hz, 2H), 2.79 (t, J = 7.8 Hz, 2H), 2.50 (tdd, J = 6.2, 2.7, 1.3 Hz, 2H), 2.11 1.88 (m, 2H), 1.56 (bs, 2H). 13 C NMR (126 MHz, CDCl 3 82.3, 62.0, 38.9 35. 7, 31.9 (E) 7 phenylhept 3 ene 1,5 diol ( E 2 102): To a cooled solution of 2 101 (0.90 mmol, 183.8 mg) in THF (4.5 mL) at 0 small portions over a few minutes, and allowed to stir for 17 hours. After this time had elapsed, the reaction was quenched by way of the n:n:3 method previously described above. Solids were removed by filtering over a bed of celite, and concentrating the filtrate to yield a crude oil, which was purified by flash col umn chromatography to yield a clear colorless oil (93%). R f (EtOAc/Hexanes 50%): 0.27. Proton NMR spectrum was

PAGE 115

115 found to match reported data 92 1 H NMR (500 MHz, CDCl 3 7.13 (m, 5H), 5.74 5.56 (m, 2H), 4.16 4.04 (m, 1H), 3.68 (dd, J = 6.7, 5.7 Hz, 2H), 2.78 2.61 (m, 2H), 2.36 2.26 ( m, 2H), 1.95 1.77 (m, 2H), 1.75 1.50 (bs, 2H). 13 C NMR (126 MHz, CDCl 3 (Z) 7 phen ylhept 3 ene 1,5 diol (Z 2 102): To a solution of 2 101 (0.37 mmol, mL) was added hydrogen gas. This mixture was allowed to stir for 17 hours, afterwards this mixture was filtered over celite to remove catalyst. The filtrate was concentrated to yield yellow crude oil, which was purified via flash column chromatography to yield a clear colorless oil (86%). R f (EtOAc/hexanes 50%): 0.27. Proton NMR spectrum was found to match reported data 92 1 H NMR (300 MHz, CDCl 3 7.08 (m, 5H), 5.77 5.48 (m, 2H), 4.42 (q, J = 7.0 Hz, 1H), 3.82 3.49 (m, 2H), 2.85 2.59 (m, 2H), 2.48 (dtt, J = 14.0, 9.0, 5.1 Hz, 1H), 2.26 (tq, J = 11.0, 5.3 Hz, 1H), 2.09 1.68 (m, 3H), 1.56 (bs, 1H). 13 C NMR (75 MHz, CDCl 3 38.8, 31.9, 31.0 2 (Prop 2 yn 1 yl oxy)tetrahydro 2H pyran (2 126): To a solution of 2 125 (20 mmol, 1.16 mL) and 3,4 dihydropyran (24 mmol, 2.19 mL) in CH 2 Cl 2 (100mL) was added pTSA (0.06 mmol, 11.0 mg). This mixture was allowed to stir for 24 hours. Reaction was quenched with NaHCO 3 in brine, extracted with CH 2 Cl 2 dried with MgSO 4 and concentrated to yield crude mixture of 2 126 Crude NMR showed only product, and as such was used without further purification. Proton NMR spectrum was found to

PAGE 116

116 match reported data 93 1 H NMR (300 MHz, CDCl 3 4.79 (m, 1H), 4.36 4.17 (m, 2H), 3.90 3.77 (m, 1H), 3.60 3.46 (m, 1H), 2.41 (t, J = 2.4 Hz, 1H), 1.92 1.45 (m, 8H). 5 Phenylpent 2 yne 1,5 diol (2 127) : To a co oled solution of 2 126 (20 mmol, 2.8036 g) in THF (63 mL) at 78 way of an addition funnel. This mixture was allowed 30 minutes to stir before addition of styrene oxide (12.5 mmol, 1.5 mL) in THF (6 mL), followed immediately afterward by addition of BF 3 etherate (18.75 mmol, 2.36 mL) This mixture was allowed to warm to ambient temperature over 28 hours and was quenched with ammonium chloride, separated, and extracted with EtOAc before being dried with m agnesium sulfate, and concentrated to yield crude mixture. Crude NMR showed both diastereomers cleanly, and was kept crude for the next step. The above crude mixture was dissolved in MeOH (63 mL) and treated with pTSA (0.04 mmol, 7.6 mg) and allowed to stir for 72 hours. The mixture was washed with sodium bicarbonate, extracted with EtOAc, dried over magnesium sulfate, and concentrated to yield crude oil. This was purified by flash column chromatography to yield a clear colorless oil (75% over three steps). R f (EtOAc/Hexanes 50%): 0.20. Proton NMR spectrum was found to match reported data 94 1 H NMR (300 MHz, CDCl 3 ) 7.18 (m, 5H), 4.42 4.26 (m, 1H), 4.21 4.03 (m, 1H), 3.99 3.78 (m, 2H), 3.78 3.64 (m, 1H), 2.85 1.86 (s, 2H). 13 C NMR (75 MHz, CDCl 3 ) 127.6, 127.1, 87.8 71.6, 51.1, 27.5

PAGE 117

117 (Z) 5 phenylpent 2 ene 1,5 diol (2 128) : To a solution of 2 127 (1.52 mmol, mL) was added hydrogen gas. This mixtu re was allowed to stir for 17 hours, afterwards this mixture was filtered over celite to remove catalyst. The filtrate was concentrated to yield yellow crude oil, which was purified via flash column chromatography to yield a clear colorless oil (78%). R f ( EtOAc/hexanes 50%): 0.30. Proton NMR spectrum was found to match reported data 95 1 H NMR (300 MHz, CDCl 3 7.18 (m, 5H), 5.93 (dddd, J = 10.9, 7.2, 6.3, 0.8 Hz, 1H), 5.80 (ddt, J = 10.7, 9.6, 1.0 Hz, 1H), 4.42 4.26 (m, 1H), 4.21 4.03 (m, 1H), 3.99 3 .78 (m, 2H), 3.78 3.64 (m, 1H), 2.85 1.86 (s, 2H). 13 C NMR (75 MHz, CDCl 3 126.3 51.1, 27.5 ((Prop 2 yn 1 yloxy)methyl)benzene (2 129): To a suspension of NaH (22 mmol, 555.8 mg) in DMF (20 mL) at 0 2 125 (20 mmol, 1.16 mL) neat. This mixture was allowed to stir for 30 minutes before the addition of benzylbromide (22 mmol, 2.62 mL). This was then allowed to reach ambient temperature over 16 hours. The reaction was quenched with HCl (1 N, 40 mL), sepa rated and extracted with EtOAc before being dried over magnesium sulfate, and concentrated to produce a crude oil. This was purified by flash column chromatography. R f (EtOAc/Hexanes 10%): 0.30. Proton NMR spectrum was found to match reported data 96 1 H NMR (500 MHz, CDCl 3 )

PAGE 118

118 7.27 (m, 5H), 4.61 (s, 2H), 4.24 (s, 1H), 4.18 (d, J = 2.4 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 ) 128.1 127.8, 74.8 7 2.3, 71.8, 71.7, 57.6 5 (Benzyloxy) 1 phenylpent 3 yn 1 ol (2 130): To a cooled solution of 2 129 (5 mmol, 715.0 mg) in THF (25 mL) at 78 by way of an addition funnel. This mixture was allowed 30 minutes to stir before addition of styrene oxide (5 mmol, 0.57 mL) in THF (2 mL), followed immediately afterward by addition of BF 3 etherate (15 mmol, 1.88 mL). This mixture was allowed to warm to ambient temperature over 20 hours and was quen ched with ammonium chloride, separated, and extracted with EtOAc before being dried with magnesium sulfate, and concentrated to yield crude mixture. This was purified by flash column chromatography to yield a clear colorless oil (28%). R f (EtOAc/Hexanes 10 %): 0.29. Proton NMR spectrum was found to match reported data 97 1 H NMR (500 MHz, CDCl 3 7.26 (m, 10H), 4.88 (t, J = 6.4 Hz, 1H), 4.53 (s, 2H), 4.16 (t, J = 2.1 Hz, 2H), 2.77 2.66 (m, 2H), 2.38 (s, 1H). 13 C NMR (126 MHz, CDCl 3 .7, 128.6, 128.4, 128.2, 128.1, 128.0, 83.3, 78.9, 72.6, 71.6, 57.7, 28.9 (Z) 5 (b enzyloxy ) 1 phenylpent 3 ene 1 ol (2 131): To a solution of 2 130 (1.77 (9 mL) was add ed hydrogen gas. This mixture was allowed to stir for 16 hours,

PAGE 119

119 afterwards this mixture was filtered over celite to remove catalyst. The filtrate was concentrated to yield yellow crude oil, which was purified via short path distillation to remove quinoline thus yielding a clear colorless oil (55%). R f (EtOAc/hexanes 20%): 0.30, but overlaps with quinoline spot. Proton NMR spectrum was found to match reported data 98 1 H NMR (500 MHz, CDCl 3 7.24 (m, 10H), 5.89 5.76 (m, 1H), 5.76 5.57 (m, 1H), 4.72 (dd, J = 8.2, 5.2 Hz, 1H), 4.50 (s, 2H), 4.01 (dddd, J = 30.7, 11.9, 6.6, 1.4 Hz, 2H), 2.66 2.40 (m, 2H), 1.58 (s, 1H). 13 C NMR (126 MHz, CDCl 3 129.8, 129.4, 128.6, 128.6, 128.5 128.1, 128.0, 127.9, 127.6, 125.9, 77.4, 77.2, 76.9, 73.4, 72.7, 66.0, 65.6, 3 7.9, 37.1 5 Metho xy 1 phenylpent 3 yn 1 ol (2 133 ): To a suspension o f NaH (22 mmol, 555.8 mg) in dioxane (100 mL) at 0 2 125 (20 mmol, 1.16 mL) neat. This mixture was allowed to stir for 30 minutes before the addition of methyliodide (20 m mol, 1.25 mL). This was then allowed to reach ambient temperature over 16 hours. Full conversion was observed by TLC. R f (EtOAc/Hexanes 20%): 0.27. The reaction was filtered to remove solid NaI, and kept as a 0.2 M solution of methyl ether 2 132 in dioxane due to the volatility of 2 132 To a cooled solution of 2 13 2 (10 mmol, 50 mL) at mmol, 3.75 mL) dropwise by way of an addition funnel. This mixture was allowed 30 minutes to stir before addition of styrene oxide (6.25 mmol, 0.71 mL) in THF (2 mL), followed immediately afterward by additi on of BF 3 etherate (9.38 mmol, 1.18 mL). This mixture was allowed to warm to ambient temperature over 2 hours and was quenched

PAGE 120

12 0 with ammonium chloride, separated, and extracted with EtOAc before being dried with magnesium sulfate, and concentrated to yiel d crude mixture. This was purified by flash column chromatography to yield 2 133 as a clear colorless oil (21% over two steps). R f (EtOAc/Hexanes 30%): 0.36. 1 H NMR (500 MHz, CDCl 3 7.27 (m, 5H), 4.94 4.80 (m, 1H), 4.08 (t, J = 2.3 Hz, 2H), 3.33 (d, J = 2.2 Hz, 3H), 2.75 2.63 (m, 2H), 2.45 2.32 (m, 1H). 13 C NMR (126 MHz, CDCl 3 83.3, 78.7, 72.6, 60.2, 57.7, 30.0 ( Z) 5 methoxy 1 phenylpent 3 ene 1 ol (2 134): To a solution of 2 133 (0.5 mmol, 100 m (2.5 mL) was added hydrogen gas. This mixture was allowed to stir for 18 hours, afterwards this mixture was filtered over celite to remove catalyst. The filtrate was concentrated to yield yellow crude oil, which was purified via short path distillation to remove quinoline, thus yielding a clear colorless oil (60%). R f (EtOAc/hexanes 30%): 0.30, but overlaps with quinoline spot. 1 H NMR (500 MHz, CDCl 3 7.21 (m, 5H), 5.83 5.72 (m, 1H), 5.72 5.61 (m, 1H), 4.74 (t, J = 6.4 Hz, 1H), 4.02 3.82 (m, 2H), 3.36 3.29 (m, 3H), 2.65 (s, 1H), 2.55 (dddd, J = 20.6, 18.8, 10.3, 6.0 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 127.6, 126.9, 125.9, 73.3, 67.9, 58.2, 37.9

PAGE 121

121 1 Phenylhex 5 en 3 ol (2 135) : To a cooled solution of 2 65 (10 mmol, 1.32 mL) in THF (33 mL) at 78 dropwise by way of addition funnel. Mixture was all owed to warm to ambient temperature over 1.5 hours, and was then quenched with dilute HCl, extracted with EtOAc, dried over magnesium sulfate, and concentrated to give crude mixture which was purified by flash column chromatograph y to yield a clear, yellow liquid (60%). R f (EtOAc/Hexanes 10%): 0.35. Proton NMR spectrum was found to match reported data. 99 1 H NMR (500 MHz, CDCl 3 7.34 7.12 (m, 5H), 5.91 5.74 (m, 1H), 5.21 5.09 (d, 2H), 3.76 3.60 (m, 1H), 2.81 (dt, J = 14.6, 7.5 Hz, 1H), 2.69 (dt, J = 14.3, 8.0 Hz, 1H), 2.40 2.27 (m, 1H), 2.25 2.12 (m, 1H), 1.86 1.73 (m, 3H), 1.58 (bs, 1H). (E) 5 Hydroxy 7 phenyl hept 2 enal (2 136): To an oven dried round bottom flask equipped with stir bar was added Grubbs second generation catalyst (0.12 mmol, 101.9 mg) while warm to the touch and allowed to cool to room temperature under a stream of nitrogen. Once cooled, the catalyst was dissolved in CH 2 Cl 2 (3.5 mL) then treated with a solution of premixed 2 135 (2.45 mmol, 431.8 mg) and crotonaldehyde ( 31.9 mmol, 2.6 mg) in CH 2 Cl 2 (1.5 mL). Bubbles were observed within a few minutes of addition. Progress was monitored by TLC until the complete disappearance of 2 135 was observed after about 3 hours. The reaction was stopped by opening the reaction vessel to air and adding 5 mL of silica gel to the mixture. This was allowed 30 minutes to stir, and remaining CH 2 Cl 2 was removed by rotary distillation. The resulting red powder was immediately purified via flash column chromatography to yield a clear, dark green liquid

PAGE 122

122 (84%). R f (EtOAc/Hexanes 25 %): 0.25 and stains bright orange with DNP stain Proton NMR spectrum was found to matc h reported data. 100 1 H NMR (300 MHz, CDCl 3 9.44 (m, 1H), 7.39 7.07 (m, 5H), 7.00 6.76 (m, 1H), 6.29 6.06 (m, 1H), 3.85 (qd, J = 6.7, 4.7 Hz, 1H), 2.76 (dddd, J = 21.8, 17.0, 14.0, 7.7 Hz, 2H), 2.63 2.39 (m, 2H), 1.97 1.72 (m, 3H), 1.57 (bs, 1H). (E) 7 phenylhept 2 ene 1,5 diol (E 2 137): To a cooled solution of 2 136 (1.96 mmol, 400.0 mg) and CeCl 3 heptahydrate (4.9 mmol, 1.8256 g) in MeOH (10 mL) at 0 4 (4.9 mmol, 185.4 mg) portionwise and was allowed to reach ambient temperature over 16 hours. An aliquot of mixture was treated with water in order to decomplex the aldehyde from cerium and thus give a clear TLC. Extra equivants of NaBH 4 were sometimes needed for full conversion. Once full conversion was observed, the reaction was q uenched with water, and extracted three times with EtOAc, dried over magnesium sulfate, and concentrated to yield crude mixture. This was purified by flash column chromatography to yield a clear colorless oil (70% ). R f (EtOAc/Hexanes 50%): 0.18. Proton NMR spectrum was found to match reported data. 100 1 H NMR (300 MHz, CDCl 3 7.12 (m, 5H), 5.84 5.62 (m, 2H), 4.22 4.04 (m, 2H), 3.75 3.60 (m, 1H), 2.91 2.58 (m, 2H), 2.42 2.11 (m, 2H), 1.91 1.44 (m, 4H). 1 Phenylhex 5 en 3 yl acrylate (2 138) : To a cooled solution of 2 135 (0.87 mmol, 179.1 mg) in CH 2 Cl 2

PAGE 123

123 followed by freshly distilled triethylamine (3 mmol, 0.42 mL) and was allowed to reach ambient temperature. TLC indicated full conversio n after 2 hours and was then filtered over celite to remove triethylamine hydrochloride salt, then washed with water, extracted with CH 2 Cl 2 dried over magnesium sulfate and concentrated to give crude mixture. This was purified by flash column chromatograp hy to produce a clear colorless oil (96%). %). R f (EtOAc/Hexanes 10%): 0.55. Proton NMR spectrum was found to match reported data. 101 1 H NMR (300 MHz, CDCl 3 7.05 (m, 5H), 6.41 (ddd, J = 17.3, 1.6, 0.7 Hz, 1H), 6.26 6.02 (m, 1H), 5.93 5.60 (m, 2H), 5.15 4.97 (m, 3H), 2.80 2.49 (m, 2H), 2.46 2.32 (m, 2H), 2.03 1.80 (m, 2H). 6 Phenethyl 5,6 dihydro 2H pyran 2 one (2 139) : To an oven dried round bottom 2 necked flask equipped with stir bar and condenser, was added Grubbs second generation catalyst (0.0043 mmol, 3.7 mg) while warm to the touch and allowed to cool to room temperature under a stream of nitrogen. Once cooled, the catalyst was dissolved in CH 2 Cl 2 (1 mL) then heated to reflux by oil bath. This was then tr eated with a solution of 2 138 (0.43 mmol, 100 mg) in CH 2 Cl 2 (1 mL). Bubbles were observed within a few minutes of addition. Progress was monitored by TLC until the complete disappearance of 2 138 was observed after about 3 hours. The reaction was stopped by opening the reaction vessel to air and adding 2 mL of silica gel to the mixture, then allowing the mixture to cool to ambient temperature. This was allowed 30 minutes to stir and remaining CH 2 Cl 2 was removed by rotary distillation. The resulting red pow der was immediately purified via flash column chromatograph y to yield an oil (50 %). R f

PAGE 124

124 (CH 2 Cl 2 /Hexanes 75%): 0.29. Proton NMR spectrum was found to match reported data. 101 1 H NMR (300 MHz, CDCl 3 7.11 (m, 5H), 6.94 6.80 ( m, 1H), 6.08 5.97 (m, 1H), 4.41 (dddd, J = 10.2, 8.4, 6.0, 4.3 Hz, 1H), 3.02 2.70 (m, 2H), 2.40 2.29 (m, 2H), 2.14 (dtd, J = 14.1, 8.7, 5.5 Hz, 1H), 1.94 (dddd, J = 13.9, 9.5, 7.2, 4.3 Hz, 1H). (Z) 7 phenylhept 2 ene 1,5 diol (Z 2 137): To a cooled solution of 2 139 (0.06 mmol, 12.8 mg) and CeCl 3 heptahydrate (0.173 mmol, 64.4 mg) in MeOH (7 mL) at 0 was added NaBH 4 (0.173 mmol, 6.5 mg) portionwise and was allowed to stir for 5 hours. An aliquot of mixture was treated with water in ord er to decomplex the aldehyde from cerium and thus give a clear TLC. Extra equivants of NaBH 4 were sometimes needed for full conversion. Once full conversion was observed, the reaction was quenched with water, and extracted three times with EtOAc, dried ove r magnesium sulfate, and concentrated to yield crude mixture. This was purified by flash column chromatography to yield a clear colorless oil (61%). R f (CH 2 Cl 2 /Hexanes 75%): 0.29. Proton NMR spectrum was found to match reported data. 102 1 H NMR (300 MHz, CDCl 3 ) 7.12 (m, 5H), 5.88 (dtt, J = 11.0, 6.9, 1.3 Hz, 1H), 5.64 (dddt, J = 10.9, 8.6, 7.5, 1.1 Hz, 1H), 4.26 4.04 (m, 2H), 2. 87 2.62 (m, 2H), 2.40 2.24 (m, 2H), 1.89 1.73 (m, 2H), 1.25 (bs, 2H).

PAGE 125

125 (E) 7 methoxy 1 phenylhept 5 en 3 ol (2 142): To a suspension o f NaH (195 mmol, 7.78 g) in dioxane (140 2 140 (166 mmol, 11.3 mL) neat. This mixture was allowed to stir for 30 minutes before the addition of methyliodide (139 mmol, 8.6 mL). This was then allowed to r each ambient temperature over 19 hours. Full conversion was observed by TLC. R f (EtOAc/Hexanes 20%): 0.27. The reac tion was filtered to rem ove solid NaI, and kept as a 1 M solution of methyl ether 2 141 in dioxane due to the volatility of 2 141 To an oven dried round bottom flask equipped with stir bar, was added Grubbs second generation catalyst (0.047mmol, 40 mg) wh ile warm to the touch and allowed to cool to room temperature under a stream of nitrogen. Once cooled, the catalyst was dissolved in CH 2 Cl 2 (5 mL) then treated with a solution of premixed 2 141 (47 mmol, 47 mL) and 2 135 (4.7 mmol, 819.8 mg) in CH 2 Cl 2 (4.5 mL). Bubbles were observed within a few minutes of addition. Progress was monitored by TLC until the complete disappearance of 2 135 was observed after about 3 hours. The reaction was stopped by opening the reaction vessel to air and adding 9 mL of silica gel to the mixture. This was allowed 30 minutes to stir, and remaining CH 2 Cl 2 was removed by rotary distillation. The resulting red powder was immediately purified via flash column chromatography to yield a clear, orange liquid (30%). R f (EtOAc/Hexanes 10 %): 0.61. Proton NMR spectrum was found to match reported data. 103 1 H NMR (300 MHz, CDCl 3 7.17 (m, 5H), 5.83 5.56 (m, 2H), 3.89 (d, J = 4.6 Hz, 2H), 3.67 (dq, J = 11.5, 5.5, 4.3 Hz, 1H), 3.32 (d, J = 1.1 Hz, 3H), 2.73 (ddt, J = 30.1, 14.6, 7.3 Hz, 2H), 2.39 2.08 (m, 2H), 1.87 1.70 (m, 2H), 1.61 (t, J = 6.4 Hz, 1H).

PAGE 126

126 (3R, 7S, Z) 1,9 diphenylnon 4 ene 3,7 diol (Z 2 152) : To a cooled solution of 2 149 (2.5 mmol, 1.0357g) 64 in CH 2 Cl 2 (5 mL) at 0 2 151 ( 2.5 mmol, 0.7158g) 104 in CH 2 Cl 2 (5 mL) and was allowed to stir for 2 hours, after which the temperature was lowered to 78 2 65 (6.25 mmol, 0.82 mL) was then added neat and allowed 4 hours to stir before the temperature was raised to ambient temperature over night. The reaction was then quenche d 24 hours after the addition of aldehyde by the addition of 3 M NaOH (2.5 mL) and H 2 O 2 (1 mL). The layers were separated, extracted with CH 2 Cl 2 dried over magnesium sulfate, and concentrated to give crude mixture. This was purified via flash column chrom atography to yield the diol as a clear colorless oil (70%). R f (EtOAc/Hexanes 30%): 0.2 1. Proton NMR spectrum was found to match reported data. 64 1 H NMR (500 MHz, CDCl 3 7.12 (m, 10H), 5.72 5.63 (m, 1H), 5.63 5.54 (m, 1H), 4.41 (ddd, J = 8.1, 7.0, 5.7 Hz, 1H), 3.78 3.66 (m, 1H), 2.84 2.59 (m, 4H), 2.46 2.32 (m, 1H), 2.29 2.18 (m, 1H), 2.00 1.87 (m, 1H), 1.86 1.73 (m, 3H) 1.56 (bs, 2H) (1S, 5S, Z) 1,7 diphenylhept 2 ene 1,5 diol (2 153) : To a cooled solution of 2 149 (2.5 m mol, 1.0357g) 64 in CH 2 Cl 2 (5 mL) at 0 2 151 (2.5 mmol, 0.71 58g) 104 i n CH 2 Cl 2 (5 mL) and was allowed to stir for 2 hours, after which the temperature was lowered to 78 Benz aldehyde 2 6 7 (2 mmol, 0.20 mL) w as then added neat and allowed 2 hours to stir before the addition of hydrocinnamaldehyde 2 65

PAGE 127

127 (4.25 mmol, 0.56 mL) which was then allowed another 2 hours before the temperature was raised to ambient temperature over night. The reaction was then quenched 24 hours after the addition of benz aldehyde by the addition of 3 M NaOH (2.5 mL) and H 2 O 2 (1 mL). The layers were s eparated, extracted with CH 2 Cl 2 dried over magnesium sulfate, and concentrated to give crude mixture. This was purified via flash column chromatography to yield the d iol as a clear colorless oil (66 %). R f (EtOAc/Hexanes 30%): 0.26 Proton NMR spectrum was found to match reported data. 64 1 H NMR (500 M Hz, CDCl 3 7.12 (m, 10H), 5.72 5.63 (m, 1H), 5.63 5.54 (m, 1H), 4.41 (ddd, J = 8.1, 7.0, 5.7 Hz, 1H), 3.78 3.66 (m, 1H), 2.84 2.59 (m, 2 H), 2.46 2.32 (m, 1H), 2.29 2.18 (m, 1H), 2.00 1.87 (m, 1H), 1.86 1.73 (m, 1 H) 1.56 (bs, 2H). (1S, 5R, E) 1,7 diphenylhept 2 ene 1,5 diol (2 158): To a cooled solution of 2 157 (2.5 mmol, 1.0357g) 64 in CH 2 Cl 2 (5 mL) at 0 2 151 (2.5 mmol, 0.7158g) 104 in CH 2 Cl 2 (5 mL) and was allowed to stir for 2 hours, after which the temperature was lowered to 78 2 67 (2 mmol, 0.20 mL) was then added neat and allowed 2 hours to stir before the addition of hydrocinnamaldehyde 2 65 (4.25 mmol, 0.56 mL), which was then allowed another 2 hours before the temperature was raised to ambient temperature over night. The reaction was then quenched 24 hours after the addition of benzaldehyde by the addition of 3 M NaOH (2.5 mL) and H 2 O 2 (1 mL). The layers were separated, extracted with CH 2 Cl 2 dried over magnesium sulfate, and concentrated to give crude mixture. This was purified via flash column chromatography to yie ld the diol as a clear colorless oil (66%). R f (EtOAc/Hexanes 30%): 0.26. Proton NMR spectrum was found to match reported data. 64 1 H NMR (500

PAGE 128

128 MHz, CDCl 3 7.12 (m, 10H), 5.72 5.63 (m, 1H), 5.63 5.54 (m, 1H), 4.41 (ddd, J = 8.1, 7.0, 5.7 Hz, 1H), 3.78 3.66 (m, 1H), 2.84 2.59 (m, 2H), 2.46 2.32 (m, 1H), 2.29 2.18 (m, 1H), 2.00 1.87 (m, 1H), 1.86 1.73 (m, 1H), 1.56 (bs, 2H). (3R, 7R, E) 1,9 dip henylnon 4 ene 3,7 diol (2 159): To a cooled solution of 2 157 (2.5 mmol, 1.0357g) 64 in CH 2 Cl 2 (5 mL) at 0 2 151 (2.5 mmol, 0.7158g) 104 in CH 2 Cl 2 (5 mL) and was allowed to stir for 2 hours, after which the temperature was lowere d to 78 2 65 (6.25 mmol, 0.82 mL) was then added neat and allowed 4 hours to stir before the temperature was raised to ambient temperature over night. The reaction was then quenched 24 hours after the addition of aldehyde by the ad dition of 3 M NaOH (2.5 mL) and H 2 O 2 (1 mL). The layers were separated, extracted with CH 2 Cl 2 dried over magnesium sulfate, and concentrated to give crude mixture. This was purified via flash column chromatography to yield the diol as a clear colorless oi l (70%). R f (EtOAc/Hexanes 30%): 0.2 1. Proton NMR spectrum was found to match reported data. 64 1 H NMR (500 MHz, CDCl 3 7.12 (m, 10H), 5.72 5.63 (m, 1H), 5.63 5.54 (m, 1H), 4.41 (ddd, J = 8.1, 7.0, 5.7 Hz, 1H), 3.78 3.66 (m, 1H), 2.84 2.59 (m, 4H), 2.46 2.32 (m, 1H), 2.29 2.18 (m, 1H), 2.00 1.87 (m, 1H), 1.86 1.73 (m, 3H) 1.56 (bs, 2H) 4.4 Acetals from Diol Scope and Other S tudies Note: Isobutyraldehyde was freshly distilled before each reaction was run. General Procedure A : V (0.01 mmol, 8.8 mg) and AgSbF 6 (0.01 mmol, 3.4 mg) were combined with molecular sieves (4 ) in a test tube under argon in a glove box. The reaction vessel was wrapped in aluminum foil before being taken out of the glove

PAGE 129

129 box, and the mixture of solids was dissolved in CH 2 Cl 2 (0.25 mL) at room temperat ure and allowed one minute to five minutes to stir in order to form the gold (I) cationic complex before the addition of isobutyraldehyde 2 62 (1.00 mmol 0.09 mL). Z 1,5 monoallylic diol (0.20 mmol ) was then added. Progress was monitored by TLC for the d isappearance of diol and reaction was quenched by filtering crude mixture over a plug of silica which was then concentrated by rotary evaporation and purified by flash column chromatography. General Procedure B: Bismuth (III) triflate (0.01 mmol, 6.6 mg) was combined with molecular sieves (4 ) in a test tube under argon in a glove box. The reaction vessel was taken out of the glove box, and the mixture of solids was dissolved in CH 2 Cl 2 (1 mL) at room temperature before the addition of isobutyraldehyde (1. 00 mmol 0.09 mL). E 1,5 monoallylic d iol (0.20 mmol ) was then added. Progress was monitored by TLC for the disappearance of diol and reaction was quenched by filtering crude mixture over a plug of silica which was then concentrated by rotary evaporation and purified by flash column chromatography. 2 Isopropyl 4 vinyl 1,3 dioxolane (2 61a): Following general procedure A, the reaction of Z 2 butene 1,4 diol ( Z 2 55 ) afforded acetal as a colorless oil (80% yield, 1:8 dr). Foll owing general procedure B, the reaction of E 2 butene 1,4 diol ( E 2 55 ) afford ed acetal as a colorless oil (55% yield, 1:4 dr). R f (CH 2 Cl 2 /hexane 40%): 0.23. Proton and carbon NMR spectra were found to match reported data. 87 1 H NMR (500 MHz, CDCl 3 5.76 (m, 1H), 5.34 (dq, J = 17.1, 1.5 Hz, 1H), 5.22 (dq, J = 10.6, 1.5 Hz, 1H), 4.79 (d, J = 4.6 Hz, 1H), 4.53 4.40 (m, 3H), 4.16 (ddd, J = 8.8, 6.3,

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130 2.2 Hz, 1H), 3.53 (ddd, J = 9.8, 7.7, 2.3 Hz, 1H), 1.94 1.76 (m, 3H), 1.02 0.87 (d, 6H). 13 C NMR (126 MHz, CDCl 3 both diastereomers 108 .6, 104.9, 70.5, 32.6, 32.4, 30.7, 30.4, 17.0, 16.9 2 Isopropyl 4 ((E) styryl) 1,3 dioxolane (2 103 ): Following gener al procedure A, the reaction Z 2 96 afford ed acetal as a colorless oil (87% yield, 1:15 dr). R f (CH 2 Cl 2 /hexane 40%): 0.20 1 H NMR (500 MHz, CDCl 3 7.20 (m, 5H), 6.70 6.60 (m, 1H), 6.17 (ddd, J = 15.8, 7.5, 0.5 Hz, 1H), 4.87 (d, J = 4.7 Hz, 1H), 4.67 4.57 (m, 1H), 4.23 (ddt, J = 8.3, 6.1, 0.4 Hz, 1H), 3.67 3.56 (m, 1H), 1.87 (dtdd, J = 13.7, 6.8, 4.7, 0.7 Hz, 1H), 1.02 0.95 (m, 6H). 13 C NMR (126 MHz, CDCl 3 128.7, 128.1, 126.8, 126.8, 108.8, 70.8, 32.5, 16.9 2 Isopropyl 4 ((E) styryl) 1,3 dioxane (2 92 ): Following general procedure A, the reaction Z 2 79 afforded acetal as a colorless oil (91% yield 1:22 dr). Following general procedure B, the reaction E 2 79 afforded acetal as a clear colorless oil (98% yield, 1:22 dr). R f (CH 2 Cl 2 /hexane 40%): 0.20 1 H NMR (3 00 MHz, CDCl 3 ) 7.19 (m, 7H), 6.61 (dd, J = 16.4, 6.5 Hz, 1H), 6.30 6.16 (m, 1H), 4.50 (dd, J = 5.5, 1.2 Hz, 1H), 4.38 4.24 (m, 2H), 4.23 4.10 (m, 1H), 3.88 3.71 (m, 1H), 1.96 1.74 (m, 3H), 0.96 (ddd, J = 11.4, 6.1, 1.4 Hz, 11H). 13 C NMR (75 MHz, CDCl 3 13 0.4, 129.7, 128.7, 127.8, 126.7, 105.8, 77.0, 66.6, 32.6, 32.0, 16.8

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131 Z 2 Isopropyl 8 phenyl 5,8 dihydro 4H 1,3 dioxocine (2 93): Following general procedure B, the reaction Z 2 79 afforded acetal as a clear color less oil (98% yield ). R f (CH 2 Cl 2 /hexane 40%): 0.20. 1 H NMR (300 MHz, CDCl 3 7.26 (m, 5H), 6.01 (dddd, J = 9.4, 4.8, 3.0, 2.2 Hz, 1H), 5.87 5.76 (m, 1H), 5.15 (dq, J = 5.3, 2.5 Hz, 1H), 4.50 (d, J = 5.4 Hz, 1H), 4 .08 3.95 (m, 1H), 3.82 (dddd, J = 11.2, 8.7, 4.2, 0.7 Hz, 1H), 2.47 2.28 (m, 1H), 1.97 1.76 (m, 1H), 0.95 (dd, J = 6.8, 0.8 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 76 .2, 63.3, 32.6, 25.3, 16.9 2 Isopropyl 4 ((E) 4 fluoro styryl) 1,3 dioxane (2 105 ): Following general procedure A, the reaction Z 2 100 afford ed acetal as a colorless oil (98% yield, 1: >25 dr). Following general procedure B, the reaction E 2 100 afforded ace tal as a clear colorless oil (80% yield, 1: >25 dr). R f (CH 2 Cl 2 /hexane 40%): 0.20. 1 H NMR (500 MHz, CDCl 3 7.31 (m, 2H), 7.07 6.95 (m, 2H), 6.58 (dd, J = 16.0, 1.4 Hz, 1H), 6.14 (dd, J = 16.0, 5.7 Hz, 1H), 4.50 (dd, J = 5.5, 1.0 Hz, 1H), 4.34 (d, J = 5.1 Hz, 1H), 4.32 4.24 (m, 1H), 4.1 7 (ddd, J = 11.3, 4.9, 1.4 Hz, 1H), 3.83 3.73 (m, 1H), 1.93 1.76 (m, 1H), 1.60 1.49 (m, 1H), 1.02 0.90 (m, 6H). 13 C NMR (126 MHz, CDCl 3 129.3, 128.2, 128.1, 115.7, 115.5, 104.9, 77.5, 66.6, 33.1, 31.9, 16.9

PAGE 132

132 2 Isopropyl 4 ((E) phenylbut 1 en yl) 1,3 dioxane (2 106): Following general procedure A, the reaction Z 2 102 afforded acetal as a colorless oil (83% yield, 1: >25 dr). Following general procedure B, the reaction E 2 102 afforded ace tal as a clear colorless oil (95 % yield, 1: >25 dr). R f (CH 2 Cl 2 /hexane 40%): 0.20. 1 H NMR (300 MHz, Chloroform 7.11 (m, 5H), 5.83 5.65 (m, 1H), 5.53 (ddt, J = 15.5, 6.0, 1.4 Hz, 1H), 4.28 (dd, J = 5.2, 1.1 Hz, 1H), 4.18 3.99 (m, 2H), 3.81 3.65 (m, 1H), 2.78 2.63 (m, 2H), 2.36 (dtt, J = 8.7, 6.5, 1.1 Hz, 2H), 1.91 1.69 (m, 3H), 0.98 0.91 (m, 6H). 13 C NMR (126 MHz, CDCl 3 77.1, 66.6, 35.7, 34.3, 33.0, 31.9, 17.5, 17.2 (2S, 4S, 6R) 2 Isopropyl 4 phenyl 6 vinyl 1,3 dioxane ( 2 143): Following 2 131 afforded acetal as a clear colorless oil (20%). R f (EtOAc/hexane 5%): 0.50. 1 H NMR (500 MHz, CDCl 3 7.19 (m, 5H), 5.98 5.84 (m, 1H), 5.33 (dt, J = 17.3, 1.6 Hz, 1H), 5.16 (dt, J = 10.6 1.5 Hz, 1H), 4.72 4.65 (m, 1H), 4.54 (d, J = 4.8 Hz, 1H), 4.42 4.36 (m, 1H), 4.32 4.23 (m, 1H), 2.03 1.89 (m, 1H), 1.85 (dt, J = 13.2, 2.5 Hz, 1H), 1.03 (dd, J = 6.9, 1.2 Hz, 6H). 13 C NMR (126 MHz, CDCl 3 125.5, 124.3, 105.3, 77.9, 76.8 39.2, 33.1, 31.5, 17. 4.

PAGE 133

133 (2S, 4S, 6R) 2 Isopropyl 4 phen ethyl 6 vinyl 1,3 dioxane (2 144 ): Follo wing general procedure A the reaction of E 2 142 afforded acetal as a clear colorl ess oil (4 0% 1 : 1 dr ). R f ( CH 2 Cl 2 /hexane 2 5%): 0.3 0. 1 H NMR (500 MHz, CDCl 3 7.19 (m, 5H), 5.98 5.84 (m, 1H), 5.33 (dt, J = 17.3, 1.6 Hz, 1H), 5.16 (dt, J = 10.6, 1.5 Hz, 1H), 4.72 4.65 (m, 1H), 4.54 (d, J = 4.8 Hz, 1H), 4.42 4.36 (m, 1H), 4.32 4.23 (m, 1H), 2.03 1.89 (m, 3H), 1.91 1.6 9 (m, 3H) 1.03 (dd, J = 6.9, 1.2 Hz, 6H). 13 C NMR (126 MHz, CDCl 3 39.2 33.1 33.0, 31.9, 17.5, 17.2 (2S, 4S, 6S) 4 P hen ethyl 6 ((E) phenylbut 1 en 1 yl) 2 (trichloromethyl ) 1,3 dioxane (2 156 ): Follo wing general procedure A the reaction of E 2 142 with chloral hydrate in leiu of isobutyraldehyde afforded acetal as a clear colorl ess oil (4 0% 1 : 1 dr ). R f ( CH 2 Cl 2 /hexane 25%): 0.3 0. 1 H NMR ( 500 MHz, CDCl 3 as a mixture of diastereomers 7.09 (m, 20H), 5.73 (dtt, J = 15.8, 6.8, 1.3 Hz, 1H), 5.63 5.44 (m, 2H), 4.58 4.53 (m, 1H), 4.34 (dd, J = 5.9, 1.2 Hz, 1H), 4.24 4.20 (m, 1H), 4.14 (dtt, J = 11.4, 5.0, 1.4 Hz, 1H), 4.00 (dt, J = 7.6, 4.9 Hz, 1H), 3.59 (tt, J = 8.8, 3.3 Hz, 1H), 3.52 (ddd, J = 11.1, 7.4, 5.0 Hz, 1H), 3.47 3.40 (m, 1H), 2.85 2.59 (m, 8H), 2.45 2.29 (m, 4H), 2.14 1.5 8 (m, 4H) 13 C NMR (126 MHz, CDCl 3 as a mixture of diastereomers 128.7, 128.6, 128.6, 128.6, 128.6, 128.5, 128.5, 128.4, 126.3, 126.2, 126.2, 126.1, 125.5, 101.0 99.2

PAGE 134

134 97.5, 97.1, 96.9, 95.6, 79.8, 71.9, 71.7, 71.0, 70.7, 53.6 38.1, 37.9, 36.6, 36.6, 35.7, 35.5, 34.7, 33.0, 32.4, 32.3, 31.7, 31.5, 31.5, 31.4, 30.7 (2R, 4R, 6R) 2 Isopropyl 4 phenethyl 6 ((E) styryl) 1,3 dioxane (2 160): Follo wing general procedure B the reaction of E 2 158 afforded acetal as a clear colorless oil (84%, 1 : 1 dr). R f (CH 2 Cl 2 /hexane 25%): 0.30. 1 H NMR (500 MHz, CDCl 3 7.15 (m, 28H), 6.60 (dt, J = 16.0, 1.6 Hz, 2H), 6.26 6.15 (m, 2H), 4.63 (d, J = 5.5 Hz, 1H), 4.58 4.55 (m, 0H), 4.53 4.43 (m, 1H), 4.30 (d, J = 5.6 Hz, 1H), 4.29 4.20 (m, 1H), 4.14 (dt, J = 11.2, 5.8 Hz, 1H), 3.60 (td d, J = 11.1, 4.1, 2.4 Hz, 1H), 2.88 2.63 (m, 5H), 2.44 (ddt, J = 19.0, 9.8, 5.1 Hz, 1H), 2.12 1.69 (m, 10H), 1.07 0.96 (m, 16H). 13 C NMR (126 MHz, CDCl 3 both diastereomers 130.5, 130.3, 129.9, 129.7, 128.7, 128.7, 128.7, 128.6 12 8.5, 127. 8, 127.8, 127.2, 126.7, 126.5, 126.1, 125.9, 105.5, 104.9, 76.7, 74.9, 72.6, 71.0, 34.6, 33.2, 33.1, 32.6, 32.5, 32.1, 17.8, 17.7, 17.4, 17.3, 17.2, 17.2, 16.9 2 Isopropyl 4 phenethyl 6 ((E) 4 phenylbut 1 en 1 yl) 1,3 dioxane (2 161 ): Following general p rocedure B, the reaction of E 2 15 9 afforded acetal as a cl ear colorless oil (70% ). R f (CH 2 Cl 2 /hexane 25%): 0.30. 1 H NMR ( 500 MHz, CDCl 3 as a mixture of diastereomers 7.09 (m, 20H), 5.73 (dtt, J = 15.8, 6.8, 1.3 Hz, 1H), 5.63 5.44 (m, 2H), 4.58 4.53 (m, 1H), 4.34 (dd, J = 5.9, 1.2 Hz, 1H), 4.24 4.20 (m, 1H), 4.14 (dtt, J = 11.4, 5.0, 1.4 Hz, 1H), 4.00 (dt, J = 7.6, 4.9 Hz, 1H), 3.59 (tt, J = 8.8,

PAGE 135

135 3.3 Hz, 1H), 3.52 (ddd, J = 11.1, 7.4, 5.0 H z, 1H), 3.47 3.40 (m, 1H), 2.85 2.59 (m, 8H), 2.45 2.29 (m, 4H), 2.14 1.58 (m, 6 H), 1.01 0.94 (m, 12H). 13 C NMR (126 MHz, CDCl 3 as a mixture of diastereomers 1 31.1, 130.5, 130.4, 128.7, 128.7, 128.6, 128.6, 128.6, 128.6, 128.5, 128.5, 128.4, 126.3, 126.2, 126.2, 126.1, 125.5, 101.0, 99.2, 97.5, 97.1, 96.9, 95.6, 79.8, 71.9, 71.7, 71.0, 70.7, 53.6, 38.1, 37.9, 36.6, 36.6, 35.7 3 5.5, 34.7, 33.0, 32.4, 32.3, 31.7, 31.5, 31.5, 31.4, 30.7 4.5 Ketals General Procedure : Bismuth (III) triflate (0.02 mmol, 13.2 mg) was combined with molecular sieves (4 ) in a test tube under argon in a glove box. The reaction vessel was taken out of the glove box, and the mixture of solids was dissolved in (CH 3 ) 2 CO (1 mL) at room tempera ture before the addition of E 1,5 monoallylic diol (0.20 mmol). Progress was monitored by TLC for the disappearance of diol and reaction was quenched by filtering crude mixture over a plug of silica which was then concentrated by rotary evaporation and pu rified by flash column chromatography. (4R, 6R) 2,2 Dimethyl 4 phenethyl 6 ((E) 4 phenylbut 1 en 1 yl) 1,3 dioxane (2 163): Following general procedure the reaction of E 2 159 afforded acetal as a clear colorless oil (76%, 1 : 2 dr). R f (CH 2 Cl 2 /hexane 50%): 0.22. Proton and carbon NMR spectra were found to match reported data. 1 H NMR (300 MHz, CDCl 3 7.02 (m, 5H), 5.65 (dt, J = 15.5, 6.7 Hz, 1H), 5.50 5.33 (m, 1H), 4.20 (ddd, J = 14.7, 6.2, 2.9 Hz, 1H), 3.89 3.65 (m, 2H), 2.74 2.49 (m, 4 H), 2.27 (q, J = 7.0 Hz, 1H), 1.84

PAGE 136

136 1.51 (m, 4H), 1.40 1.28 (m, 6H). 13 C NMR (75 MHz, CDCl 3 131.7, 131.4, 131.1, 128.7, 128.6, 125.9, 98.8, 70.4, 68.0, 67.7, 65.8, 38.3, 38.1 3 7.7, 37.4, 35.6, 34.3, 34.3, 31.8, 31.2, 30.5, 30.1, 20.1 (E) 2,2 Dimethyl 4 (4 phenylbut 1 en 1 yl) 1,3 dioxane (2 165): Following general procedure, the reaction of E 2 102 afforded acetal as a clear colorless oil (85%). R f (EtOAc/hexane 10%): 0.21 1 H NMR (300 MHz, CDCl 3 7.09 (m, 5H), 5.72 (dt, J = 13.1, 6.4 Hz, 1H), 5.56 (m, 1H), 4.34 (m, 1H), 3.91 3.56 (m, 3H), 2.79 2.55 (m, 2H), 2.37 (h, J = 8.6, 6.7 Hz, 2H), 1.32 1.21 (s, 6H). 13 C NMR (75 MHz, CDCl 3 73. 9, 54.0, 36.6, 34.0, 32.2, 29.4 2,2 Dimethyl 4 phenethyl 6 vinyl 1,3 dioxane (2 166): Following general procedure, the reaction of E 2 137 afforded acetal as a clear colorless oil (85%). R f (EtOAc/hexane 10%): 0.21. Proton NMR spectrum was found to match re ported data 105 1 H NMR (500 MHz, CDCl 3 7.13 (m, 5H), 5.88 5.76 (m, 1H), 5.28 5.18 (m, 1H), 5.12 (dd, J = 10.6, 1.6 Hz, 1H), 4.38 4.25 (m, 1H), 3.82 (ttd, J = 10.0, 7.8, 6.2, 3.7 Hz, 1H), 2.90 2.55 (m, 3H), 1.91 1.62 (m, 3H), 1.43 (s, 6H). 13 C NMR (75 MHz, CDCl 3 31.2, 30.4, 20.0

PAGE 137

137 4.6 De protection of A cetal 2 1 52 (3R, 5R, E) 1,9 diphenylnon 6 ene 3,5 diol (2 181): To a stirred solution of concentrated HCl (3 mmol, 0.092 mL) in MeOH (5 mL) was added 2 152 (0.05 mmol, 17.5 mg) and was allowed to stir 5.5 hour s before quenching with pyridine (3 mmol, 0.24 mL) .The mixture was filtered over celite to remove pyridine hydrochloride salt, and concentrated to yield crude oil which was purified by flash column chromatography to yield a clear colorless oil (47%, and 47% leftover starting material). R f (EtOAc/hexane 50%): 0 .50. 1 H NMR (299 MHz, CDCl 3 7.11 (m, 10H), 5.77 5.63 (m, 1H), 5.53 (ddt, J = 15.4, 6.4, 1.3 Hz, 1H), 4.47 4.34 (m, 1H), 3.88 (dt, J = 7.7, 3.7 Hz, 1H), 2.87 2.55 (m, 4H), 2.50 2.05 (m, 4H), 1.96 1.51 (m, 2H). 13 C NMR (75 MHz, CDCl 3 42.2 131.8, 131.7 131. 4 13 1.1, 128.7, 128.6, 125.9, 70.4, 67.7 38.3, 35.6, 34.3, 31.2, 30.1 4.7 3,6 Dihydro 2H pyran S yntheses General Procedure: V (0.005 mmol, 4.4 mg), AgSbF 6 (0.005 mmol, 1.7 mg) and pTSA (0.03 mmol, 5.7 mg) were combined with molecular sieves (4 ) in a test tube under argon in a glove box. The reaction vessel was wrapped in aluminum foil before being taken out of the glove box, and the mixture of solids was dissolved in CH 2 Cl 2 (0. 5 mL) at room temperature a nd allowed one minute to five minutes to stir in order to form the gold (I) cationic complex before the addition of (CH 3 ) 2 CO (0.5 mmol, 0.036 mL). Z 1,5 monoallylic diol (0.1 0 mmol) was then added. Progress was monitored by TLC for the disappearance of di ol and reaction was quenched by filtering crude mixture over a

PAGE 138

138 plug of silica which was then concentrated by rotary evaporation and purified by flash column chromatography. 6 Phenylethyl 3,6 dihydro 2H pyran (3 38): Following the general procedure, the re action of 3 36 afforded dihydro pyran as a clear colorless oil (62 %). R f (EtOAc/hexane 5%): 0.23. Proton and carbon NMR spectra were found to match reported data. 106 1 H NMR (300 MHz, CDCl 3 7.08 (m, 5H), 5.93 5.81 (m, 1H), 5.64 (ddt, J = 10.3, 2.4, 1.6 Hz, 1H), 4.11 (tdq, J = 6.9, 3.3, 1.8, 1.2 Hz, 1H), 4.01 (dddd, J = 11.2, 5.7, 2.6, 0.9 Hz, 1H), 3.74 3.61 (m, 1H), 2.75 (qdd, J = 13.8, 9.0, 6.7 Hz, 2H), 2.41 2.22 (m, 2H), 1. 88 1.77 (m, 2H). 13 C NMR (75 MHz, CDCl 3 130.5, 128.7, 128.5, 125.9, 125.1, 73.3, 63.6, 37.2, 31.7, 25.6. (2R, 6R) 2,6 Diphenylethyl 3,6 dihydro 2H pyran (3 40): Following the general procedure, the reaction of 3 39 afforded dihydro pyran as a c lear colorless oil ( 63 % 6 : 1 dr ). R f (EtOAc/hexane 5% ): 0.23. Proton NMR spectrum was found to match reported data. 107 1 H NMR (500 MHz, CDCl 3 7.13 (m, 10H), 5.85 5.76 (m, 1H), 5.69 (dddd, J = 10.3, 2.9, 2.4, 1.5 Hz, 1H), 4.25 4.16 (m, 1H), 3.73 (tt, J = 8.5, 4.0 Hz, 1H), 2.97 2.81 (m, 3H), 2.81 2.60 (m, 3H), 2.04 1.88 (m, 2H), 1.84 1.67 (m, 3H).

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145 B IOGRAPHICAL SKETCH Carl Ballesteros was bor n in Columbus Air Force Base to the proud parents of Tomas J. and Ileana Ballesteros. As the middle child of three and son to an Air Force Lieutenant Colonel, Carl grew up all over the world having lived as near as Panama City, Florida and as far away as Madrid, Spain. Tomas finally r etired from the Air Force in 1995, and settled down in Clermont, Florida. Carl attended South Lake High School, and graduated the s pring of 2001. Thereafter, he attended the University of Florida where he conducted undergraduate research in physical chemis try under the direction of Martin Vala, Ph.D., professor emeritus and studied interstellar radiation sources. He undergraduate research in organic synthetic chemistry und er the direction of Merle A. Battiste, Ph. D., professor e meritus. Carl graduated with a Bachelor of Sciences degree in the s pring of 2005 having majored in chemistry He went on to attend the graduate program at the University of Florida, departmen t of chemistry in 2007 and received his Doctor of Philosophy degree in the spring of 2013.