Luận án tiến sĩ: Development of metal-catalyzed silylene transfer to carbonyl compounds and applications in natural product synthesis

Table of ContentsList of Figures ViiList of Tables ViliAcknowledgements ix 2.3 Results and Discussion 15 2.3.1 Metal-Catalyzed Silylene Transfer to Esters and Ketones 152.3.2 Oxasilacycl

UNIVERSITY OF CALIFORNIA,

IRVINE

Development of Metal-Catalyzed Silylene Transfer to Carbonyl Compounds

and Applications in Natural Product Synthesis

DISSERTATION

submitted in partial satisfaction of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

in Chemistry by

Stacie Anne Calad

Dissertation Committee: Professor Keith A WoerpelProfessor Scott D RychnovskyProfessor A Richard Chamberlin

2007

UMI Number: 3243256

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publication on microfilm and digital formats:

To

my motherKathleen Calad

Thank you for your constant love and support Your caring nature and your personal

strength are an inspiration.

Table of Contents

List of Figures ViiList of Tables ViliAcknowledgements ix

2.3 Results and Discussion 15

2.3.1 Metal-Catalyzed Silylene Transfer to Esters and Ketones 152.3.2 Oxasilacyclopentene Hydrolysis 212.3.3 Reactions of Oxasilacyclopentenes 232.4 Conclusions 312.5 References 312.6 Experimental Section 34Chapter 3 Silylene Transfer to œ,B-nsaturated Esters and Subsequent Ireland—ClaisenRearrangements: Application to the Synthesis of (+)-5-epi-Acetomycin

3.1 Introduction 603.2 Background 60

3.3 Results and Discussion 69

3.3.1 Ireland—Claisen Rearrangement of Silylene Transfer Products 69

3.3.2 Functionalizations and Carbon-Silicon Bond Oxidation 723.3.3 Chirality Transfer From an Allylic Stereocenter 773.3.4 Total Synthesis of (+)-5-epi-Acetomycin 78

3.4 Conclusions ) 84

3.5 References 843.6 Experimental Section 90

3.7 X-ray Crystallographic Data 111

Chapter 4 Synthesis of (+)-epi-Stegobinone Utilizing Silacyclopropanes as Synthetic

Intermediates

4.1 Introduction 144

4.2 Background 1454.3 Results and Discussion | 150

4.4 Conclusions 1574.5 References 1584.6 Experimental Section 161

4.7 X-ray Crystallographic Data | 173

LIST OF FIGURES

Figure 2.1 Aldol transtion states for benzyl acrylate-derived oxasilacyclopentenes 30Figure 2.2 Aldol transtion states for B-substituted oxasilacyclopentenes 30Figure 2.3 Aldol transtion states for œ-substituted oxasilacyclopentenes 30

Figure 3.1 Enolization transition states 66

Figure 3.2 Silacyclopropene product | 71

Figure 3.3 Trajectory of nucleophilic attack on a silalactone 73Figure 3.6.1 Transition States for Ireland—Claisen rearrangement

Figure 4.1 Stegobinone 145

Figure 4.2 Chelation of a B-benzyloxy group in syn,syn-selective aldol reactions 148

Figure 4.3 Transition state for B-benzyloxy-substituted anti,anti-selective aldol reactions

150

Figure 4.4 Antiperiplanar approach of silyl enol ether 37 152

LIST OF TABLES

Table 2.1 Oxasilacyclopentene product formation

Table 2.2 Hydrolysis of ester-derived oxasilacyclopentenes

Table 2.3 Hydrolysis of ketone-derived oxasilacyclopentenes

Table 2.4 Lewis acid screen in the aldol reaction

Table 2.5 Optimization of aldol reaction conditions

Table 3.1 Optimization of the carbonyl reduction reaction

Table 3.2 Optimization of the carbon—silicon bond oxidation

Table 3.3 Optimization of silylene transfer reactions

Table 4.1 Syn,syn-selective aldol reaction conditions

Table 4.2 Syn,syn-selective aldol reaction conditions

Table 4.3 Anti,syn-selective aldol reaction conditions |

1921222628757681147148149

First, I would like to thank my advisor, Professor Keith Woerpel, for being a wonderfulteacher and colleague You have taught me so much about chemistry, writing, and life ingeneral Thank you for your constant encouragement and guidance It has been a truepleasure working with you

I thank the faculty at UCI for their commitment to education Specifically, I would like

to thank Professor Scott Rychnovsky and Professor Dick Chamberlin for serving on mydissertation committee and for their helpful discussions over the years

The Woerpel lab has been a great place to do science and I would like to thank the groupmembers for making lab fun and interesting Dr Jelena Cirakovic was my collaborator

on the stegobinone project and I thank her for teaching me so much about catalyzed silylene transfer chemistry and also for her friendship Dr Sidd Shenoy hasbeen one of my best friends at UCI and I’ll always remember the lunches and coffeebreaks I thank Susan Billings for being a great roommate and friend over the last years.I’m looking forward to more good times out in Philly! Janice Loy has been a fabulousbaymate over the last three years and I thank her for always lending an ear I’d like tothank all of my close girlfriends in the lab for all the fun lunches, cupcake runs, andnights out: Dr Laura Anderson, Laura Bourque, Dr Pamela Cleary, Renee Link, SarahLudlum, and Dr Deborah Smith Other past and present lab members that I would like tothank include Dr Jason Tenenbaum, Dr Tim Clark, Matt Beaver, Jason Harris, BrettHoward, Nick Leonard, Zulimar Nevarez, Armando Ramirez, Tony Romero, WalterSalamant, Andrew Thomas, Christian Ventocilla, and Mike Yang

metal-I thank my family and friends for all their love and support over the years metal-I never couldhave come this far without them Thank you, Mom, Dad, Cari, and Ryan for being such agreat family Thank you, Eric, for all of your patience and support over the years Also,

I would like to thank the Becker family for being so welcoming and encouraging Iwould like to thank Alexis, Amani, Amy, Ariel, Briita, Cathie, Karen, Katy, Lauren,Sarah, and Stefanie for being a great group of friends

I thank Dr John Greaves for mass spectrometry, Dr Phil Dennison for assistance withNMR spectroscopy, and Dr Joe Ziller for X-ray crystallography

I thank the National Institutes of Health for a predoctoral fellowship

Ph.D., Organic Chemistry, University of California, IrvineB.A., Chemistry, University of California, Berkeley

Graduate Research Associate, University of California, Irvine,

Thesis Advisor: Keith A WoerpelTeaching Assistant, University of California, IrvineUndergraduate Research Assistant, University of California,Berkeley, Research Advisor: Clayton H Heathcock

Chemistry Instructor, University of California, Berkeley,Mathematics, Engineering, and Science Achievement (MESA)

Summer Academy

General Chemistry Tutor, University of California, Berkeley

Honors and Awards

Women’s Chemist Committee/ Eli Lilly Travel Award

California Alumni Leadership Scholarship RecipientCollege of Chemistry Scholars Program

Delta Gamma Scholastic Excellence Award

Iota Sigma Pi, Calcium Chapter, Membership Activities Coordinator

Girls, Inc., presented hands-on chemistry experiments

Orange County Cal Alumni Club, college fair volunteer

Ask-a-Scientist Night, Irvine Unified School District

Publications and Presentations

7, ‘Formation of Chiral Quaternary Carbon Stereocenters by Silylene Transfer:

Enantioselective Total Synthesis of (+)-5-epi-Acetomycin.” S A Calad, K A

Woerpel Manuscript in preparation

“Synthesis of (+)-epi-Stegobinone Utilizing Silacyclopropanes as Synthetic

Intermediates.” § A Calad, J Cirakovié, K A Woerpel J Org Chem., in

press.

“Silylene Transfer to Carbonyl Compounds and Subsequent Aldol Reactions andIreland—Claisen Rearrangements,” S A Calad and K A Woerpel Presented atthe Graduate Student and Postdoctoral Colloquium, University of California,Irvine, October 7, 2005

“Silylene Transfer to Carbonyl Compounds and Subsequent Ireland—ClaisenRearrangements to Control Formation of Quaternary Carbon Stereocenters.” S

A Calad, K A Woerpel, J Am Chem Soc 2005, 127, 2046-2047

“Metal-Catalyzed Silylene Transfer to Carbonyl Compounds,” S A Calad and K

A Woerpel, Presented at the 228th National Meeting of the American ChemicalSociety, Philadelphia, PA, August 2004; paper ORGN 336.

“Investigations into the Metal-Catalyzed Reactions ofCyclohexenesilacyclopropane in the Presence of Carbonyl Compounds,” S A.Calad and K A Woerpel Presented at the Graduate Student and PostdoctoralColloquium, University of California, Irvine, April 2003

“Metal-Catalyzed Synthesis and Reactions of Silacyclopropanes: New Reactions

and Stereoselective Methods for Organic Synthesis,” K A Woerpel, S A Calad,

J Cirakovié, T B Clark, T G Driver, and S G Ludlum Presented at the 225"National Meeting of the American Chemical Society, New Orleans, LA, March

2003; paper ORGN 001

Abstract of Dissertation

Development of Metal-Catalyzed Silylene Transfer to Carbonyl Compounds and

Applications in Natural Product Synthesis

ByStacie Anne CaladDoctor of Philosophy in ChemistryUniversity of California, Irvine, 2007Professor Keith A Woerpel

Silylene transfer products can undergo stereoselective carbon-carbon bond-formingreactions, including the generation of quaternary carbon stereocenters, which demonstratetheir utility in synthetic organic chemistry Our laboratory has developed a metal-catalyzed method for di-tert-butylsilylene transfer to an alkene, providing

silacyclopropane products This dissertation describes the application of the

metal-catalyzed silylene transfer conditions to carbonyl compounds Metal-metal-catalyzed silylenetransfer to a range of œ,-unsaturated esters proved to be a general method for theformation of oxasilacyclopentene products containing a cyclic silyl ketene acetalfunctionality These oxasilacyclopentenes are useful synthetic intermediates that canundergo facile and selective aldol addition reactions and Ireland—Claisen rearrangements

to provide products with multiple contiguous stereocenters and quaternary carbon

centers By applying this methodology to enantiomerically pure esters, productscontaining chiral quaternary carbon centers have been accessed, and the total synthesis of

(+)-5-epi-acetomycin has been achieved

Chapter One:

Silylene Transfer to Carbonyl-Containing Compounds

Over the past 30 years, the reaction of silylenes (R2Si) with carbonyl compoundshas been studied extensively While several examples of stable silylenes exist, they aretypically transient species that can be generated by thermolysis, photolysis, or metal-catalysis Silylenes can react with the carbon-oxygen double bond of aldehydes, ketones,and esters to provide oxasilacyclopropane and silacarbonyl ylide intermediates Thesereactive compounds can undergo further transformations to provide cyclic siloxane andsilyl enol ether products The reactions of silylenes with carbonyl compounds oftenrequire harsh conditions or a large excess of carbonyl substrates, which restrict thesynthetic utility of these transformations

Two examples of isolated oxasilacyclopropane products derived from silylene

transfer to a ketone have been reported.'” Silylene transfer to hindered ketone 2 under

photolytic conditions provided sterically encumbered oxasilacyclopropane 4, whose

structure was confirmed by X-ray crystallography (eq 1)! Belzner and coworkers

isolated oxasilacyclopropane 8 from the thermal silylene transfer reaction ofcyclotrisilane 5 with adamantanone (eq 2).” The steric hindrance around the silicon atomand on the ketones stabilized the oxasilacyclopropanes and allowed for their isolation

Me Me Me Me

Me3Si Mes + hv Mes SiMes; (1)

Me,Si7~ Mes Cre Mes°" 61% ie]1 Me Me 3 Miig Me

2 4

Ar2 0 60°C

ay AraSi—SIiAr¿

through an initial electrophilic attack of the free silylene to the oxygen atom of the

carbonyl group, providing zwitterionic intermediate 9 (eq 3).’ Theoretical calculations

also support the formation of an oxasilacyclopropane from an initially-formed

Several reactions of oxasilacyclopropane 4 have been demonstrated, but are of

limited synthetic utility.”* Photolysis of oxasilacyclopropane 4 in the presence of

tetracyanoethylene (a known electron-transfer reagent) provided indene 12 and silanediol

13 as the major products (eq 4) Carbene 10 and silanone 11 were proposed asintermediates in the reaction A 1,2-methyl migration in carbene 10 would explain theformation of product 12 A different fragmentation pattern was observed whenoxasilacyclopropane 4 was photolyzed in the presence of methanol Under these reactionconditions, methanolysis product 14 was obtained in addition to ketone 2 (Scheme 1).When oxasilacyclopropane 4 was photolyzed in the presence of adamantanone,dioxasilacyclopentane 15 was isolated (Scheme 1) Ando and coworkers proposed that afree silylene (3) was liberated from oxasilacyclopropane 4 upon photolysis and this

intermediate reacted further with MeOH or adamantanone The formation of siloxane 15

can be explained by the formation of a new adamantanone-derived oxasilacyclopropane(similar to oxasilacyclopropane 8), which undergoes an insertion of a second ketone

intermediate (eq 5)” Belzner observed silylene transfer from cyclotrisilane 5 to

fluorenone to produce siloxane 23 with different connectivity than the derived products (eq 6).? This result was attributed to the formation of an ylide (22) with

adamantanone-a positively chadamantanone-arged silicon center adamantanone-and negadamantanone-ative chadamantanone-arge density locadamantanone-alized adamantanone-at the cadamantanone-arboncenter Similar results have been observed with metal-catalyzed silylene transfer from a

silacyclopropane (eq 7)'° and in the reaction of a stable silylene with benzaldehyde (eq

8).U

Structurally similar compounds have been synthesized from silylene transfer to

1,2-điketones.''! Thermal silylene transfer to benzil possibly occurred through an

oxasilacyclopropane intermediate!! that rearranged to form product 31 (eq 9).! Similar

products have been obtained with diimines and a-ketoimines,'® but no further reactivity

of these silacycles has been explored

1?) P

Ph h o.§ OMe M OMe

MeQ OMe 400°C Me, Ỗ >SiMe AI

nucleophilic, was thought to react through an oxasilacyclopropane intermediate to

provide siloxane 33 as a single diastereomer (eq 10).!! On the other hand, Komatsu

proposed silacarbonyl ylide 34 as the reactive intermediate in the reaction of

photochemically-generated dimesitylsilylene with crotonaldehyde (eq 11) The ylide

intermediate (34) was trapped by the carbon-carbon double bond of crotonaldehyde toafford oxasilacyclopentane 35 and by the carbonyl group to providedioxasilacyclopentane 36

0 o

CsMes C:Me |4 OWMesCs)2Sik ——————= ye CoMeg

(MesCs)2 HA ate 54% le)

26 |

32 Me

dae | tte’ » |

Me3Si., Mes _ H Me Mes~ŠF 2 Mes, 0 Mes 0

MesSi "Mes — ny | Mes ò (11)

1 34

(10)

35 36 Me

27% 25%

Seyferth and cowokers observed that reactions of aliphatic ketones with silylenes

produced dioxadisilacyclohexene products, but only in the presence of a tertiary

phosphine.'® Originally, a Wittig-type reaction was expected to occur, but when a

solution of silacyclopropane 37 was heated in the presence of triphenylphosphine and

acetone, siloxane 38 was obtained (eq 12) The phosphine was recovered from the

reaction unchanged, but it proved to be a necessary component since no product wasobtained when the phosphine was eliminated from the reaction mixture The proposed

mechanism for this transformation involves interaction of the phosphine and

silacyclopropane 37 to produce dimethylsilylenephosphorane 39 and an alkene (Scheme

2) Silylenephosphorane 39 reacted with acetone to provide intermediate 40, which

underwent elimination of phosphine to afford oxasilacyclopropane 41 This intermediateoxasilacyclopropane can dimerize to provide product siloxane 38.

a yl Số MezC-Q \ |Mac-b Me,C 0

Me Me

j

Me Me

In the absence of a tertiary phosphine, the reaction of silylene with aliphatic

ketones provided silyl enol ethers Under gas-phase pyrolysis (eq 13)!” or photolysis

conditions (eq 14),? 20 silylene transfer to enolizable ketones likely occurred throughoxasilacyclopropane or silacarbonyl ylide intermediates Silylene transfer fromcyclotrisilane 49 resulted in the formation of oxasilacyclopropane 52 and disilaoxetane

53 that rearranged to produce the corresponding silyl and disilyl enol ethers (eq 15) Noreactions of these silyl enol ethers have been reported

42 43 44

ọ Ph Ph SiMea

A ỌO Ph ©_ Ši-SIM Sí`eử Sic SiMe: Si.

(Megsijgsiph = Ft) S-gite, = G 9° —> Gu (14) hv | Et~ `Et A A Me

45 A6 Et~ `Et Et

47 48

Oxasilacyclopentene products containing a cyclic silyl enol ether functionality

were obtained from the reaction of œ,B-unsaturated esters and ketones with silylene.'*

'520 Methyl acrylate reacted with a photolytically-generated silylenes to produce silyloxy

ether 58, likely through silacarbonyl ylide 56 and oxasilacyclopentene 57 (eq 16)

Phenyl and methyl ketones afforded cyclic silyl enol ether products under thermal

weơZ eo og SiMej_ ¿PrOH

-(MeaSi);SiPh — We Wok) — ` OiPr

Aryl ketones reacted with silylenes to provide oxasilacyclopentene products just

as œ,B-unsaturated carbonyl compounds had Treatment of benzophenone with a variety

of silylenes afforded products in which the carbonyl group and the aryl ring had beenfunctionalized Ando and coworkers suggested that a transient oxasilacyclopropane

intermediate was formed in the reaction of thermally-generated dimethylsilylene withbenzophenone (eq 18).!° Oxasilacyclopropane 62 could then undergo a [1,3]-silyl

migration to the phenyl group to afford oxasilacyclopentane 64 after rearomatization.

Similar results were obtained in the reaction of a diarylsilylene.”'? In the reaction of

stable silylene 26, [1,3]-silyl migration-product 65 was isolated and no rearomatization

was observed (eq 19)."

Me; tị Me; Me;

ketones with silylene has been reported for allylic ethers Tortorelli and Tzeng

observed the formation of allyl silane products in the reaction of allylic ethers and

silylenes, and they proposed that the reaction occurred through an ylide intermediate.?!?2

For example, when dodecamethylcyclohexasilane 16) was photolyzed in the presence of

allylic ether 68, allyl silane 70 was obtained, presumably through a [2,3]-sila-Wittig

22,26 A similar rearrangement was observed upon

rearrangement of ylide 69 (eq 20)

thermal silylene transfer from silacyclopropane 71 to allylic ether 73 (eq 21) Allylicsilane 76 was isolated as the major product, and silacyclopropane 75 was observed in the

reaction mixture by Si NMR spectroscopy Formation of allylic silane 76 may result

directly from the silacyclopropane intermediate or through a ([2,3]-sigmatropic

rearrangement of ylide 74 Ishikawa also observed silacyclopropanes in the formation ofallylic silanes from the reaction of photochemically-generated silylenes with allylic

ethers.?

Silacarbonyl ylide intermediates tethered to an alkene participate in

‘227 Photolysis of silane 1 in theintramolecular 1,3-dipolar cycloaddition reactions

presence of unsaturated aldehyde 77 (30 equivalents) afforded cycloadduct 79, likelythrough silacarbonyl ylide 78 (eq 22) The tether length was also adjusted to afford bothsix- and four-membered bicylic ring structures When aldehyde 80, which contains no œ-substituents, was subjected to the silylene transfer conditions, a mixture of silyl enol ether

82 and cycloadduct 81 was obtained (eq 23) The utility of this dipolar cycloadditionreaction is restricted by the requirement for a large excess of the substrate and the limited

MoySi.MeS _ ñy „ Mes, ————~ Ms + N (23)

MeaSi Mes pol (30 equiv) Mes~

1 Mes ⁄

3 81 82

Extensive research has been conducted on the reaction of silylenes with containing compounds Oxasilacyclopropanes have been isolated as products andobserved as intermediates in silylene transfer reactions Silacarbonyl ylide intermediateshave also been proposed in these transformations Although a variety of products can beobtained from the reactions of silylene with carbonyl compounds, the application of thesetransformations to the synthesis of complex organic compounds has not been developed.Limitations to the synthetic utility of these reactions include restricted substrate scope,low product yields, and harsh conditions required for the silylene transfer.

Energy Surface." J Phys Chem 1999, 103, 4457-4464

(5) Becerra, R.; Cannady, J P.; Walsh, R "The gas-phase reaction of silylene with

acetaldehyde." Phys Chem Chem Phys 2001, 3, 2343-2351

(6) Gordon, M S.; George, C "Theoretical Study of Methylsilanone and Five of ItsIsomers." J Am Chem Soc 1984, 106, 609-611

(7) Ando, W.; Hamada, Y.; Sekiguchi, A "Reactions of Oxasilacyclopropane.Generation of Silanediyl by Photo and Thermal Induced Cycloelimination.” J Chem

Soc., Chem Commun 1983, 952-954

(8) Ando, W.; Hamada, Y.; Sekiguchi, A "Photosensitized Decompositions of

Oxasilacyclopropane; Unusual Carbene Formation." Tetrahedron Lett 1984, 25,

5057-5060

(9) Ando, W.; Ikeno, M.; Sekiguchi, A "Chemistry of Oxasilacyclopropane 2

Formations of Dioxasilacyclopentanes in the Reaction of OxasilacyclopropaneDerivatives with Adamantanone and Norbornone." J Am Chem Soc 1978, 100, 3613-

3615

(10) Franz, A K.; Woerpel, K A "Stereospecifc and Regioselective Reactions ofSilacyclopropanes with Carbonyl Compounds Catalyzed by Copper Salts: Evidence for a

Transmetalation Mechanism." J 4m Chem Soc 1999, 121, 949-957

(11) Jutzi, P.; Eikenberg, D.; Bunte, E.-A.; Méhrke, A.; Neumann, B.; Stammler, H.-G

"Decamethylsilicocene Chemistry: Reaction with Representative Aldehydes and

Ketones." Organometallics 1996, 15, 1930-1934

(12) Belzner, J "Synthese und ungewohnliche Reactivität eines Cyclotrisilans." J

Organomet Chem 1992, C51-CS55

(13) Heinicke, J.; Gehrhus, B "Zur Chemie der Silylene: Cycloadditionen von

Methoxymethylsilylen mit Heterodienen." J Organomet Chem 1992, 13-21

(14) Gehrhus, B.; Lappert, M F "Chemistry of thermally stable bis(amino)silylenes."

J Organomet Chem 2001, 209-223.

(15) Gehrhus, B.; Hitchcock, P B.; Lappert, M F "The Thermally Stable Silylene

Si[{N(CH;Bu)}zC¿H:-1,2]: Reactivity toward CO Double Bonds." Organometallics

1997, 16, 4861-4864

(16) Weidenbruch, M.; Piel, H.; Peters, K.; von Schnering, H G "Silicon Compoundswith Strong Intramolecular Steric Interactions 52 Unexpected Rearrangement ofSilylene Insertion into Cycloaddition Products." Organometallics 1993, 12, 2881-2882.(17) Sakai, N.; Fukushima, T.; Minakata, S.; Ryu, I; Komatsu, M "Novel Generation

of Silacarbonyl Ylides by Trapping of Silylene with Carbonyl Compounds and theirCycloaddition Leading to Silaheterocycles." J Chem Soc., Chem Commun 1999, 1857-

1858

(18) Seyferth, D.; Lim, T F O "Reactions of Hexamethylsilacyclopropane withCarbonyl Compounds in the Presence of Tertiary Phosphines The Possible Intermediacy

of a Dimethylsilylenephosphorane." J Am Chem Soc 1978, 100, 7074-7075

(19) Ando, W.; Ikeno, M.; Sekiguchi, A "Evidence of the Formation ofOxasilacyclopropane from the Reaction of Silylene with Ketone." J Am Chem Soc

1977, 99, 6447-6449.

(20) Ishikawa, M.; Nakagawa, K.-L; Kumada, M "Photolysis of Organopolysilanes.Reactions of Trimethylsilylphenylsilylene with Carbonyl Compounds." J Organomet.Chem 1977, C45-C49

(21) Tortorelli, V J.; Jones, J., M "Reaction of Dimethylsilylene with Allyl Ethers." J.Chem Soc., Chem Commun 1980, 785-786

(22) Tzeng, D.; Weber, W P "Regiospecific Synthesis of AllylicDimethylmethoxysilanes." J Org Chem 1980, 46, 693-696

(23) Ishikawa, M.; Nakagawa, K.; Kumada, M "Photolysis of Organopolysilanes.Reactions of Trimethylsilylphenylsilylene with Allylic Halides and Allyl Ethyl Ether." J.Organomet Chem 1981, 277-288

(24) Ishikawa, M.; Katayama, S.; Kumada, M "Photolysis of Organopolysilanes The

Reaction of Silylenes with Allyl Ethyl Ether." J Organomet Chem 1983, 251-260

(25) Palmer, W S "The Chemistry of Di-tert-butylsiliranes: Investigations of Opening, Ring-Expansion, and Silylene Transfer Reactions to Form VariousOrganosilanes." Ph.D Thesis, University of California, Irvine, 1999

Ring-(26) Kawachi, A.; Doi, N.; Tamao, K "The Sila-Wittig Rearrangement." J Am Chem

Soc 1997, 119, 233-234,

(27) Sakai, N.; Fukushima, T.; Okada, A.; Ohashi, S.; Minakata, S.; Komatsu, M.

"Intramolecular cycloaddiions of silacarbonyl ylides tethered to unactivateddipolarophiles: a new route to bicyclosilaoxolanes." J Organomet Chem 2003, 368-372

Chapter Two Metal-Catalyzed Silylene Transfer to Carbonyl Compounds

2.1 Introduction

Silylenes (R2Si) react with the carbon-oxygen double bond of carbonyl

compounds to afford a variety of products For example, silylene transfer to aldehydes

and ketones produce cyclic siloxanes’”’ and silyl enol ethers®"° via oxasilacyclopropane!!

or silacarbonyl ylide'? intermediates (see Chapter One) Reactions of silylenes with

œ,B-unsaturated ketones provide oxasilacyclopentenes containing a cyclic silyl enol ether

functionality.*'?'* Although the first reaction of a silylene with a carbonyl compoundwas reported nearly 30 years ago, these transformations have not been applied to organic

synthesis The harsh conditions required for the generation of silylenes, which include

photolysis and thermolysis, are a major obstacle to the application of silylene transfer to

the construction of valuable synthetic intermediates

Our laboratory has developed a mild, metal-catalyzed method for silylene transfer

to alkenes '*!° In our efforts to explore the functional group compatibility of this

reaction, we discovered that silylene transfer to carbonyl compounds is also a feasible

transformation using these reaction conditions This chapter describes the development

of metal-catalyzed silylene transfer to œ,B-unsaturated esters and ketones Theoxasilacyclopentenes that result from silylene transfer to œ,B-unsaturated esters undergo

alkylation and aldol reactions, which demonstrate the potential synthetic applications ofthis methodology

Scheme 1

OTIPS iM

Et 1.BnN(MeyCHO Et OTE ZN SIMOH Cul (10 mol%); 4 SnBr¿, >99%

$ ——`_—_—_ Lee = ————

si⁄“ÖU “Cusd, (aq), 53% 10-2 KH, BuOOH,

%, BU 2 Ac20, 98% :`ei-rBu BusNF, 81%

An H t-Bu

2

A metal-catalyzed method for the silacyclopropanation of alkenes has been

1516 Treatment of an alkene such as 4 with

developed in our laboratory (eq 1)

cyclohexene silacyclopropane 5 in the presence of a catalyst furnished a newsilacyclopropane 6 through metal-catalyzed silylene transfer This mild method hasshown to be tolerant of several functional groups such as benzyl and silyl ethers,pivaloate esters, and aryl groups Metal-catalyzed silylene transfer has allowed for the

synthesis of many silacyclopropanes and the development of synthetically relevant

reactions such as those shown in Scheme 1

2.3.1 Metal-Catalyzed Silylene Transfer to Carbonyl Compounds

The functional group compatibility in metal-catalyzed silacyclopropanationreactions was explored in order to extend the methodology to unsaturated carbonylcompounds If the carbonyl groups of these substrates endured the silylene transferreaction conditions, we hypothesized that silacyclopropanation of an alkene could befollowed by an intramolecular ring-expansion For example, silylene transfer to alkene 7would afford silacyclopropane 8 and insertion of the carbonyl group could provide

oxasilacyclopentane 9 (Scheme 2) Nucleophilic substitution of the resulting N,O-acetal

followed by oxidation of the carbon-silicon bond would produce alcohol 10

carbonyl additives was reported to proceed in 90% yield.'° When one equivalent of

methyl formate, dimethyl formamide, ˆ dimethylacetamide,

N.N-dimethylpropionamide, camphor, acetophenone, or ethyl acetate was added to this

reaction mixture, complex mixtures were observed by 'H NMR spectroscopic analysis.

These initial results suggested that silylene transfer to alkenes was not possible in the

presence of a variety of carbonyl additives

5 FÊU — #Buxgi (2)

AgOCOCFs (cat), Bu additive 12

Due to the successful silacyclopropanation of pivaloate ester 4 (eq 1), the silylenetransfer reaction was examined with isobutyrate 13 in the presence of a variety of metalcatalysts It was anticipated that the structural similarity of isobutyrate 13 to pivaloate 4would result in similar reactivity Instead, when isobutyrate 13 was treated withsilacyclopropane 5 and a catalytic amount of AgOTf, silylene transfer to the carbonylgroup was observed, providing silanol 14 as the major product (eq 3) Only a minor

amount of the silacyclopropane product was observed When AgOCOCF;,

(CuOTÐ;-PhMe, and Cu(OTf)2 were used as catalysts, similar results were obtained The

formation of silanol 14 by silylene transfer to the carbonyl group provides an explanation

for the failed silacyclopropanation of 1-hexene in the presence of other carbonylcompounds

A possible mechanism for the formation of silanol 14 from isobutyrate 13

involves the formation of an oxasilacyclopropane intermediate Nucleophilic attack of

the carbonyl group onto an electrophilic silver silylenoid intermediate’? likely forms asilacarbonyl ylide 15, which can cyclize to produce oxasilacyclopropane 16 Theoxasilacyclopropane may be opened by formation of an oxocarbenium ion that is

quenched upon deprotonation to form silanol 14 Analysis of the reaction mixture by 'H

NMR spectroscopy after one hour indicated the presence of an intermediate in 47%

vield.?? The resonances associated with the cyclohexene silacyclopropane /-butyl groups

(5 1.20 and 6 1.02) had completely disappeared and had collapsed into a single peak (61.16) The other resonances associated with the intermediate were of identical integration

and splitting as the starting isobutyrate, but were shifted downfield The ??Si NMR

spectrum of the reaction mixture showed peaks at § -50.3 and 8 -50.8 ppm, which are

consistent with the values expected for strained, three-membered ring silanes.”'#?!?These resonances likely correspond to oxasilacyclopropane 16 and the minor amount of

silacyclopropane byproduct The 'H NMR characteristics of the intermediate were

different than the peaks of the isolated product The presence of the isopropyl methane

proton (6 2.35 in the starting material, 6 2.45 in the intermediate) in the reaction mixturebut not in the product indicates that this proton must be removed during the aqueous

The difference in functional group reactivity of esters 4 and 13 prompted the

investigation of silylene transfer to a, -unsaturated esters to determine if both carbonyl

and alkene groups would be reactive Treatment of benzyl acrylate with silacyclopropane

metal salts that efficiently catalyze this transformation include AgOTf, Agl,(CuOT;-PhMe, and Cu(OTf)2 This reaction likely occurs by nucleophilic attack of the

carbonyl group onto an electrophilic silver silylenoid intermediate'? to form a

silacarbonyl ylide 19, which undergoes electrocyclic ring closure (eq 4).”?728

tBu

5 lems O-Si-t-Bu

A ——————> [ — (4)

pro AgOCOCF3 eno 98% eno?

18a (1-5 mol%) 19 20a

A range of a,B-unsaturated carbonyl compounds were subjected to

metal-catalyzed silylene transfer conditions to form oxasilacyclopentene (eq 5, Table 1) With

enoates 18a-f, highly reactive oxasilacyclopentenes were obtained and characterized by

NMR spectroscopy because isolation of these silyl ketene acetals proved to be

difficult.2*°° Oxasilacyclopentenes 20g-j derived from ketones 18g-j were found to be

29,30 and these compounds were isolated bymore stable than those derived from esters,

column chromatography Entry 10 is noteworthy, because silylene transfer to the

a,B-unsaturated ketone results in the synthetic equivalent of regioselective enolization.”'

In an effort to prove the structures of ester-derived oxasilacyclopentenes 20a-f,

oxasilacyclopentene 20a was isolated and recrystallized in pure form By changing the

reaction solvent from toluene to methylene chloride, oxasilacyclopentene 20a proved to

be more stable to aqueous conditions and atmospheric moisture (vide infra) When thesynthesis of oxasilacyclopentene 20 was performed in a drybox, the reaction mixture

could be filtered through Celite to remove the catalyst Lowering the catalyst load to 0.2

mol% afforded the product as a solid after filtration and concentration in vacuo.

Purification of the product was achieved by dissolving the product mixture in MeCN andwashing with hexanes to remove trace amounts of excess silacyclopropane 5 and itsdecomposition products Recrystallization of the resulting solid from n-hexane affordedoxasilacyclopentene 20a in 76% yield

Due to the increased steric bulk of the more substituted substrate, ethyl dimethylacrylate, new reactivity was observed in the silver-catalyzed silylene transferreaction Treatment of ester 21 with cyclohexene silacyclopropane 5 in the presence of acatalytic amount of AgOCOCF; provided acyl silane 22 upon aqueous workup (Scheme4) Detection of the ethoxy group by 'H NMR spectroscopic analysis of the reaction mixture suggested the presence of an intermediate oxasilacyclopropane 23°” that couldhydrolyze upon treatment with water to provide the product silane This substrate doesnot produce the previously observed oxasilacyclopentene products because the dimethylsubstituents sterically inhibit formation of the silicon—carbon bond at the B-position

3,3-Scheme 4

tBu

O Me ŠvBu O Me HO Hh AAMe

E10” `Z“`Me AgOCOCF3 t-Bu “t-Bu

in the atmosphere was sufficient to promote conversion to the silanol products

Table 2

Ca, (Bu 25 t-Bu O-Si-t-Bu HạO AA ‘OH ¬ ae O R

8 fag kK pe | R (0H @)

RoR —xooonT [ROMY ^-RÍ (1-5 mol%) R'

18a, d, e 20a,d, e 24a, d, e

Entry Oxasilacyclopentene (20) Product (24) Yield (%)

Oxasilacyclopentenes obtained by silylene transfer to œ,-unsaturated ketoneswere more stable to aqueous conditions than those derived from esters Hydrolysis ofketone derivatives 20g-i was much slower than hydrolysis of the ester derivatives.

Concentrated acid was necessary to drive the reaction to completion (Table 3) This

result is consistent with the lower nucleophilicity of silyl enol ethers compared to silyl

ketene acetals.”?””9

Table 3

Cys.

he t-Bu :

9 g TU O-Si-t-Bu | conds Oo OR oH ơi

RAR AgOCOCF3 (5 mol%) RAR R Si~-BuR" Be R" t-Bu

18g-i 20g-i 24g-i

Entry Ketone Silanol Conditions Yield (%)

an aqueous workup, silanol 25 was obtained with a deuterium atom incorporated at the

a-carbon (eq 8) This experiment provides support for our initially proposed mechanism.

When oxasilacyclopentene 20e was treated with methanol, methoxysilane 26 wasobtained (eq 9) Attack of a methoxy group onto the silicon of oxasilacyclopentene 20ewould afford a siliconate species and protonation at the a-position would provide the

methoxysilane product This same pathway likely occurs in the hydrolysis reactions withwater.

cto Me AgOCOCF3 ELOZS Mẹ 60% FIO lo188 20e : 26

When oxasilacyclopentene 20f was treated with water, B-silyl ester 27 was

obtained with 95% diastereoselectivity (eq 10)” The stereochemistry of ester 27 has not

been rigorously proven, but was assigned based on the prediction that protonation shouldoccur to the face opposite the B-methyl group.”” The high diastereoselectivity obtained inthis hydrolysis suggested that oxasilacyclopentenes might serve as useful intermediates

for stereoselective synthetic transformations

of u t-Bu o

Aa 5 tBu O-§i-£Bu | HạO jou OH

Eto” `NZM N pu ser et : Si, (19)he AgOCOCF; so” Me 70% FIO ý Ÿ~rBu

(1 mol%) Me

18f 20f 27

95:5 dr Me = t-Bu

2.3.3 Reactions of Oxasilacyclopentenes

We envisioned that oxasilacyclopentenes derived from œ,B-unsaturated carbonyl

compounds would react as silyl ketene acetals and silyl enol ethers with electrophiles.***°

To study the potential of this system, we examined alkylation reactions initially.Treatment of silyl enol ethers with primary alkyl iodides and a stoichiometric amount ofsilver trifluoroacetate has been reported alkylate the carbonyl compound at the a-

position.*° When oxasilacyclopentene 20a was treated with methyl iodide in the presence

of silver trifluoroacetate, alkylation product 28 was obtained along with the hydrolysis

product 24a (eq 11) Assuming the alkylation had not gone to completion, the reaction

time was increased from two hours to six hours, but the yield of alkylation product

decreased Alkylation of oxasilacyclopentene 20e produced silalactone 29 as the major

product, in addition to minor amounts of silanols 27 and 24e (eq 12) Addition of themethyl electrophile to the face opposite the B-methyl group of oxasilacyclopentene 20e

would provide silanol 27 with syn-stereochemistry Lactonization of this product explainsthe formation of silalactone 29

(Bu ï [on OH

O-Si-t-Bu Mel OH + mnO Sippy (9)BnO Si~y Bu:

Bno7 AgOCOCF3 Me tBu Bu

+equi

20a (equiv) 28 24a

formed in situ 47% yield 30% yield

t-Bu t-Bu, ot jee

O-Si-tBu|————~ tgự *⁄ Me †E sĩ + Eto AA sit (12) ủe Bu t-Bu

EtON AgOCOCF3 Me t-Bu (-Bu

4 equiv

206 (1 equiv) 29 24e

formed in situ 27% yield ou, yield 8% yield

The methylation of œ-substituted oxasilacyclopentenes was expected to provideproducts containing a quaternary carbon stereocenter Instead, treatment of

oxasilacyclopentene 20d with methyl iodide and AgOCOCF; provided a new

œ,B-unsaturated ester (30) in addition to hydrolysis | product 24d (eq 13) Since a

stoichiometric amount of silver trifluoroacetate was utilized for this transformation, ester

30 may result from a reaction similar to the Saegusa~Ito oxidation.” A full equivalent ofPd(OAc)2 is employed for the Saegusa—Ito oxidation, which converts a silyl enol ether to

an a,f-unsaturated carbonyl compound

t-Bu le) fe)

formed in situ 9% yield 10% yield

Since oxasilacyclopentenes behaved as nucleophilic silyl ketene acetals in

methylation reactions, the aldol reactivity of these substrates was explored.724! When

benzyl acrylate was treated with silacyclopropane 5 and a silver catalyst followed by

benzaldehyde and a Lewis acid, a single diastereomer of ring-opened aldol product 32

was obtained in addition to the ring-closed aldol products syn- and anti-31 (eq 14, Table

4) By comparison to the 'H NMR chemical shifts and coupling constants of similarly

substituted oxasilacyclopentanes previously synthesized in our laboratory, the major

diastereomer was determined to be the syn isomer.**** In all experiments, hydrolysis

product 24a was observed, but most notably in the reaction with SnCly as the Lewis acid(entry 1) This result may be due to the presence of HCl in the solution of SnCl, that wasused Lower diastereoselectivity was observed when TiCl, was used as the Lewis acid

(entry 2) compared to the tin-based Lewis acids Treatment with Me3SiOTf afforded

only the cyclized aldol product 31, but the diastereoselectivity was low (entry 4) When

boron triflouride etherate was used to promote the aldol reaction, fluorine incorporationwas seen in both products (eq 15)

fo) AgOCOCF; (cat); ack——_—> Fa + tBu (15: F BnO SỈ,|

sno Z PhCHO, "^ eu TỘBF3-OEt, (1equiv) t-Bu Ph` "OH

18a -78 to 22°C 33 34

20% yield 26% yield

With successful silylene transfer and aldol addition observed in the reaction of asimple ester, the reaction of a more substituted ester was examined Silylene transfer toethyl trans-crotonate (18e) followed by treatment with benzaldehyde and SnCl, providedaldol products with low diastereoselectivity (eq 16) When the aldol reaction was

performed with SnCl, at —78 °C for 2.5 hours, the cyclic aldol products 35 and 36 were

obtained in addition to silanol 24e Only two diastereomers of the aldol product were

observed (62:38 dr), with the major diastereomer (35) having syn,syn-stereochemistry with respect to the hydrogen substituents on the ring.*? Warming the same reaction

mixture to room temperature over 12 hours produced aldol condensation products 37 and

38 as well as aldol addition products 35 and 36 in a ratio of 86:14 (eq 17).*° Due to theseproblems of low selectivity and the formation of multiple products, the initial reaction of

benzyl acrylate was revisited to investigate the reaction more extensively

of the reagents in the first step on the second step was examined Reducing the silvertrifluoroacetate catalyst loading for the silylene transfer step provided high yields ofintermediate 20a, and lower yields of the undesired hydrolysis product (24a) in thesubsequent aldol reaction (entry 2) When this new protocol was examined with toluene

as the solvent, lower yields of the aldol products were obtained than with methylenechloride as the solvent (entry 3) In previous reactions, SnCla had provided the highestdiastereoselectivity, but also the highest yield of the undesired hydrolysis product (24a)

Using a hindered base to remove any HCl present in the SnCl, solution decreased the

amount of hydrolysis product 24a without altering the diastereomeric ratio (entry 4).Because lower catalyst loads had resulted in increased yields of the desired aldol products(entry 2), oxasilacyclopentene 20a was isolated and then treated with the new aldol