Hydride-Mediated Intramolecular Reductive Head-To-Tail Michael Reaction of Enones with Activated Alkene Tethers Moonki Seok

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2006 Tin(IV) Hydride-Mediated Intramolecular Reductive Head-to-Tail Michael Reaction of Enones with Activated Alkene Tethers Moonki Seok

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THE FLORIDA STATE UNIVERSITY

COLLEGE OF ARTS AND SCIENCES

TIN(IV) HYDRIDE-MEDIATED INTRAMOLECULAR REDUCTIVE HEAD-TO-TAIL MICHAEL REACTION OF ENONES WITH ACTIVATED ALKENE TETHERS

MOONKI SEOK

A Thesis submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Master of Science

Degree Awarded: Spring Semester, 2006

The members of the Committee approve the Thesis of Moonki Seok defended on April 5, 2006.

______Marie E. Krafft Professor Directing Thesis

______Gregory B. Dudley Committee Member

______Robert A. Holton Committee Member

______Albert E. Stiegman Committee Member

The Office of Graduate Studies has verified and approved the above named committee members.

To my parents,

wife Hyunjung and daughter Minkyung (Jean)

with love and gratitude

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ACKNOWLEDGMENTS

I would like to express appreciation to my major professor, Dr. Marie E. Kraft, for her guidance and support. I also would like to thank the members of my committee, Dr. Dudley, Dr. Holton, Dr. Stiegman and Dr. Zakarian, for their comments. I need to thank all past and present members of the Krafft group, especially Dr. Yonghao Jin, Dr. Amin Wang and James Wright for their help and advice. Finally, I would like to thank all my Korean friends.

TABLE OF CONTENTS

List of Tables ...... vii List of Figures ...... viii Standard List of Abbreviations ...... xii Abstract ...... xix

1. INTRODUCTION ...... 1

1. Enones as Latent Enolates ...... 1 2. Catalytic Hydrometallation Method ...... 2 2.1 Catalytic enolization via conjugate reduction of enones...... 2 2.2 Catalytic reductive coupling of enones ...... 4 Aldol processes...... 4 Michael processes...... 7 3. Reductive Couplings of Enones via Tin Enolates (Hydride Reduction Methods) ... 10 3.1 1,4-hydrostannation of conjugated enones by a radical process ...... 11 3.2 Ionic 1,4-hydrostannation...... 14 Summary ...... 16

2. RESULTS AND DISCUSSION ...... 17

1. Enone to Enone Reductive Coupling Reaction...... 18 2. Enone to Enoate Reductive Coupling Reaction...... 21 3. Enone to Enenitrile Reductive Coupling Reaction...... 33 Summary ...... 34

3. EXPERIMENTAL...... 36

General Considerations...... 36 Synthesis of Substrates ...... 37 Cyclization of Substrates ...... 47

APPENDIX ...... 53

REFERENCES ...... 115

BIOGRAPHICAL SKETCH ...... 119

LIST OF TABLES

Table 1: Reductive Aldol Coupling Catalyzed by Phosphine Modified Rh4(CO)12...... 5

Table 2: Radical Cyclization at the β-Carbons of Activated Alkenes...... 12

Table 3: Optimization of Michael Cyclizations of Bisenones under Radical Conditions..... 20

Table 4: Activation of Tin enolates by the Addition of Additives ...... 23

Table 5: Michael Cyclization of α,β-Unsaturated Esters Catalyzed by Bu4NBr...... 26

Table 6: NOE Observations for Cyclization Products...... 27

Table 7: Michael Cyclization of α,β-Unsaturated Ester 57 Using V-70 as a Radical Initiator 31

Table 8: Michael Cyclization of Additional Alkyl Enones ...... 32

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LIST OF FIGURES

Figure 1: 500 MHz 1H NMR Spectrum of Enone 58 ...... 54

Figure 2: 75 MHz 13C Spectrum of Enone 58 ...... 55

Figure 3: IR Spectrum of Enone 58 ...... 56

Figure 4: 500 MHz 1H NMR Spectrum of Enone 69 ...... 57

Figure 5: 75 MHz 13C Spectrum of Enone 69 ...... 58

Figure 6: IR Spectrum of Enone 69 ...... 59

Figure 7: 500 MHz 1H NMR Spectrum of Enone 71 ...... 60

Figure 8: 75 MHz 13C Spectrum of Enone 71 ...... 61

Figure 9: IR Spectrum of Enone 71 ...... 62

Figure 10: 500 MHz 1H NMR Spectrum of Alcohol 87 ...... 63

Figure 11: 75 MHz 13C Spectrum of Alcohol 87 ...... 64

Figure 12: IR Spectrum of Alcohol 87 ...... 65

Figure 13: 500 MHz 1H NMR Spectrum of Enone 73 ...... 66

Figure 14: IR Spectrum of Enone 73 ...... 67

Figure 15: 500 MHz 1H NMR Spectrum of Enone 76 ...... 68

Figure 16: IR Spectrum of Enone 76 ...... 69

Figure 17: 500 MHz 1H NMR Spectrum of Enone 77 ...... 70

Figure 18: IR Spectrum of Enone 77 ...... 71

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Figure 19: 500 MHz 1H NMR Spectrum of syn-49 ...... 72

Figure 20: 75 MHz 13C Spectrum of syn-49 ...... 73

Figure 21: IR Spectrum of syn-49 ...... 74

Figure 22: 500 MHz 1H NMR Spectrum of anti-49 ...... 75

Figure 23: 75 MHz 13C Spectrum of anti-49 ...... 76

Figure 24: IR Spectrum of anti-49 ...... 77

Figure 25: 500 MHz 1H NMR Spectrum of syn-51 ...... 78

Figure 26: 75 MHz 13C Spectrum of syn-51 ...... 79

Figure 37: IR Spectrum of syn-51 ...... 80

Figure 28: 500 MHz 1H NMR Spectrum of anti-51 ...... 81

Figure 29: 75 MHz 13C Spectrum of anti-51 ...... 82

Figure 30: IR Spectrum of anti-51 ...... 83

Figure 31: 500 MHz 1H NMR Spectrum of syn-59 ...... 84

Figure 32: 75 MHz 13C Spectrum of syn-59 ...... 85

Figure 33: IR Spectrum of syn-59 ...... 86

Figure 34: 500 MHz 1H NMR Spectrum of anti-59 ...... 87

Figure 35: 75 MHz 13C Spectrum of anti-59 ...... 88

Figure 36: IR Spectrum of anti-59 ...... 89

Figure 37: 500 MHz 1H NMR Spectrum of 61 ...... 90

Figure 38: 75 MHz 13C Spectrum of 61 ...... 91

Figure 39: IR Spectrum of 61 ...... 92

Figure 40: 500 MHz 1H NMR Spectrum of syn-62 ...... 93

Figure 41: 75 MHz 13C Spectrum of syn-62 ...... 94

Figure 42: IR Spectrum of syn-62 ...... 95

Figure 43: 500 MHz 1H NMR Spectrum of anti-62 ...... 96

Figure 44: 75 MHz 13C Spectrum of anti-62 ...... 97

Figure 45: IR Spectrum of anti-62 ...... 98

Figure 46: 500 MHz 1H NMR Spectrum of syn-70 ...... 99

Figure 47: 75 MHz 13C Spectrum of syn-70 ...... 100

Figure 48: IR Spectrum of syn-70 ...... 101

Figure 49: 500 MHz 1H NMR Spectrum of anti-70 ...... 102

Figure 50: 75 MHz 13C Spectrum of anti-70 ...... 103

Figure 51: IR Spectrum of anti-70 ...... 104

Figure 52: 300 MHz 1H NMR Spectrum of syn-78 ...... 105

Figure 53: 500 MHz 1H NMR Spectrum of anti-78 ...... 106

Figure 54: 75 MHz 13C Spectrum of anti-78 ...... 107

Figure 55: IR Spectrum of anti-78 ...... 108

Figure 56: 500 MHz 1H NMR Spectrum of syn-79 ...... 109

Figure 57: 75 MHz 13C Spectrum of syn-79 ...... 110

Figure 58: IR Spectrum of syn-79 ...... 111

Figure 59: 500 MHz 1H NMR Spectrum of anti-79 ...... 112

Figure 60: 75 MHz 13C Spectrum of anti-79 ...... 113

Figure 61: IR Spectrum of anti-79 ...... 114

STANDARD LIST OF ABBREVIATIONS

Å angstrom

Ac acetyl

acac acetylacetonate

AIBN 2,2’-azobisisobutyronitrile

anhyd anhydrous

Ar aryl

atm atmosphere(s)

9-BBN 9-borabicyclo[3.3.1]nonyl

BINAP 2,2'-bis(diphenylphosphino)-1'1-binaphthyl

Bn benzyl

BOC tert-butoxycarbonyl

bp boiling point

bpy 2,2’-bipyridine

br broad (spectral)

Bu butyl

i-Bu iso-butyl s-Bu sec-butyl t-Bu tert-butyl

°C degrees Celsius

xii

calcd calculated

Cbz benzyloxycarbonyl

CI chemical ionization (in mass spectrometry) cm centimeter(s) cod 1,5-cyclooctadienyl concd concentrated

COSY correlation spectroscopy

COT cyclooctatetraene

Cp cyclopentadienyl

Cy-hexyl cyclohexyl

δ chemical shift in parts per million downfield from tetramethylsilane d day(s); doublet (spectral)

DABCO 1,4-diazabicyclo[2.2.2]octane

DBN 1,5-diazabicyclo[4.3.0]non-5-ene

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC N,N-dicyclohexylcarbodiimide

DCE 1,2-dichloroethane

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-1,4,benzoquinone

DEAD diethyl azodicarboxylate

DIBAL diisobutylaluminum hydride

xiii

DMAP 4-(dimethylamino)pyridine

DME 1,2-dimethoxyethane

DMF dimethylformamide

DMPU dimethylpropylene urea

DMSO dimethyl sulfoxide dpm dipivaloylmethane

Me-DuPhos 1,2-bis(2,5-dimethylphospholano)benzene

E1 unimolecular elimination

E2 bimolecular elimination ee enantiomeric excess

EI electron impact (in mass spectrometry)

Et ethyl

FAB fast-atom bombardment (in mass spectrometry)

FT Fourier transform g gram(s)

GC gas chromatography h hours(s)

HMO Hückel molecular orbital

HMPA hexamethylphosphoric triamide

HOMO highest occupied molecular orbital

HPLC high-performance liquid chromatography

xiv

HRMS high-resolution mass spectrometry

Hz hertz

IP ionization potential

IR infrared

J coupling constant (in NMR) k kilo

KOH potassium hydroxide

L liter(s)

LAH lithium aluminum hydride

LDA lithium diisopropylamide

LHMDS lithium hexamethyldisilazide

LTMP lithium 2,2,6,6-tetramethylpiperidide

LUMO lowest occupied molecular orbital

μ micro m multiplet (spectral), meter(s), milli

M moles per liter m-CPBA m-chloroperoxybenzoic acid m/e mass to charge ratio (in mass spectrometry)

Me methyl

MEM (2-methoxyethoxy)methyl

Mes mesityl, 2,4,6-trimethylphenyl

MHz megahertz

min minute(s)

mM millimoles per liter

MO molecular orbital

mol mole(s)

MOM methoxymethyl

mp melting point

Ms methanesulfonyl (mesyl)

MS mass spectrometry

m/z mass to charge ratio (in mass spectrometry)

NBS N-bromosuccinimide

NMO N-methylmorpholine-N-oxide

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect

Nu nucleophile

PCC pyridinium chlorochromate

PDC pyridinium dichromate

Ph phenyl

PMB p-methoxybenzyl

PPA polyphosphoric acid ppm parts per million (in NMR)

xvi

PPTS pyridinium p-toluenesulfonate

Pr propyl

i-Pr isopropyl

psi pounds per square inch

q quartet (spectral)

re rectus (stereochemistry)

Rf retention factor (in chromatography) rt room temperature s singlet (spectral); second(s) si sinister (stereochemistry)

SN1 unimolecular nucleophilic substitution

SN2 bimolecular nucleophilic substitution

SN’ nucleophilic substitution with allylic rearrangement t triplet (spectral)

TBAB tetrabutylammonium bromide

TBDMS tert-butyldimethylsilyl

Tf trifluoromethanesulfonyl (triflyl)

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

THP tetrahydropyran

xvii

TIPS triisopropylsilyl

TLC thin layer chromatography

TMS trimethysilyl, tetramethylsilane

Tr triphenylmethyl (trityl)

Ts tosyl, p-toluenesulfonyl

TS transition state tR retention time (in chromatography)

UV ultraviolet

xviii

ABSTRACT

Intramolecular reductive coupling of enones bearing an unsaturated ketone, ester or nitrile was carried out under radical conditions. Upon exposure of these enone derivatives to tri-n- butyltin hydride in presence of AIBN, tin enolates were generated via 1,4-hydrostannation and then added to the internal activated alkenes in a Michael fashion to produce 1,2-disubstituted cyclopentane products. The reaction of bisenones smoothly produced the desired products in

good to excellent yields under optimized conditions using 1.3 equivalents of n-Bu3SnH in benzene solution. On the other hand, the coupling of enones to α,β-unsaturated esters or nitriles, which is a thermodynamically disfavorable process, was accomplished by addition of a catalytic amount of tetrabutylammonium bromide after 1,4-hydrostannation. Coordination of the bromide ion to the tin enolate enhanced its nucleophilicity and promoted the reaction. This work represents the first examples of intramolecular reductive head-to-tail coupling of enones bearing α,β-unsaturated esters or nitriles as a Michael acceptor.

xix

CHAPTER I

INTRODUCTION

1. Enones as Latent Enolates

Enolates are useful reagents for the formation of α-substituted carbonyl compounds and are important intermediates employed in many classical carbon-carbon bond-forming reactions including the aldol and Michael reactions.1 Thus, enolate chemistry plays a fundamental role in the construction of carbon frameworks for the synthesis of complex organic molecules. Numerous papers concerning the generation and utilization of enolate nucleophiles have been published.2 The selectivity issues posed by the generation of enolates, however, have been only partially resolved. Since Stork demonstrated regioselective alkylation of an enone via enolate-generation

R R R Li/NH3 Li - O O O

R R CH3I

LiO O H H

Scheme 1 by reduction under dissolving metal conditions in 1961 (Scheme 1),3 the utilization of

1 enones as latent enolates has emerged as a promising strategy for regioselective enolate formation.4 1,4-Hydrometallation methods via metal-catalyzed and metal hydride-mediated conjugate reduction of enones have been developed for this purpose. Other than the dissolving metal reduction method, the use of various transition metal reagents for regioselective enolate generation have been explored and catalytic 1,4-hydrometallation methods have been extensively studied. However, chemoselective enolate generation from enones in the presence of electrophilic partners has been another methodological challenge. Many catalytic systems for reductive coupling reactions of enones including aldol and Michael process have been devised and evolved to diastereo- and enantioselective variants.

2. Catalytic Hydrometallation Method

2.1 Catalytic enolization via conjugate reduction of enones

Various catalytic systems for generation of enolate derivatives from the conjugate reduction of enones have been reported. Among them, rhodium catalysts have been most widely used for both 1,4-reduction and reductive aldol reactions.5 In 1972 Ojima and co-workers reported that tris(tripheny1phosphine)chloro-rhodium,

(PPh3)3RhCl, catalyzed the hydrosilylation of α,β-unsaturated ketones and aldehydes with monohydrosilanes to give 1,4 adducts while reaction with dihydrosilanes gave 1,2 adducts with high selectivity.5a Chan’s group also achieved higher regioselective 1,4-reduction using hydridotetrakis(triphenylphosphine)rhodium(I) with silane reagents as hydride donors (eq 1).5b

2 O OM (PPh3)4RhH (0.1~0.5 mol %) R1 R2 R1 R2 M-H (1.1 eq), r.t., 0.5~24h (1) 1 2 M-H = PhMe2SiH 73~96% (CH2Cl)Me2SiH (C2H5O)3SiH

A proposed mechanism is described in Scheme 2. Insertion of the Rh(I) catalyst into the silane Si-H bond gives the hydrido-rhodium species 3. Then, hydrometallation of enone 1 provides intermediate 4. Reductive elimination of 4 gives the silyl enol ether, and regenerates the Rh(I) catalyst.

1 R OSiMe2Ph Rh(I)H PhMe2SiH R2

H H (III)RhH (III)Rh SiMe2Ph R1 O SiMe2Ph 3 R2 4 R1 O

Scheme 2

Next to rhodium, copper has been most often used for generation of silyl enol ethers from enones.6 Copper catalysts are mainly employed for 1,4-reduction to afford the saturated ketone or reductive alkylation product, both of which are one-pot, two-step procedures. Stryker and co-workers demonstrated conjugate reduction of α,β-unsaturated 6a ketones using [(Ph3P)CuH]6 under hydrogen pressure. Stryker’s reagent was most

3 effective when a stoichiometric amount was used or catalytic amount with hydrogen pressures around 1000 psi. Later, Lipshutz and his group developed a catalytic system 6b using the Stryker reagent with Bu3SnH or PhSiH3 as a hydride source (eq 2).

O O OSiH2Ph [(Ph3P)CuH]6 (5 mol %) H+ (2) PhSiH3 (1.5 eq), toluene, r.t. 7min 567 quantitative yield by GC

Other than rhodium and copper, platinum7 and nickel catalysts8 have also been applied to catalytic enolate generation from α,β-unsaturated carbonyl compounds.

2.2 Catalytic reductive coupling of enones

Catalytic reductive coupling reactions of enones via regioselective reduction have been demonstrated.9 Most significantly, catalytic systems for chemoselective enone conjugate reduction-electrophilic trapping in the presence of an electrophile in the same pot have been developed.10

Aldol processes

As a representative metal, rhodium is most frequently employed for reductive aldol reactions of α,β-unsaturated carbonyl compounds. The Rh-catalyzed intermolecular reductive aldol reaction was first reported in 1987. Revis et al. used RhCl3 and Me3SiH with α,β-unsaturated esters to afford the corresponding aldol products, β-siloxy esters, in good yield.10a Three years later, Matsuda and coworkers reported the successful reductive

4 aldol reaction of enones with aldehydes utilizing phosphine-modified Rh4(CO)12 and 10b Et2MeSiH (Table 1).

Table 1. Reductive Aldol Coupling Catalyzed by Phosphine Modified Rh4(CO)12.

O OSiEt Me O O 2 Rh4(CO)12 (0.5 mol %) + 1 3 1 2 3 R R R R H R MePh2P (1 mol %) Et2MeSiH R2 10 8 9

conditions product 10 entry enone aldehyde solvent °C/h yield(%) syn:anti

1 O PhCHO toluene -5/2 99 83:17

2 Hexanal hexane 15/2 80 68:32

3 CHO benzene 20/3 63 58:42

4 O PhCHO hexane 0/20 100 84:16

O 5 PhCHO benzene 20/3.5 88 55:45 Ph 6 O PhCHO benzene 20/7 86 80:20

O 7 PhCHO benzene 20/15 69 -

They proposed enolate complex 11 as a key reactive intermediate (Scheme 3). The existence of O-bound rhodium enolate complexes such as 11 have been suggested by Heathcock.11 He isolated analogous complexes from the reactions of carbonylbis(phosphine)-rhodium(I) halides and potassium enolates.

SiR O 3

R1 R2 12

[Rh]

Rh SiR O OSiR3 O O 3 R SiH R CHO 3 3 R1 R3 R1 R2 1 2 [Rh] R R R2 10 8 11

Scheme 3

Recently, rhodium-catalyzed enantioselective, and diastereoselective reductive aldol reactions have been demonstrated by Morken’s group. The [(cod)RhCl]2-DuPhos-

Cl2MeSiH catalyst system afforded aldol products in moderate yields but excellent 10c diastereoselectivity (eq 3). A catalyst derived from [(cod)RhCl]2 and chiral BINAP showed good to excellent levels of enantioselectivity (eq 4).10d

1) 2.5 mol % [(cod)RhCl] 2 OH O O O 5.5 mol % Me-DuPhos Cl MeSiH + 2 Ph OMe (3) Ph H OMe + 2) H3O Me 69% syn:anti = 23:1

1) 2.5 mol % [(cod)RhCl] 2 OH O O O 6.5 mol % R-BINAP Et MeSiH + 2 Ph OPh (4) Ph H OPh + 2) H3O Me 2R,3R

72% syn:anti = 3.4:1 e.e. 87% (syn)

6 The intramolecular reductive aldol reaction of enones under Rh(I) catalysts has also been reported by Krische.12 He achieved reductive cyclization in high diastereoselectivity under catalytic hydrogenative conditions (eq 5).

O O Rh(COD)2OTf (10 mol%) O (p-CF Ph) P (24 mol%) OH R 3 3 R H2 (1 atm), KOAc (30 mol%) n DCE (0.1 M), 25 °C n (5)

yield (syn:anti) n=2 R = Ph 89% (10:1) n=2 R = 2-naphthyl 90% (10:1) n=1 R = Ph 71% (24:1) n=2 R = CH3 65% (1:5)

In addition to Rh, examples using other transition metal catalysts such as Pd(0),10e Co(II)10f and Cu(I)10g for catalytic reductive aldol reactions have been reported. Recently, a highly diastereoselective In(III)10h and enantioselective Ir(I)-pybox catalyst system10i have also been described.

Michael processes

Compared with numerous reported reductive aldol reactions of α,β-unsaturated carbonyls, few examples of reductive Michael reaction of activated alkenes, especially head to tail coupling, exist. Catalytic hydrodimerizations of α,β-unsaturated carbonyl compounds exclusively afford products of β,β-coupling (eq 6).13 Only two metal-catalyzed methods concerning reductive Michael head-to-tail coupling reaction have been reported.14,15

7 O O CoX(PPh3)3 or CoX(bpy)2 R 2 R R (6) MX, Zn, MeOH/THF, r.t. O X = halide R = OMe, Me M = alkali metal

Krische et al. have disclosed catalytic aldol and Michael cycloreduction of enones employed Co(II) catalysts.14 Upon exposure of enones bearing aldehyde or α,β-unsaturated ketone tethers to Co(dpm)2-silane catalyst system, the corresponding aldol and Michael cycloadducts were obtained with high levels of syn- and anti-diastereoselectivity respectively (eq 7, eq 8). Moreover, Michael cycloreduction of unsymmetrical bis(enone) 16 showed chemoselectivity of the catalyst to distinguish electronic differences between enones.

O O O OH Co(dpm)2 (5 mol%) R H R (7) PhSiH3(1.2 eq.), DCE 25 °C, 30 min n n (dpm = dipivaloylmethane)

11, n=0 R = Ph 70% 12, n=1 R = Ph 87% 13, n=1 R = Me 38%

O O

O R O R 2 Co(dpm)2 (5 mol%) 2

R1 PhSiH3(2.4 eq.), DCE R1 (8) 50~70 °C, 30 min n n

substrate product

14, n=0 R1 = Ph, R2 = Ph14a 62% 15, n=1 R1 = Ph, R2 = Ph15a 73% 16, n=1 R1 = Ph, R2 = Me16a, R1=Ph, R2=Me 62% (16a/16b=3:1) 16b, R1=Me, R2=Ph

The proposed mechanism for the catalytic Michael cycloreduction is illustrated in

Scheme 4. Exposure of Co(dpm)2 to phenylsilane generates hydrido-cobalt species 17 which, upon hydrometallation of the enone, yields cobalt enolate 18. Subsequent addition to the pendant unsaturated ketone results in the formation of cobalt enolate 19. σ-Bond metathesis liberates the product to regenerate the hydrido-cobalt species 17 and complete the catalytic cycle.

O Co(dmp)2 O

O R2 SiPhH3 O R2 R1 R1 "LnCo-H" n 17 n

H-SiR3 O Ln Ln O O Co R2 Co O R2 R1

R1 n 18 n 19

Scheme 4

Very recently, a second intramolecular reductive Michael reaction has been 15 demonstrated by Hosomi and co-workers. The In(OAc)3-PhSiH3 catalytic system effected both reductive aldol and Michael cyclizations, providing five- and six-membered cyclic aldol and Michael products with similarly high levels of stereoselectivity to Krische’s work (eq 9, eq 10).

9 O O O OH In(OAc)3 (10 mol%) Ph Ph + PhSiH3 (9) THF (0.1M), EtOH (1 eq.) n reflux n

20, n=1 45 h 20a, 90% (syn:anti = >99:1) 21, n=0 4.5 h 21a, 85% (syn:anti = 62:38

COPh COPh O O In(OAc)3 (10 mol%) Ph Ph + PhSiH3 (10) THF (0.1M), EtOH (1 eq.) n reflux n

22, n=1 4.5 h anti-22a, 75% 23, n=0 3.5 h anti-23a, 89%

3. Reductive Couplings of Enones via Tin Enolates (Hydride Reduction Methods)

Compared with catalytic methods for reductive coupling reaction of enones, there have only been a few examples reported using the hydride reduction method. This is because of the lower reactivity of enones toward hydride reagents than that of other electrophilic partners, ketones, enals or aldehydes.16 The catalytic hydrometallation method is obviously reliable and efficient. However, it is largely dependent on the reaction conditions, requiring the proper ligand and hydride donor. In a view of chemoselectivity and convenience, organotin hydrides have potential advantages for 1,4-reduction and reductive coupling reactions.17 Moreover, methods to enhance reactivity of tin enolates are continuing to be developed.18

10 3.1 1,4-hydrostannation of conjugated enones by a radical process

The 1,4-addition of Bu3SnH to an enone via a radical chain process was first reported 19 by Pereyre and Valade in 1965. An α,β-unsaturated carbonyl group reacts with Bu3SnH under radical conditions to produce a resonance stabilized allylic O-stannylketyl intermediate (25↔26). Hydrogen transfer from Bu3SnH to the β-position of the intermediate leads to the tin enolate 27 (eq 11). Although this 1,4-hydrostannation method has an advantage of mildness and regioselectivity, it had not received much attention until it was extensively studied by Enholm recently.20

O Bu3SnH H OSnBu3 radical conditions 24 27 (11)

Bu Sn 3 Bu3SnH OSnBu3 OSnBu3 -Bu3Sn

25 26

Interestingly, allylic O-stannylketyl intermediates generated via this transformation have both radical and anionic sites for reactivity, which render it useful as either a homo- enolate via a radical reaction or as an enolate after hydrogen atom abstraction. Enholm’s group first reported reactions of the allylic O-stannylketyl intermediate as a homo-enolate in 1991 (Scheme 5, Table 2).20b They performed reductive cyclizations of enones having three carbons between the activated alkenes, under standard free radical conditions. Intramolecular addition of radical I to the alkene leads to II by a 5-exo-trig ring closure. Hydrogen atom transfer from tributylstannane produces tin enolate III, and then quenching with water produces the tail-to-tail coupling product. The radical cyclization afforded diastereomeric mixtures in 2.1:1~3.5:1 ratios. The cis-disubstituted compounds underwent a second cyclization from enolate III to give bicyclic products (28b, 29b, 30b).

11 Bu3SnH AIBN, 80 °C, PhH EWG O EWG O

Bu3Sn H+

5-exo-trig Bu3SnH

-Bu3Sn EWG EWG EWG O O O Bu Sn I Bu Sn III 3 Bu3Sn II 3

Scheme 5

Table 2. Radical Cyclization at the β-Carbons of Activated Alkenes.

substrate product

H H + CO CH CO CH O 2 3 2 3 O OH O 28 28a 28b 2.1:1 85%

H H + CN CN O O O NH2 29 29a 29b 3.0:1 94%

H H + COCH COCH O 3 3 O O HO CH3 30 30a3.5:1 30b 93%

12 Later, Enholm and co-workers demonstrated an intermolecular aldol,20e alkylation20f and Michael reaction of enones21 via radical 1,4-hydrostannation followed by anionic coupling in a one-pot, two-step process. Enones were treated with Bu3SnH in presence of AIBN in benzene, followed by addition of aldehydes to give aldol products in modest to good yields (eq 12). For alkylation and Michael reactions, Enholm utilized HMPA to activate the tin enolates generated from the hydrostannation (eq 13, eq 14). However, attempted Michael reactions gave rise to only low yields of desired adducts.

SnBu O O 3 O OH Bu3SnH RCHO R AIBN n 80 °C, PhH n n (12) syn:anti n=1 R = Ph 73% (6:1) n=1 R = cyclohexyl 59% (6:1) n=0 R = Ph 79% (1:1) n=0 R = cyclohexyl 62% (3:1)

SnBu O O 3 O

Bu3SnH RCH2X R AIBN HMPA (13) 80 °C, PhH

RCH2X = allyl bromide 71% benzyl bromide 69% hexyl iodide 61%

SnBu O O 3 O O activated Bu3SnH alkene R AIBN HMPA (14) 80 °C, PhH

activated alkene = cyclohexenone 41% methyl vinyl ketone 31% isodecyl acrylate 38%

13 They also extended the aldol reaction to the intramolecular version in which an aldehyde coexists in the radical step.21 Cyclohexenones substituted with aldehydes provided decalone alcohol 32 and bicyclic alcohol 34 in 81% and 62% respectively. Despite low yields (30~50% yield) in intermolecular aldol reactions that were performed with an enone and aldehyde in the same pot, the hydrostannation of enone as an intramolecular reaction proceeded with chemoselectivity and in good yield.

O H H Bu SnH O 3 OH CHO AIBN, 80 °C, PhH H 81% 31 32

(15) O O H Bu3SnH CH3 AIBN, 80 °C, PhH H CHO 62% HO 33 34

3.2 Ionic 1,4-hydrostannation

1,4-Hydrostannation of conjugated enones via an ionic process using modified tin hydride reagents has been reported by Baba and co-workers.22,23 An equimolar mixture of 24 Bu2SnIH and Bu3SnI prepared from the reaction between Bu3SnH and Bu2SnI2 (eq 16) exhibited quite low reducing ability toward aldehydes but good reactivity for 1,4-reduction of enones. This is contrary to the reactivity of Bu3SnH, which predominantly reduces aldehydes in presence of enones. Aldol reactions were performed at –30 °C with the iodotin hydride reagent to give aldol products in good yields with high syn-selectivity (eq 17).22

14 Bu3SnH + Bu2SnI2 Bu2SnIH + Bu3SnI (16)

R1 Ph R Bu SnIH/Bu SnI Ph R 1 + R CHO 2 3 2 (17) 2 -30 °C to r.t., 3h O O OH

R1 = Ph, Me, H R2 = Ph, c-hex, i-Pr 47~74% (syn:anti = 80:20~>99:1)

Baba and co-workers23 also tried aldol and Michael cyclizations of enones using

Bu2SnIH to promote enone conjugate reduction. Both reactions were carried out at room temperature in THF, and afforded cyclized products with high stereoselectivity (eq 18, eq 19). The same results were obtained when the reaction was performed in the presence of a

H CHO CHO Bu SnIH H+ Ph 2 Ph H (18) Ph THF, r.t., 5h O O OH O Bu2ISn 35 36 37 71%

H O Bu2SnIH Ph Ph (19) THF, r.t., 5h Ph O O Ph H O 38 39 64% (>99% d.s.) radical inhibitor, thus ruling out the possibility of a radical pathway. It was suggested that chemoselectivity arises from the high nucleophilicity of the tin-iodine bond and lower nucleophilicity of the Sn-H bond, which resulted in 1,4-addition of iodide to the enone followed by exchange of the resulting enol stannane with the C-I bond (Scheme 6).

15 I O I O H O SnBu2H H SnBu2 I SnBu2

Scheme 6

Summary

Research efforts studying the use of enones as latent enolates have been conducted and resulted in the development of methods effecting chemo- and regioselective enolate generation from enones and their subsquent carbon-carbon bond-forming reactions. Catalytic hydrometallative methods using transition metals with hydride sources have been most widely studied, and various catalytic systems for reductive coupling of enones with electrophiles, mainly aldehydes and activated alkenes, have been developed. Although hydride reduction methods have rarely been explored due to the difficulty of chemoselectivity control with labile electrophilies, chemoselective 1,4-stannations employing tin hydride reagents have been developed as viable alternatives. It has been shown that reductive coupling reactions of enones can be achieved chemo- and regioselectively by treatment of tin hydride under radical conditions or utilizing modified tin hydride reagents.

CHAPTER II

RESULTS AND DISCUSSION

Modern technologies have led to the development of highly diastereo- and enantioselective reductive coupling reactions of enones via regioselective enolate generation. Significantly, chemoselective inter- and intramolecular coupling reactions, in which chemically labile electrophiles coexist, are involved. Although there have been several reports on intermolecular reductive coupling reactions of enones including aldol10 and Michael addition,21 examples of reductive Michael cyclizations are difficult to find. Moreover, most reported examples are β,β-couplings of a homo-enolate intermediates,20b or limited to the use of bisenone derivatives resulting in diketone products.14,15,23 We hoped to examine the reductive Michael cyclization of enones via regioselective enolate formation under radical conditions and develop a method effective with various activated alkenes as Michael acceptors. This thesis describes a head-to-tail reductive Michael cyclization of enones bearing activated alkene tethers using organotin hydride, providing a useful synthetic route to 1,2- disubstituted cyclopentanes.

It has been demonstrated from the pioneering work by Enholm that radical 1,4- stannation of enones is useful for the regio- and chemoselective generation of enolates under mild and neutral conditions.20 In his early work Enholm demonstrated β,β-coupling of enones by a radical process (Scheme 5).20b We envisioned that if there were two carbons between the radical center in enolate intermediate 42 and the alkene tether, hydrogen transfer would occur instead of 4-exo-trig radical addition that is unfavorable because of

17 ring strain. Subsequent conjugate addition of tin enolate 43 would give cyclic intermediate 44. It would provide a head-to-tail coupled cyclopentane product 45 after workup (Scheme 7).

R R R Bu3Sn OEWG OEWG OEWG Bu3Sn Bu3Sn 40 41 42

Bu3SnH R 1,4-addition workup R R SnBu3 -Bu3Sn OEWG O EWG O EWG Bu3Sn 45 43 44

Scheme 7

1. Enone to Enone Reductive Coupling Reaction

Bisenones 47 and 48 were readily prepared in two steps starting from 1,5- cyclooctadiene (eq 20). Ozonolysis25 followed by Wittig reaction26 gave the corresponding enones in 67% and 46% yield respectively.

18 O Ph3PCHCOCH3

CH2Cl2, rt O O3, CH2Cl2 47 -78 °C; O O 67% (2 steps) (20) Me2S O 46 Ph PCHCOPh 3 Ph Ph THF, reflux O 48 46% (2 steps)

In initial cyclization attempts, bisenone 47 was treated with 1.1 equivalents of nBu3SnH in the presence of a radical initiator in benzene (1.0 mL/mmol) at 80 °C to give cyclopentane 49 in 66% yield (Table 3, entry 1). The reaction conditions were optimized using varying amounts of hydride reagent and different reaction concentrations. It was found that the use of 1.3 equivalent of nBu3SnH in benzene (0.17 mL/mmol) was optimal. Under optimized conditions, methyl enone 47 produced cyclopentane 49 in good yield (83%) in a 1:0.7 diastereomeric ratio (entry 6), and phenyl enone 48 gave the diketone 51 in excellent yield (95%) with a syn:anti ratio of 1:22 (entry 7). An interesting concentration effect was observed. While intramolecular radical reactions are generally performed in dilute solutions to suppress intermolecular reactions, in the present reaction the higher concentration led to the improved product yield in a reduced reaction time. This opposite observation could be attributed to increased availability of nBu3SnH, which accelerates formation of the tin(IV) enolate 43 from allylic O-stannyl ketyl (41 ↔ 42). Consequently, it decreases the chance of intermolecular radical reactions. Enolate 43 is then cyclized faster to form the desired product than anionic intermolecular reaction forming an undesired product.

19 Table 3. Optimization of Michael Cyclizations of Bisenones under Radical Conditions.

Bu3Sn R n-Bu3SnH, AIBN (0.2 eq) R R + benzene, 80 °C O O O OR OR OR

47, R = Me 49 50(~3%) 48, R = Ph 51 -

n-Bu SnH concentration time yield entry substrate 3 syn:anti (mmol) sub. (mmol)/PhH (mL) (h) (%) 1 47 (R=Me) 0.66 0.60/0.60 5 66 1:1.3 2 47 (R=Me) 0.78 0.60/0.60 5 75 1:1.6 3 47 (R=Me) 0.90 0.60/0.60 5 73 1:1.5 4 47 (R=Me) 0.78 0.60/1.20 5 70 1:1.4 5 47 (R=Me) 0.78 0.60/0.30 3 78 1:0.9 6 47 (R=Me) 0.78 0.60/0.10 2 83 1:0.7 7 48 (R=Ph) 0.45 0.34/0.06 2 95 1:22

In addition to the major product, stannane 50 was obtained as a minor byproduct (~3%). The tin free radical can also undergo 1,4-addition27 to enone 47 to form stannane 52 which undergoes subsequent radical Michael addition and hydrogen transfer to lead to diketone 50 (eq 21). Enones are commonly employed as radical acceptors rather than precursors. Under these reaction circumstances, however, formation of the allylic O-stannyl ketyl radical is more energetically favorable than formation of radical 52, which is responsible for generation of the desired product 49. The tin-containing minor products from this pathway are observed in varing amounts (up to 15%) in all reactions of the substrates used in this study.

20 Bu3Sn Bu3Sn Bu3Sn Bu3SnH R 50 (21) O O O O OR O 47 52 53

2. Enone to Enoate Reductive Coupling Reaction

With the encouraging results above, we extended the research scope to the coupling of enones bearing α,β-unsaturated esters as a Michael acceptor. Enones 57 and 58 were prepared as shown in Scheme 8. DIBAL reduction of γ-butyrolactone followed by Wittig 28 reaction afforded alcohol 55. PCC oxidation and treatment with Ph3PCHCOCH3 or

Ph3PCHCOPh provided the corresponding enones 57 and 58.

O Ph PCHCO CH DIBAL 3 2 3 OH O OH MeO O CH2Cl2, -78°C O DCE, 80 °C 54 55 80% (E/Z 9:1) O O PCC, MS 4 Å O Ph3PCHCOCH3 MeO MeO CH2Cl2, rt CH2Cl2, rt 56 57 O 76% (E/Z 10:1) 97% (E/Z 15:1)

O Ph3PCHCOPh Ph MeO THF, reflux 58 O 95% (E/Z 10:1)

Scheme 8

21 Enones 57 and 58 were treated with nBu3SnH under standard free radical conditions (eq 22). The reaction results were in sharp contrast to that of bisenones 47 and 48. The desired product 59 was obtained only in 19% yield, and only a trace amount of 62 was observed on TLC. The acyclic reduced products (60, 63) that are formed from protonation of enolates during workup were isolated as the major products in 29% and 67% respectively. Other than these compounds, tin compounds 61 and 64, which formed from double Michael type addition of the tin free radical described in eq 21, were also produced in small amounts along with unknown polar materials.

Bu3Sn n-Bu3SnH (1.1 eq) R AIBN (0.2 eq) R R + + MeO (22) benzene (1.0 M) O O O O OOMe 80 °C, 4h OOMe OOMe OR

57, R = CH3 59, 19% 60, 29% 61, 6% 58, R = Ph 62, trace 63, 67% 64, 6%

A few examples of Michael reactions of ketone enolates to α,β-unsaturated esters have been reported and compared to the reaction between ketone enolates and α,β- unsaturated ketones. Baba and coworkers rationalized the results using a theoretical calculation of the energy difference, ΔE, between the product and the starting systems in reactions of different types of enolates (Scheme 9).18b The addition of a ketone enolate to an α,β-unsaturated ester showed the most disfavorable energy change. Because ester enolates are generally more labile than ketone enolates, transformation from ketone enolates into ester enolates is not preferred thermodynamically.

22 MeO Me MeO Me + ΔE = -33.50 kcal/mol O- O O O-

Me Me Me Me + ΔE = -29.92 kcal/mol O- O O O-

MeO OMe MeO OMe + ΔE = -29.62 kcal/mol O- O O O-

Me OMe Me OMe + ΔE = -24.97 kcal/mol O- O O O-

Scheme 9

Table 4. Activation of Tin enolates by the Addition of Additives.

n-Bu3SnH(1.1 eq), AIBN (0.2 eq) Ph benzene (1.0 M), 80 °C; Ph O solvent, additive O OOMe OOMe 58 62

entry additive (eq.) solvent temp (°C) time (h) yield (%)

1 BF3⋅OEt2 (1.0) THF -78 → rt 12 0 2 TMSCl (2.0) THF rt 12 12 3 HMPA (5.0) - 80 24 21

4 Bu4NBr (0.2) THF 60 12 82

Accordingly, cyclization of tin (IV) enolates generated from enones 57 and 58 appeared to require an additional activator for either the enolate or ester moiety in order to promote cyclization. We examined the effects of Lewis acids with expectation of activation of the α,β-unsaturated ester by coordination to the carbonyl oxygen, which, ultimately,

23 stabilizes the ester enolates formed after the 1,4-addition (Table 4). Lewis acids were added after 1,4-stannation of phenyl enone 58 under standard radical conditions. The use of

BF3⋅OEt2 was not effective at all (entry 1) and TMSCl afforded a low yield of the desired product (entry 2). HMPA was also used for activation of the tin-oxygen bond in the enolate (entry 3). The high coordinating ability of HMPA allows it to act as a Lewis base and increase the polarity of the tin (IV) enolate.20f However, it afforded only 21% of the cyclic product. Baba and coworkers have been reported very efficient intermolecular Michael addition of tin (IV) enolates to α,β-unsaturated esters catalyzed by tetrabutylammonium 29,18b bromide (Bu4NBr). Coordination of bromide ion to the tin (IV) metal center increases the nucleophilicity of the enolate (eq 23). When Baba’s method was used, the yield of the coupling reaction of 58 was dramatically increased giving rise to diketone 62 in 82% yield (entry 4).

Br Bu R Br- Sn 1 R Bu 2 Bu (23) - OSnBu3 -Br O R1

R2 63 64

A plausible mechanism for the cyclization of 58, based on Baba’s rationale, is illustrated in Scheme 10. The tin enolate exists in keto- and/or enol-forms, and the bromide anion coordinates to only the enol-form to give 66. The high coordination state of tin(IV) enhances the nucleophilicity of enolate 66 which adds to the internal unsaturated ester. After conjugate addition, ester enolate 67 readily tautomerized to ester-form 68 which is thermodynamically stabilized. This step takes place with dissociation of the bromide anion because the tin center bearing only carbons is reluctant to accept a bromide ligand. The product 62 is obtained after workup.

Ph Ph SnBu 3 Br- O OOMe O Bu3Sn OOMe 65 work-up 68 tautomerization coordination

O Ph OOMe Ph R4N O R4N O OOMe 62 OOMe Bu3Sn Br SnBu3 Br 66 67 conjugate addition

Scheme 10

With this successful result, optimization of reaction conditions for enones 57 and 58 was carried out (Table 5). The yield of the coupling reaction of enone 57 was improved to

43% when Bu4NBr was used as an activator (entry 1). The reaction of enone 57 was also affected by concentration, as in the case of bisenone 47, but the effect was insignificant. The reaction in the optimal concentration (0.17 mL/mmol) used in the cyclization of bisenone 47 gave a 10% better yield than when the reaction was conducted in 1.0 mL/mmol of the benzene solution (entry 1 and 3). Even more concentrated conditions were not effective (entry 5 and 6). The other hand, the yield for the reaction of phenyl-substituted enone 58 was not dependant on concentration, although there was only a small change in syn:anti selectivity (entry 7 and 8).

25 Table 5. Michael Cyclization of α,β-Unsaturated Esters Catalyzed by Bu4NBr.

n-Bu3SnH, AIBN (0.2 eq) R benzene, 80 °C; R Bu NBr (0.2 eq) O 4 O OOMe THF (0.1 M), 60 °C, 12 h OOMe

57, R = CH3 59 58, R = Ph 62

n-Bu SnH concentration time yield entry substrate 3 syn:anti (mmol) sub. (mmol)/PhH (mL) (h) (%) 1 57 (R=Me) 0.61 0.55/0.55 4 43 1:1.7 2 57 (R=Me) 0.72 0.55/0.55 4 43 1:1.2 3 57 (R=Me) 0.61 0.55/0.09 3 55 1:1.8 4 57 (R=Me) 0.72 0.55/0.09 3 55 1:1.4 5 57 (R=Me) 0.72 0.55/0.06 3 54 1:1.2 6 57 (R=Me) 0.72 0.55/0 (neat) 3 53 1:1.3 7 58 (R=Ph) 0.41 0.37/0.06 4 82 1:7.8 8 58 (R=Ph) 0.41 0.37/0.06 2 82 1:5.8

The stereochemistry of cyclopentanes 59 and 61 was determined by 1H NOE spectroscopic difference studies summarized in Table 6. Irradiation of the hydrogen at C1 of syn-59 resulted in a NOE enhancement of the signal for the hydrogen at C2 while the signal for hydrogen at C1 was not enhanced by irradiation of the hydrogen at C2 of anti-59. Additionally, the cis and trans relationship of diastereomers produced from other substrates were readily distinguished by a characteristic down field shift of the hydrogens at C1 of syn-isomers in NMR spectra. In the case of stannane 61, irradiation of the hydrogens at C1 showed a strong NOE enhancement of the signal for C2 hydrogen and the trans relationship of C5 hydrogen to the hydrogens at C1 and C2 was determined by the enhancement of the signals for C8 instead of C2 when it was irradiated. A stronger NOE enhancement of the

26 hydrogen at C11 than that of C5 by irradiation of C1 hydrogen also supported this interpretation.

Table 6. NOE Observations for Cyclization Products.

11 H' H' H' H' (H3C(H2C)2H2C)3Sn H' 3 3 H 5 H H 5 H H 5 3 H 1 2 1 2 1 2 H H MeO H H H H H H 8 H H 8 H H 8 O O O OOMe OOMe OCH3 10

syn-59 anti-59 61

syn-59 anti-59 irradiation H1 H8 H2 H8

NOE H2 H2 H3’ H3 observation H5 H8

61 irradiation H1 H5 H8

H2 (8.0) H1 (2.3) H3’ (2.4) NOE H (2.9) H (1.4) H observation (%) 5 8 2 H11 (3.5) H10 (1.2)

The stereochemical consequences of cyclization of 57 and 58 are illustrated in Scheme 11. For enone 57, the pre-cyclization conformations 57b and 57d which have minimum steric interactions in transition states should lead to anti-59 as a major product. It is anticipated that 1,4- hydrostannation of enone 58 would predominantly form the (Z)-enolate due to A1,3-interaction of (E)-enolate. The steric interactions between the phenyl substituent

27 and the ester group in conformation 58a would result in preference for the trans product formation from 58b.

(Z)-enolate of 57 H H BrBu Sn 3 O OMe OMe H H O H O H BrBu3SnO 57a 57b

syn-59 anti-59

(E)-enolate of 57 H H OMe OMe H O O H O H H SnBu3Br OSnBu3Br 57c 57d

syn-59 anti-59

Scheme 11

(Z)-enolate of 58 H H BrBu Sn 3 O OMe OMe H H O Ph O H Ph H BrBu3SnO 58a 58b

syn-62 anti-62

(E)-enolate of 58 H H H H Ph OMe OMe H H H O H O H O H SnBu3Br OSnBu Br Ph 3 58c 58d

syn-62 anti-62

Scheme 11 (continued)

The coupling reaction of enone 57 occurred in moderate yield, and polar byproduct mixtures were observed on TLC. Unfortunately, the identification of these compounds was not possible and it was only in the IR spectrum that an alcohol functional group was detected in the side product mixture. It is presumed that the alcohol is formed from an intermolecular dimerization via 1,4-addition of the enolate radical followed by aldol cyclization (Scheme 12, a). Considering the facile cyclization of bisenone 47 without an additive (Table 3), it is also feasible that an intermolecular anionic polymerization occurs to form the rest of the side products (Scheme 12, b). Whereas, in case of enone 58 a thermodynamically stabilized enolate and O-stannylketyl radical are formed, and these are

29 not likely to have enough reactivity to undergo intermolecular side reactions readily. The low yields of the reaction of the methyl-substituted enones are a common issue found in other hydrometallative coupling methods as well.14,15,20e,22 The related studies did not suggest an explanation for the side reactions, but it is presumably caused from the intrinsic high reactivity of the enolate formed from methyl ketones toward an intermolecular reaction. a. radical dimerization

R R R R R R R R

O O OH O O Bu Sn O 3 Bu Sn O 3 Bu3Sn O b. anionic polymerization

R R R O Bu Sn 3 O n R = CH2CH2CH=CHCO2CH3 O

Scheme 12

With these assumptions about side reactions, we explored the temperature dependence of the coupling reaction of enone 57. Judging from the fact that the reaction of 57 partially proceeds at 80 °C without the additive as shown in eq 22, it was speculated that elevation of the reaction temperature could shift the equilibrium toward the product to complete the reaction. The reaction of enone 57 was performed at 110 °C in toluene and all starting substrate was consumed in 8 hours (eq 24). No acyclic reduction product 60 was, indeed,

30 detected. However, the yield of the product was instead decreased to 23%. Unfortunately, the side reactions were predominant at the higher temperature.

n-Bu3SnH (1.1 eq), AIBN (0.2 eq) (24) toluene (6.0 M), 110 °C, 8h O O OOMe OOMe 57 59, 23%

Conversely, it was envisioned that the side reaction could be suppressed by lowering the temperature. A more efficient radical initiator was needed, and 2,2’-azobis(2,4- dimethyl-4-methoxyvaleronitrile (V-70) was employed as a substitute for AIBN.30 It has

Table 7. Michael Cyclization of α,β-Unsaturated Ester 57 Using V-70 as a Radical Initiator.

n-Bu3SnH (1.1 eq), V-70 (0.1 eq) dichloroethane (6.0 M), temp., time; Bu NBr (0.2 eq), THF (0.1 M) O 4 O OOMe 60 °C, 12 h OOMe 57 Me 59 MeO CN Me Me NN Me Me CN OMe Me V-70

entry temp (°C) time (h) yield (%) 1 40 16 15 2 60 6 33 3 80 6 47 the same half-life time of decomposition at 40 °C as AIBN at 80 °C. In the presence of V- 70 the coupling reactions for enone 57 were carried out as a function of temperature (Table

31 7). The reaction of 57 afforded cyclopentane 59 in only 15% yield at 40 °C along with 30% of the unreacted enone (entry 1). Although the half-life time of decomposition for V-70 is 0 at 60 °C, the reaction at 80 °C gave a higher yield than at the lower temperature (entry 3). Thermal conditions needed to promote the radical enolate generation. These results show that use of temperature to improve the yield in the cyclization of enone 57 was not successful.

Table 8. Michael Cyclization of Additional Alkyl Enones.

yield (syn:anti) entry substrate product (%)

Ph(CH2)2 Ph(CH2)2 1 42 (1:1) O O OOMe OOMe 69 70

O OMe O O O OMe 2 49a

71 72

O O OMe MeO 3 O 41a

O 74 73 General conditions: reactions were carried out with 1.1 eq of nBu3SnH and 0.2 eq of AIBN in benzene (0.17 mL/mmol) at 80 °C for 4 h, then diluted with THF (0.1 M), followed by addition of 0.2 eq of Bu4NBr with subsequent stirring at 60 °C for 12 h. a An inseparable mixture of diastereomers was obtained.

To examine substituent effects and test the scope of the method, we performed the reductive coupling reaction with other alkyl-substituted enones including cyclic enones

32 under optimum conditions (Table 8 and eq 25). The substrates shown in Table 8 were readily prepared via Wittig reaction with corresponding aldehydes, or cross-metathesis using Grubbs’ catalyst with corresponding alkene precursors. The detailed synthetic routes are described in the Experimental Section. The reaction of enone 69 having a longer chain than enone 57 led to the formation of cyclopentane 70 in 42% yield as a 1:1 diastereomeric mixture (entry 1). Cyclic enones 71 afforded the bicyclic products 72 in 49% yield (entry 2) as a diastereomeric mixture. Enone 73 provided cis-fused bicycle 74 in 41% yield (entry 3) as a complex mixture of diastereomers. Alkyl-substituted enones typically resulted in moderate yields regardless of the structures.

3. Enone to Enenitrile Reductive Coupling Reaction

α,β-Unsaturated nitriles as a Michael acceptor variant were also examined. Enones 76 and 77 bearing an α,β-unsaturated nitrile tether were synthesized via cross-metathesis

Hoveyda-Grubbs' II (5 mol%) CN O O CN , CH Cl , reflux 2 2 75 75% (E/Z 3:1)

O Ph PCHCOCH 75 3 3 CH Cl , rt CN 2 2 76 91% (E/Z 3:1)

O Ph3PCHCOPh Ph CN THF, reflux 77 83% (E/Z 3:1)

Scheme 13

33 between 4-pentenal and acrylonitrile using Hoveyda-Grubbs’ 2nd generation catalyst,31 followed by treatment with the corresponding Wittig reagents. Wittig reactions of aldehyde 75 led to inseparable isomeric mixtures (E/Z 3:1) of both 76 and 77 (Scheme 13).

Enones 76 and 77 were subjected to the same coupling conditions using Bu4NBr (eq 25). The reactions exhibited characteristics similar to reactions of enones 57 and 58 bearing an unsaturated methyl ester as a coupling partner. Phenyl-substituted enone 77 afforded cyclopentane product 78 in high yield with a syn:anti ratio of 1:6. Methyl enone 76 produced cyclopentane 78 in moderate yield similar to other alkyl-substituted enones such as 57. Surprisingly, the reaction of enone 76 showed a higher level of anti- diastereoselectivity (1:11) than phenyl enone 77.

n-Bu3SnH (1.1 eq) AIBN (0.2 eq) benzene (6.0 M), 80 °C, 2~3 h; R R (25) Bu4NBr (0.2 eq) OCN THF (0.1 M), 60 °C, 12 h O CN

76, R = CH3 78 54% (syn:anti 1:11) 77, R = Ph 79 88% (syn:anti 1:6)

Summary

We have demonstrated tin(IV)-mediated intramolecular reductive coupling reactions of enones bearing activated alkenes as Michael acceptors. Tin(IV) enolates were generated via regioselective hydrostannation of enones under radical conditions and subsequent conjugate addition to internal acceptors provided synthetically useful 1,2-disubstituted cyclopentanes. The reductive coupling of bisenones afforded cyclopentanes in high yield under concentrated reaction conditions. Meanwhile, enone-to-enoate and enone-to- enenitrile coupling reactions required Bu4NBr as an additional activator to facilitate the Michael addition of tin enolates generated from 1,4-hydrostannation. Phenyl-substituted

34 enones generated cyclopentanes in high yield in Bu4NBr catalyzed cyclization whereas alkyl-substituted enones provided the products generally in moderate yields.

CHAPTER III

EXPERIMENTAL

General Considerations

Solvents were reagent grade and in most cases dried prior to use. All other commercially available reagents were used as received unless otherwise noted. The organic extracts were dried over anhydrous MgSO4. Tetrahydrofuran (THF) was distilled from lithium aluminum hydride (LiAlH4) prior to use. Methylene chloride (DCM), and hexamethylphosphoric triamide (HMPA) were distilled from calcium hydride. Diethyl ether

(Et2O) was distilled from sodium-benzophenone ketyl. AIBN and Bu4NBr were dried under high vacuum and used without purification. All reactions were run under an atmosphere of argon, unless otherwise indicated. Infrared (IR) spectra were recorded as thin films on sodium chloride plates using a Perkin-Elmer FT-IR Paragon 1000 Fourier Transform spectrometer with frequencies given in reciprocal centimeters (cm-1). Proton nuclear magnetic resonance (1H NMR) spectra were recorded with a Varian Fourier Transform 500 (500 MHz) spectrometer. Chemical shifts are reported in delta (δ) units, parts per million (ppm) downfield from tetramethylsilane (δ 0.00). The following abbreviations are used to describe peak patterns where appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constants (J) are reported in Hertz unit (Hz). Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Varian Fourier Transform 300 (75 MHz) and were routinely run with broadband decoupling. Chemical shifts are reported in ppm relative to the centerline of the triplet for chloroform-d at 77.0 ppm or that for benzene-d6 at 128.0 ppm. Mass spectra were obtained on a Jeol JMS-600. Elemental

36 Analysis was performed by Atlantic Microlab Inc, Norcross, GA. Diastereomeric ratios were determined by integration of well-resolved signals in the 1H NMR spectra. Flash chromatography refers to separation using a silica gel filled column.

Synthesis of Substrates

Succinaldehyde (46). A solution of 1,5-cyclootadiene (4.9 g, 43.5 mmol) in CH2Cl2 (80 ml) was ozonolized at -78 °C until the solution turned light blue. The mixture was stirred with Me2S at room temperature for 16 h. After evaporation of the solvent the crude product was used without any further purification.25

(3E,7E)-Deca-3,7-diene-2,9-dione (47). To a mixture of 3.9 g (45.3 mmol) of succinaldehyde 46 and 80 mL of CH2C12 was added a solution of 28.8 g (90.6 mmol) of 1- (triphenylphosphoranylidene)-2-propanone. After the mixture was stirred for 5 h, the solvent was removed with a rotary evaporator, the solid residue was rinsed with 100 mL of ether, filtered, and the filtrate was concentrated on a rotary evaporator. Flash chromatography of the residue afforded 5.0 g (67%) of 47 as a liquid.26

(2E,6E)-l,8-Dioxo-l,8-diphenylocta-2,6-diene (48). Phenacyl triphenylphosphonium bromide (9.2 g, 20.0 mmol) was suspended in a mixture of water (250 mL) and methanol (250 mL) and the mixture was stirred for 1 h. Aqueous sodium hydroxide (2.0 M) was added to the mixture until a pH between 7 and 8 was reached. The mixture was then stirred vigorously for 1 h. The phosphorane precipitate was filtered and washed water. After drying in vacuo, the phosphorane was recrystallized from ethyl acetate and dried under vacuum to obtain 6.77 g (89%, white crystal) of phenacylidene-triphenylphosphorane.32 A solution of succinaldehyde 46 (0.23 g, 2.72 mmol) in THF (50 mL) and phenacylidene-triphenylphosphorane (2.38 g, 6.26 mmol) was stirred for 24 h at 65 °C. After removal of solvent, the residue was rinsed with 10 mL of ether, filtered, and the

37 filtrate was concentrated on a rotary evaporator. Flash chromatography of the residue afforded 0.37 g (46%) of 48 as a pale yellow solid.33

Tetrahydrofuran-2-ol (54). Diisobutylaluminum hydride (69.0 mL of 1 M in hexane, 69.0 mmol) was added dropwise to γ-butyrolactone (4.95 g, 57.5 mmol) in CH2C12 (50 mL) at - 78 ºC. After the solution was stirred for 2 h, the extra DIBAL was quenched with MeOH (0.47 mL, 11.5 mmol). The reaction mixture was diluted with 600 ml of diethyl ether and then ground sodium sulfate decahydrate (18.5 g, 57.5 mmol) was added slowly. The reaction mixture was slowly warmed to room temperature and stirred overnight. Filtration through Celite and removal of the solvent afforded the crude product as a colorless oil. The crude product was used directly for the next step without further purification.35

Methyl (E)-6-Hydroxy-2-hexenoate (55). To a solution of 54 (4.14 g, 47.0 mmol) in dichloroethane (60 mL) was added methyl triphenylphosphoranylideneacetate (15.7 g, 47.0 mmol). The resulting clear solution was allowed to stir at 80 ºC for 12 h, concentrated, and diluted with pentane. The precipitate formed was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to afford 5.44 g (80 %) of ester 55 as a clear oil.28

Methyl (E)-6-Oxo-2-hexanoate (56). Pyridinium chlorochromate (7.5 g, 34.7 mmol) was added to a round-bottom flask containing 4Å molecular sieves (13.0 g). The solids were suspended in 200 mL of CH2Cl2. A solution of ester 55 (E/Z = 9/1, 2.5 g, 17.3 mmol) in 2.0 mL of CH2Cl2 was added dropwise over 5 min. The resulting dark brown solution was allowed to stir vigorously at room temperature for 1 h. The reaction mixture was filtered through a short pad of silica gel, washed with ether (100 mL), CH2Cl2 (100 mL), and EtOAc (100 mL), and concentrated in vacuo. The crude product was purified by flash chromatography to afford 1.7 g of aldehyde (E)-56 and 0.17 g of (Z)-56 as clear oils in a combined yield of 76%.28

38 (2E,6E)-Methyl 8-oxonona-2,6-dienoate (57). A solution of aldehyde 56 (0.8 g, 5.63 mmol) in CH2Cl2 (50 mL) and 1-(triphenylphosphoranylidene)-2-propanone (2.15 g, 6.75 mmol) was stirred for 12 h at room temperature. After removal of solvent, the residue was rinsed with 10 mL of ether, and filtered, and the filtrate was concentrated on a rotary evaporator. Flash chromatography of the residue afforded 0.06 g of (E)-57 and 0.93 g of (Z)-57 in combined yield of 97%.26

(2E,6E)-Methyl 8-oxo-8-phenylocta-2,6-dienoate (58). To a solution of phenacylidene- triphenylphosphorane (2.38 g, 6.26 mmol) in THF (40 mL) was added a solution of aldehyde 56 (0.89 g, 6.26 mmol) in THF (10 mL). After the mixture was refluxed for 24 h, the solvent was removed with a rotary evaporator, the solid residue was rinsed with 10 mL of ether, and filtered, and the filtrate was concentrated on a rotary evaporator. Flash chromatography of the residue afforded 0.13 g of (E)-58 and 1.32 g of (Z)-58 in combined 1 yield of 95%. H NMR (500 MHz, CDCl3): δ 7.92 (m, 2H, aromatic H), 7.56 (tt, J = 1.3, 7.3, 1H, aromatic H), 7.47 (m, 2H, aromatic H), 7.02 (td, J = 6.4, 15.6, 1H,

CH=CHC=OPh), 6.98 (td, J = 6.4, 16.0, 1H, CH=CHCO2CH3), 6.91 (td, J = 1.3, 15.3, 1H,

CH=CHC=OPh), 5.89 (td, J = 1.4, 15.6, 1H, CH=CHCO2CH3), 3.73 (s, 1H, CO2CH3), 13 2.53-2.43 (m, 4H, CHCH2CH2CH). C NMR (75 MHz, CDCl3): δ 189.7, 166.2, 146.9, 137.3, 132.3, 128.1, 127.9, 126.2, 121.5, 50.9, 30.5, 30.1. IR (neat, NaCl): 3058, 2949, 1968, 1720, 1670, 1620, 1436, 1279, 1219, 980, 694 cm-1. HRMS (EI) m/z calc. for + C15H16O3 (M ) 244.1100, found 244.1099. Anal. Calcd. For C15H16O3: C, 73.75; H, 6.60. Found: C, 73.53; H, 6.62.

Preparation of (2E,6E)-methyl 8-oxo-10-phenyldeca-2,6-dienoate (69):

Enone 69 was prepared according to Scheme 14.

39 O OH O Vinyl-MgBr PCC H Et2O, 0 °C CH2Cl2, rt

80, 55% 81, 76%

Grubbs' II O Ph Ph3PCHCO2CH3 (5 mol%) O CH2Cl2, rt OMe 81 O , CH2Cl2 OOMe reflux 82, 81% 69, 42%

Scheme 14

5-Phenylpent-1-en-3-ol (80). A solution of 2.25 g (16.8 mmol) of hydrocinnamaldehyde in 5 mL of anhydrous ether was added dropwise over a period of 5 min to 40.3 mL of 1.0 M vinylmagnesium bromide-tetrahydrofuran solution at 0 ºC in an ice water bath. After this mixture had been stirred at 0 ºC for 20 min, the reaction was quenched by the dropwise addition of 5 mL of saturated aqueous NH4Cl solution and subsequently diluted with 200 mL of saturated brine. After extraction of the product with EtOAc, the organic phase was separated, dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography afforded 1.49 g (55%) of allylic alcohol 80.36

5-Phenylpent-1-en-3-one (81). A solution of 1.0 g (6.61 mmol) of allylic alcohol 80 in 10 mL of dichloromethane was rapidly added dropwise to 5.05 g (23.4 mmol) of pyridinium chlorochromate in 20 mL of dichloromethane. After this mixture was stirred vigorously at room temperature for 90 min, it was transferred with 120 mL of ether and 150 mL of 1 M aqueous NaOH to a separatory funnel. After separation of the layers, the organic layer was washed sequentially with a 1 M aqueous sodium hydroxide solution, 2 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. Isolation of the product from the organic extract in the usual manner, followed by flash chromatography, afforded 0.75 g (76%) of enone 81.37

(E)-Methyl hepta-2,6-dienoate (82). A solution of 4-pentenal (1.94 g, 24.06 mmol) in

CH2Cl2 (100 mL) and methyl triphenylphosphoranylideneacetate (9.25 g, 27.67 mmol) was stirred for 12 h at room temperature. After removal of solvent, the residue was rinsed with 100 mL of ether, and filtered, and the filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography on silica gel to afford 2.72 g (81 %) of ester 82 as a colorless oil.38

(2E,6E)-Methyl 8-oxo-10-phenyldeca-2,6-dienoate (69). Ester 82 (0.26 g, 1.87 mmol, 1.0 equiv) and enone 81 (0.30, 1.87 mmol, 1.0 equiv) were added simultaneously to a stirred nd solution of Grubbs’ 2 generation catalyst (79 mg, 0.094 mmol, 5.0 mol%) in CH2Cl2 (3.7 mL, 0.5 M) under an argon atmosphere. The flask was fitted with a condenser and heated at reflux under argon for 12 hours. The reaction mixture was then concentrated in vacuo, and the residue was purified directly by flash chromatography to provide enone 69 as a clear 39 1 colorless oil (214 mg, 42%). H NMR (500 MHz, CDCl3): δ 7.30-7.18 (m, 5H, aromatic

H), 6.92 (m, 1H, CH=CHCO2CH3), 6.77 (m, 1H, CH2C=OCH=CH), 6.13 (d, J = 16.0, 1H,

CH2C=OCH=CH), 5.85 (d, J = 15.6, 1H, CH=CHCO2CH3), 3.73 (s, 3H, CO2CH3), 2.95- 13 2.84 (m, 4H, PhCH2CH2C=O), 2.37 (br t, J = 3.0, 4H, CHCH2CH2CH). C NMR (75

MHz, CDCl3): δ 199.2, 166.7, 147.1, 145.0, 141.1, 130.9, 128.5, 128.3, 126.1, 122.0, 51.5, 41.9, 30.6, 30.5, 30.0. IR (neat, NaCl): 2950, 1950, 1723, 1436, 1275, 1204, 980, 700 cm-1. + HRMS (EI) m/z calc. for C17H20O3 (M ) 272.1413, found 272.1408. Anal. Calcd. For

C17H20O3: C, 74.97; H, 7.40. Found: C, 74.90; H, 7.37.

Preparation of (E)-methyl 5-(3-oxocyclohex-1-enyl)pent-2-enoate (71):

Enone 71 was prepared according to Scheme 15.

41 O O ClMgCH2CH2CH2OMgCl PCC THF, -15 °C CH Cl , rt OH 2 2 OEt 83, 51%

O OMe O O Ph3PCHCO2CH3 CH Cl , rt O 2 2

84, 85% 71, 83% (E/Z = 17:1)

Scheme 15

3-(3-Hydroxypropyl)cyclohex-2-enone (83). Methylmagnesium chloride (2.9 M solution in tetrahydrofuran) was added dropwise to a solution of 3-chloropropanol (1.0 g, 10.59 mmol) in tetrahydrofuran (15 mL) cooled to -20 ºC. The mixture was permitted to warm to room temperature, and then magnesium turnings (0.32 g, 13.24 mmol) were added. Dibromoethane (four drops) was then added, and the solution was refluxed for 12 h. The reaction was cooled to -15 ºC, and 3-ethoxy-2-cyclohexenone (0.99 g, 7.06 mmol) was added. The solution was stirred for 2 h at -15 ºC and warmed to 0 ºC, and a solution of saturated aqueous ammonium chloride was added dropwise to destroy excess Grignard reagent. Aqueous hydrochloric acid (3 N, 7 mL) was then added to the mixture, and the aqueous layer was immediately extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), dried with anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue purified by flash column chromatography to yield 83 as a colorless oil (0.56 g, 51% yield).40

42 3-(3-Oxocyclohex-1-enyl)propanal (84). Following the procedure used for the synthesis of methyl (E)-6-Oxo-2-hexanoate 56, aldehyde 84 was obtained from alcohol 83 (0.50 g, 3.24 mmol) in 85% yield (0.42 g).41

(E)-Methyl 5-(3-oxocyclohex-1-enyl)pent-2-enoate (71). Following the procedure used for the synthesis of (E)-methyl hepta-2,6-dienoate 82, (E)-71 (373 mg) and (Z)-71 (22 mg) were obtained from aldehyde 84 (0.50 g, 3.24 mmol) as clear oils in a combined yield of 1 83%. H NMR (500 MHz, CDCl3): δ 6.93 (td, J = 6.4, 15.6, 1H, CH=CHCO2CH3), 5.88 (br s, 1H, CH2C=OCH), 5.86 (partly obscured td, J = 1.4, 15.6, 1H, CH=CHCO2CH3), 3.73 (s,

3H, CO2CH3), 2.46-2.40 (m, 2H, CH2CH=CHCO2CH3), 2.40-2.35 (m, 4H,

CH2CH2CH=CHCO2CH3, CH2C=OCH), 2.29 (br t, J = 5.6, 2H, CH2CH2CH2C=O), 2.03- 13 1.97 (m, 2H, CH2CH2CH2C=O). C NMR (75 MHz, CDCl3): δ 198.7, 165.9, 163.6, 146.6, 125.3, 121.3, 50.8, 36.7, 35.4, 29.1, 28.7, 22.0. IR (neat, NaCl): 2949, 1720, 1670, 1435, -1 + 1324, 1273, 1254, 1204, 1039, 967 cm . HRMS (EI) m/z calc. for C12H16O3 (M ) 208.1100, found 208.1102.

Preparation of methyl (E)-cis-3-(2-(3-oxobut-1-enyl)cyclohexyl)acrylate (73):

Enone 73 was prepared according to Scheme 16.

43 O O OH NaBH4 DIBAL Ph PCHCO CH O 3 2 3 THF, 0 °C O CH2Cl2, -78°C O DCE, 80 °C O 85, 90% 86

O O O OMe OMe PCC OMe Ph3PCHCOCH3

CH2Cl2, rt THF, reflux OH O O 87, 74% 88 73, 48% (E/Z = 1.5:1)

Scheme 16 cis -Hexahydrophthalide (85). A mixture of NaBH4 (1.17 g, 30.8 mmol) in THF (8 mL) was stirred and cooled in an ice bath while cis-1,2-cyclohexanedicarboxylic anhydride (4.75 g, 30.8 mmol) in THF (30 mL) was added over 5 min. The ice bath was removed and stirring was continued for 1 h. Hydrochloric acid (12 mL, 6 N) was added and the mixture was diluted with 70 mL of water. Extraction with Et2O followed by flash chromatography afforded lactone 85 in 90% yield (3.89 g).42

cis-Octahydroisobenzofuran-1-ol (86). Following the procedure used for the synthesis of tetrahydrofuran-2-ol 54, the crude product 86 was obtained from lactone 85 (2.5 g, 17.85 mmol).43

Methyl (E)-cis-3-(2-hydroxymethyl-cyclohexyl)acrylate (87). Following the procedure used for the synthesis of methyl (E)-6-Hydroxy-2-hexenoate 55, alcohol 87 was obtained from lactol 86 (2.0 g, 14.06 mmol) as a viscous oil in 74% yield (2.07 g). 1H NMR (500

MHz, CDCl3): δ 7.17 (dd, J = 8.9, 15.6, 1H, CH=CHCO2CH3), 5.87 (dd, J = 1.0, 15.6, 1H,

44 CH=CHCO2CH3), 3.73 (s, 3H, CO2CH3), 3.45 (d, J = 7.3, 2H, CHCH2OH), 2.69 (tdd, J =

4.1, 4.5, 8.9, 1H, CHCH=CHCO2CH3), 1.88-1.81 (m, 1H, CHCH2OH), 1.77-1.70 (m, 1H, cyclohexane H), 1.68-1.47 (m, 5H, cyclohexane H), 1.42-1.33 (m, 2H, cyclohexane H). 13C

NMR (75 MHz, CDCl3): δ 166.9, 149.9, 120.9, 64.0, 51.0, 42.1, 38.9, 29.9, 24.7, 24.4, 21.9. IR (neat, NaCl): 3422, 2928, 2858, 1723, 1649, 1437, 1271, 1172, 1026 cm-1. HRMS (EI) + m/z calc. for C11H18O3 (M ) 198.1256, found 198.1254. Anal. Calcd. For C11H18O3: C, 66.64; H, 9.15. Found: C, 66.28; H, 9.34.

Methyl (E)-cis-3-(2-formylcyclohexyl)acrylate (88). Following the procedure used for the synthesis of methyl (E)-6-Oxo-2-hexanoate 56, aldehyde 88 was obtained from alcohol 87 (1.0 g, 5.04 mmol).44

Methyl (E)-cis-3-(2-(3-oxobut-1-enyl)cyclohexyl)acrylate (73). To a solution of 1- (triphenylphosphoranylidene)-2-propanone (1.22 g, 3.82 mmol) in THF (30 ml) was added a solution of aldehyde 88 (0.50 g, 2.55 mmol) in THF (5 mL). After the mixture was refluxed for 24 h, the solvent was removed with a rotary evaporator, the solid residue was rinsed with 5 mL of ether, and filtered, and the filtrate was concentrated on a rotary evaporator. Flash chromatography of the residue afforded a mixture of (E)- and (Z)-73 in yield of 48% (0.28 g, E/Z 1.5:1). IR (neat, NaCl): 2929, 2856, 1724, 1675, 1435, 1269, -1 + 1171, 983 cm . HRMS (EI) m/z calc. for C14H20O3 (M ) 236.1413, found 236.1412. Anal.

Calcd. For C14H20O3: C, 71.16; H, 8.53. Found: C, 71.18; H, 8.61.

6-Oxohex-2-enenitrile (75). To a mixture of 4-pentenal (485 mg, 5.77 mmol) and acrylonitrile (612 mg, 11.54 mmol) in dichloromethane (115 mL) was added Hoveyda- Grubbs’ 2nd generation catalyst (181 mg, 5 mol%). The resulting mixture was stirred at 45 °C for 2 h. The solvent was removed under reduced pressure. Flash chromatography of the crude residue gave a mixture of (E)- and (Z)-75 in 75% yield (473 mg, E/Z 3:1).45

45 (6E)-8-oxonona-2,6-dienenitrile (76). Following the procedure used for the synthesis of 57, enone 76 was obtained from aldehyde 75 (0.19 g, 1.74 mmol) as a mixture of E, Z- isomers (3:1) in 91% yield (0.24 g). IR (neat, NaCl): 3006, 2941, 2220, 1674, 1627, 1428, -1 + 1362, 1255, 979, 744 cm . HRMS (EI) m/z calc. for C9H11ON (M ) 149.0841, found 149.0845.

(6E)-8-oxo-8-phenylocta-2,6-dienenitrile (77). Following the procedure used for the synthesis of 58, enone 77 was obtained from aldehyde 75 (0.41 g, 3.76 mmol) as a mixture of E, Z-isomer (3:1) in 83% yield (0.66 g). IR (neat, NaCl): 3063, 2938, 2220, 1971, 1671, -1 + 1621, 1447, 1350, 1288, 1225, 976, 695 cm . HRMS (EI) m/z calc. for C14H13ON (M )

211.0993, found 211.1000. Anal. Calcd. For C9H11ON: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.40; H, 6.28; N, 6.62.

46 Cyclization of Substrates

1-(2-Acetylcyclopentyl)propan-2-one (49). Bisenone 47 (100 mg, 0.60 mmol), tributyltin hydride (234 mg, 0.78 mmol, 1.3 equiv), and azobis(isobutyronitrile) (19.7 mg, 0.12 mmol, 0.2 equiv) were added to a reaction tube under argon. The mixture was dissolved in 0.1 mL of benzene and degassed for 15 min. under a stream of argon. The solution in the sealed tube was stirred for 2 h at 80 °C and then cooled to room temperature. After addition of MeOH (2 mL), the reaction mixture was stirred for 30 min. and concentrated in vacuo. The residue was purified by flash column chromatography to afford a mixture of syn- and anti- 49 (1:0.7, 83.5 mg, 83%). 1 Syn-49: H NMR (500 MHz, CDCl3): δ 3.12 (ddd, J = 7.4, 7.5, 7.7, 1H, CH3C=OCH),

2.66-2.57 (m, 2H, CHCHHC=OCH3), 2.45-2.38 (m, 1H, CHHC=OCH3), 2.13 (s, 3H,

C=OCH3), 2.09 (s, 3H, C=OCH3), 1.87-1.70 (m, 4H, cyclopentane H), 1.63-1.54 (m, 1H, 13 CH2CHHCH2), 1.43 (tdd, J = 7.0, 7.7, 12.5, 1H, CHHCHCH2C=OCH3). C NMR (75

MHz, CDCl3): δ 211.8, 208.2, 53.7, 44.5, 37.5, 32.1, 31.2, 30.2, 27.8, 23.2. IR (neat, NaCl): -1 + 2956, 2873, 1708, 1422, 1356, 1168 cm . HRMS (EI) m/z calc. for C10H16O2 (M )

168.1150, found 168.1146. Anal. Calcd. For C10H16O2: C, 71.39; H, 9.59. Found: C, 71.11; H, 9.66. 1 Anti-49: H NMR (500 MHz, CDCl3): δ 2.58 (obscured ttd, J = 7.6, 7.5, 14.7, 1H,

CHCH2C=OCH3), 2.51 (m, 1H, CH3C=OCH), 2.51 (ABd, JAB = 16.1, J = 6.1, 1H,

CHHC=OCH3), 2.44 (ABd, JAB = 16.1, J = 7.7, 1H, CHHC=OCH3), 2.16 (s, 3H, C=OCH3),

2.12 (s, 3H, C=OCH3), 1.99-193 (m, 2H, cyclopentane H), 1.72-1.64 (m, 3H, cyclopentane 13 H), 1.43 (dtd, J = 7.0, 7.7, 12.5, 1H, CHHCHCH2C=OCH3). C NMR (75 MHz, CDCl3): δ 210.8, 208.3, 58.1, 49.0, 37.4, 32.6, 30.0, 29.7, 28.8, 24.6. IR (neat, NaCl): 2950, 2870, -1 + 1709, 1423, 1357, 1161, 969 cm . HRMS (EI) m/z calc. for C10H16O2 (M ) 168.1150, found 168.1152.

2-(2-Benzoylcyclopentyl)-1-phenylethanone (51). Following the procedure used for the synthesis of 1-(2-acetylcyclopentyl)propan-2-one 49, cyclopentane 51 was obtained from

47 enone 48 (100 mg, 0.34 mmol) as a diastereomeric mixture (syn:anti 1:22) in 94% yield (956 mg).34 + Syn-51: HRMS (EI) m/z calc. for C20H20O2 (M ) 292.1463, found 292.1462. Anal. Calcd.

For C20H20O2: C, 82.16; H, 6.89. Found: C, 82.02; H, 6.91. + Anti-51: HRMS (EI) m/z calc. for C20H20O2 (M ) 274.1463, found 274.1565. Anal. Calcd.

For C20H20O2: C, 82.16; H, 6.89. Found: C, 82.20; H, 6.86.

Methyl 2-(2-acetylcyclopentyl)acetate (59). Enone 57 (100 mg, 0.549 mmol), tributyltin hydride (176 mg, 0.604 mmol, 1.1 equiv), and azobis(isobutyronitrile) (18.0 mg, 0.11 mmol, 0.2 equiv) were added to a reaction tube under argon. The mixture was dissolved in benzene (0.09 mL) and degassed for 15 min. under a stream of argon. The solution in the sealed tube was stirred under the conditions noted in Table 5. After dilution with THF (0.1 M), tetrabutylammonium bromide (354 mg, 0.11 mmol) was added to the solution. The reaction was stirred for 12 h at 60 °C. After addition of MeOH (2 mL), the reaction mixture was stirred for 30 min. and concentrated in vacuo. The residue was purified by flash column chromatography to afford a mixture of syn- and anti-59 (1:1.8, 554 mg, 55%) along with stannane 61 (10 mg). 1 Syn-59: H NMR (500 MHz, C6D6): δ 3.31 (s, 3H, CO2CH3), 2.63 (ddd, J = 7.2, 7.3, 7.7,

1H, CH3C=OCH), 2.42 (ABd, JAB = 15.3, J = 7.3, 1H, CHHCO2CH3), 2.37 (partly obscured dtt, J = 7.0, 7.0, 7.2, 1H, CHCH2CO2CH3), 2.16 (ABd, JAB = 15.3, J = 6.7, 1H,

CHHCO2CH3), 1.78 (s, 3H, C=OCH3), 1.69 (tdd J = 6.8, 8.6, 14.8, 1H,

CHHCHCH2CO2CH3), 1.62-1.53 (m, 2H, cyclopentane H), 1.51-1.40 (m, 2H, cyclopentane 13 H), 1.34-1.25 (m, 1H, cyclopentane H). C NMR (75 MHz, C6D6): δ 209.3, 173.1, 53.7, 50.9, 39.2, 35.1, 32.0, 30.7, 27.9, 23.3. IR (neat, NaCl): 2953, 2873, 1737, 1706, 1436, -1 + 1367, 1257, 1171 cm . HRMS (EI) m/z calc. for C10H16O3 (M ) 184.1100, found 184.1100.

Anal. Calcd. For C10H16O3: C, 65.19; H, 8.75. Found: C, 65.22; H, 8.90. 1 Anti-59: H NMR (500 MHz, C6D6): δ 3.32 (s, 3H, CO2CH3), 2.61 (ttd, J = 7.5, 7.7, 7.7,

1H, CHCH2CO2CH3), 2.20 (obscured ddd, J = 7.3, 8.1, 8.9, 1H, CH3C=OCH), 2.16 (ABd,

JAB = 15.0, J = 7.3, 1H, CHHCO2CH3), 2.06 (ABd, JAB = 15.0, J = 7.3, 1H, CHHCO2CH3),

48 1.79 (s, 3H, C=OCH3), 1.76 (m, 1H, CHHCHCH2CO2CH3), 1.52-1.27 (m, 4H, 13 cyclopentane H), 1.02 (dtd J = 7.8, 8.2, 12.4, 1H, CHHCHCH2CO2CH3). C NMR (75

MHz, C6D6): δ 210.4, 173.0, 57.8, 51.5, 39.2, 38.3, 32.6, 29.8, 28.9, 24.6. IR (neat, NaCl): 2952, 2871, 1738, 1709, 1436, 1359, 1251, 1197, 1163 cm-1. HRMS (CI) m/z calc. for + C10H17O3 (M + 1) 185.1178, found 185.1177. Anal. Calcd. For C10H16O3: C, 65.19; H, 8.75. Found: C, 65.26; H, 8.94. 1 61: H NMR (500 MHz, CDCl3): δ 3.62 (s, 3H, CO2CH3), 2.89 (dd, J = 8.3, 9.6, 1H,

CHCO2CH3), 2.65 (dtt, J = 7.0, 7.2, 7.4, 1H, CHCH2C=OCH3), 2.59 (dd, J = 7.0, 16.9, 1H,

CHHC=OCH3), 2.37 (dd, J = 7.2, 16.9, 1H, CHHC=OCH3), 2.10 (s, 3H, C=OCH3), 2.03 (dtd J = 3.5, 8.0, 12.4, 1H, SnCHCHH), 1.90 (dtd J = 3.2, 7.2, 12.1, 1H,

CHHCHCH2C=OCH3), 1.71 (ddd, J = 8.3, 9.7, 11.0, 1H, SnCH), 1.58-1.50 (m, 1H,

SnCHCHH), 1.48-1.42 (m, 6H, (CH3CH2CH2CH2)3Sn), 1.35-1.28 (obscured m, 7H,

CHHCHCH2COCH3, (CH3CH2CH2CH2)3Sn), 0.89 (t, J = 7.3, 9H, (CH3CH2CH2CH2)3Sn), 13 0.82 (obscured t, J = 8.3, 6H, (CH3CH2CH2CH2)3Sn). C NMR (75 MHz, CDCl3): δ 207.9, 176.2, 51.3, 50.8, 45.2, 38.4, 33.4, 30.2, 29.9, 29.2, 27.5, 25.3, 13.7, 8.4. IR (neat, NaCl): 2954, 2925, 2871, 2854, 1729, 1463, 1434, 1376, 1359, 1165 cm-1. HRMS (CI) m/z calc. + for C22H43O3Sn (M + 1) 475.2234, found 475.2251. Anal. Calcd. For C22H42O3Sn: C, 55.83; H, 8.94. Found: C, 56.12; H, 8.95.

Methyl 2-(2-benzoylcyclopentyl)acetate (62). Following the procedure used for the synthesis of 59 and conditions in Table 5, cyclopentane 62 (74.5 mg, 82%) was obtained from enone 58 (90 mg) as a diastereomeric mixture (syn:anti 1:5.8). 1 Syn-62: H NMR (500 MHz, CDCl3): δ 7.96 (m, 2H, aromatic H), 7.55 (tt, J = 1.3, 7.5, 1H, aromatic H), 7.46 (m, 2H, aromatic H), 3.97 (ddd, J = 7.0, 7.4, 7.5, 1H, PhC=OCH), 3.49 (s,

3H, CO2CH3), 2.75 (dtt, J = 7.5, 7.6, 7.7, 1H, CHCH2CO2CH3), 2.31 (ABd JAB = 13.2, J =

7.3, 1H, CHHCO2CH3), 2.28 (ABd, JAB = 13.2, J = 8.3, 1H, CHHCO2CH3), 2.09-2.02 (m, 1H, cyclopentane H), 1.98-1.85 (m, 3H, cyclopentane H), 1.72-1.59 (m, 2H, cyclopentane 13 H). C NMR (75 MHz, CDCl3): δ 202.6, 173.4, 137.7, 132.9, 128.6, 128.2, 51.3, 48.2, 40.0, 35.4, 32.3, 28.9, 23.7. IR (neat, NaCl): 2952, 2871, 1975, 1738, 1681, 1596, 1580, 1447,

49 -1 + 1372, 1219, 1002, 697 cm . HRMS (CI) m/z calc. for C15H19O3 (M + 1) 247.1334, found

247.1328. Anal. Calcd. For C15H18O3: C, 73.15; H, 7.37. Found: C, 73.16; H, 7.37. 1 Anti-62: H NMR (500 MHz, CDCl3): δ 7.96 (m, 2H, aromatic H), 7.55 (tt, J = 1.3, 7.3, 1H, aromatic H), 7.47 (m, 2H, aromatic H), 3.55 (s, 3H, CO2CH3), 3.52-3.48 (m, 1H,

PhC=OCH), 2.87 (dtt, J = 7.7, 7.8, 8.2, 1H, CHCH2CO2CH3), 2.43 (ABd, JAB = 14.7, J =

7.0, 1H, CHHCO2CH3), 2.36 (ABd, JAB = 14.7, J = 7.7, 1H, CHHCO2CH3), 2.17-2.03 (m, 2H, cyclopentane H), 1.80-1.70 (m, 3H, cyclopentane H), 1.41 (tdd, J = 8.2, 8.6, 12.4, 1H, 13 CHHCHCH2CO2CH3). C NMR (75 MHz, CDCl3): δ 202.0, 172.9, 137.0, 132.8, 128.5, 128.3, 51.8, 51.3, 39.0, 38.8, 32.6, 31.5, 24.7. IR (neat, NaCl): 2951, 2871, 1972, 1738, -1 1681, 1597, 1580, 1448, 1374, 1221, 1002, 701 cm . HRMS (EI) m/z calc. for C15H18O3 + (M ) 246.1256, found 246.1255. Anal. Calcd. For C15H18O3: C, 73.15; H, 7.37. Found: C, 73.09; H, 7.49.

Methyl 2-(2-(3-phenylpropanoyl)cyclopentyl)acetate (70). Following the procedure used for the synthesis of 59 and conditions in Table 8, cyclopentane 70 was obtained from enone 69 (100 mg) as a 1:1 diastereomeric mixture in 42% yield (437 mg). 1 Syn-70: H NMR (500 MHz, CDCl3): δ 7.29-7.16 (m, 5H, aromatic H), 3.62 (s, 3H,

CO2CH3), 3.07 (ddd, J = 7.2, 7.3, 7.3, 1H, CH2C=OCH), 2.91-2.69 (m, 4H, PhCH2CH2CO),

2.55 (tdd, J = 7.3, 7.3, 7.3, 1H, CHCH2CO2CH3), 2.32 (ABd, JAB = 16.0, J = 7.3, 1H,

CHHCO2CH3), 2.24 (ABd, JAB = 16.0, J = 8.0, 1H, CHHCO2CH3), 1.84-1.72 (m, 4H, 13 cyclopentane H), 1.64-1.50 (m, 2H, cyclopentane H). C NMR (75 MHz, CDCl3): δ 212.2, 173.5, 141.2, 128.4, 128.3, 126.0, 53.2, 51.4, 45.5, 39.3, 35.0, 31.9, 29.5, 27.9, 23.1. IR (neat, NaCl): 3027, 2951, 1950, 1732, 1704, 1604, 1454, 1435, 1257, 1196, 1174, 700 cm-1. + HRMS (EI) m/z calc. for C17H22O3 (M ) 274.1569, found 274.1569. Anal. Calcd. For

C17H22O3: C, 74.42; H, 8.08. Found: C, 74.50; H, 8.02. 1 Anti-70: H NMR (500 MHz, CDCl3): δ 7.29-7.17 (m, 5H, aromatic H), 3.62 (s, 3H,

CO2CH3), 2.90 (obscured dd, J = 7.3, 8.3, 2H, PhCH2CH2), 2.81 (ABt, JAB = 23.8, J = 6.9,

1H, PhCH2CHH), 2.75 (ABt, JAB = 23.8, J = 7.2, 1H, PhCH2CHH), 2.59 (m, 2H,

CH2C=OCH, CHCH2CO2CH3), 2.33 (ABd, JAB = 15.2, J = 6.7, 1H, CHHCO2CH3), 2.29

50 (ABd, JAB = 15.2, J = 7.3, 1H, CHHCO2CH3), 1.97-1.88 (m, 2H, cyclopentane H), 1.67- 13 1.58 (m, 3H, cyclopentane H), 1.28 (tdd, J = 7.8, 8.0, 12.8, 1H, CHHCHCH2CO2CH3). C

NMR (75 MHz, CDCl3): δ 215.8, 177.3, 145.6, 132.8, 132.7, 130.3, 61.4, 55.8, 47.9, 43.5, 42.6, 36.9, 34.2, 34.1, 28.9. IR (neat, NaCl): 3027, 2951, 1950, 1732, 1712, 1604, 1454, -1 + 1436, 1252, 1196, 1176, 700 cm . HRMS (EI) m/z calc. for C17H22O3 (M ) 274.1569, found 274.1565. Anal. Calcd. For C17H22O3: C, 74.42; H, 8.08. Found: C, 74.46; H, 7.97.

Methyl 2-(7-oxo-octahydro-1H-inden-1-yl)acetate (72). Following the procedure used for the synthesis of 59 and conditions in Table 8, cyclopentane 72 was obtained from enone 71 (100 mg) as an inseparable mixture of diastereomers in 49% overall yield (49.1 mg).

Anal. Calcd. For C12H18O3: C, 68.54; H, 8.63. Found: C, 68.51; H, 8.68.

Methyl 2-(2-acetyl-octahydro-1H-inden-1-yl)acetate (74). Following the procedure used for the synthesis of 59 and conditions in Table 8, cyclopentane 74 was obtained from enone 73 (100 mg) as an inseparable mixture of diastereomers in 41% overall yield (41.1 mg).

Anal. Calcd. For C14H22O3: C, 70.56; H, 9.30. Found: C, 70.44; H, 9.25.

2-(2-Acetylcyclopentyl)acetonitrile (78). Following the procedure used for the synthesis of 59 and conditions in eq 26, cyclopentane 78 was obtained from enone 76 (100 mg) as a diastereomeric mixture (syn:anti 1:11) in 54% yield (550 mg). 1 Syn-78: H NMR (300 MHz, CDCl3): δ 3.12 (ddd, J = 6.5, 6.8, 7.8, 1H, CH3C=OCH),

2.55-2.34 (m, 3H, CHCH2CN), 2.22 (s, 3H, C=OCH3), 2.00-1.64 (m, 5H, cyclopentane H), 1.36-1.23 (m, 1H, cyclopentane H). 1 Anti-78: H NMR (500 MHz, CDCl3): δ 2.69 (ddd, J = 8.4, 8.5, 8.9, 1H, CH3C=OCH),

2.55-2.51 (m, 1H, CHCH2CN), 2.50 (ABd, JAB = 16.8, J = 5.1, 1H, CHHCN), 2.42 (ABd,

JAB = 16.8, J = 6.4, 1H, CHHCN), 2.20 (s, 3H, C=OCH3), 2.18-2.11 (m, 1H,

CH3C=OCHCHH), 1.99 (dtd J = 4.8, 7.7, 12.4, 1H, CHHCHCH2CN), 1.82-1.65 (m, 3H, 13 cyclopentane H), 1.51 (dtd J = 7.5, 8.6, 12.4, 1H, CHHCHCH2CN). C NMR (75 MHz,

C6D6): δ 209.0, 118.5, 56.8, 36.8, 31.5, 29.9, 29.2, 24.1, 21.7. IR (neat, NaCl): 2958, 2873,

51 -1 + 2246, 1707, 1425, 1357, 1171 cm . HRMS (CI) m/z calc. for C9H14ON (M + 1) 152.1075, found 152.1073. Anal. Calcd. For C9H13ON: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.59; H, 8.62; N, 9.13.

2-(2-Benzoylcyclopentyl)acetonitrile (79). Following the procedure used for the synthesis of 59 and conditions in eq 26, cyclopentane 79 was obtained from enone 77 (100 mg) as a diastereomeric mixture (syn:anti 1:6) in 88% yield (891 mg). 1 Syn-79: H NMR (500 MHz, CDCl3): δ 7.96 (m, 2H, aromatic H), 7.59 (m, 1H, aromatic H), 7.49 (t, J = 7.8, 2H, aromatic H), 3.96 (ddd, J = 7.4, 7.5, 7.7, 1H, PhC=OCH), 2.64 (dtt,

J = 7.5, 7.5, 7.8, 1H, CHCH2CN), 2.36 (d, J = 8.0, 2H, CH2CN), 2.11-1.97 (m, 3H, 13 cyclopentane H), 1.94-1.71 (m, 3H, cyclopentane H). C NMR (75 MHz, CDCl3): δ 201.3, 136.9, 133.5, 128.8, 128.5, 128.3, 119.3, 48.3, 40.2, 31.8, 28.8, 23.3, 18.8. IR (neat, NaCl): 3061, 2956, 2873, 2245, 1674, 1596, 1580, 1448, 1226, 1002 cm-1. HRMS (EI) m/z calc. + for C14H15ON (M ) 213.1154, found 213.1157. Anal. Calcd. For C14H15ON: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.46; H, 7.14; N, 6.39. 1 Anti-79: H NMR (500 MHz, CDCl3): δ 7.97 (m, 2H, aromatic H), 7.58 (tt, J = 1.3, 7.3, 1H, aromatic H), 7.48 (m, 2H, aromatic H), 3.53 (ddd, J = 8.0, 8.0, 8.5, 1H, PhC=OCH), 2.83

(br m, 1H, CHCH2CN), 2.55 (ABd, JAB = 16.9, J = 4.8, 1H, CHHCN), 2.43 (ABd, JAB = 16.9, J = 6.4, 1H, CHHCN), 2.29-2.23 (m, 1H, PhC=OCHCHH), 2.12-2.06 (dddd, J = 4.0,

7.5, 7.5, 12.0, 1H, CHHCHCH2CN), 1.88-1.83 (m, 1H, CH2CHHCH2), 1.81-1.71 (m, 1H, 13 PhC=OCHCHHCHH), 1.63 (tdd, J = 7.7, 11.1, 12.5, 1H, CHHCHCH2CN). C NMR (75

MHz, CDCl3): δ 200.8, 136.3, 133.2, 128.6, 128.4, 118.5, 51.3, 37.5, 31.5, 24.4, 21.3. IR (neat, NaCl): 3060, 2955, 2872, 2245, 1678, 1597, 1580, 1448, 1222, 1002, 700 cm-1. + HRMS (EI) m/z calc. for C14H15ON (M ) 213.1154, found 213.1154. Anal. Calcd. For

C14H15ON: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.80; H, 7.18; N, 6.59.

APPENDIX

53 O Ph MeO O 54

Figure 1. 500 MHz 1H NMR Spectrum of Enone 58

O Ph MeO O 55

Figure 2. 75 MHz 13C Spectrum of Enone 58

O Ph MeO O 56

Figure 3. IR Spectrum of Enone 58

Ph O OOMe 57

Figure 4. 500 MHz 1H NMR Spectrum of Enone 69

Ph O OOMe 58

Figure 5. 75 MHz 13C Spectrum of Enone 69

Ph O OOMe 59

Figure 6. IR Spectrum of Enone 69

O OMe O 60

Figure 7. 500 MHz 1H NMR Spectrum of Enone 71

O OMe O 61

Figure 8. 75 MHz 13C Spectrum of Enone 71

O OMe O 62

Figure 9. IR Spectrum of Enone 71

OMe

OH 63

Figure 10. 500 MHz 1H NMR Spectrum of Alcohol 87

OMe

OH 64

Figure 11. 75 MHz 13C Spectrum of Alcohol 87

OMe

OH 65

Figure 12. IR Spectrum of Alcohol 87

OMe

O 66

Figure 13. 500 MHz 1H NMR Spectrum of Enone 73

OMe

O 67

Figure 14. IR Spectrum of Enone 73

CN 68

Figure 15. 500 MHz 1H NMR Spectrum of Enone 76

CN 69

Figure 16. IR Spectrum of Enone 76

Ph CN 70

Figure 17. 500 MHz 1H NMR Spectrum of Enone 77

Ph CN 71

Figure 18. IR Spectrum of Enone 77

O O 72

Figure 19. 500 MHz 1H NMR Spectrum of syn-49

O O 73

Figure 20. 75 MHz 13C Spectrum of syn-49

O O

Figure 21. IR Spectrum of syn-49

O O 75

Figure 22. 500 MHz 1H NMR Spectrum of anti-49

O O 76

Figure 23. 75 MHz 13C Spectrum of anti-49

O O

Figure 24. IR Spectrum of anti-49

O OPh 78

Figure 25. 500 MHz 1H NMR Spectrum of syn-51

O OPh 79

Figure 26. 75 MHz 13C Spectrum of syn-51

O OPh 80

Figure 27. IR Spectrum of syn-51

O OPh 81

Figure 28. 500 MHz 1H NMR Spectrum of anti-51

O OPh 82

Figure 29. 75 MHz 13C Spectrum of anti-51

O OPh 83

Figure 30. IR Spectrum of anti-51

O OOMe 84

Figure 31. 500 MHz 1H NMR Spectrum of syn-59

O OOMe 85

Figure 32. 75 MHz 13C Spectrum of syn-59

O OOMe 86

Figure 33. IR Spectrum of syn-59

O OOMe 87

Figure 34. 500 MHz 1H NMR Spectrum of anti-59

O OOMe 88

Figure 35. 75 MHz 13C Spectrum of anti-59

O OOMe 89

Figure 36. IR Spectrum of anti-59

Bu3Sn MeO

O O 90

Figure 37. 500 MHz 1H NMR Spectrum of 61

Bu3Sn MeO

O O 91

Figure 38. 75 MHz 13C Spectrum of 61

Bu3Sn MeO

O O 92

Figure 39. IR Spectrum of 61

O OOMe 93

Figure 40. 500 MHz 1H NMR Spectrum of syn-62

O OOMe 94

Figure 41. 75 MHz 13C Spectrum of syn-62

O OOMe 95

Figure 42. IR Spectrum of syn-62

O OOMe 96

Figure 43. 500 MHz 1H NMR Spectrum of anti-62

O OOMe 97

Figure 44. 75 MHz 13C Spectrum of anti-62

O OOMe 98

Figure 45. IR Spectrum of anti-62

O OOMe 99

Figure 46. 500 MHz 1H NMR Spectrum of syn-70

O OOMe 100

Figure 47. 75 MHz 13C Spectrum of syn-70

O OOMe 101

Figure 48. IR Spectrum of syn-70

O OOMe 102

Figure 49. 500 MHz 1H NMR Spectrum of anti-70

O OOMe 103

Figure 50. 75 MHz 13C Spectrum of anti-70

O OOMe 104

Figure 51. IR Spectrum of anti-70

O OCN 105

Figure 52. 300 MHz 1H NMR Spectrum of syn-78

O OCN 106

Figure 53. 500 MHz 1H NMR Spectrum of anti-78

O OCN 107

Figure 54. 75 MHz 13C Spectrum of anti-78

O OCN 108

Figure 55. IR Spectrum of anti-78

O OCN 109

Figure 56. 500 MHz 1H NMR Spectrum of syn-79

O OCN 110

Figure 57. 75 MHz 13C Spectrum of syn-79

O OCN 111

Figure 58. IR Spectrum of syn-79

O OCN 112

Figure 59. 500 MHz 1H NMR Spectrum of anti-79

O OCN 113

Figure 60. 75 MHz 13C Spectrum of anti-79

O OCN 114

Figure 61. IR Spectrum of anti-79

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BIOGRAPHICAL SKETCH

Moonki Seok was born in 1970. He graduated from Korea University and received a Bachelor of Science in Chemistry in 1992. In 1994, he received a Master of Science from Korea University in Organic Chemistry. After working in the chemical industry for five years he came to Florida State University in September 2001 to pursue graduate studies in Organic Chemistry.

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