Benzopinacolate Promoted Radical Carbon-Carbon Bond Forming

Bis(trimethylstannyl)benzopinacolate Promoted Radical Carbon-Carbon Bond

Forming Reactions and Related Studies

Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy

in the Graduate School of The Ohio State University

Franklin Lee Seely

Graduate Program in Chemistry

The Ohio State University

2010

Dissertation Committee:

Robert S. Coleman, Co-Advisor

David J. Hart, Co-Advisor

T. V. RajanBabu

Abstract

This research has dealt primarily with the development of novel methods for radical carbon-carbon bond formation. A major focus of this research has been the hydrogen atom free generation of trialkyltin radicals. The bulk of this thesis will deal with the use of bis(trimethylstannyl)benzopinacolate 1 in mediating radical reactions. We have demonstrated that these conditions allow a wide variety of inter and intramolecular free radical addition reactions. We have given evidence that these reactions proceed via a novel non-chain free radical mechanism.

Dedication

This thesis is dedicated to Tracy Lynne Court.

You have given me the courage to try again.

iii

Acknowledgments

I would like to sincerely thank Dr. David J. Hart for all his help, the countless hours of work he put in, and for making this possible. I would like to thank Dr. Robert S. Coleman for agreeing to act as my advisor, and all the support and guidance he has given. I would like to than Dr. T. V. RajanBabu for reading my thesis and all his thoughtful suggestions.

Vita

Education

1981-1985 ………………………………………………………..B.S., The University of Utah 201 0 …………………………………………….……………Ph.D., The Ohio State University Major Field of Study: Chemistry Experience

1982-1985 ………………………………………Research Assistant, The University of Utah 1985-1990 …………………………………..Research Assistant, The Ohio State University 1990-1994 ………………………………….Principle Investigator, Pfizer, Central Research

Awards

Graduate Research Award – The Ohio State University ……………………………….1990 Conoco Graduate Research Fellowship – The Ohio State University ………………..1986 Special Chemistry Department Scholarship – The University of Utah …………1981-1986

Publications

Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631.

Hart, D. J.; Krishnamurthy, R.; Pook, L. M.; Seely, F. L. Tetrahedron Lett. 1993, 34, 7819.

Dener, J.M.; Hart, D. J.; Huang, H. C.; Seely, F. L.; Wu, S. C. “Radical Reactions for Use in Organic Synthesis” in Organic Free Radicals for Use in Organic synthesis” in Organic Free Radicals, Fischer, H., and Haimgartner, H., Eds, Springer Verlag, Berlin, 1989, 77.

Takacs, J. M.; Anderson, L. G.; Madhaven, G. V. B.; Seely, F. L. Angew. Chem. Chem. Int. Ed. Engl. 1987, 26, 1013.

Takacs, J. M., Helle, M.A., Seely, F. L. Tetrahedron Lett. 1986, 11, 1257.

Takacs, J. M.; Anderson, L. G.; Madhaven, G. B. V.; Creswell. M. W.; Seely, F. L.; Devroy, W. F. Organometallics 1986, 5, 2395.

Table of Contents

Abstract ………………………………………………………………………………………….ii

Dedication ………………………………………………………………………………………iii

Acknowledgments ….………………………………………………………………………….iv

Vita ………………………………………………………………………………………...... v

List of Schemes …………………………………………………………………………...... vii

List of Tables ….………………………………………………………………………………vii

Chapter 1. Introduction .…………………………………………………………………...... 1

Chapter 2. A Free Radical One Carbon Homologation .…………………………………..31

Chapter 3. Bis(trimethylstannyl)benzopinacolate Mediated Free Radical

Conjugate Additions ....……………………………………………………………….54

Chapter 4. Mechanistic Studies Concerning Bis(trimethylstannyl)benzopinacolate

Mediated Free Radical Carbon-Carbon Bond Forming Reactions …....……...…67

Chapter 5. Studies Concerning Reagent Development Using Alternative

Tin Sources and Pinacols .…..……………………………………..….………….93

Chapter 6. Experimental ……………………………………………………………………105

References……………………………………………………………………………………163

List of Schemes

Scheme 1. A Typical Chain Reaction …………………………………………...……………2

Scheme 2. Trialkyltin Hydride Mediated Conjugate Addition …..…………………………..5

Scheme 3. Mechanism of Cobalt Mediated Coupling Reactions ………….…………….22

Scheme 4. A Possible Endgame for Pleurotin ……………………………………………..31

Scheme 5. Predicted Behavior of Iodooxime 100 …………………………………………42

Scheme 6. Synthesis of Radical Cyclization Precursors 133 and 135 ……………...... 54

Scheme 7. Potential Mechanisms for Diethyl Fumarate Reduction ……………………..64

Scheme 8. A Potential Chain Mechanism …………………………………………………68

Scheme 9. A Non-Chain Reaction Mechanism …………………………………………...78

Scheme 10. A Non-Chain One Carbon Homologation ……………………………………80

Scheme 11. Proposed Mechanism for the Hexamethylditin Mediated

Coupling of Cyclohexyl Bromide and Benzophenone ………………...…………..84

Scheme 12. A Proposed Mechanism for the Formation of 137 and 138 ………………85

Scheme 13. The Barton Reaction …………………………………………………………..87

Scheme 14. Equilibrium Formed Upon Mixing N,N-Diethyltrimethyl-

stannylamine and benzopinacol 234 ……………………………………...………..97

vii

Bis(trimethylstannyl)benzopinacolate Promoted Radical Carbon-Carbon Bond

Forming Reactions and Related Studies

Chapter 1. Introduction.

This research has dealt primarily with the development of novel methods for radical carbon-carbon bond formation. The major focus of this thesis will deal with the use of bis(trimethylstannyl)benzopinacolate 1 in mediating radical conjugate addition reactions. Since the expanding role of radical reactions has been covered in several excellent reviews,1 I will not review this broad field of recent research. However, I will discuss some key features of radical addition reactions which are especially attractive to synthetic chemists with an emphasis on intermolecular formation of carbon-carbon bonds.

A. Historical.

Organic radicals are species with an odd unpaired electron. Their lack of charge, and high reactivity lead to important differences with heterolytic processes.2 In heterolytic bond constructions, like-charged species repel one another and generally will not undergo self reaction. It is quite common to form concentrated solutions of anions, and under certain conditions, cations.3 This is not the case with free radical chemistry.

Scheme 1. A Typical Chain Reaction

Radicals, being uncharged and having a single unpaired electron, can come together to form a bond without encountering any significant energy barrier.4 The very low

activation energy of radical termination means the lifetime of individual radicals is extremely short. The extremely short lifetimes of radicals dominates the behavior of such species and accounts for many differences between homolytic and heterolytic processes. Examination of the following pages will demonstrate a plethora of examples of radical bond constructions in which diverse functionality is tolerated. Radical reactive intermediates have such short lifetimes that interference by other functional groups rarely presents a problem. Free radicals are generally formed via thermal or photochemical bond homolysis (Scheme 1: eq.1a).5 The freshly generated radical may undergo various processes including atom transfer (eq. 1b), rearrangement (eq. 1c), addition (eq. 1d), and fragmentation (eq. 1e). These propagation steps involve unimolecular reaction of a radical, or reaction of a radical with a non-radical species to liberate a new radical species. The new species is likely to be as reactive as the original radical and rapidly undergo another transformation. The number and nature of these propagation steps is governed by competitive pathways for a given substrate. Thus, with appropriately designed substrates, and proper reaction conditions, more than one carbon-carbon bond can be formed in a single pot. This series ends when two radicals find each other in solution. Radicals may terminate via recombination (eq. 1f) or disproportionation. The sequence of radical formation (initiation), followed by steps which generate a new radical (propagation), and reactions between two radical species which generate a stable species (termination) is called a chain reaction. Although, as this thesis will attempt to demonstrate, not all radical processes are chain reactions, the chain process may be regarded as typical of free radical behavior.

The first organic free radicals were studied by Gomberg.6 During the period from

1850 to 1900, valence theory served as the one reliable guide with regard to structure in

organic chemistry. A key aspect of valence theory with respect to organic molecules was the tetravalent nature of carbon. During the infancy of organic chemistry, countless numbers of compounds were assigned definitive structures which adhered to valence theory. In 1900, Gomberg published the first account of an observable compound which did not fit valence theory.7 The original intent of the author was to prepare hexaphenylethane via the reaction of metallic silver with triphenylmethyl chloride. The resulting substance had none of the characteristics of a saturated alkane. Instead of being relatively inert, the product reacted instantly with oxygen and iodine. Gomberg correctly surmised that the triphenylmethyl radical either didn't dimerize or the dimerization was rapidly reversible and the equilibrium favored the triphenylmethyl radical (eq. 2). The next major advance came in the 1920's when Paneth showed that non-stabilized alkyl radicals exist and measured the lifetime for their decay.8 The first organic synthesis involving free radical intermediates came in 1937 when Waters and

Hey described the benzoyl peroxide mediated phenylation of aromatic compounds.9 In that same year, Kharasch recognized the anti-Markovnikov addition of hydrogen bromide was a free radical process.10 The onset of World War II set the stage for a period of rapid growth in the understanding of organic free radicals Building equipment for the war effort brought a need for an increased production of rubber and plastics.

This, combined with lowered trade with Southeast Asia made the development of synthetic polymers a national priority. In resulting studies, Mayo, Walling, and Lewis discovered the rules of radical copolymerization.11 In further studies, many of the key

Scheme 2. Trialkyltin Hydride Mediated Conjugate Addition

features of free radical chemistry which are important in today's synthetic uses of radicals were uncovered. The results of these early studies have been compiled in a text by Kochi.12

Perhaps the most important advance in synthetic radical chemistry came with the demonstration by Kuivila that trialkyltin hydrides can act as efficient hydrogen atom donors.13 The tin hydride method has become the dominant method for free radical formation of carbon-carbon bonds.1, 14 A typical tin hydride mediated conjugate addition reaction is outlined in Scheme 2. The process begins when an initiator (usually AIBN) undergoes thermolytic or photolytic homolysis to liberate an alkyl radical. These alkyl radicals become reduced by tin hydride to liberate a tin radical. The tin radical abstracts 5

a halogen from an organic halide. The radical thus formed has two major competitive pathways which it might follow. It might simply abstract a hydrogen atom from tin hydride liberating a reduced product and a tin radical (kred). Under proper conditions, the radical may be given sufficient lifetime to add intramolecularly or intermolecularly to an electron deficient olefin (kadd). The new radical now undergoes tin hydride mediated reduction to produce the desired product and a tin radical. This tin radical will again abstract a halogen, thus completing the chain process. The important feature in designing reaction conditions in which to conduct these reactions becomes controlling the relative rates of the reduction and

addition steps. Thus, under conditions in which (kred) [R3SnH] = (kadd)[olefin], a one to one mixture of reduced to addition products is achieved. A ten-fold increase in the tin hydride concentration will cause the reduction mode to predominate, and a ten-fold increase in olefin concentration will allow the cross coupling reaction to dominate. Adjustment of the tin hydride and activated olefin concentration provides great control in affecting the course of these radical reactions.

A key feature in the tin hydride method is the extreme ease and selectivity with which radicals can be generated.15 A tin radical shows substantial selectivity towards atom abstraction in polyfunctional systems. For alkyl halides the general trend RI > RBr > RCI » RF is observed. The high selectivity of tri-n-butyltin hydride reductions allows the partial reduction of polyhalogenated compounds (Table 1). Thus, geminal diiodides (entry 1), dibromides (entries 2 and 3), and dichlorides (entry 4) undergo efficient partial reduction. The reason for the substantially increased reactivity of geminal dihalides lies in the substantial stabilizing effect imparted by the remaining halide on the incipient radical intermediate. The stereoselectivity of these reductions does not reflect a preference for abstraction of the least hindered halide. Example 5 demonstrates a bromine atom is readily abstracted from either face of the cupped molecule. However, hydrogen atom abstraction from tri-n-butyltin hydride preferentially occurs on the exo

Table 1. Tri-n-butyltin Hydride Mediated Reduction of Polyhalides

face of the molecule regardless of the stereochemistry of the starting halide. This is explained by a relatively low barrier for radical inversion. Thus, two diastereomeric radicals are in rapid equilibrium and hydrogen atom abstraction occurs from the least hindered face (eq. 3). Several interesting exceptions to this behavior have been noted

(entries 5 and 6). Fluorine substituted cyclopropanes show a different behavior (entries 7 and

8). These compounds show retention of configuration regardless of the stereochemistry of the starting dihalide. This has been explained on the basis of a high barrier to inversion of fluorine substituted cyclopropyl radicals.

Substrates other than simple alkyl halides serve efficiently in trialkyltin hydride mediated radical reactions. Acyl halides undergo tri-n-butyltin hydride mediated reduction. This reduction is highly dependent on the reaction conditions. In the presence of Pd(0) or Pd(II) complexes, the corresponding aldehyde can be isolated in good yield..24 In these reductions, tri-n-butyltin hydride presumably forms a Pd-H species which is ultimately responsible for the partial reduction.25 Under typical free radical conditions a different mode of reduction is seen. In these reactions the intermediate acyl radical generally undergoes decarbonylation faster than reduction.

This offers an alternative for the decarboxylation of carboxylic acid derivatives.26 Recent studies have demonstrated that group VI derivatives such as telluro-,27 seleno-,28 and thiophenols29 do not form radicals in trialkyltin hydride mediated reactions. However, hydroxyl compounds can easily be converted to xanthate derivatives which undergo 8

Table 2. Relative Rates for Addition of Cyclohexyl Radicals to Activated Olefins at 293 K

Table 3. Absolute Rate Constants for the Addition of Alkyl Radicals to Activated Olefins

trialkyltin hydride mediated radical formation. This constitutes a valuable procedure for replacement of a hydroxyl group with a hydrogen atom in highly functionalized substrates.30 Generation of alkyl radicals from primary and secondary nitro compounds proves too slow to be useful in trialkyltin hydride mediated reactions. However, tertiary nitro compounds react at a sufficient rate to make this type of reduction useful.31 10

Of tremendous importance in designing radical cross coupling reactions is the rate constant for the addition of the radical to the olefin. In order to gauge the effect of substituents on the reactivity of alkyl radicals towards a double bond, Table 2 lists the relative reactivity of cyclohexyl radicals with various substituted olefins.32 To put these data in some perspective, Table 3 gives some absolute rate data for this process.33-43

Giese has summarized the effect of olefin substitution on radical reactivity.44 Giese concludes that -substituents exert mainly polar effects. He attributes this effect to changing the position of the LUMO of the alkene. Substituents that lower the LUMO of the alkene accelerate the addition of nucleophilic radicals, and dramatically retard the rate of electrophilic radical addition. Electron donating substituents, which raise the olefin LUMO, enhance the rate of electrophilic radical addition. Contributions by - substituents are largely steric. Substitution by alkyl, and other non-activating groups significantly reduces the addition rate. A small polar effect is seen since electron withdrawing groups provide very modest acceleration. Substituents on the radical center exert polar effects. Substituents that raise the SOMO of the radical accelerate the addition to electron deficient alkenes. This accounts for rapid addition of t-butyl radicals to electron deficient olefins relative to methyl radicals.

Studies by Giese have demonstrated that trialkyltin hydride mediated additions of alkyl radicals to activated ethylenes is a generally useful process when conducted under the appropriate conditions.45 Yields of addition products of alkyl radicals generated from alkyl iodides, bromides, phenylselenides, xanthates, and tertiary nitro compounds generally range from 60 - 90% on addition to ethyl acrylate.46 A variety of activated olefins can be used. Giese has demonstrated that -unsaturated nitriles, esters, aldehydes, and ketones, vinyl sulfides, and vinyl nitro compounds serve as efficient

radical acceptors.45 These additions are generally limited to terminal alkenes because addition generally fails due to the the deactivating effect of -alkyl groups. For instance, methyl acrylate serves as a good substrate in these addition processes. However, cross couplings to methyl crotonate generally fail. In general, a substrate must have an addition rate constant on the order of 105 sec-1 to prove useful as substrates in these cross coupling processes.

The synthetic utility of these intramolecular cross coupling reactions has been demonstrated by several groups. A recent synthesis of (-)-malyngolide (2) demonstrates several of the attractive features of these bond constructions (eq. 4).46 Homochiral epoxyalcohol 3 is readily synthesized via a Sharpless epoxidation. This alcohol is quickly transformed into iodide 4 via a two step procedure. The radical addition reaction was carried out using conditions originally developed by Corey.47 Under these conditions, tri-n-butytin hydride is produced in situ. Thus, warming a solution of 4 with methyl methacrylate, a catalytic amount of tri-n-butyltin chloride, and a stoichiometric amount of 12

Table 4. M-H Bond Strengths for Group IV Hydrides

sodium borohydride, produced 5. The synthesis was completed via hydrogenolytic removal of the benzylidine protecting group.

To influence the product ratio between simple reduction and conjugate addition products, other group IV hydrides have been examined as sources of hydrogen atoms.

The M-H bond dissociation energy gives a good measure of these compounds ability to donate a hydrogen atom. This dissociation energy decreases upon going down the periodic table (Table 4).48 To influence the ratio of addition product to simple reduction product it is desirable to have M-H sources in which the M-H bond dissociates less readily than tri-n-butyltin hydride. However, the M-H bond strength must be weak enough such that radicals will abstract a hydrogen atom faster than they diffuse together and undergo recombination. Toward this end, Hershberger has studied the ability of tri- n-butylgermyl hydride to mediate intermolecular conjugate addition reactions.49 Thus,

Hershberger found that warming a solution of benzyl iodide, acrylonitrile, tri-n- butylgermanium hydride, and catalytic amounts of AIBN in refluxing benzene, allowed the isolation of the desired cross coupling product 6 in 76% yield (eq. 5). The reaction offers several advantages over tin hydride mediated conjugate addition reactions. Under these conditions, relatively high concentrations of hydride donor may be tolerated (0.1

M) without the use of a syringe pump aided addition to produce high yields of the desired addition product. Further, a large excess of addend is not required. Unfortunately, the 13

rare nature of germanium compounds certainly limits the synthetic utility of these processes.

Recent developments in the use of silicon hydrides offer a group IVA metal- hydride which is readily available. The strong Si-H bond in trialkylsilanes makes these compounds of little synthetic importance as radical reducing agents because alkyl radicals do not react at a sufficient rate to promote a chain reaction. However, silicon hydrogen bonds can be significantly weakened by the addition of trialkylsilyl groups at the silicon center. For instance, tris(trimethylsilyl)silane (7) has a silicon-hydrogen bond

43 dissociation energy that is 11 kcal/mol less than that of Et3SiH. Thus, 7 acts as a powerful hydrogen donor. In 1969, Burger and Kilian prepared 7 and demonstrated that

it reacts exothermically with carbon tetrabromide (eq. 6).50 This observation went virtually unnoticed for nearly two decades. In 1988, Chatgilialoglu demonstrated that 7 can be used in less facile reductions (eq. 7).51 Giese has studied the ability of 7 to mediate bimolecular radical cross coupling reactions.52 For instance, warming an equimolar solution of cyclohexyl iodide, ethyl acrylate, and 7 in the presence of catalytic

AIBN produces 3-cyclohexylpropionate 10 in 85% yield (eq. 8). By using excess electron deficient olefin, even poor radical addends such as crotonitrile compete effectively with hydrogen atom reduction.

To eliminate the competitive hydrogen atom abstraction mode, while retaining the attractive features of the tri-n-butyltin hydride mediated cross coupling reaction, several groups have examined methods for the hydrogen atom free generation of a tin radical. In the tin hydride method, the propagation step involves a hydrogen atom abstraction from tin hydride to form a stable product and a tin radical. Another method which has been extensively studied involves a fragmentation reaction as an important propagation step.

In a synthesis of perhydrohistrionicotoxin intermediate 13, Keck required a method to attach an alkyl side chain in a situation in which two electron approaches proved cumbersome.53 Early work by Migata and Pereye demonstrated that allyl tri-n- butylstannanes will accept alkyl radicals and undergo a fragmentation reaction to liberate an allylated product (eq. 9).54 Keck has studied the reaction systematically and demonstrated the synthetic power of this process.55 For instance, he has demonstrated that warming bromide 11 in the presence of AIBN affords the equatorially allylated product 12 in good yield

(88%) as a single stereoisomer.56 The stereoselectivity of the reaction came as a surprise, and was in fact the wrong stereochemistry for the total synthesis. Nevertheless, accommodations were readily made, and the synthesis was rapidly completed. Other studies in the Keck laboratory have demonstrated that this reaction is successful for a variety of substrates.57 These reactions can be initiated either thermally in the presence of AIBN or photolytically. The photochemical reactions can be carried out at reduced temperatures allowing for more mild and selective reaction conditions. The allylation reaction has been applied to several other total synthesis. The radical chain nature of the reaction has made it 16

particularly useful in the functionalization of carbohydrate derivatives. Keck was able to demonstrate the utility of this process in a total synthesis of pseudomonic acid 17.57 He rapidly converted lyxose 14 into acetonide 15. He found that photolysis of 15 in the presence of 2 equivalents of allyl tri-n-butylstannane afforded 16 in 93% yield. The stereochemical outcome of this reaction was as expected. He found that the allylation takes place on the exo face of the cupped trioxabicyclo[4.3.0]nonane system. Keck envisioned the upper appendage of psuedomonic acid might also be attached via a radical allylation.

However, two electron approaches proved more economical in this instance.

The power of this method in the functionalization of carbohydrates has been further demonstrated in a synthesis of compactin 20.58 In the synthesis of the lactone portion of compactin, Keck demonstrated that photochemically initiated allylation of 18 produced 19 in 87% yield (eq. 12). Stereochemistry is not an issue in this example

because the allylation occurs at a non-stereogenic center. Ozonolysis of 19 allowed the decalin portion of 20 to be attached to the lactone moiety via a Wittig reaction.

The allylation has been applied to the intramolecular formation of carbon-carbon bonds. Keck has demonstrated that warming 21 in the presence of AIBN produces alkene 22 in good yield (eq. 13).59 Johnson-Lemieux oxidation followed by reduction produced isoretronecanol 23. Substituents greatly influence the reactivity of the allyl stannane.60 Substituents in the 2-position are handled without problem. Thus, 2-

(methyl)allyl-tri-n-butylstannane serves as a good radical acceptor. The introduction of substituents at the 1- and 3-position is not feasible. Introduction of a substituent at the

1-position is hampered by a fast rearrangement reaction to produce a 3-substituted allyl stannane. Introduction of a substituent at the 3-position causes steric retardation of the

already slow addition rate. These allyl stannanes are not reactive under normal conditions. When higher temperatures are used, a hydrogen atom abstraction occurs from 3-(methyl)allyl-tri-n-butylstannane to produce 1,3-butadiene.

Another method for generating -stannyl radicals involves addition of an alkyl radical to the carbon - to tin. Curran has demonstrated that intramolecular additions to vinyl stannanes can be conducted in good yield (eq. 14).61 When trying to conduct this type of intermolecular vinylation, the steric deactivation of the tin substituent precludes addition under standard conditions. Baldwin has demonstrated that introduction of an activating group vicinal to the vinyl stannane allows these reactions to be conducted quite readily (eq. 15).62 After early discouraging results, Keck has used this type of vinylation process in an entry into prostaglandins.5 Russell has demonstrated that these types of reactions are not limited to tin as the radical leaving group.63 He has shown that halides,64 mercuric halides,65 and thio derivatives66 will propagate free radical chains in a fashion similar to tin.

Another interesting radical addition reaction of which we were aware at the onset of this work was an intriguing one carbon homologation developed by Stork.67 He demonstrated that alkyl radicals will add to isonitrile 29 (eq. 16). The adduct has two important resonance structures 30 and 31. A different fragmentation reaction is

available for each of these structures. Scission from 31, the structure in which the unpaired electron is centered on carbon, is simply the reverse of the initial radical addition reaction. However, cleavage from nitrogen centered radical 30 forms nitrile 32 as an isolable product. A problem with this method lies in the fate of the t-butyl radical generated in this reaction step. Potentially, the t-butyl radical can become involved in an addition reaction with 29. This result is isomerization of 29 to 2,2-dimethylpropionitrile.

Alternatively, the presence of tri-n-butyltin hydride (generated in low concentration via the reaction of tri-n-butyltin chloride and sodium borohydride), the t-butyl radical

eventually abstracts a hydrogen from tri-n-butyltin hydride to liberate 2-methylpropane and a tin radical. The tin radical formed can abstract a halogen, generating an alkyl radical, and completing the chain sequence. Hexaphenylditin photolysis also serves as an effective method of tin radical formation to promote this process. Under these conditions the t-butyl radicals cannot undergo an adequate chain transfer step and these free radical reactions proceed via a non-chain process.

This one carbon homologation reaction has been used in the synthesis of prostaglandin precursors (eq. 18).68 Thus, Stork has demonstrated that bromo acetal 33 undergoes free radical cyclization to produce a cis fused [3.3.0] system. This cupped molecule traps the one carbon addend from the exo face to produce 34 with stereochemistry at four contiguous asymmetric centers established.

Scheme 3. Mechanism of Cobalt Mediated Coupling Reactions

Sheffold and co-workers first demonstrated that vitamin B12 can be a powerful mediator of radical cross coupling reactions to electron deficient olefins.69 In these processes, the alkyl halide is warmed with the electron deficient olefin, a stoichiometric source of electrons such as zinc metal, and a catalytic amount of vitamin B12.

The mechanism of these reactions has been studied in detail.70 Apparently, the process begins when a cobalt(l) species oxidatively adds to an alkyl halide to produce a cobalt(III) species (eq. 3a). This newly formed alkyl cobalt bond is extremely weak in certain instances. Primary alkylcobalamines have a Co-C bond energy of > 30 kcal/mol and are stable at room temperature. Secondary, tertiary, or benzylic alkylcobalamines decompose rapidly under mild conditions to produce a cobalt(II) species and an alkyl radical (eq. 3b).71

This alkyl radical is free to undergo reactions characteristic of free radicals. In the presence

of electron deficient olefins, these conditions provide suitable lifetimes for bimolecular additions (eq. 3c).72 Termination proceeds via a radical-radical coupling between a cobalt(II) species and the adduct radical, generating a cobalt enolate (eq. 3d). This cobalt enolate is reduced and the subsequent enolate protonated to produce the desired organic product and a cobalt(I) species which can re-enter the catalytic cycle (eq. 3e).

As will be seen, these cross coupling reactions are of particular interest to us because of a possible mechanistic relationship to the bis(trimethylstannyl)benzopinacolate mediated reactions that will be the focus of this thesis.73 Like the tin hydride method, the B12 mediated cross coupling reactions tolerate a diverse array of functionality. Some representative examples are given below. These conditions allow the efficient formation of C-glycosides (eq. 18).74 Additionally, these conditions have been used in the enantioselective synthesis of a series of biologically active elm bark beetle

75 phermones (eq. 19). For instance, B12 was used to mediate the addition of readily

available iodide 37 to methyl vinyl ketone. Acid catalyzed hydrolysis of 38 followed by intramolecular ketalization produces (+)-endo-brevicomin 39 in good yield (84% from

37).

Simpler organocobalt complexes can be used to mediate these radical addition reactions. For instance, cobalt(I) species ligated by salophens 40 and dmgH 41 have been used in these bond constructions. The procedure for these bond constructions differs from the B12 mediated couplings. In these reactions, the alkyl halides are warmed with a stoichiometric amount of cobalt(l) species (eq. 20). The resulting cobalt(III) species are isolable, and have been characterized. If an intramolecular conjugate addition is the desired mode of radical reaction, the electron deficient olefin is then added. The reaction mixture is then subjected to photolysis. The exact nature of the final product is dependent on the reaction conditions. In the presence of an appropriate reducing agent, organocobalt species 43 is reduced, and the organic product becomes

protonated to produce 42, the product of simple hydrogen atom reduction. If no reducing agent is present, a different mode of reaction is seen. In these instances, -hydride elimination occurs to produce alkene 44 as the final product.78

Other organometallic species are synthetically useful precursors for alkyl radicals. Brown has shown that triakylboranes prove to be useful precursors to alkyl radicals in carbon-carbon bond forming chain reactions with ,-unsaturated ketones and aldehydes.80 Additionally, Giese has demonstrated alkylmercury hydrides prove appropriate precursors to alkyl radicals for intramolecular conjugate addition reactions under a variety of conditions.81

B. Advantages of Intramolecular Radical Carbon-Carbon Bond Formations.

1. Regloselectivity

The explosion in interest of radical reactions has been fueled by their contrasting behavior with their two electron counterparts. Radical addition reactions accomplish

accomplish a net addition of what are classically considered anionic precursors, for example halides, to olefins. These conjugate addition reactions show quite different selectivities from their anionic counterparts. Alkyl radicals substituted with electron donating groups are nucleophilic. These radicals show rapid addition rates with electron deficient olefins and a very modest addition rate with electron rich olefins.82 Conversely, radicals which are substituted by one or more electron withdrawing groups add with fast rates to electron rich olefins and generally will not add to electron deficient olefins in a useful manner. A synthetic consequence of this selective reactivity is that free radicals show an intrinsically different behavior from polar bond constructions. For instance, polar bond constructions to glycosyl bromide 45 generally take place via carbocation 46a

(eq. 21). The formation of this cation is facilitated via the ability of the -oxygen substituent to donate electron density to the electron deficient center. Oxonium ion 46a becomes trapped by nucleophiles to produce product 47. In contrast, radical bond constructions achieve a net 1, 4-conjugate addition of an anion equivalent. Thus, radical

46c can be trapped by electron deficient olefins to produce products such as 48 after hydrogen atom abstraction.83 This radical bond construction is noteworthy for other

reasons. Attempts to generate anion 46b ultimately meet with failure. This is due to facile -elimination in this transient anion. The ability to tolerate a -leaving group in radical bond formations is perhaps the most attractive feature of these bond constructions.

Radicals substituted by electron withdrawing groups also show different behavior from polar bond constructions. Polar bond constructions with malonate anion 49 generally involve Micheal addition to electron deficient olefins (eq. 22). Giese has demonstrated that malonate radicals derived from 51 undergo addition to electron rich olefins (eq. 23).84

2. Stereoselectivity

There have been several attempts to determine the stereochemical outcome of radical reactions in which radical precursors are derived from optically active substrates.

Doering studied the decarbonylation of optically active aldehyde 53 (eq. 24).85 He found that the reaction proceeded with complete racemization. Similar observations have been made for the Kolbe electrolysis,86 Hunsdieker reaction,87 and the decomposition of azo compounds and peroxides88 for simple acyclic substrates. Two interpretations of these results have been presented. First, a planar radical intermediate can abstract hydrogen from either face.89 Alternatively, a tetrahedral radical rapidly interconverts, with equal probability of hydrogen abstraction from either structure. The stereochemistry of simple free radicals has been examined by ESR spectroscopy. These studies have concluded that many stabilized radicals have nearly planar geometries, however, radicals which show extreme distortions from planarity are common.90 An important

criteria for a synthetically useful processes is the ability of remote asymmetric centers to affect the stereochemical course of bond constructions. Since radical reactions generally occur via an early transition state, they have often been thought of with skepticism in this area. Recent studies have demonstrated that this is not necessarily the case. In a recent synthesis of pleurotin, it was demonstrated that four contiguous asymmetric centers could be related in a single reaction. Thus, warming a solution of 56 with tri-n-butyltin hydride produced 60 in 82% yield.91 It is not surprising that radical 58 undergoes cyclization in a stereoselective fashion to afford 59.92 However, it is quite surprising that hydrogen atom abstraction from the radical 59 takes place in a 28

stereoselective fashion. A possible explanation for this asymmetric induction is that cyclization produces a sterically congested radical. Because of this hinderance, hydrogen atom abstraction from tri-n-butyltin hydride occurs at rate much faster than rotation about the C(9)-C(10) bond of 61. To test this mechanistic hypothesis, olefin 57 was synthesized. It was found that variation of the olefin, geometry did not significantly affect the stereochemistry of this reduction. An explanation based on asymmetric inductions models proposed by Houk has been offered.93 It was suggested that the intermediate radical 61 is planar. This reactive conformation is one in which A(1,3) interactions are minimized and the largest allylic substituent is position perpendicular the radical -system. Reduction of this radical takes place from the less hindered face on a trajectory such that torsional strain is minimized.

Many examples of stereoselective bond construction in intermolecular reactions have been reported.94 A large number of these stereoselective bond constructions involve a rigid radical in which one face of the radical is more sterically hindered than the other.

These radicals typically undergo addition on the least hindered face. For instance, Giese has demonstrated that xanthate 62 undergoes radical C-C bond formation to afford 63.95

Nitrile 63 arises from conjugate addition to the exo face of the fused bicyclo[3.3.0] system.

C. Conclusions

The last few decades have seen remarkable growth in the birth of new methods for radical carbon-carbon bond formation and in the frequency that established methods are used in organic synthesis. The most widely used method involves the generation of radicals from alkyl halide precursors via tri-n-butyltin hydride and AIBN. This is due to the high selectivity of halide abstraction and the relatively mild conditions needed to generate tri-n–butyltin radicals. A problem arises when attempting to perform slow radical cyclizations and in the addition of alkyl radicals to poor radical acceptors. This problem results from competitive chain transfer steps. Problems arise when hydrogen atom reduction of the initially formed radical overwhelms radical cyclization or addition. To avoid these problems while retaining the attractive features of tri-n-butyltin hydride mediated reactions investigators have studied methods for the hydrogen atom free generation of tin radicals. During the course of this study we hoped to complement existing radical carbon-carbon bond forming methodology by developing new methods for the hydrogen atom free generation of tin radicals.

Chapter 2. A Free Radical One Carbon Homologation.

A. Results and discussion

We began this investigation with a model study related to a total synthesis of pleurotin 67. 96 Previous studies in this laboratory had shown that a synthesis of radical precursor 63 was plausible. We felt a possible endgame in this synthesis might involve radical cyclization from benzylic radical 64 to generate the new radical 65. We had hoped to capture this radical with a suitable one carbon addend generating derivatives of type

66. It would be particularly advantageous if this one carbon addend could be readily oxidized to a carbonyl compound. Trying to devise appropriate one carbon addends was complicated by the problems associated with addition of radicals to carbonyl compounds. Radical additions to alkenes are generally highly thermochemically favorable processes. For example, Table 5 gives some kinetic and thermodynamic data

Scheme 4. A Possible Endgame for Pleurotin

Table 5. Thermochemical Data for the Addition of Methyl Radicals to Ethylenes

for addition of methyl radicals to a variety of substituted ethylenes, and examination of the data demonstrates that these reactions are quite exothermic.97 The kinetic data illustrate that the forward reactions proceed at a reasonable rate, but the reverse reactions are extremely slow. The exothermic nature of radical additions to olefins is generally rationalized on the basis of bond formation and breakage during this process.

In these addition reactions, a relatively weak C-C  bond is broken and a stronger C-C  bond is formed. The much stronger C-C  bond causes a drastically different thermodynamic behavior on addition of radicals to aldehydes and ketones. Radical addition to carbonyl compounds generally tend to be thermoneutral to endothermic.

Table 6 describes some kinetic and thermodynamic data for radical additions to acetone.98 Thus, the addition of methyl radical to acetone is a slightly exothermic

Table 6. Thermochemical Data for the Addition of Alkyl Radicals to Acetone

process, although not nearly as exothermic as the addition of methyl radical to simple olefins. Conversely, the addition reaction of the stabilized benzylic radical to acetone is endothermic by 12.3 kcal/mol. The kinetic data concerning the addition of alkyl radicals to acetone establishes that the forward reaction proceeds at a reasonable rate at room temperature. However, the reverse reaction occurs at a faster rate, and these reactions are readily reversible.

The fact that radical cyclization onto a C=O  bond is facile and reversible has been used to synthetic advantage on several occasions. One example involves a clever ring expansion. Dowd has studied the tri-n-butyltin hydride mediated reduction of iodides such as 68.99 He demonstrated that radical 69 cyclized to produce an oxygen centered radical 70 which undergoes fragmentation and reduction to liberate 72 in good yield.

Because of the reversibility of the addition of an alkyl radical to a carbonyl group, it was long thought that this type of reactivity would not be a synthetically useful process. 33

However, experiments by Fraser-Reid suggested that this might not be the case. He demonstrated that tri-n-butyltin hydride mediated cyclization onto an aldehyde can produce a good yield of secondary alcohols in a carbohydrate based substrate.100

Feeling that this observation might be due to the unique nature of the carbohydrate derived substrate, he set out to explore this addition in simpler systems. Thus, he

studied the tri-n-butyltin hydride mediated cyclization of 73. The kinetic behavior of 73 demonstrates that 5-exo-cyclization of an unsubstituted alkyl radical with an aldehyde can compete with rapid 5-hexenyl type cyclization (eq. 28).101 Cyclization involving aldehydes of the 6-exo type appear to be particularly facile as 76 produces exclusively the carbonyl addition product 77 (eq. 29).

To avoid the problems inherent with radical additions to carbonyl groups, we explored the addition of alkyl radicals to compounds which might undergo hydrolysis or oxidation to liberate a carbonyl group. We reasoned that by replacement of the carbonyl oxygen by a suitable heteroatomic group which could provide stabilization for the incipient radical, we could design an addition reaction in which thermodynamics favored

formation of the desired product (eq. 30). We first chose to study N-alkoxy-N-alkylamino radicals 78. Danen and co-workers first detected N-alkoxy-N-alkylamino radicals by EPR spectroscopy.102 They noted that these radicals were quite persistent. These radicals were also studied in detail by Ingold.103 He proved that N-alkyloxy-N-alkylamino, N-alkoxyamino, and N-alkoxyaryl radicals are persistent.

Particularly interesting observations were made regarding the N-t-butoxy-N-t- butylaminyl radical 80.104 Ingold demonstrated that this radical can be generated by the t-butoxide radical or silver oxide induced oxidation of amine 79 (eq. 31). He found that

unlike other N-alkoxyamines, these radicals decayed with first order kinetics. He concluded that this decay involves -scission of the amino radical87 to produce nitroso compound 81 and a t-butyl radical. The t-butyl radical ultimately attacks the nitroso compound to produce the stable nitroxyl radical 82. He estimated that this -scission must have an activation energy of > 28 kcal/mol given the lifetime of these radicals.

With this information in hand, we began this investigation by studying the reaction outlined in eq. 32. We envisioned a process in which hexamethylditin photochemistry would generate alkyl radicals from alkyl halide precursors. We felt that under the appropriate conditions these radicals might add intermolecularly to formaldoxime derivatives 83, 84, or 85.

We had hoped that the incipient persistent alkoxylamino radical 86 would cleave to generate (in the case of R = PhCH2) benzyl radicals and an alkyl nitroso compound

87. In nitroso compound 81 studied by Ingold, no protons are present  to the nitro

group. We hoped that in cases where an acidic proton was present, tautomerization to oxime 88 would protect 87 from radical addition. Oxime 88 could be readily hydrolyzed to liberate a one carbon homologated aldehyde function.

Literature precedent suggested that oxime ether derivatives are good radical acceptors. The earliest example of the addition of an alkyl radical to an oxime derivative came when Woodward added aryl radicals to formaldoxime in the synthesis of the tryptophan portion of reserpine (eq. 33).105 More recently, Corey had demonstrated that ketyl 91 undergoes efficient radical cyclization (eq. 34).106 During the course of this research, Bartlett has used the tin hydride method to perform exocyclic radical cyclizations with a variety of oxime ether derivatives.107

Our initial task involved the synthesis of various formaldoxime derivatives. A survey of the literature demonstrated that 0-tri-n-butylstannylformaldoxime (84) had been prepared as a potential insecticide.108 We were able to prepare this oxime derivative via the action of bis(hexabutylstannyl)ether on formaldoxime trimer 94 (eq. 35).109 Formaldoxime hydrochloride was purchased from Aldrich Chemical Co. It was easily transformed into known oxime ether derivative 83 (79%) via the addition of sodium bicarbonate or pyridine to an aqueous solution of 0-benzylhydroxylamine hydrochloride and formaldehyde. The synthesis of the 0-t-butylformaldoxime 85 was accomplished as outlined in eq. 36. Thus,

alkylation of N-hydroxyphthalimide 95 with t-butyl acetate afforded 96. Treatment of 96 with hydrazine followed by salt formation produced 97.110 We found that the t-butyl derivative

85 was readily synthesized in 89% yield via treatment of 97 with pyridine in aqueous formaldehyde.

Having synthesized the requisite formaldoxime ethers, we were ready to study the cross coupling reaction (eq. 32). We were quite excited to find that photolysis of an equimolar solution cyclohexyl iodide, O-benzylformaloxime 83, and hexamethylditin afforded the desired oxime 88. However, the yield was less than 10% at best.

Substituting 84 as the radical addend produced a similar result. Further, experiments performed in an NMR tube suggested that the cyclohexyl iodide was possibly being converted into cyclohexane and cyclohexene. This is in accord with the observations of

Kropp concerning the photolytic behavior of alkyl Iodides. Kropp demonstrated that photolysis of cyclohexyl iodide in benzene affords cyclohexane and cyclohexene in unequal amounts.111 Mechanistic experiments suggest that these products are formed via radical, cationic, and carbenic intermediates.

To avoid problems associated with the photochemical instability of alkyl iodides, we turned our attention to thermal sources of tin radicals. We felt that by proper design of a thermal tin radical source, one might retain the attractive non-reducing aspects of hexamethylditin photochemistry while extending the applicability to photoactive substrates. Examination of the literature demonstrated that no well precedented thermal compliment to hexamethylditin photochemistry had been exploited by synthetic chemists. However, we were intrigued by reports by Neuman.112 He reported that photolysis of a solution of hexamethylditin and benzophenone produced bis(trimethylstannyl)benzopinacolate 1 (m.p. 120°C (d)). He found 1 had an extremely weak central

carbon-carbon bond. The bond had a dissociation energy of 23 kcal/mol and underwent reversible homolytic cleavage at room temperature. At temperatures above 60°C a cleavage reaction occured which liberated a trimethyltin radical and benzophenone (eq.

37). In the absence a tin radical trap, the tin radicals underwent dimerization to produce hexamethylditin. Thus, photolysis of hexamethylditin and benzophenone produces 1.

Thermolysis of 1 produces the reverse reaction to afford benzophenone and hexamethylditin.

Amongst the experimental evidence provided by Neuman for the intermediacy of a tin radical in the thermal decomposition of 1 was a reaction with allyltriethylstannane. Thus, warming a solution of 1 with allyltriethylstannane produced a product mixture in which the tin atoms were scrambled (eq. 38).

Having found a potentially interesting thermal source of tin radicals, we began to investigate the chemistry of 1. Due to our lack of success in attempting to add radicals to

O-benzylformaldoxime 83 under hexamethylditin photochemical conditions, we chose to study a process which underwent efficient reaction under the tri-n-butyltin hydride method. Thus, previous studies in these laboratories had demonstrated that oxime ether

100 undergoes efficient radical cyclization to afford amine 101 as a mixture of stereoisomers.113

The synthesis of 100 was accomplished using a protocol developed by Chaung and

Huang as is outlined in eq. 40.93 Thus, reductive alkylation of benzoic acid produced acid

102. It is known that iodolactonization of such acids produces mainly -lactones.

However, iodolactonization of tertiary amides produces mainly -lactones. Thus treatment of acid 102 with pyrrolidine and DPPA produced amide 103.114 lodolactonization of 103 afforded -lactone 104. Hydrolysis and oxime ether formation completed the synthesis of 100.

Having synthesized cyclization precursor 100, we began our investigation. We predicted that cyclization mediated by 1 would follow the behavior predicted in Scheme

5. We anticipated that tin radicals generated in the thermolysis of 1 would abstract an iodine atom from oxime 100. Radical 105 would undergo cyclization to produce

Scheme 5. Predicted Behavior of Iodooxime 100

persistent radical 106. As in previous studies, we predicted this radical would undergo a fragmentation to produce nitroso compound 107. This nitroso compound would be in equilibrium with the desired oxime 108. We were greatly surprised to find that treatment of a 0.3 M solution of 100 with 1 in refluxing benzene for 5 hours produced hydroxylamine 101 in 87% yield as a 1:1 mixture of stereoisomers (eq. 42). We were quite surprised to find that under these conditions the same products were produced as in the tri-n-butyltin hydride mediated reaction. We were puzzled by the source of the hydrogen atom. However, we were pleased that 0-alkoxylamine radical 106 appeared to undergo a useful termination event, and a product of radical cyclization was isolated in high yield.

Table 7. One Carbon Homologation with Simple Alkyl Substrates

Encouraged by our success, we reinvestigated intermolecular radical additions to

O-benzylformaldoxime 83. We found that treating a 0.3 M solution of cyclohexyl iodide,

O-benzylformaldoxime 83, and a slight excess of 1 produced the cross coupling product

109 in 76% yield (eq. 43). We found that color changes during the reaction were diagnostic of an active reagent. Ketyl radical 98 absorbs light in the visible region at 555 nm.115 Thus, when warming 1 in benzene with an alkyl iodide, a deep burgundy color is observed. The color fades as 1 is consumed. After about an hour the pink color barely is noticed. However, the reaction has not advanced to completion. By heating the reaction an additional three hours, high yields of cross coupled products are realized as demonstrated in Table 7.116 The reaction requires quite active radical precursors such as iodides, bromides, and phenylselenide to produce moderate to high yields of homologated products. Unfortunately, chlorides and xanthates did not produce cross coupled products under normal conditions. Additionally, the reaction is successful for primary, secondary, tertiary and aryl radicals.

A recent tactic which has emerged in radical chemistry involves radical rearrangement or cyclization followed by intermolecular capture of an addend.117 In this way several carbon-carbon bonds can be constructed in a single pot, and complex molecules can be rapidly assembled. Experiments conducted in our laboratories suggest that 1 will accommodate such ploys (eq. 44). For instance, treatment of 5-

hexenyl bromide 113 with 1 and benzylformaldoxime 83 affords mixtures of cyclized amine 114 and uncyclized amine 115. Under the appropriate conditions an isolated yield as high as 65 % of a 12:1 mixture of isomers can be realized.

Oximes have several modes of polar bond construction. For instance, electron density from the lone pair of electrons on oxygen make this species somewhat nucleophilic. Thus, oximes may act as nucleophiles as depicted in eq. 45. Further, the ability of nitrogen to stabilize a negative charge allows oximes to react with nucleophiles

(eq. 46).118

Because of this dual reactivity, we couldn't predict whether 83 would behave as an electron rich or electron deficient olefin in radical cross coupling reactions.

Experiments with stabilized radicals demonstrate that 83 shows radical reactivity that

parallels that of an electron deficient olefin. Hence, reaction mediated by 1 with benzyl bromide produces only tertiary alcohol 116 (eq. 47), and ethyl 2-bromo-3-methylbutyrate does not produce a cross coupled product (eq. 48).

Other factors affect this cross coupling reaction. Experiments with substituted oximes suggest that the cross coupling reaction will be limited to formaldoxime derivatives.

Thus, attempted coupling of cyclohexyl iodide to 0-benzylacetyloxime 117 gave no cross coupled products even when a large excess of acceptor was used (eq. 49). Apparently, the deactivating affect of an -alkyl substituent prevents this cross coupling reaction.

Having proven the viability of this one carbon homologation with simple alkyl substrates, we next focused our attention on more complex radical precursors. Because

-alkoxy radicals show virtually no propensity towards -elimination, the products of iodo-, bromo-, and selenolactonization have become popular substrates for radical addition reactions.119 To test whether radical precursors containing a leaving group would be useful in coupling reactions mediated by 1, we prepared iodolactone 118.120 We found that warming a solution of iodolactone 118, 1, and three equivalents of 83 produced stereoisomers 119 and 122 in equal amounts (57% for the mixture) along with lactam 121

(32%) (eq. 50). We found that extensive chromatography over silica gel allowed partial separation of stereoisomers 119 and 120 allowing independent characterization of these

products. The rigid nature of the oxabicyclo[3.2.1] system allowed an unambiguous proof of stereochemistry of 119 and 120. Stereoisomer 119 is locked in a conformation in which cyclization to form a lactam is not viable. Thus, lactam 121 formed during the course of the reaction, must arise via amine 120 (eq. 51). Upon warming a mixture of 119 and 120 with trimethyltin bromide in benzene, the disappearance of one set of signals in the 1H and 13C NMR was observed. Simultaneously, the growth of a set of signals which corresponds to lactam 121 were detected. By comparison of the spectra in which 119 and 120 had been separated and independently characterized with spectra from this experiment, a definitive stereochemical assignment of 119 and 120 was made as shown above.

Anionic bond construction at the anomeric position of sugars is fraught with difficulty. Anions formed at this position undergo rapid -elimination reactions.

Furthermore, typical anionic conditions are generally incompatible with common carbohydrate protecting groups. To avoid such difficulties, while accomplishing a net anionic bond construction, researchers have extensively studied radical reactions in

such scenarios.121 Toward this end, we attempted a one carbon homologation with glycosyl bromide 35 (eq. 52). We found that warming a benzene solution of 35, 1, and 3 equivalents of 83 gave two products in nearly equal amounts. Our initial assumption concerning the identity of the two products formed in this reaction was that they were simply the two stereoisomeric amines 122 and 123. However, examination of the 1H

NMR spectrum of these compounds did not support this notion. Examination of the 1H

NMR spectrum demonstrated that both 122 and 124 showed a C(1)H-C(2)H coupling constant of 6 Hz indicative of an axial-equatorial alignment of hydrogen atoms.

In fact, with the exception of chemical shift differences, the two compounds showed identical 1H-1H coupling patterns. More bewildering was the behavior of the system when exposed to long reaction times. Although starting material (35) was consumed after about 4 hours, the yield of 124 increased over time. When the reaction was stopped after 18 hours, product 124 was isolated in high yield (79%). This led us to conclude that the two products simply differ by the position of the C(2) acetyl group.

Therefore, after short reaction periods 122 and 124 are formed. After long reaction periods, a facile acetyl transfer via a six membered ring transition state occurs, and the thermodynamically more stable 125 is isolated. To confirm that 122 and 124 differ only by the placement of an acetyl group we independently subjected the isomers to acylation. We found that we isolated pentaacetate 125 regardless of the starting compound (eq. 53). We demonstrated that we can eliminate the problems associated with this rearrangement reaction by acylating the crude reaction mixture (eq. 54).

Removal of the benzyl protecting group produced crystalline hydroxamic acid 126 (89%).

The stereoselectivity of the radical conjugate addition of glycosyl derived radicals to electron deficient olefins has been extensively studied.122 Our results demonstrate a propensity to form the -anomer and are consistent with these findings. Giese has offered an explanation for these findings. He proposes that radical 127 adopts a boat conformation due to a favorable interaction between the HOMO of the -acetoxy group

and the SOMO of the radical. Unfavorable 1,3-interactions between the -acetoxy group and the incoming olefin preclude reaction from the top face of 127. Therefore, bottom face addition is the major mode of attack.123 ESR studies are consistent with a boat conformation for radical 127.124

We next examined a reaction in which the glycosyl halide precursor of the radical was unstable and underwent hydrolytic cleavage at a rate that prohibited its use in radical cross coupling reactions. This is the case with most ribosyl halides.125 Glycosyl selenide derivatives tend to be quite stable toward hydrolytic cleavage relative to the corresponding glycosyl halides. Further, these compounds serve as efficient precursors to alkyl radicals. We felt that by preparing an appropriate selenide derivative, we might be able to accomplish a radical addition to systems which normally prove quite difficult.

Ribosyl selenide 128 was easily prepared in one step (60%) from commercially available

127. In this process the anomeric acetoxy group was readily exchanged by stirring a

concentrated solution of 127 with selenophenol and p-toluenesulfonic acid (eq. 55).

Phenylselenide 128 readily undergoes one carbon homologation. Thus, treatment of 128 to standard one carbon homologation-acylation conditions afforded the desired acetamide 129 in 69% yield as a 5:1 mixture of stereoisomers.

B. Conclusions

During the initial course of this study we were able to demonstrate that hexamethylditin photochemistry could promote a radical one carbon homologation with formaldoxime derivatives. However, despite our best efforts, we could not find reaction conditions to make this a synthetically useful process. We did find that 1 could efficiently promote radical additions to formaldoxime 83, although it did not produce the cleavage reaction we expected. We tested this carbon-carbon bond forming reaction under a fairly diverse set of circumstances. We found it to be successfull with electron rich radical precursors, and with radical precursors that are fairly reactive with tin radicals.

Chapter 3. Bis(trimethylstannyl)benzopinacolate Mediated Free Radical Conjugate

Additions

A. Results and Discussion

A particularly exciting facet of this research was revealed when we found that electron deficient olefins also underwent radical addition reactions when warmed with 1 and a suitable radical precursor in benzene solution. Thus, this study was not limited to a simple one carbon homologation. Again, we began the investigation by studying a radical cyclization which afforded perhydroindans as the final products. The syntheses of cyclization substrate 133 and 135 are outlined in Scheme 6. Radical cyclization precursor 133 was readily synthesized from m-toluic acid using a known reaction sequence. Thus, reductive alkylation (77%) of 130, followed by iodolactonization (68%) of 131, acetal hydrolysis (70%) of 132, and Wittig olefination (65%) of the resulting aldehyde afforded iodoolefin 133.120 The synthesis of the known radical cyclization

Scheme 6. Synthesis of Radical Cyclization Precursors 133 and 135

precursor 135 involved hydrolysis of 132, an intermediate in the synthesis of oxime 100, and treatment with carbethoxymethylidene-triphenylphosphorane in benzene.126

Previous studies in these laboratories had demonstrated that tri-n-butyltin hydride mediated cyclization of substrate 133 proceeds with high regio- and stereochemical control.126 We found that warming a 0.3 M solution of 133 with 1.8 equivalents of 1 in refluxing benzene gave perhydroindan 134 in 83% yield (: = 4.5:1). The stereoselectivity of this radical cyclization has been explained in terms of non-bonding interactions.93 The cyclization is thought to be stereoselective at the site of initial radical generation because of a preference for the formation of a cis fused oxabicyclo[3.3.0]nonane. The acetic ester sidechain favors an -position due to unfavorable non-bonding interactions in the transition state leading to the minor diastereomer.127 Tri-n-butyltin hydride mediated cyclization of iodolactone 133 produces

Table 8. Addition of Cyclohexyl Radicals to Electron Deficient Olefins

a similar stereochemical result. It is important to note that unlike the tri-n-butyltin hydride mediated cyclizations, under these reaction conditions no good hydrogen atom donor is present. Despite this fact, this reaction appears to terminate as if a hydrogen atom abstraction from a good hydrogen atom donor occurs. In a similar fashion, iodolactone

135 undergoes efficient cyclization promoted by 1 to afford perhydroindan 136 in 71% yield (: = 5:1).

Having shown that 1 would mediate intramolecular additions to electron deficient olefins, we next examined the promotion of intermolecular addition reactions. Table 6 gives optimization results for the coupling of cyclohexyl radicals formed via the thermolysis of 1 in the presence of cyclohexyl iodide with various electron deficient olefins. In an early experiment we warmed a 0.3 M solution of cyclohexyl iodide with 1.5 equivalents of ethyl acrylate and one equivalent of 1 in refluxing benzene. After aqueous potassium fluoride work-up and column chromatography, ethyl 3- cyclohexylpropionate 139 was isolated in 79% yield. Capillary VPC analysis of the crude reaction mixture allowed the detection of 137 and 138 as side products. These products were detected throughout the course of this study. These reaction conditions allow for the intermolecular coupling to other electron deficient olefins. Giese has demonstrated that substituents in the -position of an electron deficient olefin exhibit mainly polar effects on free radical addition reactions.82 Simple alkyl substituents in the -position generally have little effect on addition rates. Therefore, 2-substituted acrylates behave in a manner similar to the parent acrylate in radical cross coupling reactions. We observed that ethyl methacrylate underwent bimolecular cross coupling with cyclohexyl iodide to give 140 in 73% yield when 1.5 equivalents of addend was used. Alkyl groups in the -position of ,-unsaturated esters slow radical addition rates due to steric effects. Thus, tri-n-butyltin hydride mediated cross couplings to methyl crotonate generally fail even when a large excess of addend is used.127 We found that drastic changes in the reaction conditions were needed to produce appreciable amounts of addition product to methyl crotonate when 1 is used to generate radicals from cyclohexyl iodide. When the cyclohexyl iodide and 1 concentration were held constant at 0.3 M, we

Table 9. Addition of Cyclohexyl Radicals to ,-Unsaturated Lactones

found that 10 equivalents of methyl crotonate were needed in order to produce a moderate yield (62%) of 141.

Other -substituted olefins which are known to be good radical acceptors undergo a radical addition reaction under these conditions. Thus, reaction of cyclohexyl

iodide, 1, and three equivalents of crotonitrile produced 142 (68%) under standard conditions.

It is important to mention a major drawback in the above radical addition chemistry. At the end of the reaction period, at least two equivalents of benzophenone are present in the crude reaction mixture. Purification of the desired product from benzophenone often require tedious chromatographic procedures which do not always afford analytically pure products when non-polar substrates are used. For instance, when attempting to isolate ester 141 from the crude reaction mixture by repeated column chromatography over silica gel, small signals which correspond to benzophenone were detected in the 13C NMR spectrum of the purified material.

Having established that cyclohexyl radicals generated from cyclohexyl iodide by the thermolysis of 1 survived long enough to undergo addition reactions with poor addends such as methyl crotonate, we next chose to examine other -substituted olefins. Our results with ,-unsaturated lactones are outlined in Table 9. Using 3 equivalents of furanone 143 gave 144 in 61% yield. Ten equivalents of 145 were needed to produce a similar yield of 146 (71%).

Unfortunately, many addends did not exhibit the desired mode of cross coupling.

When warming a solution of cyclohexyl iodide, maleic or citraconic anhydride, and 1 in

benzene a polymer immediately formed. Examination of the 1H NMR spectrum from these reactions exhibited that cyclohexyl iodide had been retained, but the anhydride had been consumed. We speculate that this polymer was formed by non-radical chemistry. Maleic anhydride, a difunctional electrophile, may undergo reaction with bis(trimethylstannyl)ether 138 to produce polymers such as outlined in eq. 57.

Other activated olefins gave no cross coupled products. Extremely puzzling results were obtained in attempts to add alkyl radicals to difunctional olefins such as N- methyl maleimide and diethyl fumarate. Upon warming a 0.3 M solution of olefin, cyclohexyl iodide, and 1, an immediate reaction occurred. In successful conjugate addition reactions, a deep burgundy color which is characteristic of ketyl 98 appears and slowly fades over the course of the reaction. When N-methyl maleimide or diethyl fumerate were used as activated olefins this burgundy color immediately dissipates, a white polymer is formed, and the reaction is complete in less than 5 minutes.

Examination of the 1H NMR of this reaction mixture after an aqueous potassium fluoride 60

work-up and filtration demonstrated that olefin was consumed but large quantities of unreacted cyclohexyl iodide were retained. Upon product analysis, N-methylmaleimide afforded N-methylpyrrole-2,4-dione (eq. 58; 30%) and diethyl fumerate afforded diethyl succinate (eq. 59; 82%).

We found these results extremely remarkable. However, examination of the literature suggested that neutral ketyl radicals will reduce olefins which are vicinally substituted with electron withdrawing groups.128 For instance, Zimmerman studied the photochemistry of dione 147 in methanolic solvent. He found that upon direct irradiation

of a solution of 147 in methanol, enol ether 151 was isolated (eq. 60). He suggested that this reaction occurs via photoexcitation of the C=0  bond. This species undergoes cyclization into the aromatic ring to produce a diradical 149. This diradical undergoes fragmentation to give 150. Ketene 150 undergoes addition of methanol to produce the observed product 151. A different mode of reactivity was observed when benzophenone was used as a photosensitizer (eq. 61). Under these conditions the reduced dione 152 was observed. Apparently, a triplet state of benzophenone abstracts a hydrogen atom from methanol (eq. 62). We speculate that ketyl 153 undergoes single electron transfer to produce radical anion 155 (eq. 63). This radical anion undergoes protonation and further reduction to afford the observed product (eq. 64).

Other electron deficient olefins do not produce the desired cross coupled products under standard reaction conditions. When addition of cyclohexyl iodide was attempted using acrylonitrile or 3-cyclohexenone as the addend, another side reaction took place. Like the reactions with N-methyl maleimide and diethyl fumerate the characteristic burgundy color immediately dissipated. Further, analysis of the crude 62

reaction mixture demonstrated that cyclohexyl iodide was retained and the olefin was consumed. Product analysis revealed that different types of products were formed with acrylonitrile and 3-cyclohexenone. The observed product for these reactions came from a net conjugate addition of ketyl 98 to the electron deficient olefin. Hence, acrylonitrile produced 156 (eq. 65; 60%) and 3-cyclohexenone gave 157 (eq. 67; 51%).

The use of 1 in mediating conjugate additions appears to support and extend known methods for radical conjugate additions. The method appears particularly useful for additions to what are classically considered radical "poor" substrates. These substrates show a sufficiently sluggish rate that intermolecular addition cannot compete with hydrogen atom transfer under standard tri-n-butyltin hydride conditions. However, 1 allows radical addition to previously inaccessible substrates such as ,-unsaturated lactones. Under standard conditions, the cross coupling appears to be limited to moderately reactive substrates. When a highly reactive substrate such as crotonitrile is used, reaction of ketyl 98 with the addend is apparently faster than fragmentation to give benzophenone and a tin radical, and the described mode of reaction is not observed. 63

Scheme 7. Potential Mechanisms for Diethyl Fumerate Reduction

To better understand, and potentially eliminate, problems associated with using 1 as a reagent to effect radical coupling of cyclohexyl iodide with highly reactive olefins, we studied potential side reactions of 1 with reactive olefins in more detail. We felt that at least two reasonable mechanistic possibilities might explain our observations. One explanation simply involves a conjugate addition of ketyl 98 to the reactive olefin

(Scheme 7). In the case of diethyl fumarate this conjugate addition would produce radical 158. Radical 158 might undergo radical-radical coupling with 98 to afford 159.

The bis(stannyloxyester) 159 could undergo two retro-aldol reactions and subsequent protonation to afford the observed product. An alternate explanation might involve a single electron transfer from 98 to the electron deficient olefin. In the case of diethyl fumarate this would afford radical anion 160 plus cation 161. There are a number of

possible mechanisms which one can then propose for the formation of diethyl succinate from radical anion 160. This single electron transfer mechanism would be consistent with the formation of -hydroxydiphenylmethyl substituted adducts 156 and 157 with acrylonitrile and 2-cyclohexenone if a rapid coupling followed electron transfer (eq. 67).

In the case of 2-cyclohexenone cation 161 and radical anion 162 would form radical 163.

Radical 163 is converted to the observed product 157 after termination and hydrolytic work-up.

To differentiate these mechanistic possibilities, we studied the reaction of 1 with monoketal 165. Monoketal 165 has been used as a mechanistic probe to test for the propensity of anions to ungergo single electron transfer reactions with enones.129 If a single electron transfer to 165 occurs, the intermediate radical anion 166 undergoes a rapid -elimination to give radical 167 (eq. 68). The isolation of p-methoxyphenol 168 indicates that single electron transfer is important in the system under investigation. If

single electron transfer is not important in our system, we would expect to obtain 164 due to conjugate addition of ketyl 98 to 165. In performing this experiment, we warmed a 0.3 M solution of cyclohexyl iodide, 165, and 1 in refluxing benzene. Again, we observed a rapid loss of the burgundy color and consumption of the electron deficient olefin. Product analysis demonstrates that p-methoxyphenol 69 is indeed formed under these conditions. However, a possible Grob fragmentation of the hypothetical - stannyloxydiphenylmethyl ketone 170 could also explain this observation (eq. 70).

B. Conclusions

In this stage of the study we demonstrated that 1 can mediate conjugate addition reactions with certain radical addends. With certain addends it fails. It appears that single electron transfer chemistry becomes important, thwarting additions in systems which highly stabilize an anionic charge.

Chapter 4. Mechanistic Studies Concerning Bis(trimethylstannyl)benzopinacolate

Mediated Free Radical Carbon-Carbon Bond Forming Reactions.

A. Results and Discussion

It is notable that although no good hydrogen atom donors are present in the reaction mixture, the radical addition reactions mediated by 1 give products that are identical to those obtained in tin hydride mediated reactions. Intuitively, we guessed that tin enolates were important intermediates in these reactions and we felt that the hydrogen atom was being introduced during the aqueous work-up. Naturally, our initial thoughts concerning reaction mechanism involved chain processes. The chain reaction which we considered most plausible is outlined in Scheme 8. In this chain reaction a reversible bond homolysis of 1 generates two equivalents of ketyl-like radical 98.

Radical 98 undergoes a slow fragmentation reaction to generate benzophenone and a trimethylstannyl radical. The trimethylstannyl radical generated in this fragmentation reaction abstracts a halogen atom from an alkyl halide. This alkyl radical undergoes a conjugate addition reaction to generate 172 when ethyl acrylate is used as an acceptor.

Thus far in the sequence, all steps are well precedented and quite common in radical chemistry. However, we were at a loss to think of a well described propagation step which regenerated ketyl 98, and transformed radical 172 into a species which would eventually give the observed products. Ketyl 98 must be generated in a subsequent step for a chain process to be operational. Our best guess concerning this propagation step involved a collision between 1 and adduct radical 172. We imagined that the proposed 67

Scheme 8. A Potential Chain Mechanism

transition would generate enolate(s) 173 and/or 174 and an activated pinacol such as

175. The tin enolate would become protonated during hydrolytic work-up and radical

175 would rapidly undergo fragmentation to release benzophenone and ketyl 98. Ketyl

98 could either undergo reversible recombination to give 1, or a fragmentation reaction to afford benzophenone and a trimethylstannyl radical completing the chain sequence.

This mechanistic possibility was disproven by the products formed upon reaction of 1 with simple alkyl halides. If the above chain sequence were operational, the reaction of 1 with cyclohexyl iodide should produce cyclohexyl-tri-methylstannane. We

found that warming a solution of cyclohexyl iodide and 1 in benzene gave 137 and 138 after an aqueous potassium fluoride work-up and column chromatography. We speculate that these products are formed via a radical-radical recombination between a cyclohexyl radical and ketyl 98. Radical-radical coupling of cyclohexyl radicals with resonance structure 98 forms stannyl ether 177 which gives tertiary alcohol 137 after an aqueous work-up (eq. 72). Radical-radical coupling through resonance structure 176 affords tin enolate 178. This type of enolate is known to undergo rapid air oxidation. In this case, air oxidation of 178 affords 4-substituted benzophenone derivative 146. To rigorously prove the structure of 137, we attempted to prepare it via a well known reaction. Therefore, we reacted benzophenone with an excess of cyclohexyl magnesium bromide. Much to our surprise, we isolated 137 and 138 from this Grignard

reaction. These are the same products isolated when 1 was reacted with cyclohexyl iodide (eq. 73). Products 137 and 138 presumably result from a radical-radical coupling of cyclohexyl radicals and ketyl 179 generated via a single electron transfer reaction from cyclohexylmagnesium bromide to benzophenone. Examination of the literature demonstrated that this reaction is related to a family of coupling reactions involving benzophenone ketyls.131 There are two common methods for generating metal ketyls

180 in the presence of alkyl radicals. The first method is related to a common method for drying many organic solvents.132 This procedure involves a distillation of solvent from a mixture of sodium metal and benzophenone. The sodium benzophenone ketyl radicals generated under these conditions will rapidly undergo reaction with water and oxygen. The appearance of a deep blue color confirms the presence sodium benzophenone ketyl radical, and acts as a convenient indicator of dry solvent. On adding alkyl halide to this mixture, the ketyl undergoes a single electron transfer to the halide to generate a species which rapidly dissociates to give an alkyl radical and a halide anion (eq. 74). These alkyl radicals undergo radical-radical coupling with a second equivalent of sodium benzophenone ketyl to generate the observed products.

The second method relates mechanistically to our observation regarding the addition of cyclohexylmagnesium bromide to benzophenone (eq. 75). Certain alkyl metal species undergo single electron transfer with benzophenone generating a metal ketyl and an alkyl radical. These radicals undergo recombination to produce 181 and 182 after work- up. 70

To investigate the generality of this aspect of reactions mediated by 1, we examined the reaction of alkyl radicals with benzophenone ketyls in some detail. Table

9 summarizes results for radical-radical coupling of benzophenone ketyls and simple alkyl radicals generated via three different methods (eq. 75-76). These ketyl radical anions are associated with various metals such as lithium, sodium, potassium, magnesium, and trimethyltin. In many instances, the nature of the products from these reactions depended on the relative ease with which electron transfer occurs under the reaction conditions. Reactions between metallated derivatives of 5-hexenyl bromide have been extensively studied (eq. 77). Substituted 5-hexenyl systems have been used as probes for free radical intermediates in a variety of anionic processes.135 The 5- hexenyl system proves useful as a probe for free radical intermediates because the

Table 10. Coupling of Radicals to Benzophenone Ketyls

rates of cyclization of a variety of 5-hexenyl anions and 5-hexenyl radicals have been measured and are very different.136 Cyclization via the 5-hexenyl radical occurs many orders of magnitude more rapidly than cyclization of the 5-hexenyl anion. The isolation of cyclic products from reactions involving 5-hexenyl anions is considered indicative of free radical intermediates. A generic example involving coupling of 5-hexenyl magnesium bromide 189 and benzophenone is presented in eq. 77. Upon addition of benzophenone to a solution of the Grignard reagent, unsubstituted substrates (R = H) typically undergo

nucleophilic addition to give 190. In substrates containing substituents which stabilize radicals, another mode of reaction is often observed. In these substrates the Grignard reagent donates an electron to benzophenone generating ketyl 189 and 5-hexenyl radical 191. Radical 191 undergoes a rapid cyclization affording 192. Radical 192 has two pathways which will lead to the observed product. This radical might simply undergo a radical recombination with 189 generating 194 directly. Radical 192 might also accept an electron from 189 to give 193 and benzophenone. This species undergoes nucleophilic addition to benzophenone to liberate 195 after aqueous work-up.

Literature precedent indicates that treatment of 5-hexenyl bromide with magnesium metal followed by benzophenone and aqueous work-up yields only uncyclized tertiary alcohol (eq. 78).137 This result has been explained on the basis of relatively slow electron transfer to benzophenone in Grignard reactions with non- stabilized primary alkyl substrates. Treatment of 5-hexenyl bromide with 1 produces drastically different behavior. Warming a 0.3 M solution of 5-hexenyl bromide and 1 in benzene at 70°C gave a 2:1 mixture of adducts 198 and 199 (58%) along with trace amounts of 6-membered ring products. Capillary VPC analysis of the crude reaction mixture demonstrated that less than 3% of the mixture was uncyclized 197. This indicated that alkyl radicals generated under these conditions have long lifetimes. In comparison to the tin hydride method, reduction of 5-hexenyl bromide with tri-n-butyltin hydride at a concentration of 0.33 M at 70°C produces a 1:1 mixture of cyclized to uncyclized products.138

To probe stereochemical features of this reaction, we performed the coupling reaction with 4-t-butylcyclohexyl bromide 200. Warming a benzene solution of 1 and 200 produced four products by capillary VPC analysis in an approximate ratio of 2:2:1:1.

GC-MS analysis indicated this material was a mixture of diastereomeric tertiary alcohols

201 and 202. The cis:trans ratio in each case was 1:1.

An interesting result was found when we performed this coupling reaction with iodolactone 118, (eq. 81). We found that treatment of 118 with 1 afforded a crystalline product in 70% yield (Mp 220-223°C). Examination of the 13C NMR spectrum of this compound demonstrated that it was a 1:1 adduct between 118 and benzophenone. The

1H NMR showed significant deviations from our prediction for a simple benzophenone adduct. For instance, examination of the 1H NMR spectra of a series of closely related oxabicyclo[3.2.1]octanones previously prepared in this group demonstrated that the tertiary methyl group typically had a chemical shift of 1.5 - 1.8 ppm. A lone singlet integrating to three protons appears at  0.83 ppm in the 1H NMR spectrum of the major product from this reaction. Fearing a rearrangement of the oxabicyclo[3.2.1]octanone

system had taken place, we undertook an X-ray crystallographic study to confirm the structure of this product. This study demonstrated that tertiary alcohol 203 was indeed the correct structural assignment. Examination of this X-ray structure suggested that the equivocal 1H NMR behavior of 203 was due to extreme steric compression around the newly generated carbon-carbon bond. Additionally, we were intrigued by the stereoselectivity of this reaction, particularly in light of the contradictory behavior of 118 when subjected to one carbon homologation (eq. 50). Although we were unable to explain this stereochemical outcome, we were gratified to find that even relatively complex radicals undergo combination reactions.

Having demonstrated that alkyl radicals generated in the presence of 1 can couple with 98, an explanation for the net hydrogen atom reduction of adduct radicals such as adduct 172 emerged. As an example, the proposed termination sequence, for the coupling of cyclohexyl iodide to ethyl acrylate is outlined in eq. 82. Radical 172 undergoes a familiar radical-radical coupling with ketyl 98 generating -trimethyl- 76

stannyloxy ester 204. This ester can then undergo a facile retro-aldol reaction liberating tin enolate 205 and benzophenone. The hydrogen atom is introduced as a proton during hydrolytic work-up.

To discount the possibility that the mechanism of radical termination changed in the presence of olefins, we sought a facile radical addition reaction to an olefin which was not substituted by a strong electron withdrawing group. Styrene is an addend which reacts rapidly with cyclohexyl radicals.139 However, a phenyl group will not facilitate a retro-aldo reaction. We found that the cross coupling reaction between cyclohexyl iodide and three equivalents of styrene produced a product in 72% yield with spectral features consistent with structure 206 (eq. 83). Unfortunately, small amounts of impurities complicated the aromatic region of the 13C NMR spectrum. We proved the structure of 206 via synthesis (eq. 84). Generation of phenylacetic acid dianion followed by quenching with cyclohexylmethyl bromide afforded 207. Esterfication of acid 207

Scheme 9. A Non-Chain Reaction Mechanism

followed by reaction with phenylmagnesium bromide cleanly afforded 206. Comparison of the products from the two reaction sequences demonstrated that the material from eq.

84 consisted of 206 contaminated by small aromatic impurities.

Having established the nature of the termination event, we proposed a new mechanism for additions of cyclohexyl iodide to alkenes mediated by 1. This mechanism is outlined in Scheme 9. The process begins with a reversible homolysis of

pinacol 1 generating ketyl 98 (eq. 85). Ketyl 98 undergoes a fragmentation reaction to generate a trimethylstannyl radical and benzophenone (eq. 86). The tin radicals generated are free to add to a molecule of benzophenone (k-frag) or abstract a halogen atom from an alkyl halide (kabs) (eq. 87). Depending on the reaction conditions the resulting alkyl radicals add intermolecularly to the electron deficient olefin (eq. 88), or terminate via coupling with ketyl 98. The incipient radical 172 undergoes termination with ketyl 98 (eq. 89). The resulting -trimethylstannyloxy ester undergoes a retro-aldol reaction liberating benzophenone and tin enolate 205 (eq. 90). The tin enolate is stable to the reaction conditions and survives until aqueous work-up.

An uncommon feature of this reaction mechanism relative to familiar radical processes is that radical 172 undergoes recombination with another radical to generate a non-radical species. In typical radical processes, the final radical entity leading to the desired product undergoes a chain transfer step which liberates a neutral species and a radical which is transformed into the radical which originated the chain sequence. This leads to propagation of the free radical chain. Because radical 172 does not generate a new radical species, the proposed reaction mechanism is non-chain in nature.

Other free radical methods are thought to proceed via a non-chain mechanism.

A good example is a unique radical one carbon homologation.67 The process relies on the ease with which isonitriles act as free radical acceptors (Scheme 10). The process begins when hexaphenylditin undergoes a photochemical homolysis producing triphenyltin radicals (eq. 91). The triphenyltin radicals abstract an iodine atom from an

Scheme 10. A Non-Chain One Carbon Homologation

alkyl iodide (eq. 92). The resulting alkyl radical undergoes an intermolecular addition with isonitrile 29 (eq. 93). Radical 31 undergoes a fragmentation reaction to afford the desired nitrile 32 and a t-butyl radical (eq. 94). The t-butyl radical generated in this step cannot participate in a chain transfer step and is destined to terminate via recombination with another radical species. The non-chain nature of this process leads to complications. Because the t-butyl radicals generated in eq. 91 undergo termination via recombination, they live long enough to undergo intermolecular addition to isonitrile 29.

Ultimately, this leads to nitrile 207. This problem is avoided by use of a large excess of isonitrile 29. The undesired nitrile 207 is volatile and can be removed from the crude reaction mixture in vacuo.

Aware of inherent problems with conducting free radical reactions via non-chain mechanisms, we were uneasy accepting the mechanism outlined in Scheme 9. One question which caused us a great deal of concern was why did the reaction of 1 with cyclohexyl iodide only afford cross termination products 137 and 138. This question bothered us because radical-radical recombination reactions are intrinsically non- selective. The mechanism outlined in Scheme 9 includes five different radical intermediates. Of the various recombination products which are possible from the five radical species, we only observe cross termination between alkyl radicals and ketyl 98.

No dimerization products formed via radical recombination of. like-species is observed.

We were able to glean insight into this puzzle from a series of photochemical experiments. We hoped to use information collected during this study in the design of synthetically useful transformations. We were particularly interested in exploiting the reaction of photoexcited carbonyl compounds with hexamethylditin. In this elementary reaction the photoexcited carbonyl compound extracts a trimethyltin molecule from hexamethylditin producing a ketyl radical and a trimethylstannyl radical. For example, when benzophenone is used as the photolytically active ketone, radical 98 is the ketyl generated. Our primary interest was in developing useful carbon-carbon bond forming reactions. We felt that an alkyl halide would be able to intercept the trimethyltin radical generated upon photolysis of an active ketone in the presence of hexamethylditin. We hoped that the resulting alkyl radical would then couple with the intermediate ketyl radical. Several examples are cited in the literature in which a photoactivated carbonyl compound reacts with a substrate containing an abstractable hydrogen atom producing a carbon-carbon bond. In one example diethylketomalonate 208 was photolyzed in cyclohexane and 209 were observed as outlined in eq. 96.141 In this process diethyl

ketomalonate is excited to a triplet state (eq. 99). The excited ketone abstracts a hydrogen atom from cyclohexane giving ketyl 208 and a cyclohexyl radical. The cyclohexyl radical and 208 couple to give 209. Similarly, photolysis of oxime 210 in cyclohexane solvent gives 211 (eq. 97). Benzophenone exhibits selectivity for hydrogen atoms adjacent to nitrogen upon photolysis with N-methyl-2-pyrrolidinone 212 (eq.

98).142 This reaction affords mainly pyrrolidinone 213.

In these examples, the hydrogen atom abstraction occurs either from a molecule in which all hydrogen atoms are equivalent, or from a molecule in which a set of hydrogen atoms are particularly prone to undergo hydrogen atom abstraction. We felt

that by using hexamethylditin photochemistry, one could accomplish similar transformations using alkyl halides. This process would offer the bonus of sight selective radical generation. In our first experiment, a solution of cyclohexyl bromide, benzophenone, and hexamethylditin in benzene was subjected to photolysis (eq. 100).

Product analysis indicated that the familiar cross termination products 137 (31%) and

138 (16%) were formed. Additionally, cyclohexylcyclohexane 214 (8%) was isolated from this reaction. Capillary VPC analysis indicated that 214 comprised 18% of the product mixture. However, 214 was volatile and difficult to isolate in a representative yield.

The formation of cyclohexylcyclohexane 214 from this photochemical experiment produced a great deal of mechanistic insight. A mechanistic proposal concerning this experiment is outlined in Scheme 11. Benzophenone absorbs light and is excited to a triplet state. The excited benzophenone abstracts a trimethylstannyl group from hexamethylditin to give 98 and a trimethylstannyl radical. If hexamethylditin does not undergo photolytic homolysis under these conditions, and all trimethylstannyl radicals are formed via the benzophenone abstraction reaction, a 1:1 ratio of ketyl 98 and trimethylstannyl radicals would result. The trimethylstannyl radical may react in two different ways. First, it may undergo addition to benzophenone to give another

Scheme 11. Proposed Mechanism for the Hexamethylditin Mediated

Coupling of Cyclohexyl Bromide and Benzophenone

equivalent of 98. The other mode of reaction involves abstraction of bromine from cyclohexyl bromide. If trimethylstannyl radicals abstract bromine from cyclohexyl bromide faster than they add to benzophenone, a 1:1 ratio of cyclohexyl radicals and ketyl 98 results. This accounts for the formation of cyclohexylcyclohexane 214 in this photochemical experiment. Since cyclohexyl radicals are present in near equal concentration with 98, and radical-radical coupling between 98 and cyclohexyl radicals

Scheme 12. A Proposed Mechanism for the Formation of 137 and 138

and dimerization should occur at competetive rates, one would expect cross termination products 137 and 138 and dimer 214 to be observed in this reaction.

A very different concentration of radicals results upon warming 1 with cyclohexyl iodide (Scheme 12). Pinacol 1 is in equilibrium with ketyl 98. Ketyl 98 undergoes fragmentation to afford a trimethylstannyl radical. If the fragmentation of 98 is slow, trimethylstannyl radicals should be present in a lower concentration than the persistent ketyl 98. This translates into a difference in radical concentration between cyclohexyl radicals and ketyl 98 after the trimethylstannyl radical abstracts a halogen from cyclohexyl iodide. Since ketyl radical 98 is present in a much higher concentration than any other radical in solution, a cyclohexyl radical will find ketyl 98 in solution much more frequently than it encounters another cyclohexyl radical. We believe this difference in free radical concentration causes the cross termination.

Other photoactive ketones participated in similiar radical cross coupling reactions. For instance, photolysis of a 0.3 M solution of diethyl ketomalonate, hexamethylditin, and cyclohexyl bromide produced tertiary alcohol 209 (38%). In addition to tertiary alcohol

209, cyclohexylhexane 214 was detected via capillary VPC analysis and it appears that the dimer of 208 was also produced in this reaction (NMR). Acetophenone produced styrene 215 (33%) along with 214 when photolyzed in the presence of cyclohexyl bromide and hexamethyldlitin. Styrene 215 presumably came from elimination of an intermediate tertiary alcohol.

During the course of this study, the importance of persistent radicals in non-chain processes was advanced to explain other well-studied radical reactions. The Barton reaction is an example of a reaction which falls into this class. The Barton reaction transforms nitrite esters with an extractable -hydrogen atom into 4-hydroxyoximes

(Scheme 13).143 This reaction occurs via photolytic homolysis of the weak N-O bond in nitrite 216 liberating alkoxy radical 218 and a persistent nitrous oxide radical. Alkoxy

Scheme 13. The Barton Reaction

radical 218 abstracts a -hydrogen atom to give alkyl radical 219. The alkyl radical 219 then couples with nitrous oxide to give nitroso alkane 220, which tautomerizes to the observed oxime product 217. A surprising aspect of the Barton reaction is that only cross termination between alkyl radical 219 and nitrous oxide is observed. This is startling because alkyl radicals undergo recombination rapidly, and one would predict to observe dimerization product 222 if the reaction truly involved free radical intermediates.

Investigators have attributed this selective cross termination to a propensity for solvent caging.144 They speculate that alkoxy radical 218 and nitrous oxide remain associated in solution. Radical 218 rearranges to 219 and is trapped selectively by nitrous oxide due to its proximity. Solvent caging effects are often used to explain phenomenon associated with cation-anion pairs.145 However, any attraction due to solvent caging should be slight in the Barton reaction since no Coulombic forces exist between neutral radical species. Recently, an alternative explanation has been advanced (eq. 108).73 It was postulated that dimerization does indeed occur in the

Barton reaction. Nitrous oxide undergoes a well known dimerization, and is in equilibrium with N2O4. At room temperature this equilibrium lies to the side of nitrous oxide. Very early in the reaction, radical 218 also undergoes dimerization as well as cross termination with nitrous oxide at competitive rates. Since the dimerization of nitrous oxide is reversible and the dimerization of 219 is not, radical 219 is consumed 88

faster than nitrous oxide. This leads to a difference in free radical concentrations. The persistent nitrous oxide radical concentration increases relative to 219. Because nitrous oxide is available in a higher concentration than any other radical in the mixture, radical

219 is likely to encounter nitrous oxide more often than other radical species. This difference in radical concentrations causes cross termination to dominate.

Having gathered inferential evidence suggesting tin enolates were important intermediates in the conjugate addition reactions, we set out to gather experimental evidence for their existence. Initially, we attempted to quench the presumed tin enolate with deuterium oxide. When the radical cyclization of ester 135 was mediated by 1 and worked-up with D20, deuterium incorporations ranging from 30 to nearly 100 percent was obtained (eq. 109). Further, reactions run with deuterobenzene as solvent showed no deuterium incorporation (eq. 100). We believe that the low deuterium incorporation on certain occasions is due to contamination by 234 due to partial hydrolysis of 1.

Having collected information suggesting tin enolates were intermediates in these conjugate addition reactions, we set out to design a synthetically useful transformation.

Modeled after analogous silyl ketene acetal rearrangements,146 we conducted conjugate additions with judiciously designed acrylate 225. Acrylate 225 was favored over acrylate

224 simply because attempts to synthesize 224 via condensation between the requisite acid chloride and an allylic alcohol lead to rapid polymerization. When 1 was used to mediate coupling of cyclohexyl iodide with 225, acid 226 was isolated in 68% yield. 90

Presumably, acid 226 is formed in this reaction via a sigmatropic rearrangement of trimethylstannylketene acetal 228 (eq. 111). In probing the generality of this reaction, we found that when t-butyl bromide was used as the alkyl halide, acid 230 could be isolated in 71% yield (eq. 112). However, we found this reaction to be extremely capricious. We speculated that the inconsistency of this reaction was due to protonation of ketene acetal 228. In fact, our thoughts concerning this problem lead to important advances in reagent development as will be apparent in the next chapter of this thesis.

Another aspect of the proposed mechanism which deserves scrutiny is the retro- aldol reaction. Literature precedent suggests that aldol-type condensations between trialkylstannyl ketene acetals and aldehydes are reversible.147 The success and failure of these condensations depends on the position of the equilibrium for a given system.

We performed the series of experiments outlined in eq. 113 to test the position of an equilibrium set-up between -stannyloxy ester 204, ketene acetal 205 and benzophenone (see Scheme 9). We treated ethyl 3-cyclohexylpropanoate 139 with LDA at -78°C. The resulting enolate was reacted with benzophenone, presumably forming lithium alkoxide 230. Half of the reaction mixture was quenched with water. Product analysis demonstrated that this portion of the reaction mixture consisted mainly of tertiary alcohol 231. To the remainder of the reaction mixture was added an excess of trimethyltin chloride. The resulting mixture was warmed at reflux in benzene for 4 h. This portion of the reaction mixture consisted of starting 139 and benzophenone. Additionally, prolonged warming of 231 in benzene solution produced no reaction. However, warming a benzene solution of 230 in the presence of trimethyltin bromide produces ester 139 and benzophenone. These experiments suggest that the proposed retro-aldol reaction

(eq. 90) is reasonable.

B. Conclusions

In this stage of the study we presented evidence that reactions mediated by 1 proceed via a non-chain mechanism. We presented evidence that alkyl radicals terminate via coupling with ketyl 98. We found evidence to suggest that benzophenone is liberated from the adduct post termination in successful cross coupling reactions via a retro aldol or similar fragmentation reaction.

Chapter 5. Studies Concerning Reagent Development Using Alternative Tin

Sources and Pinacols

A. Results and Discussion

At this stage in the study, we had made intriguing mechanistic observations. We recognized that technical, biological, and economic problems involved in making, storing, and using 1 detracted from its use in organic synthesis. Many of these problems center around the use of trimethyltin compounds. A major concern when dealing with trimethyltin compounds is their toxicity. Trimethyltin compounds generally have an LD50

148 of 5-20 mg/kg. Comparable tri-n-butyltin compounds generally have an LD50 which is

100-1000 times greater. The biohazard of these compounds, is amplified by their high volatility and almost total lack of regard for the protective powers of biological membranes. The last and perhaps the most prohibitive problem which faced this chemistry was the difficulties encountered in preparing 1. After 2 years of experimentation, we developed a procedure for the preparation of 1 which was capricious at best. An ideal situation would arise if we could use the insights gleaned from previous studies and address the unfavorable issues in designing new transformations. During the final stages of this research we conducted a very limited number of experiments that suggest this might be possible.

A failed experiment lead us on a course of research which addressed all of the aforementioned problems. In this experiment, a collaborator attempted to perform a

conjugate addition of cyclohexyl iodide to acrylate 225 (eq. 114). Using, by mistake, a batch of 1 which presumably contained substantial amounts of benzopinacol 234, the non-rearranged ester 233 as well as 236 was observed. What was so surprising was examination of the crude NMR spectrum of this reaction demonstrated the conjugate addition had advanced to completion even though 13C NMR analysis demonstrated that

1 comprised much less than half of the composition of the reagent used in this reaction.

What this suggested was that a single trimethyltin molecule could generate several radicals. We felt that this was due to the highly basic nature of the tin enolates generated over the course of the reaction. Thus, it would be favorable for the tin enolate to become protonated by the benzopinacol 234 present in the reactive media. This would generate the observed product. More interestingly, a balanced chemical equation suggested that a stannylated benzopinacol might be formed (eq. 115). This immediately suggested processes which would be catalytic in tin.

With this information in hand we performed a very limited number of experiments in which 1 was used in less than stoichiometric quantities. We first tried to couple cyclohexyl iodide with methyl crotonate. Recall that under standard tin hydride conditions, radical additions to methyl crotonate generally fail due to its low addition rate with alkyl radicals. Coupling mediated by stoichiometric quantities of 1 were only successful when a large excess of crotonate was used. However, stirring a solution of cyclohexyl iodide (1.0 equivalent), methyl crotonate (1.5 equivalents), benzopinacol 234

(1.0 equivalent) and 1 (0.2 equivalents) in benzene gave the desired coupling product

235 in 47% yield (eq. 116).

These reaction conditions offer other benefits when compared to the stoichiometric use of 1. Under standard conditions, attempted cross coupling of cyclohexyl iodide to diethyl fumerate gave reduced product 142. In contrast, use of 0.2 equivalents of 1 along with 1 equivalent of benzopinacol 234 in refluxing toluene gave the desired cross coupling product 236 in 67% yield (eq. 130).

We were fascinated by this result, but the use of catalytic 1 did not solve all of the aforementioned problems. One problem was that volatile trimethyltin compounds were still being used. Thus, we sought to replace 1 with the corresponding tri-n-butylstannyl counterpart. Unfortunately, Neuman reported attempted preparation of 240 via photolysis of hexabutylditin and benzophenone met with failure.115 Results that implied

234 acted as a proton source, generating a stannylated pinacol, suggested it might be possible to generate 1 in situ via a stannylation of benzopinacol 234 by reaction with an electrophilic tin species. We felt that the basicity of N-trialkylstannylamines make these compounds particularly promising electrophilic tin species.

To test this hypothesis we prepared N,N-diethyltrimethylstannylamine and N,N- diethyltri-n-butylstannylamine via known procedures.149 In this process, treatment of an ethereal solution of the requisite amine with n-butyllithium and trialkylstannyl chloride followed by filtration and distillation produced moderate to high yields of the desired stannylamines. The stannylamines are air sensitive. However, we found that they can be stored in a refrigerator in a dry flask equipped with a sealed septum. The amines may be weighed in a fume hood, or more conveniently measured directly from the storage flask via syringe.

To determine the position of the equilibrium depicted in Scheme 14 we conducted 13C NMR experiments. In these experiments, we mixed 2.2 equivalents of

Scheme 14. Equilibrium Formed Upon Mixing N,N-Diethyltrimethyl-

stannylamine and benzopinacol 234.

N,N-diethyltrimethylstannylamine with benzopinacol 234 in deuterobenzene. This experiment demonstrated that this equilibrium lies far to the side of 1. The aromatic region of this 13C NMR spectrum was identical to 1 formed via the photolysis of hexamethylditin and benzophenone. In fact, this experiment generated a cleaner spectrum of 1 than our best result with the hexamethylditin photochemistry.

Having demonstrated that 1 could be generated in situ, we next looked to see if these reaction conditions were amenable to free radical chemistry. Toward this end we studied the one carbon homologation outlined in eq. 118. We found that warming equimolar amounts of cyclohexyl iodide, formaldoxime 83, pinacol 234, and N,N- diethyltrimethylstannylamine produced 109 in 61% yield.

We generated a result that suggested tri-n-butylstannylpinacol 240 could be generated in situ and functionally used as outlined in equation 119. Warming a solution of cyclohexyl iodide, formaldoxime 83, pinacol 234, and N,N-diethyltri-n-butylstannylamine produced the familiar oxime ether 109 (48%).

Conjugate addition reactions mediated by stoichiometric amounts of 1 were not as general as we would like. Attempts to mediate conjugate addition reactions to substrates other than simple alkyl iodides often met with failure. These failures might be explained, albeit only in part, by problems centered around the proposed retro-aldol reaction. For instance, attempts to add ethyl acrylate to glycosyl bromide 35 gave a complex mixture consisting of the desired product 237 and an inseparable mixture of benzophenone adducts. Surprisingly, reaction conditions using stoichiometric quantities of 234 and N,N-diethyltri-n-butylstannylamine is more successful. Thus, warming a 98

solution of glycosyl bromide 35 (1.0 equivalents), ethyl acrylate (1.5 equivalents), pinacol

234 (1.3 equivalents), and N,N-dimethylaminotri-n-butylstannane (2.6 equivalents) affords the desired cross coupled product 237 (71%) as an 8:1 mixture of stereoisomers

(eq. 120). At present, we do not fully understand why these reaction conditions offer such advantages. We speculate that benzopinacol 234 inherently present with 1 caused an intermediate -stannyloxy ester to become protonated. Earlier in this study we demonstrated that such -hydroxy esters show little tendancy towards retro aldol reaction when warmed in benzene.

We were quite gratified to find reaction conditions in which trimethyltin compounds were avoided. Having found such conditions, one of our initial goals set forth in the beginning of this section remained to be addressed. This involved finding a simple means by which the benzophenone could be separated from the desired product. In previous studies the benzophenone was removed via tedious chromatographic procedures. We felt this chemistry would be more attractive if a non-chromatographic procedure could be developed in which the major portion of benzophenone could be removed. We had two major strategies for accomplishing this goal. One strategy involved impregnating a polymer backbone with benzopinacol units. We felt that the free hydroxyl groups of this polymer could be stannylated, using stannylamines. We hoped

that this stannylated polymer would undergo chemistry analogous to 1. A retro-aldol reaction and protonation would free the desired product from the polymeric backbone.

Because of our lack of experience in dealing with polymeric systems, we adopted another strategy. This strategy involved forming a benzopinacol derivative which can be extracted into aqueous solution. Very early in the study, we envisioned a process in which photochemistry with hexamethylditin and Michler's ketone (238) might produce pinacol 239. Neumann reported that several derivatives of 1 could be synthesized.112

These include the tetra-4-substituted methyl-, tert-butyl-, and methoxyl- derivatives.

However, he reported that Michler's ketone was not active under these conditions.

Michler's ketone forms a deep blue opaque solution when dissolved in organic solvents.

Thus, it is not surprising that photochemical experiments would fail. We felt that this problem might be solved by using a non-photochemical method for this dimerization.

Toward this end, we treated an ethereal solution of 238 with lithium. From this slurry we were able to isolate the desired pinacol 239 in 51% yield. We hoped that treatment of

239 with stannylamine derivatives would produce a species which would show a similar behavior to 1. Hence, treatment of a solution of 239 with a dialkylaminotrialkylstannane 100

would generate pinacol 240 (eq. 136). Warming this pinacol might cause bond homolysis to liberate two molecules of ketyl 241. Ketyl 241 might undergo fragmentation, and in the absence of any reactive partner return Michler's ketone and hexaalkylditin. In order to test whether 239 would be useful in mediating radical addition reactions, we studied the cross coupling reaction of ethyl acrylate to cyclohexyl iodide. In this experiment we treated a benzene solution of pinacol 239 with N,N-dimethylaminotri-n-butylstannane.

To this solution we added cyclohexyl iodide and ethyl acrylate. Under these conditions we isolated 139 in 43% yield. The yield increased to 63% when toluene was substituted as the solvent.

101

The work-up for this reaction was radically different than previous experiments.

This reaction was worked-up by diluting with ether. We washed the ethereal solution with three portions of 3 N hydrochloric acid. The tin is easily removed by a procedure developed by Curran.151 Thus, adding a stoichiometric quantity of DBU, followed by filtration through silica gel and concentration produced a mixture which consisted of 60-

80% of the desired product by Capillary VPC and 1H NMR analysis. The impurities present were very polar, and simple column chromatography liberated pure products.

In choosing systems for this very limited study, we payed particular attention to systems in which separation of benzophenone proved problematic, or on reactions which were difficult to carry out by other measures. Tri-n-butyltin hydride mediated conjugate addition to methyl crotonate generally fail due to the slow reactivity of the crotonate. We have demonstrated that by use of an excess of addend, 1 can facilitate such transformations. However, we find that tedious chromotagraphy is needed to isolate a pure product. Using 239 as the benzopinacol provides a nice solution to this problem.

102

We found that warming a solution of cyclohexyl iodide (1 equivalent), methyl crotonate (5 equivalents), 239 (1.3 equivalents), and N,N-dimethylaminotri-n- butylstannane (2.6 equivalents) affords ester 141 in 77% yield (eq. 125). The crude 1H

NMR spectrum of this reaction demonstrated that no aromatic contaminants and only small amounts of tin residues were present. Therefore, a simple chromatographic procedure allowed isolation of pure 141. In a similiar vein, use of 5 equivalents of furanone 143 allowed the preparation of lactone 144 in 61% yield.

B. Conclusions

In the final stages of this study we presented evidence that tin radicals can be recycled during the use of 1. Further, we demonstrated that 1 and analogues thereof can be generated in situ and mediate radical transformations. Finally, we provided preliminary experiments that suggested using 239 as the pinacolate in this family of coupling reactions facilates removal of pinacol by products and may lead to more convenient and synthetically usefull transformations.

103

Chapter 6. Experimental

A. General Experimental

All melting points were taken with a Thomas-Hoover capillary melting point apparatus and are uncorrected as are all boiling points. Proton nuclear magnetic resonance spectra were recorded on a Varian Associates EM-360, Varian Associates

EM-390, Bruker WP-200, Bruker AM-250, Bruker WM-300, or Bruker AM-500 spectrometers and are recorded in parts per million from internal tetramethylsilane on the  scale. The 1H NMR spectra are reported as follows: [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in hertz, integration, interpretation]. 13C NMR data were obtained with a Bruker WP-80, Bruker AM-250 or

Bruker AM-500 spectrometer. Infrared spectra were taken with a Perkin-Elmer 457 instrument. Mass spectra were obtained on a Kratos MS-30 or Kratos VG70-250s instrument at an ionization energy of 70ev. Compounds for which an exact mass is reported exhibited no significant peaks at m/e greater than that of the parent.

Combustion analysis were performed by Micro-Analysis, Inc., Wilmington, DE. Capillary

VPC analysis was performed with a Hewlett Packard 5890 instrument using a 30 meter

5% phenyl-methyl silicon gum column (Ultra II), or a 25 meter carbowax column.

Integration was performed using a flame ionization detector and recorded via a Hewlett

Packard 3390 integrator. All integrated ratios are corrected for relative response factors.

Relative response factors were determined by injection of an equimolar solution of

104

standard compounds. Capillary VPC conditions are reported as follows: [column: initial temperature (hold time) to final temperature (heating rate)].

Solvents and reagents were dried and purified prior to use when deemed necessary: tetrahydrofuran, diethyl ether, and benzene were distilled from sodium metal; dichloromethane was distilled over calcium hydride. Reactions requiring an inert atmosphere were run under argon. Analytical thin-layer chromatography was conducted using EM Laboratories 0.25 mm thick precoated silica gel 60E-254 plates. Column chromatography was performed over EM medium pressure liquid chromatography

(MPLC) was performed using EM Laboratories Lobar prepacked silica gel columns.

Organometallic reagents (Grignard, organolithiums) were titrated prior to use with 2- butanol using 1,10-phenanthroline as the indicator when deemed necessary.

B. Experimental

Bis(trimethylstannyl)benzopinacolate (1).113 A 500 mL

photochemical reaction assembly (Ace Glass Catalog # 840-

180) was purged with argon and charged with 18.37 g (56.1

mmol) of hexamethylditin and 20.42 g (112 mmol) of benzophenone in 500 mL of anhydrous benzene. The reaction vessel was placed in an ice bath and subjected to photolysis through a Pyrex filter using a 450 Watt Hanovia medium pressure lamp. The reaction mixture was photolyzed for 4.5 h with complete loss of the benzophenone C=0 stretch (1675 cm-1) as noted by infrared spectroscopy.

At this time the reaction mixture exhibited the formation of a large amount of white crystals. The reaction mixture was concentrated to approximately two thirds of its total 105

volume and the crystals were collected using vacuum filtration. The crystals were washed with 50 mL of hexane and dried at 1 mm Hg and room temperature for 30 min to afford 15.27 g (39%) of bis(trimethylstannyl)benzopinacolate (1) as small white crystals

(mp 115-120°C). The mother liquor was concentrated to afford a yellow precipitate. The yellow precipitate was washed with 150 mL of hexane and dried at 1 mm Hg to give an additional 16.47 g (42%) of bis(trimethylstannyl)benzopinacolate (1) as a white precipitate (mp 105-110°C). Both crops were suitable for use in subsequent reactions:

13 C NMR (C6D6)  -2.914, 88.02, 125.15, 126.07, 130.9, 149.99. This material was contaminated by trace amounts of a substance that exhibited peaks at  133.64, 131.46,

130.51, 130.12, and 129.33.

(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-bromo-

tetrahydro-2H-pyran-3,4,5-triyl triacetate (35).74 To a

cooled (0°C) solution of 40.00 mL acetic anhydride and 0.5

mL of perchloric acid was added 10.00 g (55.0 mmol) of

dextrose in small portions over a 30 min period. The

solution was warmed to room temperature and stirred for 30 min, again cooled to 0°C and 3.02 g of phosphorous (96.7 mmol) was added in small portions over a 30 min period. Bromine (18 g, 11.25 mmol) was then added in small portions over a 30 min period. The reaction vessel was stoppered and stirred at room temperature for 2.5 h. The solution was poured into 80 mL of ice water and extracted with 100 mL of chloroform. The organic extract was washed with three 50-mL portions of ice water followed by two 50-mL portions of sodium bicarbonate. The solution was dried

106

(MgSO4) and concentrated in vacuo to yield 19 g of a thick yellow oil which recrystallized

1 from diethyl ether to yield 18.36 g (81%) of 35: mp 83-86°C; H NMR (CDCI3)  2.00 (s,

3 H, OAc), 2.01 (s, 3 H, OAc), 2.10 (s, 3 H, OAc), 2.11 (s, 3 H, OAc), 4.13 (d, 1 H, J =

11.3 Hz, 1 H, C(6)H), 4.31 (m, 2 H, C5H and C(6)H), 4.83 (dd, J = 11.3, 4.5 Hz, 1 H,

C2H), 5.17 (t, J = 9.1 Hz, 1 H, C4H), 5.56 (t, 1 H, J = 9.1 Hz, C3H), 6.62 (d, J = 3.7 Hz, 1

13 H, C1H); C NMR (CDCl3)  20.23 (q, two carbons), 20.32 (q, two carbons), 60.74 (t),

66.95 (d), 69.95 (d), 70.32 (d), 71.97 (d), 86.50 (d), 169.12 (s), 169.41 (s), 169.46 (s),

170.10 (s).

0-Benzylformaldoxime (83).109 To a solution of 11.05 mL

(135 mmol) of a 36.6% aqueous solution of formaldehyde in 75 mL of water was added 32.0 mL (405 mmol) of pyridine and 21.60 (135 mmol) of 0- benzylhydroxylamine hydrochloride. The flask was tightly stoppered and the mixture was heated at 70°C for 1 h. The mixture was cooled, acidified with 45 mL of 3 N aqueous hydrochloric acid, and extracted with three 200-mL portions of ether. The combined ethereal solutions were dried (MgSO4), and concentrated in vacuo. The oily residue was distilled to produce 14.26 g (79%) of oxime ether 83 as a colorless liquid; bp

-1 1 77-81°C (20 mm Hg); IR (neat) 1015, 735, 695 cm ; H NMR (CDCI3)  5.01 (s, 2 H,

OCH2), 6.27 (d, J= 8.3 Hz, 1 H, =CH), 6.95 (d, J= 8.3 Hz, 1 H, =CH), 7.25 (s, 5 H, ArH);

13 C NMR (CDCI3) 75.81 (t), 127.75 (d), 128.06 (d), 128.25 (d), 137.31 (t), 137.40 (s); exact mass calcd for C8H9NO m/e 135.0684, found m/e 135.0681.

107

O-tert-Butylformaldoxime (85).150 To a solution of

2.09 g (17 mmol) of O-tert-butylhydroxylamine

hydrochloride 97 and 1.52 g (19 mmol) of a 37% (w/w) aqueous formaldehyde solution in 5 mL of water was slowly added 1.43 g (17 mmol) of sodium bicarbonate. This mixture was sealed in a Pyrex bomb tube and heated at 70°C for 1 h. The tube was cooled in an ice-water bath and 0.5 g of ammonium chloride was added producing a two-phase mixture. The upper phase was removed and distilled (bp

66-67°C) to afford 1.52 g (89%) of oxime 85 as a colorless oil; IR (neat) 1610 cm-1, 1H

NMR (CDCI3)  1.23 (s, 9 H, CH3), 6.21 (d, J= 15 Hz, 1 H, =CH), 6.85 (d, J= 15 Hz, 1 H,

=CH).

Cyclohexanecarboxaldoxime (88): Method A. A

solution of 0.63 g (3.0 mmol) of cyclohexyl iodide, 0.41 g

(3.0 mmol) of O-benzylformaldoxime 83, and 0.98 g (3.0 mmol) of hexamethylditin in 2.0 mL of anhydrous benzene was irradiated for 24 h through a Pyrex filter using a 450 watt Hanovia medium pressure mercury arc lamp. The reaction mixture was stirred with 100 mL of diethyl ether and 50 mL of a saturated aqueous potassium fluoride solution for 30 min. The organic phase was separated, dried

(MgSO4), and concentrated in vacuo. The residual oil (0.62 g) was chromatographed over 100 g of silica gel (hexane:ethyl acetate, 9:1) to give 38 mg (8%) of impure oxime

-1 1 88 as a colorless oil; IR (neat) 3300, 1650 cm ; H NMR (CCI4)  1.10-2.00 (m, 10 H,

CH2 manifold), 2.33 (m, 0.5 H, CHC=N), 2.96 (m, 0.5 H, CHC=N), 6.43 (d, J= 7 Hz, 0.5

H, CH=N), 7.22 (d, J= 6 Hz, 0.5 H, CH=N), 9.20 (br s, 1 H, OH); exact mass calcd for

C7H13NO m/e 127.0997, found m/e 127.0992. An authentic sample of 88 prepared from

108

the reaction of cyclohexane carboxaldehyde with hydroxylamine, aided in the identi- fication of this material.

Method B. A solution of 0.13 g (0.6 mmol) of cyclohexyl iodide, 0.20 g (0.6 mmol) of O-tri-n-butylstannylformaldoxime 85,108, 153 and 0.20 g (0.6 mmol) of hexamethyl-ditin in 0.5 mL benzene-d6 was irradiated through a Pyrex fitter using a 450 watt Hanovia medium pressure mercury arc lamp. The progress of the reaction was monitered via 1H NMR. After 20 h the reaction exhibited complete loss of cyclohexyl iodide, and formation of considerable amounts of cyclohexene, along with small amounts of the desired product. The reaction mixture was stirred with 100 mL of diethyl ether and

50 mL of a saturated aqueous potassium fluoride solution for 30 min. The organic phase was separated, dried (MgSO4), and concentrated in vacuo. The residual oil was subjected to column chromatography over 30 g of silica gel (hexane-ethyl acetate, 20 :1) to give 9 mg (9%) of oxime 88 as a colorless oil.

N-tert-Butoxyphthalimide (96). A solution

of 16.40 g (100 mmol) of N-hydroxyphthalimide,

80.0 mL (54.3 g) of t-butyl acetate, and 1 mL of a

70 % aqueous perchloric acid solution in 500 mL of

dioxane was stirred at room temperature for 20 h.

The reaction mixture was carefully quenched by the slow addition of 700 mL of saturated aqueous sodium bicarbonate. The resulting colloid was extracted with three 250-mL portions of dichloromethane. The combined extracts were dried (MgSO4), and concentrated in vacuo to produce 19.31 g (84%) of 96 as a pale yellow solid: mp 109-

1 110°C; IR (CHCI3) 1790, 1740, 1370; H NMR (CCI4) 1.40 (s, 9 H, CH3), 7.77 (m, 4 H,

ArH). 109

0-tert-Butylhydroxylamine hydrochloride (97).152 A solution of 18.73 g (85 mmol) of N-tert-butoxyphthalimide 94 and 9.32 g (186 mmol) of hydrazine in 300 mL of t-butyl alcohol was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and dissolved in 800 mL of a saturated sodium bicarbonate solution. This solution was extracted with three 200-mL portions of diethyl ether and the combined organics were dried (Na2SO4). To the dried solution was added

20 mL of a 1.2 N solution of concentrated hydrochloric acid in diethyl ether. The resulting solution was concentrated in vacuo to give 9.83 g (92 %) of the desired salt 97 as a white solid: mp 149-151°C (lit153 mp 150-151 oC). IR (KBr) 3400 cm-1; 1H NMR

(D2O)  81.40 (s, 9 H, CH3).

Hexamethylditin (99).155 To a solution of 49.63 g (0.25 mol) of

trimethyltin chloride in 100 mL of anhydrous tetrahydrofuran was condensed 600 mL ammonia with the formation of a fluffy white precipitate. The precipitate was broken with a spatula such that vigorous stirring, using a magnetic stirrer was achieved, and 6.32 g (0.28 mol) of sodium was added in small portions over a 30 min period. The ammonia was allowed to evaporate under argon, and the residue was washed with 300 mL of hexanes and filtered free of inorganic precipitate. The organic solution was concentrated in vacuo to afford 35.34 g of a colorless oil that was subjected to vacuum distillation (78-84°C at 15 mm Hg) to give 29.32 g (71%) of hexamethylditin

110

1 13 as a colorless oil which solidified upon refrigeration: H NMR (C6D6)  0.2; C NMR

(C6D6) 2.05.

E- and Z-rel-3-((1S,5S,8S)-8-Iodo-7-oxo-6-

oxabicyclo-[3.2.1]oct-2-en-1-yl)propanal O-ben-

zyl oxime (100). A solution of 0.65 g (2.3 mmol) of

aldehyde 104,93, 96 0.33 g (2.3 mmol) of 0-benzyl-

hydroxylamine hydrochloride and 0.52 g (6.6 mmol)

of pyridine in 10 mL of tetrahydrofuran-water (3:2)

was heated at 70°C for 3 h. The reaction mixture was cooled to room temperature and diluted with 100 mL of ether. The solution was washed with 50 mL of 10% aqueous hydrochloric acid, 50 mL of saturated brine, dried

(MgSO4), and concentrated in vacuo to give 0.83 g (87%) of an oily solid which was a mixture of the E- and Z-isomers of 100. This material had the following spectral

-1 1 characteristics: IR (neat) 1770, 1420 cm ; H NMR (CDCI3)  1.82 (m, 1 H, CH), 2.10

(m, 1 H, CH), 2.30 (m, 1 H, CH), 2.45 (m, 1 H, CH), 2.57 (m, 1 H, CH), 2.77 (m, 1 H,

CH), 4.46 (m, 1 H, CHI), 4.68 (m, 1 H, OCH), 5.07 (s, 1 H, Z-CH2O), 5.13 (s, 1 H, E-

CH20), 5.38 (m, 1 H, =CH), 5.82 (m, 1 H, =CH), 6.77 (t, J= 5.5 Hz, 0.5 H, NCH), 7.34 (m,

5 H, ArH), 7.48 (t, J= 5.5 Hz, 0.5 H, N=CH). This solid was subjected to crystallization from hexane and ethyl acetate to produce 0.24 g of the pure Z-isomer: mp 120-123°C;

-1 1 IR (neat) 1770, 1420 cm ; H NMR (CDCI3)  1.82 (ddd, J = 14, 10, 6 Hz, 1 H, CH), 2.10

(ddd, J= 14, 10, 6 Hz, 1 H, CH), 2.3 - 2.8 (m, 3 H, aliphatic CH), 2.79 (dq, J = 11, 3 Hz, 1

H, CH), 4.46 (dd, J = 5, 2 Hz, 1 H, CHI), 4.68 (m, 1 H, OCH), 5.07 (s, 2 H, CH2O), 5.38

111

(dt, J = 11, 3 Hz, 1 H =CH), 5.82 (m, 1 H, =CH), 6.74 (t, J = 5.5 Hz, 1 H, =CH), 7.26-7.36

(m, 5 H, ArH); exact mass calcd for C17H18NO3 m/e 411.0332, found m/e 411.0339.

Anal calcd for C17H18NO3 C, 46.63; H, 4.41. Found C, 46.28; H, 4.30.

(3S,4S,7R)-3-((Benzyloxy)amino)-1,2,3,4,5-hexa-

hydro-4,7-(epoxymethano)inden-8-one and (3S,4S,

7S)-3-((benzyloxy)amino)-1,2,3,4,5-hexahydro-4,7a-

(epoxymethano)inden-8-one (101). A solution of

186 mg (0.45 mmol) of imine 100, and 0.48 g (0.68

mmol) of bis(trimethylstannyl)benzopinacolate (1) in

3.0 mL of anhydrous benzene was heated at 72°C for

4 h. The reaction mixture was cooled to room temperature and dissolved in 50 mL ether. The organic solution was stirred with 25 mL of saturated aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo. The residual colorless oil (0.63 g) was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 4:1) to give 55 mg (42%) of the desired perhydroindan 101 (Rf = 0.46; silica gel,

-1 hexane-ethyl acetate, 2:1) as a white solid mp 98-100°C: IR (CH2Cl2) 3020, 1720 cm ;

1 H NMR (CDCI3)  1.60 (m, 1 H, aliphatic CH), 1.80 (ddd, J = 13, 11, 7, Hz, 1 H, CH),

2.13 (d, J = 8 Hz, 1 H, CH), 2.30 (ddd, J = 13, 9, 4, 1 H, CH), 2.40 (m, 1 H, CH), 2.48 (m,

2 H, CH), 3.30 (dd, J = 16, 9 Hz, 1 H, aliphatic CH), 4.78 (bs, 1 H, CHN), 4.67 (s, 2 H,

PhCH2), 4.78 (bs; 1 H, OCH), 5.50 (bs, 1 H, NH), 5.60 (ddt, J= 10, 4, 1 Hz, 1 H, =CH),

5.80 (dt, J= 9, 2 Hz, 1 H, =CH), 7.25 (m, 5 H, ArH), exact mass calcd for C17H19NO3 m/e

285.1365, found m/e 285.1341; and 53 mg (41%) of the diasteriomeric perhydroindan

112

1 1 (Rf = 0.38; silica gel, hexane-ethyl acetate, 2:1); IR (CH2Cl2) 3060, 1775 1250 cm- ; H

NMR (CDCI3)  1.50 (m, 1 H, CH), 1.70 (ddd, J = 16, 10, 6 Hz, 1 H, CH), 2.28 (d, J = 6

Hz, 1 H, CH), 2.40 (ddd, J = 13, 6, 3 Hz, 1 H, CH), 2.48 (dq, J = 19, 2.5 Hz, 2 H, CH),

2.54 (dq, J = 19, 2.5 Hz, 2 H CH), 3.74 (bs, 1 H, NCH), 4.67 (d, J = 11 Hz, 1 H, ArCH),

4.76 (d, J = 11 Hz, 1 H, ArCH), 5.12 (d, J = 1 Hz, 1 H, OCH), 5.20 (bs, 1 H, NH), 5.60

(ddt, J = 9, 3, 2 Hz, 1 H,=CH), 6.00 (dt, J = 9, 2 Hz, 1 H, =CH), 7.30 (m, 5 H, ArH); exact mass calcd for C17H19NO3 m/e 285.1365, found m/e 285.1326.

N-(Cyclohexylmethyl)-0-benzylhydroxylamine

(109): Method A. A solution of 0.53 g (2.5 mmol) of

cyclohexyl iodide, 0.238 g (2.5 mmol) of O-

benzylformaldoxime (83) and 1.73 g (2.5 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 8.0 mL of anhydrous benzene was heated at

75°C for 4 h. The reaction mixture was cooled to room temperature and 50 mL of ether was added. To the resulting solution was added 25 mL of a 10% aquesous potassium fluoride solution and the mixture was stirred for 30 min. The organic phase was separated, dried (MgSO4) and concentrated in vacuo to give 1.53 g of a colorless oil.

This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 6:1) to produce 0.42 g (76%) of the desired hydroxylamine 109 as

-1 1 a colorless oil: IR (neat) 3225 cm ; H NMR (CDCI3)  0.92 (m, 2 H, CH), 1.21 (m, 3 H,

CH), 1.73 (m, 6 H, CH), 2.76 (d, J= 8 Hz, 2 H, NCH2), 4.69 (s, 2 H, OCH2), 7.23 (m, 5 H,

13 ArH); C NMR (CDCI3)  25.99 (t), 26.62 (t), 31.40 (t), 35.46 (d), 58.74 (t), 76.00 (t),

127.70 (d), 128.33 (d; two sets of two degenerate carbon atoms based on relative intensity), 138.14 (s); mass spectrum, m/e (relative intensity) 149 (21), 91 (100).

113

Method B. A solution of 0.33 g (2.0 mmol) of cyclohexyl bromide, 0.27 g (2.0 mmol) of O-benzylformaldoxime (83) and 1.40 g (2.0 mmol) of bis(trimethylstannyl)- benzopinacolate (1) in 6.0 mL of anhydrous benzene was heated at 75°C for 4 h. The reaction mixture was cooled to room temperature and 75 mL of ether was added. The resulting solution was stirred with 25 mL of a 10% aqueous potassium fluoride solution for 30 min. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.53 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 6:1) to produce 267 mg (61%) of

N-(cyclohexylmethyl)-O-benzylhydroxylamine (109) as a colorless oil. Early fractions gave 19 mg (4%) of ketone 138 and 87 mg (16%) of alcohol 137 (vide infra).

Method C. A solution of 0.47 g (2.0 mmol) of cyclohexyl phenyl selenide, 0.27 g

(2.0 mmol) of O-benzylformaldoxime (83), and 1.40 g (2.0 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 6.0 mL of anhydrous benzene was heated at 75°C for 4 h.

The reaction mixture was cooled to room temperature and 75 mL of ether was added.

The resulting solution was stirred with 25 mL of a 10% aqueous potassium fluoride solution for 30 min. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 0.94 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 6:1) to produce 350 mg

(79%) of N-(cyclohexylmethyl)-O-benzylhydroxylamine (109) as a colorless oil.

Method D. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.14 g (1.0 mmol) of O-benzylformaldoxime (83) of benzopinacol 234, and 0.67 g (2.0 mmol) of N,N- dimethyltri-n-butylstannylamine in 3 mL anhydrous benzene was warmed at reflux for 5 h. The reaction mixture was cooled to room temperature and 25 mL of a 10 % aqueous potassium fluoride was added. The reaction mixture was extracted with 75 mL 114

anhydrous ether. The organic phase was dried (MgSO4), and concentrated in vacuo to give 1.31 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 6:1) to give 105 mg (52%) of hydroxylamine 109 as a colorless oil.

0-Benzyl-N-nonylhydroxylamine (110). A solution of 240 mg (1.0 mmol) of n-octyl iodide, 138 mg (1.0 mmol) 0-benzylformaldoxime (83), and 0.70 g (1.0 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 3.0 mL of anhydrous benzene was heated at 75°C for 6 h. The reaction mixture was cooled to room temperature and dissolved in 75 mL of ether. The resulting solution was stirred with with 25 mLof a 10% aqueous potassium fluoride for 30 min. The organic phase was separated, dried

(MgSO4), and concentrated in vacuo to give 0.85 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl- acetate, 95:5) to produce 0.19 g (77%) of the desired hydroxylamine 110 as a colorless

1 oil: H NMR (CDCI3)  0.83 (t, J= 8 Hz, 3 H, CH3), 1.27 (m, 14 H, CH2), 2.90 (t, J = 6 Hz,

13 2 H, NCH2), 4.67 (s, 2 H, OCH2), 5.32 (s, 1 H, NH), 7.30 (s, 5 H, ArH); C NMR CDCl3 

14.1 (q), 22.68 (t), 27.13 (t), 27.38 (t), 29.28 (t), 29.55) (t; two carbon atoms based on relative intensities), 31.90 (t), 52.25 (t), 76.20 (t), 127.73 (d), 128.35 (d; two degenerate aryl carbons based on relative intensities), 138.14 (s); exact mass calcd for C16H27NO m/e 149.2092, found m/e 249.2094.

115

O-Benzyl-N-neopentylhydroxylamine (111). A

solution of 0.342 g (2.5 mmol) of t-butyl bromide, 0.378 g

(2.8 mmol) of 0-benzylformaldoxime (83) and 1.75 g (2.5

mmol) of bis(trimethylstannyI)benzopinacolate (1) 8.0 mL of anhydrous benzene was heated at 75°C for 6 h. The reaction mixture was cooled to room temperature and dissolved in 75 mL of ether. The resulting solution was stirred with 25 mL of a 10% aqueous potassium fluoride for 30 min. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.42 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 6:1) to produce 0.405 g (84%) of the desired hydroxyl-

1 amine 111 as a colorless oil: H NMR (CDCI3)  0.93 (s, 9 H, CH3), 2.73 (d, J = 8 Hz, 2

13 H, NCH2), 4.67 (s, 2 H, OCH2), 5.60 (t, J = 8 Hz, 1 H, NH), 7.3 (m, 5 H, ArH); C NMR

(CDCI3)  28.09 (q), 30.96 (s), 63.06 (t), 75.70 (t), 127.64 (d), 128.25 (d), 128.44 (d),

138.04 (s); exact mass calcd for C12H19NO m/e 193.1467, found m/e 193.1457. Signals in the 13C NMR indicate this material was contaminated by trace amounts of benzophenone.

N,O-Dibenzylhydroxylamine (112). A

solution of 204 mg (1.0 mmol) of iodobenzene, 135

mg 0-benzylformaldoxime (90) and 695 mg (1.1 mmol)

of bis(trimethylstannyl)benzopinacolate (1) in 3.0 mL of anhydrous benzene was heated at 75°C for 6 h. The reaction mixture was cooled to room temperature and dissolved in 75 mL of ether. The resulting solution was stirred

116

with 25 mL of a 10% aqueous potassium fluoride solution for 30 min. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 0.85 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 95:5) to produce 0.149 g (67%) of the desired hydroxylamine 112

1 as a colorless oil: H NMR (CDCI3)  4.03 (s, 2 H, NCH2), 4.63 (s, 2 H, OCH2), 5.30 (s, 1

13 H, NH), 7.33 (s, 10 H, ArH); C NMR (CDCI3)  56.51 (t), 76.28 (t), 127.40 (d), 127.75

(d), 128.31 (d), 128.37 (d), 128.13 (d), 128.90 (d), 137.59 (s), 137.89 (s); exact mass calcd for C14H15NO m/e 213.1154, found m/e 213.1153.

O-Benzyl-N-(2-cyclopentylethyl)hydroxylamine

(114) and O-Benzyl-N-(hept-6-en-1-yl)hydroxylamine

(115). A solution of 0.16 (1.0 mmol) of 5-hexenyl bromide,

0.14 g (1.0 mmol) of oxime ether 83 and 0.90, g (1.3

mmol) of bis(trimethylstannyl)benzopinacolate (1) in 30 mL

anhydrous benzene was placed in an oil bath which had

been preheated to 75°C. The reaction mixture was heated

for 12 h, cooled to room temperature and diluted with 75

mL ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo.

Capillary VPC analysis (Ultra II: 100°C (2 min) to 300°C (150C/min)) of the residual oil

(0.63 g) indicated the presence of hydroxyl amine 114 (tr = 9.14) and 115 (tr = 9.30) in a

13:1 ratio. The crude oil was subjected to medium pressure liquid chromatography

(Lobar size B; hexane) to give 153 mg (70%) of a 13:1 mixture of hydroxylamine 114 (tr

= 9.14) and 115 (tr = 9.30). The major hydroxylamine 114 had the following spectral

1 characteristics: H NMR (CDCI3)  1.11 (m, 2 H, CH), 1.59 (m, 5 H, CH), 1.78 (m, 4 H, 117

CH), 2.97 (t, J= 8 Hz, 2 H NCH2), 4.73 (s, 2 H, OCH2), 5.60 (bs, 1 H, NH), 7.34 (m, 5 H,

13 ArH); C NMR (CDCI3)  25.07 (t), 32.67 (t), 33.61 (t), 37.94 (d), 51.52 (t), 76.13 (t),

+ 127.69 (d), 128.28 (d, 2 carbons),138.0 (s); exact mass calcd for C14H20N (M -OH) m/e

202.1595, found 202.1599. This material was contaminated by a minor compound indicative of 115. The presence of 115 was inferred from signals in the 1H NMR

13 spectrum ( 5.0 (m, =CH), 5.8 (m, =CH)) and C NMR spectrum ( 77.90 (OCH2), 114.1

(=CH2)). When the reaction was run with higher concentrations of 1, the 114:115 ratio’s decreased. These samples, enriched in 115, aided in the analysis of spectral data.

1,1,2-Triphenylethanol (115)

and 4-(Phenylmethyl)diphenylketone

(187): Method A. A solution of 0.34 g

(2.0 mmol) of benzyl bromide and 1.52

g (2.2 mmol) of bis(trimethylstannyl)-

benzopinacolate (1) in 6.0 mL of

anhydrous benzene was heated at 70°C

for 4 h. The reaction mixture was

dissolved in 75 mL ether, washed with

25 mL saturated aqueous potassium

fluoride, dried (MgSO4), and con-

centrated in vacuo. VPC analysis (Ultra

II: 100°C (2 min) to 300°C (15°C/min)) of the residual oil (0.96 g) demonstrated that 1,1,2-triphenylethanol (116) (tr = 13.4 min) and 4-benzyldiphenylketone (187) (tr = 14.8 min) were present in a 13:1 ratio. The oil was subjected to flash chromatography over 100 g of silica gel (hexane-ethyl acetate, 118

10:1) to give 0.44 g (81%) 1,1,2-triphenylethanol (116) as a white precipitate mp 84-

-1 1 86°C; IR (CHCI3) 3600 cm ; H NMR (CDCI3)  2.25 (bs, 1 H, OH), 3.57 (s, 2 H, CH2),

13 6.85 (m, 2 H, ArH), 7.19 (m, 9 H, ArH), 7.40 (m, 4 H, ArH); C NMR (CDCl3)  47.92 (t),

77.78 (s), 126.18 (d), 126.58 (d) 126.72 (d), 127.89 (d, 2 carbons), 130.80 (d), 135.80

(s), 146.58 (s); mass spectrum (GC-MS) m/e 183 (38), 182 (11), 105 (100), 92 (18), 91

(11), 77 (45); exact mass for C20H18O calcd m/e 256.1272, found m/e 256.1252. This material contained trace aromatic contaminates by 13C NMR consistent with 187. The structure of 187 is based on GC-MS data collected on the material with tr = 14.8 min

(vide supra): m/e 272 (67), 195 (100), 105 (57). This fragmentation pattern is consistent with the assigned structure.

Method B. A solution of 0.34 g (2.0 mmol) of benzyl bromide and 0.049 g (2.0 mmol) of magnesium were dissolved in 30 mL anhydrous ether. The reaction mixture was gently warmed until self reflux was maintained. The reaction mixture was stirred at room temperature another 6 h and 0.23 g (1.3 mmol) of benzophenone was added in one portion. The reaction mixture was stirred another 3 h, diluted with 50 mL ether and washed with 50 mL of 3 N aqueous hydrochloric acid. The organic phase was dried

(MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C

(15°C/min)) of the residual oil (0.53 g) demonstrated that 1,1,2-triphenylethanol (116) and 4-benzyldiphenylketone (187) were present in a 13:1 ratio. The oil was subjected to flash chromatography over 100 g of silica gel (hexane-ethyl acetate, 9:1) to give 0.37 g

(70%) of 116 as a white solid mp 83-87°C.

Method C. A solution of 0.34 g (2.0 mmol) of benzyl bromide, 2.72 g (20 mmol) of 0-benzylformaldoxime and 1.40 g (2.0 mmol) of bis(trimethylstannyl)benzopinacolate

119

(1) in 6 mL anhydrous benzene was heated at 75°C for 6 h. The reaction mixture was cooled to room temperature and 75 mL of diethyl ether was added. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo to yield 3.23 g of a crude oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 8:1) to afford a

0.46 g (84%) of alcohol 116 as a colorless oil.

3-((1R,5S,8R)-8-(((Benzyloxy)amino)methyl)-5-

methyl-7-oxo-6-oxabicyclo[3.2.1]oct-2-en-1-yl)propan-

enitrile (119), and 3-((1R,5S,8S)-8-(((Benzyloxy)amino)

methyl)-5-methyl-7-oxo-6-oxabicyclo[3.2.1]oct-2-en-1-

yl)propanenitrile (120), and 3-((3R,7S,7S)-2-(Benzyl-

oxy)-7-hydroxy-7-methyl-3-oxo-2,3,3,6,7,7-hexahydro-

1H-isoindol-3-yl)propanenitrile (121). A solution of

0.390 g (0.85 mmol) of iodolactone 118,120 0.334 g 2.6

(mmol) of 0-benzylformaldoxime (83) and 0.881 g (1.3

mmol) of bis(trimethylstannyl)benzopinacolate (1) was

heated at 63°C for 6 h. The reaction mixture was cooled

to room temperature and dissolved in 75 mL of ether.

The resulting solution was washed with 50 mL of 10%

aqueous potassium fluoride, separated, dried (MgSO4),

and concentrated in vacuo. The oil (0.9 g) was subjected

to medium pressure liquid chromatography (65 g silica

gel; hexane-ethyl acetate; 2:1) to produce 228 mg (57%)

of an oily 1:1 diastereomeric mixture of amines 119 and

120

120 (Rf = 0.47; silica gel, ethyl acetate-hexane, 2:1), and 156 mg (30%) of lactam 121

o (Rf = 0.21; silica gel, ethyl acetate-hexane, 2:1) as a white solid (mp 145-145 C) recrystallization provided a pure sample of 121 mp 151-153°C; IR (CH2Cl2) 2300, 1700

-1 1 cm ; H NMR (CDCI3)  1.30 (s, 3 H, CH3), 1.82 (m, 2 H, CH and OH), 2.00-2.40 (m, 6

H, CH2), 3.32 (dd, J = 10, 7 Hz, 1 H, NCH), 3.34 (t, J= 10 Hz, 1 H, NCH), 4.97 (s, 2 H,

OCH2Ph), 5.63 (dt, J= 11, 2 Hz, 1 H, =CH), 5.82 (dt, J= 11, 5 Hz, 1 H, =CH), 7.40 (m,

13 5H, ArH); C NMR (CDCI3) 12.51 (t), 28.60 (q), 31.66 (t), 36.18 (t), 42.75 (d), 46.00 (t),

47.30 (s), 69.27 (s), 76.49 (t), 119.41 (s), 126.22 (d), 127.35 (d), 128.54 (d), 129.03 (d),

129.54 (d), 134.89 (s), 169.91 (s); exact mass calcd for C19H22N2O3 m/e 326.1631, found m/e 326.1620.

Anal calcd for C19H22N203 C, 69.92; H, 6.79. Found C, 69.72; H, 6.81.

The mixture of diasteriomeric lactones 119 and 120 gave the following spectral data: IR

-1 (neat) 2250, 1770 cm ; exact mass calcd for C19H22N203 m/e 326.1631, found m/e

326.1650. Extensive chromatography over silica gel afforded samples which were enriched (approximately 4:1 in both instances) in each diastereomer. Although these samples contained trace amounts of unidentified material, spectra recorded on these samples and the aforementioned 1:1 mixture allowed the following NMR signals to be

1 assigned. Lactone 119: H NMR (CDCI3)  1.44 (s, 3 H, CH3), 1.8 - 2.5 (m, CH and CH2 manifold), 2.98 (dd, J = 11, 5 Hz, 1 H, CHN), 3.09 (dd, J =11, 5 Hz, 1 H, CHN), 4.63 (s, 2

H, CH2O), 5.67 (dt, J = 10, 1.5 Hz, 1 H, =CH), 5.79 (dt, J = 10, 3.5 Hz, 1 H, =CH), 7.30

13 (m, ArH); C NMR (CDCI3)  12.61 (t), 22.13 (q), 25.20 (t), 39.72 (t), 47.49 (d), 47.63 (t),

49.50 (s), 76.22 (t), 83.09 (s), 119.17 (s), 127-130 (poorly resolved aromatic signals)

1 137.49 (s), 176.01 (s). Lactone 120: H NMR (CDCI3)  1.46 (s, 3 H, CH3), 1.9 - 2.6 (m,

121

CH and CH2 manifold), 2.82 (dd, J = 13, 5 Hz, 1 H, CHN), 2.96 (dd, J = 13, 6 Hz, 1 H,

CHN), 4.68 (s, 2 H, CH2O), 5.47 (dt, J = 10, 1.5 Hz, 1 H, =CH), 5.83 (dt, J = 10, 3.5 Hz, 1

13 H, =CH), 7.35 (m, ArH); C NMR (CDCI3)  12.14 (t), 23.73 (q), 27.72 (t), 34.37 (t),

46.64 (d), 47.36 (t), 49.15, (s), 76.22 (t), 83.60 (s), 119.51 (s), 126.5-129.3 (poorly resolved aromatic signal), 137.24 (s), 175.70 (s). Treatment of a 1:1 mixture of 119 and

o 120 with trimethylstannyl bromide in 2 mL of benzene-d6 at 65 C for 20 h showed the appearance of 121 and the disappearance one of the diasteriomers (presumably 120) by

1H NMR. This experiment served as the basis for the spectral assignments presented here.

(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-

((benzylamino)methyl)tetrahydro-2H-pyran-3,-

4,5-triyl triacetate (122), and (2R,3R,4R,5S,6R)-

2-(acetoxymethyl)-6-((N-benzylacetamido)met-

hyl)-5-hydroxytetrahydro-2H-pyran-3,4-diyl di-

acetate (124). A solution of 0.84 g (2.0 mmol) of

glucopyranosyl bromide 35, 0.58 g (6.0 mmol) of

O-benzylformaldoxime and 1.38 g (3.0 mmol) of

bis(trimethylstannyl)benzopinacolate (1) in 6.0 mL

anhydrous benzene was heated at 75°C for 2 h.

Saturated aqueous potassium fluoride (10 mL) was added and the reaction mixture was cooled to room temperature. The reaction mixture was dissolved in 75 mL chloroform, washed with 25 mL of saturated aqueous potassium fluoride solution, dried (MgSO4), and concentrated in vacuo. The residual 122

yellow oil (1.85 g) was subjected to medium pressure liquid chromatography (Lobar size

B; hexane-ethyl acetate, 1:1) to produce 0.16 g (18%) of 122 as an oil. This material

13 -1 1 contained trace contaminants by C NMR; IR (neat) 3400, 1735 cm ; H NMR (CDCI3) 

2.02 (s, 3 H, OAc), 2.04 (s, 6 H, OAc), 2.07 (s, 3 H, OAc), 3.07 (dd, J = 15, 4 Hz, 1 H,

C1H), 3.24 (dd, J = 15, 10 Hz, 1 H, C1H), 3.88 (m, 1 H, C6H), 4.09 (dd, J = 13, 3 Hz, 1 H,

C7H), 4.24 (dd, J = 13, 6 Hz, 1 H, C7H), 4.46 (m, 1 H, C2H), 4.62 (s, 2 H, PhCH2), 4.98 (t,

J= 9.6 Hz, 1 H, C5H), 5.10 (dd, J= 9.5 Hz, 1 H, C3H), 5.20 (t, J= 9.6 Hz, 1 H, C4H), 7.39

13 (m, 5 H, ArH), the NH was not recorded; C NMR (CDCI3)  20.53 (q; two carbons),

48.23 (t), 62.00 (t), 68.23 (d), 68.89 (d), 69.34 (d), 69.86 (d), 70.18 (d), 76.10 (t), 127.81

(d), 128.29 (d), 128.31 (d), 137.68 (d), 169.40 (s; two carbons), 169.79 (s), 170.55 (s), one carbon was not recorded; exact mass for C22H29NO10 calcd m/e 467.1791, found m/e 467.1735; and 0.24 g (25%) of 124 as a colorless oil: IR (neat) 3300, 1735, 1650

-1 1 cm ; H NMR (CDCI3)  2.03 (s, 3 H, CH3), 2.05 (s, 3 H, CH3), 2.08 (s, 3 H, CH3), 2.10

(s, 3 H, CH3), 3.51 (broad s, 1 H, OH), 3.80 (dd, J= 14, 5 Hz, 1 H, NCH), 3.92 (dd, J= 8,

6 Hz, 1 H, C3H), 3.98 (d, J = 12 Hz, 1 H, C2H) 4.09 (m, 1 H, C6H) 4.25 (m, 2 H, NCH and

C7H) 4.40 (q, J = 5 Hz, 1 H, C2H), 4.83 (d, J = 11 Hz, 1 H,CH2O), 4.88 (d, J = 11, 1 Hz, 1

H, CH2O), 4.92 (t, J = 8 Hz, 1 H, C5H), 5.10 (t, J = 8 Hz, 1 H, C4H), 7.39 (s, 5 H, ArH);

13 C NMR (CDCI3)  20.18 (q), 20.53 (q; two carbons), 20.68 (q), 41.67 (t), 61.96 (t),

68.16 (d), 68.52 (d), 70.01 (d), 70.95 (d), 73.13 (d), 76.31 (t), 128.59 (d), 128.93 (d),

129.11 (d), 134.05 (s), 169.59 (s), 170.51 (s; two carbons), 173.24 (s); exact mass

+ (chemical ionization) calcd for C22H29N010 + H m/e 468.17, found m/e 468.14.

123

(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-((N-

benzylacetamido)methyl)-5-hydroxytetrahydro-

2H-pyran-3,4-diyl diacetate (124). A solution of

0.84 g (2.0 mmol) of glucopyranosyl bromide 35,

0.57 g (6.0 mmol) of 0-benzylformaldoxime (83)

and 1.38 g (3.0 mmol) of bis(trimethylstannyl)- benzopinacolate (1) in 5.0 mL of anhydrous benzene was heated at 75°C for 6 h. The reaction mixture was cooled to room temperature and dissolved in 200 mL of chloroform.

The solution was stirred with 50 mL of 10% aqueous potassium fluoride for 30 min. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.94 g of a crude oil. The oil was subjected to medium pressure liquid chromatography over 70 g of silica gel (ethyl acetate-hexane, 1:3) to yield 0.78 g (81%) of 124 as a colorless oil.

(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-((N-

benzylacetamido)methyl)tetrahydro-2H-pyran-3,4,

5-triyl triacetate (125): Method A. A solution of

0.82 g (2.0 mmol) of glycosyl bromide 35, 0.58 g (6.0

mmol) of O-benzylformaldoxime (83) and 1.30 g (2.6 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 6 mL of benzene was heated at

70°C for 5 h. The mixture was cooled to room temperature, 1.02 g (10 mmol) of acetyl chloride and 0.02 g of 4-(dimethylamino)pyridine were added, and the solution was stirred for 30 min. The reaction mixture was diluted with 100 mL chloroform and stirred with 50 mL of saturated aqueous potassium fluoride for 30 min. The organic phase was removed, dried (MgSO4), and concentrated in vacuo. The residual oil (2.34 g) was 124

subjected to medium pressure chromatography (Lobar size B; hexane-ethyl acetate, 1:1) to produce 0.78 g (79%) of the desired sugar 125 as a colorless oil: []D = 33.5 (c = 10,

-1 1 CHCI3); IR (neat) 1735, 1655 cm ; H NMR (CDCI3)  1.96 (s, 3 H, OAc), 1.97 (s, 3 H,

OAc), 1.99 (s, 3 H, OAc), 2.00 (s, 3 H, OAc), 2.11 (s, 3 H, NAc), 3.19 (dd, J = 14.8, 2.7

Hz, 1 H, CHN), 3.94 (dd J = 12.1, 2.3 Hz, 1 H, C7H), 4.02 (m, 1 H, C6H), 4.16 (dd, J =

12.1 , 4.4 Hz, 1 H, C7H), 4.39 (dd, J = 14, 12 Hz, 1 H, C1H), 4.53 (m, 1 H, C2H), 4.79 (AB q, J = 11.1 Hz, 2 H, CH2Ar), 4.96 (t, J = 9.4 Hz, 1 H, C6H), 5.09 (dd, J = 9.5, 5.8 Hz, 1 H,

13 C3H), 5.20 (t, J = 9.6, 1 H, C4H), 7.45 (m, 5 H, ArH); C NMR (CDCI3)  20.16 (q), 20.36

(q), 20.40 (q), 20.45 (q; two carbons based on relative intensity), 41.62 (t), 61.81 (t),

68.09 (d), 68.85 (d), 69.13 (d), 69.66 (d), 70.16 (d), 76.93 (t), 128.61 (d), 128.87 (d),

129.06 (d), 134.41 (s), 169.00 (s), 169.21 (s), 169.64 (s), 170.27 (s), 173.32 (s).

Method B. A solution of 0.103 g (0.22 mmol) of 122, 0.089 g (0.88 mmol) of triethylamine, 0.090 g (0.88 mmol) of acetic anhydride and 0.020 g of 4- diethylaminopyridine in 3.0 mL anhydrous dichloromethane was stirred at room temperature for 2 h. The reaction mixture was dissolved in 50 mL dichloromethane. The organics were washed with 20 mL water, 20 mL 10% aqueous hydrochloric acid, and 20 mL saturated aqueous sodium bicarbonate to produce a yellow oil. This oil was subjected to flash chromatography (90 g silica, hexane-ethyl acetate 1:2) to produce 52 mg (55%) of 125 as a colorless oil.

Method C. A solution of 96 mg (0.21 mmol) of 124, 86 mg (0.84 mmol) of triethylamine, 87 mg (0.84 mmol) of acetic anhydride and 0.020 g of 4-dimethylaminopyridine in 3.0 mL anhydrous dichloromethane was stirred at room temperature for

2 h. The reaction mixture was dissolved in 50 mL dichloromethane. The organics were

125

washed with 20 mL water, 20 mL 10% aqueous hydrochloric acid, and 20 mL saturated aqueous sodium bicarbonate to produce a yellow oil. This oil was subjected to flash chromatography (90 g silica, hexane-ethyl acetate, 1:2) to produce 54 mg (60%) of 125 as a colorless oil.

(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-((N-

hydroxyacetamido)methyl)tetrahydro-2H-pyran-3,4,5

-triyl triacetate (132): A solution of 3.38 g (6.7 mmol)

of 125 in 20 mL absolute ethanol was subjected to

hydrogenation in a Parr hydrogenation apparatus for 6 h. When the pressure became constant, the mixture was filtered through a pad of celite using 75 mL ethanol and concentrated in vacuo. The resulting solid (mp 133-145°C;

2.75 g) was from recrystallized from hexane and ethyl acetate to give 2.42 g (88%) of

-1 1 126 as white needles: mp 154-156°C; IR (CHCI3) 3300, 1735 cm ; H NMR  2.02 (s, 3

H, OAc), 2.05 (s, 9 H, OAc), 2.13 (s, 3 H, NAc), 3.45 (d, J = 14 Hz, 1 H, C1H), 4.05, (m, 2

H, C3H and C7H), 4.28 (m, 1 H, C7H), 4.35 (m, 1 H, C1H), 4.45 (m, 1 H, C2H), 4.91 (t, J =

7.8 Hz, 1 H, C4H), 5.05 (t, J= 7.7 Hz, 1 H, C6H), 5.19 (t, J = 7.9 Hz, 1 H, C5H), 8.20 (bs, 1

13 H, OH); C NMR (CDCI3)  20.17 (q), 20.56 (q; three carbon based on relative intensity),

20.59 (q), 44.29 (t), 61.73 (t), 67.85 (d), 68.52 (d), 68.77 (d), 69.60 (d), 70.57 (d), 169.51

(s; three carbons), 171.21 (s), 172.54 (s); exact mass (chemical ionization) calcd for

+ C17H26NO11 + H m/e 420.15, found m/e 420.16.

126

(2R,3R,4R,5S)-2-(Acetoxymethyl)-5-(phenylselenyl)-

tetrahydrofuran-3,4-diyl diacetate (128). A solution of 10.0

g (33 mmol) g of tetraacetate 127, 5.6 g (36 mmol) of

selenophenol, and 0.30 g (4 mmol) of p-toluenesulfonic acid

in 15 mL of anhydrous dichloromethane was stirred at room temperature for 52 h. The reaction mixture was subjected to column chromatography over 200 g silica gel (hexane-ethyl-acetate, 5:1) to give 7.15 g (60%) of 128 as a yellow

-1 1 oil: IR (CHCl3) 1730 cm ; H NMR (CDCI3)  2.01 (s, 3 H, CH3), 2.03 (s, 3 H, CH3), 2.05

(s, 3 H, CH3), 4.08 (m, 1 H, C5H), 4.2-4.35 (m, 2 H, C5H and C4H), 5.27 (t, J = 6 Hz, 1 H,

C3H) 5.41 (dd, J = 6, 5 Hz, 1 H, C2H), 5.55 (d, J = 5 Hz, 1 H, C1H), 7.30 (m, 3 H, ArH),

7.60 (m, 2 H, ArH); 13C NMR  20.22 (q), 20.27 (q), 20.53 (q), 62.98 (t), 71.00 (d), 75.26

(d), 79.84 (d), 82.97 (d), 126.97 (s), 128.31 (d), 128.98 (d), 135.29 (d), 169.08 (s),

169.29 (s), 170.12 (s); exact mass calcd for C17H20O7Se m/e 416.045, found m/e 416.00.

(2R,3R,4S,5S)-2-(Acetoxymethyl)-5-((N-

(benzyloxy)acetamido)methyl)tetrahydrofuran-

3,4-diyl diacetate (129). A solution of 0.42 g (1.0

mmol) of 128, 0.41 g (3.0 mmol) of O-benzyl-

formaldoxime, and 0.90 g (1.3 mmol) of bis(tri- methylstannylbenzopinacolate (1) in 3 mL anhydrous benzene was warmed at reflux for

12 h. The reaction mixture was cooled to ambient temperature and 1.0 mL acetic anhydride and 35 mg 4-dimethylaminopyridine was added. The reaction mixture was stirred for 2 h, and then stirred with 50 mL of 10% aqueous potassium fluoride. The mixture was extracted with 50 mL of chloroform. The combined organic phases were dried (MgSO4), and concentrated in vacuo. The residual oil (1.18 g) was subjected to 127

flash column chromatography over 45 g silica gel (hexane-ethyl acetate, 1:1) to afford

-1 1 324 mg (69%) of 129 as an oil: IR(neat) 1750, 1660 cm ; H NMR(CDCI3)  2.43 (s, 6 H,

CH3), 2.65 (s, 3 H, CH3), 2.80 (s, 3 H, CH3), 3.74 (dd, J= 15, 7 Hz, 1 H, C1H), 3.92 (dd, J

= 15, 5 Hz, 1 H, C1H), 4.13 (m, 2 H, C5H and C6H), 4.23 (m, 1 H, C2H), 4.29 (dd, J = 12,

2 Hz, 1 H, C6H), 4.87 (m, 2 H, CH2Ph), 5.07 (t, J = 6 Hz, 1 H, C3H), 5.17 (t, J = 5 Hz, 1

H, C4H), 7.47 (m, 5 H, ArH); exact mass calcd for C21H27NO9 m/e 437.1706, found m/e

437.1729. Minor signals, most likely do to the C(2) diastereomer of 129, were apparent

1 in the H NMR spectrum:  4.50 (m, 1 H), 4.94 (s, 2 H, CH2O), 5.23 (dd, J = 8, 6 Hz, 1 H,

C3H), 5.4 (t, J = 6 Hz, 1 H, C4H).

E-Ethyl rel-5-((1S,5S,8S)-8-iodo-5-methyl-

7-oxo-6-oxabicyclo[3.2.1]oct-2-en-1-yl)pent-2-

eno-ate (133). A solution of 9.76 g (15 mmol) of

132,93, 96 in 100 mL of 80% aqueous formic acid

was stirred at 0°C for 4 h. The reaction mixture

was extracted with two 100 mL portions of

dichloromethane. The combined extracts were washed with two 100-mL portions of brine, three 100 mL portions of saturated aqueous sodium bicarbonate, two 100 mL portions of brine, dried (MgSO4), and concentrated in vacuo to give 6.01 g (74%) of crude aldehyde as an oil. A solution of 5.32 g (17 mmol) of the crude aldehyde and 6.35 g of (carbomethoxymethylidine)triphenylphosprane in

200 mL of benzene was stirred at room temperature for 10 h. The reaction mixture was

128

concentrated in vacuo to afford 13.64 g of a crude solid. This solid was subjected to column chromatography (silica gel, hexane-ethyl acetate, 7:1) to afford 4.21 g (48% from

132) of the pure E-ester 133 as a white solid. Further elution provided an additional 1.74 g (27%) of material which was a mixture of E and Z ester isomers. Ester 133 exhibited

-1 1 the following spectral characteristics: IR (CHCl3) 1778, 1705, 1635 cm ; H NMR

(CDCI3)  1.29 (t, J= 8 Hz, 3 H, CH3), 1.51 (s, 3 H, CH3), 1.76 (m, 1 H, CO), 2.08 (m, 1

H, C5H), 2.31 (q, J= 10 Hz, 2 H, C4H), 2.48 (d, J= 18 Hz, 1 H, C4H), 2.63 (d, J= 18 Hz, 1

H, C4H), 4.20 (m, 3 H, OCH2 and C3H), 5.43 (d, J= 10 Hz, 1 H, C2H), 5.57 (m, 2 H, C2H

13 and C3H), 6.96 (dt, J= 15, 7 Hz, 1 H, =C3H); C NMR (CHCI3) 14.15 (q), 22.69 (d),

25.97, (q), 28.71 (d), 31.91 (d), 35.88 (d), 51.04 (t), 60.10 (s), 82.71 (s), 122.09 (d),

128.32 (d), 129.02 (d), 147.14 (d), 166.07 (s), 171.52 (s).

Ethyl rel-2-((3R,4S,7R)-4-methyl-8-oxo-

1,2,3,3,4,5-hexahydro-4,7-(epoxymethano)inden-

3-yl)acetate (134). A solution of 0.61 g (1.6 mmol)

of iodolactone 133, and 2.02 g (3.0 mmol) of

bis(trimethyl-stannyl)benzopinacolate (1) in 6 mL of

anhydrous benzene was warmed at 72°C for 8 h.

The reaction mixture was cooled to room

temperature and dissolved in 50 mL of ether. The ethereal solution was washed with 30 mL of saturated aqueous potassium fluoride, separated, dried (MgSO4), and concentrated in vacuo. The resulting viscous oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl

129

acetate, 4:1) to give 343 mg of 134 as a colorless oil. Capillary VPC and GC mass spectral analysis (Ultra II: 200°C (2 min) to 230 (2°C/min) to 280°C (15oC/min)) demonstrated that this oil was a 5:1 mixture of isomers (CI-GC-MS tr = 7.53 (m/e +1 =

265; minor isomer), tr= 7.95 (m/e +1 = 265; major isomer)). The major stereoisomer exhibited the following spectral characteristics: IR (neat) 1765, 1720 cm-1; 1H NMR

(CDCI3)  1.24 (t, J= 7 Hz, 3 H, CH3), 1.58 (s, 3 H, CH3), 1.70 (m, 1 H), 1.80 (m, 1 H),

1.93 (m, 1 H), 2.10 (dd, J = 17, 12 Hz, 1 H), 2.30 (d, J = 10 Hz, 1 H, CH), 2.35-2.5 (m, 3

H), 2.57 (dq, J = 16, 1 Hz), 2.70 (m, 1 H), 4.15 (q, J = 7 Hz, 2 H, OCH2), 5.56 (dt, J = 9.2,

2.2 Hz, 1 H, =CH), 6.02 (dt, J = 9, 2 Hz, 1 H, CH); Exact mass calcd for C15H20O4 - CO2 m/e 220.3143, found m/e 220.3162. The NMR spectrum of this material was identical to that of material prepared by an alternate route.120

E-Ethyl rel-5-((1S,5S,8S)-8-iodo-7-oxo-6-oxabi-

cyclo[3.2.1]oct-2-en-1-yl)pent-2-enoate) (135). A

solution of 2.84 g (9.0 mmol) of aldehyde 134 and 3.42

g (10.2 mmol) of (carbomethoxymethylidine)triphenyl-

phosphorane benzene was stirred at room

temperature for 2 h. The reaction mixture was concentrated in vacuo to afford 6.37 g of a crude solid. This solid was chromatographed over 200 g of silica gel (hexane-ethyl acetate, 3:1) to afford 2.94 g (84%) of the desired

-1 1 ester 135 as a colorless oil: IR (CHCI3) 1775, 1705, 1650 cm ; H NMR (CDCI3)  1.28 (t,

J= 8 Hz, 3 H, CH3), 1.71 (m, 1 H, C5H), 2.08 (m, 1 H, C5H), 2.30 (q, J = 10 Hz, 2 H, C4H),

2.58 (d, J = 18 Hz, 1 H, C4H), 2.80 (d, J = 18 Hz, 1 H, C4H), 4.19 (q, J = 8 Hz, 2 H,

130

OCH2), 4.49 (d, J = 2 Hz, 1 H, C8H), 4.76 (d, J = 2 Hz, 1 H, C5H), 5.42 (d, J = 10 Hz, 1 H,

13 =C2H), 5.90 (m, 2 H, =CH) and C2H), 6.97 (dt, J = 15, 7 Hz, 1 H, =CH); C NMR (CHCl3)

 13.95 (q), 23.14 (d), 25.68 (t), 27.94 (t), 29.67 (t), 47.83 (s), 59.82 (t), 75.79 (d), 121.82

(d), 126.74 (d), 129.00 (d), 146.70 (d), 165.72 (s), 170.81 (s). This material was approximately an 85:15 mixture of E and Z isomers by NMR. Only the predominate peaks are reported above.

Ethyl 2-((3aR,4S,7aR)-8-Oxo-1,2,3,3,4,5-hexa-

hydro-4,7-(epoxymethano)inden-3-yl)acetate (136). A

solution of 0.38 g (1.0 mmol) of iodolactone 135, and

0.90 g (1.3 mmol) of bis(trimethylstannyl)benzo-

pinacolate (1), in 3 mL of anhydrous benzene was

warmed at 75°C for 7 h. The reaction mixture was cooled to room temperature and 25 mL of saturated aqueous potassium fluoride was added. The aqueous solution was extracted with 75 ml of diethyl ether. The ethereal solution was dried (MgSO4), and concentrated in vacuo to give 0.69 g of a crude oil.

VPC analysis (Ultra II: 200oC (2 min) to 230oC (2oC/min to 280oC (15oC/min)) demonstrated that this oil was a 4.5:1 mixture of isomers. Chromatography of the mixture over 150 g of silica gel (hexane – ethyl acetate 3:1) gave 178 mg (71 %) of 135 as an impure mixture of isomers. The major isomer had the following spectral

-1 1 characteristics: IR (neat) 1765, 1720 cm ; H NMR (CDCl3)  1.34 ( t, J = 8 Hz, 3 H,

CH3) 1.36-286 (m, 10 H), 4.13 (q, J = 8 Hz, 2 H, OCH2), 4.72 (s, 1 H, OCH), 5.68 (dt, J =

13 9 Hz, 1 H, =CH), 6.07 (dt, J = 9, 2 Hz, 1 H, =CH); C NMR (CHCl3)  14.08 (q) 26.86 (t),

131

31.32 (t), 33.25 (t), 33.64 (t), 52.70 (d), 54.04 (s), 60.38 (t), 75.86 (d), 126.94 (d), 129.98

(d), 172.81 (s), 178.91 (s); Exact mass calcd for C14H18O4 -CO2 m/e 206.1307, m/e found

206.1324. The NMR spectrum of this material was identical to that of material prepared by an alternate route.120

4-Cyclohexyldiphenylketone (137), and Cyclohexyldiphenylmethanol

(138): Method A. A solution of 0.33 g (2.0 mmol) of cyclohexyl bromide and 1.40 g

(2.0 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 6.0 mL anhydrous benzene was heated at 75°C for 4 h. The reaction mixture was cooled to room temperature and dissolved in 100 mL ether. The ethereal solution was stirred with 50 mL saturated aqueous potassium fluoride for 30 min. The organic phase was dried (MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C (150C/min)) of the residual oil (0.9 g) demonstrated that cyclohexyldiphenylmethanol (138), (tr = 10.98 min)

and cyclohexyldiphenylketone (138) (tr = 12.46)

were formed in a 3.2:1 ratio. The oil was subjected

to medium pressure liquid chromatography (Lobar

size B; hexane-ethyl acetate, 95:5) to give 85 mg

(17%) of 4-cyclohexyldiphenylketone (137) (Rf =

0.68, silica gel, hexane-ethyl acetate, 4:1): IR

-1 1 (neat) 1655 cm ; H NMR (CDCI3)  1.0-2.5 (m,

11 H), 7.40 (m, 5 H, ArH), 7.80 (m, 4 H, CH); 13C

NMR (CDCI3) 25.95 (t), 26.65 (t), 34.06 (t), 44.59

(d), 126.65 (d), 128.00 (d), 129.80 (d), 130.20 (d),

132

131.70 (d), 135.15 (s), 137.91 (s), 152.97 (s), 196.25 (s); exact mass calcd for C19H20O m/e 264.1514, found m/e 264.1531; and 0.23 g (42%) cyclohexyldiphenylmethanol (137)

-1 1 as an oil (Rf = 0.58, silica gel, hexane-ethyl acetate, 4:1): IR (neat) 3550 cm ; H NMR

13 (CDCI3)  1.0-2.5 (m, 11 H), 2.08 (s, 1 H, OH), 7.0-8.0 (m, 10 H, ArH); C NMR (CDCI3)

 26.47 (t), 26.66 (t), 27.22 (t), 45.70 (d), 80.33 (s), 125.77 (d), 126.75 (d), 128.00 (d),

136.37 (s); exact mass calcd for C19H22O m/e 266.1670, found mle 266.1718.

Method B. To a stirred slurry of 0.51 g (21 mmol) of magnesium in 5 mL of anhydrous ether was added 0.50 g (3.1 mmol).of cyclohexyl bromide. The suspension was gently heated until self-reflux was maintained. To the refluxing suspension was added 2.50 g (15.4 mmol) of cyclohexyl bromide in 100 mL anhydrous ether over a 30 min period. The reaction mixture was stirred an additional 2 h and 2.23 g (12.3 mmol) of benzophenone was added in one portion. The reaction mixture was carefully quenched by 100 mL of 3 N aqueous hydrochloric acid. The organic phase was, dried (MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15°C/min)) of the residual oil (4.61 g) demonstrated that cyclohexyldiphenylmethanol (137) and 4- cyclohexyldiphenylketone (138) are formed in a 3.4:1 ratio. The oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 95:5) to give 0.58 g (18%) of 138 and 1.77 g (54%) of 137 as colorless oils.

Method C. A solution of 0.32 g (2.0 mmol) of cyclohexyl bromide, 0.65 g (2.0 mmol) of hexamethyditin, and 0.36 (2 mmol) of benzophenone in 6 mL of anhydrous benzene was subjected to photolysis for 7 h through a pyrex filter via a 450 watt Hanovia medium pressure mercury arc lamp. The reaction mixture was stirred with 25 mL of a saturated aqueous potassium fluoride solution for 30 min. The resulting mixture was

133

extracted by 75 mL ether. The ethereal solution was dried (MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15oC/min)) of the residual oil

(1.43 g) demonstrated that cyclohexylcyclohexane, 137 and 138 are formed in a

0.9:3.1:1 ratio. The residual oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to give 80 mg (16%) of 138 and 169 mg (31%) of 137 as colorless oils.

Ethyl 3-Cyclohexylpropionate (139): Method A.

A solution of 0.26 g (1.3 mmol) of cyclohexyl iodide, 0.19 g

(2.0 mmol) of ethyl acrylate, and 0.88 g (1.3 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 3.0 mL of anhydrous benzene was heated at

70°C for 4 h. The reaction mixture was cooled to room temperature and 50 mL of ether was added. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride. The organic phase was dried (MgSO4), and concentrated in vacuo to produce 0.89 g of a yellow oil. VPC analysis (Ultra II: 100°C (2 min) to 300°C

0 (15 C/min)) demonstrated the presence of ethyl 3-cyclohexylpropionate (139) (tr = 6.29 min), cyclohexyldiphenylmethanol (137) (tr = 12.91 min), and 4-cyclohexyldiphenylketone

(138) (tr =14.40 min) in a 91:7:2 ratio. The oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to afford 189 mg (79%) of the desired ester 139

-1 1 as a colorless oil: IR (neat) 1735 cm ; H NMR (CDCI3)  0.88 (bq, J = 10 Hz, 2 H, CH),

1.17 (m, 4 H, CH), 1.21 (t, J = 8 Hz, 3 H, CH3), 1.48 (q, J = 9 Hz, 2 H, CH2), 1.66 (m, 5

13 H, CH), 2.26 (t, J = 9 Hz, 2 H, CH2CO), 4.08 (q, J = 8 Hz, 2 H, OCH2); C NMR (CDCI3)

134

 13.98 (q), 26.03 (t), 26.34 (t), 31.69 (t), 32.15 (t), 32.78 (t), 37.06 (d), 59.80 (t), 173.69

(s); exact mass calcd for C11H20O2 m/e 184.1463, found m/e 184.1458.

Method B. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.15 g (1.5 mmol) of ethyl acrylate, 0.40 g (1.1 mmol) of benzopinacol 234, and 0.83 mg (2.5 mmol) of N,N-dimethyltri-n-butylstannylamine in 2 mL anhydrous benzene was warmed at 75°C for 3.5 h. The mixture was cooled to room temperature and 25 mL of saturated aqueous potassium fluoride was added. The mixture was extracted by 75 mL ether, dried

(MgSO4), and concentrated in vacuo. This crude oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to produce 123 mg (67%) of the desired ester 139 as a colorless oil. This oil contained trace amounts of benzophenone under

GC analysis.

Method C. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.15 g (1.5 mmol) of ethyl acrylate, 0.59 g (1.1 mmol) of benzopinacol 239, and 0.24 mg (1.0 mmol) of N,N-diethyltrimethylstannylamine in 3 mL anhydrous tetrahydrofuran was warmed at

75°C for 3.5 h. The mixture was cooled to room temperature and diluted with 75 mL ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, three 25 mL portions of 3 N hydrochloric acid, dried (MgSO4), and concentrated in vacuo. This crude oil was subjected to column chromatography (silica gel; petroleum ether) to produce 127 mg (69%) of the desired ester 139 as a colorless oil. The purity of this material was not rigourously established.

Method D. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.15 g (1.5 mmol) of ethyl acrylate, 0.59 g (1.1 mmol) of benzopinacol 239, and 240 mg (1.0 mmol) of N,N-diethyltrimethylstannylamine in 3 mL anhydrous toluene was warmed at 75°C for

135

16 h. The mixture was cooled to room temperature and diluted with 75 mL ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, three

25-mL portions of 3 N hydrochloric acid, dried (MgSO4), and concentrated in vacuo. This crude oil was subjected column chromatography (silica gel; hexane) to produce 112 mg

(61%) of the desired ester 139 as a colorless oil.

Method E. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide 200 mg (2.0 mmol) ethyl acrylate, 0.59 g (1.1 mmol) of benzopinacol 239, and 240 mg (1.0 mmol) of

N,N-diethyltrimethylstannylamine in 3 mL anhydrous benzene was warmed at 75°C for

15 h. The mixture was cooled to room temperature and diluted with 75 mL ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, three

25-mL portions of 3 N hydrochloric acid, dried (MgSO4), and concentrated in vacuo. This crude oil was subjected medium pressure liquid chromatography (Lobar size B; hexane) to produce 79 mg (43%) of the desired ester 139 as a colorless oil

Method F. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.15 g (1.5 mmol) of ethyl acrylate, 0.59 g (1.1 mmol) of benzopinacol 239, and 0.73 mg (2.2 mmol) of N,N-diethyltri-n-butylstannylamine in 3 mL anhydrous tetrahydrofuran was warmed at-

75°C for 16 h. The mixture was cooled to room temperature and diluted with 75 mL ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, three 25-mL portions of 3 N hydrochloric acid, dried (MgSO4), and concentrated in vacuo. This crude oil was subjected column chromatography (silica gel; hexane) to produce 198 mg (70%) of the desired ester 139 as a colorless oil.

Method G. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.15 g (1.5 mmol) of ethyl acrylate, 0.59 g (1.1 mmol) of benzopinacol 239, and 0.87 mg (2.2 mmol)

136

of N,N-diethyltriphenylstannylamine in 3 mL anhydrous toluene was warmed at 75°C for

16 h. The mixture was cooled to room temperature and diluted with 75 mL ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, three

25-mL portions of 3 N hydrochloric acid, dried (MgSO4), and concentrated in vacuo. This crude oil was subjected column chromatography (silica gel; hexane) to produce 105 mg

(61%) of the desired ester 139 as a colorless oil.

Ethyl 3-cyclohexyl-2-methylpropionate

(140). A solution of 0.42 g (2.0 mmol) of cyclohexyl

iodide, 0.34 g (3.0 mmol) of ethyl methacrylate, and

1.40 g (2.0 mmol) of bis(trimethylstannyl)benzopinacolate (1) were dissolved in 6.0 mL anhydrous benzene and heated at 70°C for 4 h.

The reaction mixture was diluted with 75 mL of ether and washed with 25 mL of saturated aqueous potassium fluoride. The organic phase was removed, dried (MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15°C/min)) of the oil (1.14 g) demonstrated the presence of ethyl 3-cyclohexyl-2-methylpropionate

(140) (tr = 6.17 min) cyclohexyldiphenylmethanol (137) (tr = 12.67 min); and 4- cyclohexyldiphenylketone (138) (tr =14.21 min) in a 79:16:5 ratio. The oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane to methylene chloride,

6:1) to afford 298 mg (75%) of the desired ester 140 as a colorless oil: IR (neat) 1745

-1 1 cm ; H NMR (CDCI3)  1.19 (m with d at  1.11 and t at 1.33, 16 H, CH), 1.79 (m, 3 H,

13 CH), 2.47 (m, 1 H, CHCO), 4.05 (q, J = 8 Hz, 2 H, OCH2); C NMR (CDCI3) 14.17 (q),

17.49 (q), 26.18 (t, 2 carbons based on relative intensity), 26.51 (t), 33.15 (t), 33.23 (t),

137

35.40 (d), 36.83 (d), 41.51 (t), 59.80 (t), 177.07 (d); exact mass calcd for C12H2202 m/e

198.1620, found m/e 198.1603.

Methyl 3-cyclohexylbutyrate (141): Method A.

A solution of 1.20 g (5.5 mmol) of cyclohexyl iodide, 5.50 g

(55 mmol) of methyl crotonate, and 5.7 g (8.3 mmol) of

bis(trimethylstannyl)benzopinacolate (1) in 9.0 mL anhydrous benzene was heated at 70°C for 4 h. The reaction mixture was cooled to room temperature, and 100 mL ether was added, and the solution was stirred for 30 min with 50 mL of saturated aqueous potassium fluoride. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 3.95 g of a colorless oil. VPC analysis

(Ultra II: 100°C (2 min) to 300°C (150C/min)) of the oil demonstrated the presence of methyl 3-cyclohexylbutyrate (141) (tr = 6.11 min); cyclohexyldiphenylmethanol (137) (tr =

13.11 min) and 4-cyclohexyldiphenylketone (138) (tr = 14.58 min) in a 75:19:6 ratio. This oil was subjected to careful fractional distillation. The fraction boiling at 125-132°C (16 mm Hg) was isolated to afford 0.60 g (59%) of methyl 3-cyclohexylbutyrate (141) as a

-1 1 colorless oil: IR (neat) 1745 cm ; H NMR (CDCI3)  0.89 (d, J= 6 Hz, 3 H, CH3), 0.9-1.9

(m, 12 H, aliphatic CH), 2.00 (dd, J = 15, 8 Hz, 1 H, CHCO), 2.33 (dd, J= 15, 4 Hz, 1 H,

13 CHCO), 3.62 (s, 3 H, CH3); C NMR (CDCI3)  16.49 (q), 26.57 (t), 26.62 (t), 26.66 (t),

28.94 (t), 30.25 (t), 35.34 (d), 38.99 (t), 42.60 (d), 51.24 (q), 174.15 (s); exact mass calcd for C11H20O2 m/e 184.1463, found m/e 184.1494.

Method B. A solution of 0.42 g (2.0 mmol) of cyclohexyl iodide and 0.55 g (6.0 mmol) of methyl crotonate in 2.0 mL of anhydrous benzene was heated at 70°C for 4 h.

The reaction mixture was cooled to room temperature, and 75 mL of ether was added,

138

and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.32 g of a colorless oil. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15°C/min)) of the oil demonstrated the presence of methyl 3-cyclohexylbutyrate (141) (tr = 6.11 min), cyclohexyldiphenylmethanol (137) (tr = 13.11 min), and 4-cyclohexyldiphenylketone

(138) (tr = 14.58 min) in a 80:15:5 ratio. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to afford 0.22 g (62%) of 141 as a colorless oil.

Method C. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.50 g (5.0 mmol) of methyl crotonate, 0.70 g (1.3 mmol) of benzopinacol 239, and 0.67 g (2.0 mmol) of N,N-dimethyltri-n-butylstannylamine in 3.0 mL of tetrahydrofuran was warmed at reflux for 14 h. The mixture was cooled to room temperature and 75 mL of ether was added. This solution was washed by three 25-mL portions of 3 N aqueous hydrochloric acid, and 25 mL of saturated aqueous sodium bicarbonate. To the ethereal solution was added 0.41 g of DBU, and 3 drops of a 1 N solution of iodine in diethyl ether with the formation of a white precipitate. This ethereal solution was filtered through 40 g of silica gel and concentrated in vacuo. The residual oil (0.37 g) was subjected to flash chromatography (hexane-ethyl acetate, 10:1) to give 144 mg (77 %) of the desired ester

141 as a colorless oil.

3-Cyclohexylbutyronitrile (142). A solution of 0.42

g (2.0 mmol) of cyclohexyl iodide, 0.40.g (6.0 mmol) of

crotonitrile and 1.40 g (2.0 mmol) of bis(trimethylstannyl)-

benzopinacolate (1) in 6.0 mL anhydrous benzene was heated at 70°C for 4 h. The reaction mixture was cooled to room temperature and diluted with 75 mL of ether. The ethereal solution was washed with 25 mL of saturated aqueous 139

potassium fluoride, dried (MgSO4), and concentrated in vacuo to produce 1.24 g of a crude yellow oil. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15°C/min)) of the oil demonstrated the presence of 3-cyclohexylbutyronitrile (142) (tr = 6.01 min), cyclohexyldiphenylmethanol (137) (tr = 12.93 min) and 4-cyclohexyldiphenylketone (138) (tr = 14.39 min) in a 79:16:5 ratio. This oil was subjected to medium pressure liquid chromatography

(Lobar size B; hexane) to produce 193 mg (64%) of a colorless oil: IR (neat) 2230 cm-1;

1 H NMR (CDCI3)  0.99 (d, J = 7 Hz, 3 H, CH3), 1.1-1.8 (m, 12 H, CH), 2.19 (dd, J= 16, 8

13 Hz, 1 H, CHCN), 2.31 (dd, J= 16, 6 Hz, 1 H, CHCN); C NMR (CDCI3)  16.30 (q),

21.90 (t), 26.07 (t), 26.16 (t, 2 carbons), 28.81 (t, two carbons), 30.12 (t), 35.43 (d),

41.47 (d), 119.12 (s); exact mass calcd for C10H17N m/e 151.1361, found, m/e 151.1329.

4-Cyclohexyldihydrofuran-2(3H)-one (144): Method

A. A solution of 0.17 g (2.0 mmol) of 2,5-dihydrofuranone, 0.42

g (2.0 mmol) of cyclohexyl iodide, and 1.52 g (2.2 mmol) of

bis(trimethylstannyl)benzopinacolate (1) in 6.0 mL of anhydrous

benzene was heated at 70°C for 5 h. The reaction mixture was

cooled to room temperature, and 75 mL ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride.

The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give

1.13 g of a yellow oil. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15°C/min)) of the oil demonstrated the presence 144 (tr = 8.53 min), 137 (tr = 13.19 min), and 138 (tr =

14.66 min) in a 34:48:15 ratio. The crude oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to afford 68 mg (21%) of the desired lactone as

-1 1 a colorless of IR (neat) 1760 cm ; H NMR (CDCI3)  0.95 (m, 2 H CH2), 1.23 (m, 4 H,

CH2), 1.65 (m, 5 H, CH2), 2.25 (m, 2 H, CHCO and CH), 2.52 (dd, J= 8, 9 Hz, 1 H, 140

13 OCCH), 3.95 (t, J = 9 Hz, 1 H, OCH), 4.37 (dd, J= 9, 8 Hz, 1 H, OCH); C NMR (CDCI3)

 25.70 (t), 25.77 (t), 26.08 (t), 30.42 (t), 31.04 (t), 32.59 (t), 41.31 (d), 41.60 (d), 72.07

(t), 177.00 (s); Exact mass calcd for C10H1602 m/e 168.1151, found m/e 168.1142.

Compound 137 was also isolated from this reaction mixture in 29% yield.

Method B. A solution of 84 mg (6.0 mmol) of 2,5-dihydrofuranone, 0.42 g (2.0 mmol) of cyclohexyl iodide, and 1.50 g (2.2 mmol) of bis(trimethylstannyl)benzopinacolate (1) in 6.0 mL anhydrous benzene was heated at 70°C for 5 h. The reaction mixture was cooled to room temperature, and 75 mL of ether was added, and the solution was stirred for 30 min with 50 mL of saturated aqueous potassium fluoride. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.39 g of a yellow oil. VPC analysis (Ultra II: 100°C (2 min) to 3 0 00C (150 C/min)) of the oil demonstrated the presence of 144 (tr = 8.53 min), 137 (tr = 13.19 min), and 138 (tr =

14.66 min) in a 68:25:7 ratio. The crude oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 98:2) to produce 0.20 g (61%) of the desired lactone as a colorless oil.

Method C. A solution of 0.21 g (1.0 mmol) of cyclohexyl iodide, 0.42 g (5.0 mmol) of 2,5-dihydrofuranone, 0.65 g (1.2 mmol) of benzopinacol 239, and 0.67 g (2.0 mmol) of N,N-dimethyltri-n-butylstannylamine in 3.0 mL of tetrahydrofuran was warmed at reflux for 13 h. The mixture was cooled to room temperature and 75 mL of ether was added. This solution was washed with three 25-mL portions of 3 N aqueous hydrochloric acid, and 25 mL of saturated aqueous sodium bicarbonate. To the ethereal solution was added 0.31 g (2.0 mmol) of DBU with the formation of a white precipitate. This solution was filtered through 15 g of silica gel and concentrated in vacuo. The residual oil was

141

subjected to flash chromatography (silica gel; hexane-ethyl acetate, 8:1) to give 103 mg

(61%) of the desired lactone 144 as a colorless oil.

4-Cyclohexyltetrahydro-2H-pyran-2-one (146):

Method A. A solution of 0.42 g (2.0 mmol) cyclohexyl

iodide, 0.59 g (6.0 mmol) of 5,6-dihydro-2H-pyran-2-

one, 1.50 g (2.2 mmol) of bis(trimethylstannyl)benzo-

pinacolate (1) in 6.0 mL anhydrous benzene was

heated at 70oC for 4 h. The reaction mixture was cooled

to room temperature, and 75 mL ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride.

The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give

0.80 g of a crude oil. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15°C/min)) of the oil demonstrated the presence of 146 (tr = 9.94 min), cyclohexyldiphenylmethanol (137) (tr =

13.17 min), and 4-cyclohexyldiphenylketone (138) (tr = 14.64 min) in a 41:46:13 ratio.

This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to produce 0.14 g (30%) of the desired lactone as a colorless oil: IR (neat) 1735

-1 1 cm ; H NMR (CDCI3)  0.95 (m, 2 H, CH), 1.20 (m, 4 H, CH), 1.70 (m, 7 H, CH), 1.95

(m, 1 H, CH), 2.20 (dd, J = 18, 11 Hz, 1 H, CHCO), 2.67 (dd, J = 18, 6 Hz, 1 H, CHCO),

13 4.21 (m, 1H, OCH), 4.38 (m, 1 H, OCH); C NMR (CDCI3)  26.15 (t; two carbons),

26.30 (t), 26.36 (t), 29.58 (t), 29.67 (t), 34.02 (t), 36.93 (d), 42.17 (d), 68.59 (t), 171.93

+ (s); exact mass calcd for C5H702 (M -C6H11) m/e 99.0446 found, m/e 99.0451. Trace impurities were detected in this material by 1H and 13C NMR.

142

Method B. A solution of 0.21 g (1.0 mmol) cyclohexyl iodide, 0.98 g (10.0 mmol) of 6-dihydro-2H-pyran-2-one, 1.50 g (1.0 mmol) of bis(trimethylstannyl)benzopinacolate

(1) in 3.0 mL of anhydrous benzene was heated at 70°C for 4 h. The reaction mixture was cooled to room temperature, and 75 mL of ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.38 g of a crude oil. VPC analysis (Ultra II: 100°C (2 min) to 300°C (150C/min)) of the oil demonstrated the presence of 146 (tr = 9.90 min), cyclohexyldiphenylmethanol (137) (tr =

13.11 min), and 4-cyclohexyldiphenylketone (138) (tr = 14.58 min) in a 83:13:4 ratio. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to produce 0.13 g (71%) of the desired lactone as a colorless oil.

1-Methylpyrrolidine-2,5-dione (140). A solution of 0.33 g

(2.0 mmol) cyclohexyl bromide, 0.22 g (2.0 mmol) N-methyl

maleimide, and 1.40 g (2.0 mmol) bis(trimethylstannyl)-

benzopinacolate (1) 6.0 mL anhydrous benzene was heated at 70°C

for 4 h. The reaction mixture was cooled to room temperature, 75

mL ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride. The organic phase was separated, dried

(MgSO4), and concentrated in vacuo to give 0.86 g of a colorless oil. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 3:1) to afford 0.068 g (30%) 1-methylpyrrolidine-2,4-dione 140 as a white solid:

-1 1 m.p. 98-100°C; IR (CHCI3) 1680, 1770 cm ; H NMR (CDCI3)  2.71 (s, 4 H, CH2), 2.99

143

13 (s, 3 H, CH3); C NMR (CDCI3)  24.49 (q), 28.96 (t), 176.95 (s); exact mass calcd for

C5H7NO2 m/e 113.0477, found m/e 113.0485.

Diethyl succinate (142). A solution of 0.33 g (2.0 mmol)

cyclohexyl bromide, 0.35 g (2.0 mmol) of bis(trimethylstannyl)-

benzopinacolate (1) in 6.0 mL of anhydrous benzene was heated at 70°C

for 4 h. The reaction mixture was cooled to room temperature, 75 mL

ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride. The organic phase was separated, dried

(MgSO4), and concentrated in vacuo to give 1.24 g of a crude oil. NMR analysis of this oil indicated that cyclohexyl iodide was not consumed. The cyclohexyl iodide was removed via rotovap (bath temp 50°C), and the resulting oil was subjected to bulb-to- bulb distillation (room temperature and 3 mm Hg) to produce 0.29 g (82%) diethyl

-1 1 succinate as a colorless oil: IR (neat) 1740 cm ; H NMR (CDCI3) 1.20 (t, J= 8 Hz, 6

13 H, CH3), 2.61 (s, 4 H, CH2), 4.15 (q, J = 8 Hz, 4 H, OCH2); C NMR (CDCI3)  13.94 (d),

28.97 (t), 60.34 (t), 171.98 (s); exact mass calcd for C6H14O4 m/e 174.0892, found m/e

174.0862.

4-Hydroxy-4,4-diphenylbutanenitrile (156). A

solution of 0.42 g (2.0 mmol) of cyclohexyl iodide,

0.11 g (2.0 mmol) of acrylonitrile, and 1.40 g (2.0 mmol)

of bis(trimethylstannyl)benzopinacolate (1) in 6.0 mL at 70°C for 5 h. The reaction mixture was cooled to room temperature, and 75 mL ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous

144

potassium fluoride. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give 1.12 g of a crude oil. This oil was subjected` to column chromatography

(100 g silica gel; hexane-ethyl acetate, 4:1) to produce 0.29 g (60%) of 156 as a white

-1 1 solid: mp 88-91°C; IR (CHCI3) 3550, 2250 cm ; H NMR (CDCI3)  2.28 (t, J = 8.5 Hz, 2

13 H, CH2), 2.39 (bs, 1 H, OH), 2.66 (t, J = 8.5 Hz, 2 H, CH2), 7.35 (m, 10 H, ArH); C NMR

(CHCI3)  12.07 (t), 37.60 (t), 77.00 (s), 120.14 (s), 125.80 (s), 127.48 (d), 128.45 (d),

145.10 (s); exact mass calcd for C16H15NO m/e 237.1153, found m/e 237.1115.

3-(Hydroxydiphenylmethyl)cyclohexanone (157). A

solution of 0.42 g (2.0 mmol) of cyclohexyl iodide, 0.29 g (3.0

mmol) of cyclohexenone, and 1.50 g (2.2 mmol) of bis(tri-

methytstannyl)benzopinacolate (1) in 6 mL of anhydrous

benzene was heated at 70°C for 4 h. The reaction mixture was

cooled to room temperature, and 75 mL ether was added, and the solution was stirred for 30 min with 25 mL of saturated aqueous potassium fluoride.

The organic phase was separated, dried (MgSO4), and concentrated in vacuo to give

0.71 g of an oily solid. The oily solid was washed with 3 mL of chloroform, and recrystallized from chloroform to produce 0.27 g (51%) of 157 as yellow solid: m.p. 148-

-1 1 150°C; IR (CHCI3) 3600, 1700 cm ; H NMR (CDCI3)  1.5-2.5 (m, 8 H, aliphatic CH),

2.62 (s, 1 H, OH), 2.94 (m, 1 H, CH), 7.23-7.6 (m, 10 H, ArH); 13C NMR  24.71 (t),

25.69 (t), 41.09 (t), 42.75 (t), 46.15 (d), 79.63 (s), 125.64 (d), 126.13 (d), 128.18 (d),

128.25 (d), 129.95 (d), 132.32 (d), 144.88 (s), 145.67 (s), 212.27 (s); exact mass calcd

145

for C19H20O2 m/e 262.1358, found m/e 262.1343. This material was contaminated by trace amounts of material which was most likely 3-cyclohexylcyclohexanone and benzophenone by NMR.

4-Methoxyphenol (180). A solution of 0.21 g (1.0 mmol) of

cyclohexyl iodide, 0.16 g (1.0 mmol) of monoketal 168, 0.41 g (1.1 mmol)

of pinacol 234, and 0.73 g of (2.2 mmol) of N,N-dimethyl(tri-n-

butylstannyl)amine in 3 mL of anhydrous benzene was heated at 80°C for

15 min. To the ethereal solution was added 0.31 g (2.0 mmol) of DBU with

the formation of a white precipitate. This solution was filtered through 15 g

of silica gel and concentrated in vacuo. The residual oil (0.76 g) was subjected to flash chromatography (silica gel; hexane-ethyl acetate, 8:1) to give 67 mg

1 (54%) of 169 as a white solid: mp 53-55°C; H NMR (CDCI3)  3.73 (s, 3 H, CH3), 6.48

13 (s, 1 H, OH), 6.80 (m, 4 H, ArH); C NMR (CDCI3)  55.96, 114.86, 116.11, 149.45,

153.31.

146

2,2-Dimethyl-1,1-diphenylpropan-1-ol

(185) and (4-(tert-Butyl)phenyl)-

(phenyl)methanone: Method A. A

solution of 0.27 g (2.0 mmol) of 1,1-di-

methylethyl bromide, and 1.40 g (2.0

mmol) of bis(trimethylstannyl)benzopin-

acolate (1) in 6.0 mL anhydrous benzene

was heated at 70°C for 4 h. The reaction

mixture was cooled to room temperature

and dissolved in 75 mL ether. The organics

were stirred with 25 mL of saturated

aqueous potassium fluoride, dried

(MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C

0 (15 C/min)) of the residual oil (0.84 g) demonstrated that 185 (tr = 10.62 min; m/e

(relative intensity) 240.18 (1), 183.12 (100), 105.01 (69)) and 186 (tr = 12.44 min; m/e

(relative intensity) 238.12 (27), 223.14 (100), 105.04 (69)) were formed in a 12.5:1 ratio.

The oil was subjected to flash chromatography over 100 g of silica gel

(hexane-methylene chloride, 10:1) to give 0.35 (63%) of 185 as a colorless oil: IR (neat)

-1 1 3600 cm ; H NMR (CDCI3) 1.17 (s, 9 H, CH3), 7.22 (m, 6 H,.ArH), 7.51 (m, 4 H, ArH);

13 C NMR (CDCl3)  27.60 (q), 39.24 (s), 82.93 (s), 125.49 (d), 127.21 (d), 128.55 (d),

+ 146.21 (s): exact mass calcd for C17H20O (M - H20) m/e 222.1408, found m/e 222.1405.

This material is contaminated by impurities by NMR.

Method B. To a stirred slurry of 80 mg (3.8 mmol) of magnesium in 2 mL of anhydrous ether was added 0.41 g (3.0 mmol) of 2-bromo-2-methylpropane The 147

suspension was gently heated until self-reflux was maintained. The reaction mixture was stirred an additional 2 h and 0.37 g (3.0 mmol) of benzophenone was added in one portion. The reaction mixture was carefully quenched by 25 mL of 3 N aqueous hydrochloric acid, and diluted with 50 mL of ether. The organic phase was dried

(MgSO4), and concentrated in vacuo. The residual oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 95:5) to give 216 mg (30%) of 185 as a colorless oil.

2-Cyclopentyl-1,1-diphenylethanol

(198) and (4-(Cyclopentylmethyl)phen-

yl)(phenyl)methanone (199). A solution of

0.33 g (2.0 mmol) of 5-hexenyl bromide and

1.40 g (2.0 mmol) of bis(trimethylstannyl)-

benzopinacolate (1) in 6.0 mL of anhydrous

benzene was placed in an oil bath which had

been preheated to 73°C. The reaction mixture was heated for 4.5 h, cooled to room temperature and dissolved in 75 mL anhydrous ether. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo. Capillary VPC (Ultra II:

1000C (2 min) to 300°C (150C/min)) analysis of the residual oil (0.93 g) indicated the presence of 198 (tr = 12.81; m/e = 266) and 199 (tr = 14.18; m/e = 266) in a 2:1 ratio.

Further VPC analysis indicated that trace amounts of 137 and 138 were present. The crude oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to produce 314 mg (59%) of a colorless oil which was a 1.8:1 mixture 198 and 148

-1 1 199 respectively: IR (neat) 3600, 1675 cm ; H NMR  1.2-2.2 (m, 9 H, CH and CH2)

2.20 (broad s, 1 H, OH), 2.36 (d, J = 6 Hz, 1.3 H, CH2CO from 198), 2.69 (d, J = 8 Hz,

0.7 H, CH2Ar from 199), 7.16 (m, 1 H, ArH), 7.27 (m, 3 H, ArH), 7.41 (m, 3 H, ArH), 7.52

13 (m, 1 H, ArH), 7.74 (m, 1 H, ArH); C NMR (CHCI3)  24.80 (t), 24.87 (t), 32.44 (t), 34.31

(t), 36.07 (d), 41.66 (d), 42.08 (t), 47.93 (t), 78.50 (s from 198), 126.00 (d), 126.54 (d),

127.93 (d), 128.09 (d), 128.60 (d), 129.86 (d), 130.18 (d), 131.99 (s), 132.26 (s), 147.46

(s), 147.62 (s), 192.00 (s from 199). This material was contaminated by a small amount of olefinic material (vinyl group at  5.0 and 5.7 in 1H NMR) and a few aromatic impurities were detectable by 13C NMR.

cis and trans (4-tert-Butylcyclohexyl)-

diphenylmethanol (201) and cis and trans 4-(4-

tert-Dibutylcyclohexyl)diphenylketone (202). A

solution of 0.22 g (1.0 mmol) of 4-tert-

butylcyclohexyl bromide 200 and 0.90 (1.3 mmol),

of bis(trimethylstannyl)benzopinacolate (1) in 3 mL

anhydrous benzene was warmed at 80°C for 5 h.

The reaction mixture was cooled to room

temperature and 25 mL of saturated aqueous

potassium fluoride was added. The aqueous phase was extracted with 75 mL ether, and the organic phase was dried (MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C (150C/min)) of the residual oil (0.62 g) demonstrated that cis and trans 201 (tr = 14.54 min; m/e (relative

149

intensity) 322.30 (0.1), 139.03 (63), 183.10 (100), 104.95 (12)); and tr = 14.64 min; m/e

(relative intensity) 322.20 (0.1), 139.10 (0.6), 183.14 (100), 104.95 (12)) and cis and trans 202 (tr = 15.86 min; m/e (relative intensity) 320.20 (88), 264.10 (100); and tr =

16.11; m/e (relative intensity) 320.20 (100), 264.10 (59)) were formed in a 3:1 ratio. Due to the complexity of the mixture, NMR spectra were difficult to analyze.

3-((1R,5S,8R)-8-(Hydroxydiphenylmethyl)-5-

methyl-7-oxo-6-oxabicyclo[3.2.1]oct-2-en-1-yl)propane-

nitrile (203). A solution of 0.40 g (1.3 mmol) of iodolactone

118 and 0.93 g (1.4 mmol) of bis(trimethylstannyl)-

benzopinacolate (1) in 6 mL of anhydrous benzene was

heated at 75°C for 4.5 h. The reaction mixture was cooled to ambient temperature and dissolved in 75 mL ether. The ethereal solution was stirred with 50 mL of a 10 % aqueous potassium fluoride solution for 1 h. The organic phase was separated, dried (MgSO4), and concentrated in vacuo to produce 1.24 g of a yellow oil. The oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 1:4) to afford 382 mg (76%) of 203 as a solid m.p. 220-223°C.

Crystallization from hexane-ethyl acetate provided 127 mg of an analytical sample: m.p.

o -1 1 221-223 C; IR (CH2Cl2) 3620, 3400, 2250, 1765 cm ; H NMR (CDCI3)  0.83 (s, 3 H,

CH3), 1.23 (m, 1 H, CH), 1.60 (m, 1 H, CH), 2.35 (m, 3 H, CH), 2.83 (dt, J = 18, 3 Hz,

1H, CH), 3.31 (s, 1 H, OH), 3.55 (s, 1 H, CH), 5.74 (d, J = 11.4 Hz, 1 H, =CH), 6.24 (dt, J

13 = 11.4, 3.1 Hz, 1 H, =CH), 7.30 (m, 7 H, ArH), 7.65 (m, 3 H, ArH); C NMR (CDCI3) 

12.15 (t), 25.42 (q), 27.84 (t), 36.68 (t), 49.14 (s), 54.50 (d), 77.12 (s), 84.49 (s), 119.11

150

(s), 125.01 (d), 125.62 (d), 126.20 (d), 127.50 (d), 128.11 (d), 128.31 (d), 128.73 (d),

+ 132.40 (d), 143.85 (s), 145.56 (s), 174.08 (s); exact mass calcd for C11H11 NO2 (M -

C13H110) m/e 189.0789, found m/e 189.0725.

Anal calcd for C24H23NO3N C, 77.19; H, 6.21; N, 3.75 Found C, 76.48; H, 5.93;

N, 3.63.

3-Cyclohexyl-1,1,2-triphenylpropan-1-ol (206): Method

A. A solution of 0.42 g (2.0 mmol) of cyclohexyl iodide, 0.64 g

(6.0 mmol) of styrene, and 0.88 g (1.3 mmol) of bis(trimethyl-

stannyl)benzopinacolate (1) in 3.0 mL of anhydrous benzene

was heated at 70°C for 4 h. The reaction mixture was cooled to

room temperature and 50 mL of ether was added. The ethereal solution was washed with 25 mL of saturated aqueous potassium fluoride. The organic phase was dried (MgSO4), and concentrated in vacuo to produce a yellow oil. This oil was subjected to bulb-to-bulb distillation (oven temperature set at 100°C; 0.2-0.3 mm

Hg) to remove the bulk portion of the benzophenone. The residual oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to afford 0.53 g (72%) of

-1 1 206 as white solid: mp 110-115°C; IR (neat) 3600 cm ; H NMR (CDCI3)  1.1-2.2 (m, 13

H), 2.67 (s, 1 H, OH), 4.11 (dd, J= 13, 3 Hz, 1 H, CHPh), 7.27 (m, 6 H, ArH), 7.45 (m, 3

H, ArH), 7.54 (m, 2 H, ArH), 7.67 (m, 1 H, ArH), 7.79 (m, 2 H, ArH), 8.03 (m, 1 H, ArH);

13 C NMR (CDCI3)  26.02 (t), 26.15 (t), 26.63 (t) 31.95 (t), 34.76 (t), 34.96 (d), 37.79 (t),

51.00 (d), 80.97 (s), 125.64 (d), 125.97 (d), 126.21 (d), 126.35 (d), 126.62 (1), 127.48

151

(d), 127.62 (d), 128.23 (d),130.00 (d), 140.10 (s), 145.98 (s), 146.45 (s). This material contained minor impurities by 1H and 13C NMR.

Method B. To a cooled (0°C) solution of 3.84 g (38 mmol) of diisopropylamine in

50 mL anhydrous tetrahydrofuran was added 24 mL (38 mmol) of 1.6 M n-butyllithium in hexane. A solution of 2.0 g (15 mmol) of phenylacetic acid in 5 mL tetrahydrofuran was added over 20 min. The resulting solution was warmed to room temperature and stirred

30 min. The reaction mixture was cooled in a dry ice/acetone bath and stirred 30 min. To this solution was added 2.65 g (15 mmol) of cyclohexylmethyl bromide and the resulting solution warmed to room temperature and stirred overnight. The reaction mixture was quenched by the slow addition of 30 mL of water followed by the addition of 10 mL of concentrated hydrochloric acid. The mixture was extracted with 100 mL of chloroform.

The organics were washed with three 50mL portions of 3 N aqueous hydrochloric acid, dried (MgSO4), and concentrated in vacuo to produce 3.21 g (92%) of a crude acid. A portion (3.02 g, 13 mmol) of the crude acid was dissolved in 100 mL anhydrous benzene and 10 mL (22 mmol) of ethanol, and 0.21 g of p-toluenesulfonic acid was added. The reaction mixture was warmed at reflux for 4 h, cooled to room temperature, washed with three 25-mL portions of a saturated aqueous sodium bicarbonate solution, dried

(MgSO4), and concentrated in vacuo. The residual oil (2.42 g) was subjected to column chromatography (silica gel; hexane-ethyl acetate, 4:1) to produce 2.42 g (72%) of 207 as a solid: mp 162-166°C. A solution of 1.03 g (4 mmol) of 207 in 10 mL of ether was added to a cooled (-78°C) solution of 5.0 mL (10 mmol) of 2.0 M phenyllithium in cyclohexane diluted with 10 mL ether. The resulting solution was stirred 45 min, quenched by the slow addition of 50 mL of water and 8 mL concentrated hydrochloric acid. The aqueous solution was extracted by 200 mL chloroform. The organic phase was dried (MgSO4),

152

and concentrated in vacuo. The residual oil was subjected to column chromatography

(silica gel; hexane-ethyl celate/ 10:1) to give 1.34 g (88%) of 206 as a white solid mp

(151-157oC). This material was more pure than the material produced by method A (1H and 13C NMR).

Diethyl 2-cyclohexyl-2-hydroxymalonate (222).141

A solution of 0.33 g (2.0 mmol) of cyclohexyl bromide, 0.35 g

(2.0 mmol) of diethyl ketomalonate (208), and 0.66 g (2.0

mmol) of hexamethylditin (99) in 6.0 mL anhydrous benzene

was photolyzed in a Pyrex bomb tube using a 450 watt

Hanovia medium pressure lamp for 16 h. The reaction mixture was dissolved in 75 mL of ether and washed with 25 mL of saturated aqueous potassium fluoride. The organics were dried (MgSO4), and concentrated in vacuo. VPC analysis of the residual oil (0.51 g) indicated that unreacted diethyl ketomalonate, cyclohexylcyclohexane (214), and 209 were present in a 1:3.7:23 ratio. This oil was subjected to MPLC chromatography (Lobar size B; hexane-ethyl acetate, 10:1) to produce 0.21 g (38%) of the desired ester 209 as a colorless oil: IR (neat) 1730, 3500

-1 1 cm ; H NMR (CDCI3)  1.2-1.8 (m, with triplet at  1.29, J = 8 Hz, 16 H, CH3 and aliphatic CH2), 2.30 (m, 1 H, CH), 3.66 (broad s, 1 H, OH), 4.27 (q, J= 8 Hz, 4 H, CH2);

13 C NMR (CDCI3)  14.00 (q), 25.94 (t), 26.07 (t), 26.39 (t), 42.71 (d), 62.35 (t), 82.26 (s),

+ 170.41 (s); exact mass calcd for C7H11O5 (M -C6H11) m/e 175.0606, found m/e

175.0622. This material was contaminated with material suspected to be the dimer of

1 13 208 by H NMR (CH3 (t) at  0.85 and 1.28, CH2 (q) at 2.05, OH at  3.7) and C NMR

(7.3 (q), 62.3 (t), 79.3 (s), 170.5 (s)).

153

(1-Cyclohexylvinyl)benzene (215). To a dry, degassed,

Pyrex bomb tube was added a solution of 325 mg (2.0 mmol) of

cyclohexyl bromide, 240 mg (2.0 mmol) acetophenone, and 0.65

g (2.0 mmol) hexamethylditin in 6.0 mL anhydrous benzene. The

solution was subjected to photolysis for 12 h using a 450 watt

Hanovia medium pressure lamp. The reaction mixture was diluted with 75 mL ether, and stirred for 30 min with 25 mL of saturated aqueous potassium fluoride. The organic phase was dried (MgSO4), and concentrated in vacuo to produce 0.44 g of a crude colorless oil. VPC analysis of this crude oil (0.44 g) indicated

,that 215 and 1,1'-bi(cyclohexane) 214 formed in a 1.9:1 ratio. This oil was subjected to flash chromatography over 100 g of silica gel (hexane-ethyl acetate, 5:1) to produce 264 mg of an oil which was predominately a 2:1 mixture of 215 and 214. This oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 98:2) to give 134 mg (38%) 215 as an oil: IR (neat) 890, 780, 700 cm-1; 1H NMR

(CDCI3) 1.25 (m, 5 H, CH2), 1.80 (m, 5 H, CH2), 2.43 (broad t, J= 7 Hz, 1 H, =CCH),

13 4.98 (broad s, 1 H, =CH), 5.12 (broad s, 1 H, CH), 7.25 (m, 5 H, ArH), C NMR (CDCI3)

 26.50 (t), 26.88 (t), 32.77 (t), 42.71 (d), 110.34 (t), 126.26 (d), 126.9 (d), 128.09 (q),

143.03 (s), 155.03 (s); exact mass calcd for C14H18 m/e 186.1408, found m/e 186.1397.

2-Propen-1-yl 2-Methyl-2-propenoate (225). To a

cooled (0°C) solution of 13.80 g (238 mmol) of allyl alcohol

in 50 mL tetrahydrofuran was added 4.92 g (48 mmol) of

methacryloyl chloride over a 40 min period. The resulting

154

solution was stirred 4 h and carefully added to 100 mL of ice water. The aqueous solution was extracted by two 150 mL portions of diethyl ether. The combined ethereal solutions were washed by two 100 mL portions of saturated aqueous sodium bicarbonate, and two 100-mL portions of brine, dried (MgSO4), and concentrated in vacuo. The residual oil (6.48 g) was distilled to give 5.32 g (88%) of the desired ester

1 225 as a colorless oil: bp 75-81°C at 28 mm Hg; H NMR (CDCI3)  1.91 (s, 3 H, CH3),

4.53 (d, J = 12, 2 H, OCH2), 5.18 (dd, J= 12, 1 Hz, 1 H, =CH), 5.27 (d, J = 18 Hz, 1 H,

13 =CH), 5.51 (s, 1 H,=CH), 5.91 (m, 1 H, =CH), 6.06 (s, 1 H, =CH); C NMR (CDCI3)

18.0 (q), 64.9 (t), 117.5 (t), 125.1 (t), 132.1 (d), 136.1 (s), 166.5 (s); exact mass calcd for C7H10O2 m/e 126.0680, found m/e 126.0691.

2-(Cyclohexylmethyl)-2-methylpent-4-enoic acid

(226). A solution of 0.25 g (2.0 mmol) of 225, 0.21 g (1.0

mmol) of cyclohexyl iodide, and 0.76 g (1.1 mmol) of bis(tri-

methylstannyl)benzopinacolate (1) in 3.0 mL of anhydrous

benzene was heated at reflux for 10 h. The reaction mixture

was cooled to room temperature and dissolved in 75 mL ether.

The ethereal solution was washed with 25 mL of 3 N aqueous

hydrochloric acid saturated with aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo. The residual oil (0.74 g) was subjected to flash chromatography (100 g silica gel; hexane-ethyl acetate, 3:1) to produce 0.143 g

-1 1 (68%) of 226 as a yellow oil: IR (neat) 3500, 2500, 1700 cm ; H NMR (CDCI3)  0.97

(m, 2 H, CH), 1.14 (s, 3 H, CH3), 1.24 (m, 3 H, CH), 1.37 (m, 2 H, CH), 1.64 (m, 6 H,

155

aliphatic CH), 2.14 (dd, J = 14, 8 Hz, 1 H, CHC=), 2.41 (dd, J = 14, 7 Hz, 1 H, CHC=),

5.03 (m, 1 H, terminal =CH), 5.08 (m, 1 H, terminal =CH), 5.75 (m, 1 H, =CH), the CO2H

13 was not present; C NMR (CDCI3) 20.95 (q), 26.24 (t), 26.38 (t), 26.40 (t), 33.74 (t),

34.34 (d), 34.83 (t), 44.37 (t), 45.25 (s), 46.49 (t), 118.27 (t), 133.69 (d), 184.25 (s).

2-Methyl-2-neopentylpent-4-enoic acid (230). A

solution of 0.14 g (1 mmol) of t-butyl bromide, 0.26 g .(2.0

mmol) of 225, and 0.90 g (1.3 mmol) of bis(trimethyl-

stannyl)benzopinacolate (1) in 3.0 mL of anhydrous toluene

was heated at 80°C for 4 h. The oil bath temperature was

raised to 110°C and the solution was warmed at 110-115°C

for 8 h. The reaction mixture was cooled to room temperature and 75 mL of ether was added. The solution was washed with 25 mL of saturated aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo to produce 0.86 g of a crude oil. This oil was subjected to flash column chromatography over 100 g of silica (hexane-ethyl acetate, 3:1) to afford 132 mg (71%) of the desired

-1 1 acid as a colorless oil: IR (neat) 3500-2500, 1700 cm ; H NMR (CDCI3)  0.92 (s, 9 H,

CH3), 1.17 (s, 3 H, CH), 1.36 (d, J = 10 Hz, 1 H, CH), 1.84 (d, J = 15 Hz, 1 H, CH), 2.04

(dd, J = 15, 8 Hz, 1 H, =CCH), 2.37 (dd, J = 15, 8 Hz, 1 H, =CCH), 4.98-5.03 (m, 2 H,

13 =CH2), 5.65 (m, 1 H, =CH), the CO2H was not observed; C NMR (CDCl3)  21.5 (q),

30.9 (q), 31.8 (q), 45.8 (s), 46.6 (t), 52.2 (t), 118.6 (t), 133.4 (d), 184.2 (s); exact mass

+ calcd for C10H19 – (M - CO2H) m/e 139.1487, found m/e 139.1520.

156

Ethyl 2-(Cyclohexylmethyl)-3-hydroxy-3,3-

diphenylpropanoate (231): Method A. To a cooled

(0°C) solution of 0.62 g (6.2 mmol) of

diisopropylamine in 100 mL of anhydrous

tetrahydrofuran was added 1.72 mL (4.3 mmol) of a

2.5 M solution of n-butyllithium. The reaction mixture was cooled to -78°C and 0.64 g

(4.0 mmol) of 147 was added dropwise. The reaction mixture was stirred for 30 min and

0.74 g (4.1 mmol) of benzophenone was added. The reaction mixture was stirred an additional 30 min and 0.5 g of ammonium chloride was added. The tetrahydrofuran was removed in vacuo, and the residue was dissolved in 100 mL of ether. The organics were washed sequentially with 100 mL of a 1 N aqueous hydrochloric acid solution, 100 mL of a saturated brine solution, dried (MgS04), and concentrated in vacuo to produce 1.50 g of a crude white precipitate. This precipitate was recrystallized from hexane and ethyl

1 acetate to give 0.96 g (64%) of 231 as a white powder: m.p. 98-100°C; H NMR (CDCI3)

 0.71 (m, 1 H, CH), 0.85 (m, 1 H, CH) 1.02 (t, J = 7 Hz, 3 H, CH3), 1.20 (m, 6 H, CH),

1.60 (m, 4 H, CH), 1.90 (m, 2 H, CH), 3.73 (dd J = 12, 4 Hz, 1 H, CHCO2), 3.98 (q, J = 7

13 Hz, 2 H, OCH2), 4.70 (s, 1 H, OH), 7.24 (m, 4 H, ArH), 7.56 (m, 4 H, ArH); C NMR

(CDCl3)  13.88 (q) 26.02 (t), 26.19 (t), 26.37 (t), 31.96 (t), 34.01 (t), 35.35 (t), 35.68 (d),

50.29 (d), 60.54 (t), 78.87 (s), 125.19 (d), 125.37 (d), 126.48 (d), 126.72 (d), 128.03 (d),

128.10 (d), 144.27 (s), 147.35 (s), 177.07 (s).

Method B. To a cooled (0°C) solution of 0.28 g (2.8 mmol) of diisopropylamine in

50 mL THF was added 1.2 mL (2.9 mmol) of n-butyllithium in hexanes. The reaction mixture was cooled in a dry ice acetone bath and 0.50 g (2.8 mmol) of ethyl 3- cyclohexylpropanoate 139 was added over a 30-min period. To the resulting solution

157

was added 0.49 g (2.8 mmol) of benzophenone. The reaction mixture was stirred for 10 min and a 25 mL portion of the reaction mixture was removed and quenched with 50 mL of ice water. The aqueous solution was extracted with 75 mL of diethyl ether. The extract was washed with two 50-mL portions of 3 N aqueous hydrochloric acid, washed with 50 mL of saturated aqueous sodium bicarbonate, dried (MgSO4), and concentrated in vacuo to afford 184 mg (31%) of 231 as a white precipitate (mp 98-100°C). To the remaining portion of the reaction mixture was added 0.83 g (4.2 mmol) of trimethyltin chloride. The reaction mixture was warmed to room temperature and the solvent was removed in vacuo. The resulting oily suspension was dissolved in 3 mL benzene, filtered free of the inorganic salts, and warmed at 75°C for 4 h. The reaction mixture was cooled to room temperature and dissolved in 75 mL ether. The etheral solution was washed by 25 mL of a saturated aqueous potassium fluoride solution, dried (MgSO4), and concentrated in vacuo. 1H NMR analysis of the residual oil demonstrated an absence of 231 (no signal at

 3.73). The oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to afford 78 mg (31%) of recovered ethyl 3-cyclohexylpropionate 139 as a sweet smelling oil.

1,1,2,2-Tetraphenylethane-1,2-diol (234). A 500 mL

immersion-well photoreactor was dried and purged with argon.

The reactor was charged with 41.24 g (225 mmol) of

benzophenone and 480 mL of isopropyl alcohol was added followed by five drops of glacial acetic acid. The mixture was subjected to photolysis through Pyrex 450 watt Hanovia medium pressure lamp. After 2 h with the photolysis was stopped and the precipitate was isolated via vacuum filtration to give 13.24 g of 158

crude 234. The photoreactor was cleaned and the filtrate was subjected to the above procedure three additional times to produce 11.27 g, 8.61 g, and 5.14 g of crude 234.

The four samples of 234 were combined (32.26 g; 78%) and recrystallized from 360 mL of hot glacial acetic acid to afford 31.18 g (76%) of 234 as small white crystals: mp 183-

o o 1 1 186 C (lit 184-186 C); IR (CHCI3) 3600 cm ; H NMR (CDC13)  3.02 (s, 2 H, OH), 7.16

13 (m, 12 H, ArH), 7.24 (m, 8 H, ArH); C NMR (CDCl3)  82.91 (s), 126.78 (d), 127.12 (d),

128.47 (d), 144.06 (s).

Ethyl 3-Cyclohexylbutanoate (235). A

solution of 0.21 g (1.0 mmol) of cyclohexyl iodide,

0.18 g (1.5 mmol) of ethyl crotonate, 0.14 g (0.2

mmol) of bis(trimethylstannyl)benzopinacolate (1) and

0.37 g (1.0 mmol) of benzopinacol 234 in 2.0 mL anhydrous toluene was placed in an oil bath which had been preheated to 106°C. The reaction mixture was heated for 16 h, cooled to room temperature, and 75 mL of diethyl ether was added. The solution was washed with 25 mL of saturated aqueous potassium fluoride, dried (MgSO4), and concentrated in vacuo. VPC analysis (Ultra II: 100°C (2 min) to 300°C (15oC/min)) of the residual oil (0.80 g) demonstrated the presence of 235

(tr = 6.04 min), cyclohexyldiphenylmethanol (137) (tr = 13.11 min), and 4-cyclohexyldiphenylketone (138) (tr =14.58 min) in a 75:11:10 ratio. The oil was subjected to medium pressure liquid chromatography (Lobar size B; hexane) to give 94 mg (47%) of

-1 1 the desired ester as a colorless oil: IR (neat) 1745 cm ; H NMR (CDCl3)  0.89 (d, J = 7

Hz, 3 H, CH3), 0.97 (m, 3 H, CH), 1.1-1.9 (m with triplet centered at 1.39, J = 8 Hz, 12 H, aliphatic CH), 2.09 (dd, J = 13, 8 Hz, 1 H, CHCO), 2.39 (dd, J = 13, 5 Hz, 1 H, CHCO),

13 4.23 (q, J = 8 Hz, 2 H, OCH2); C NMR (CDCI3) 14.28 (q), 16.46 (q), 26.62 (t), 26.67 159

(t), 27.72 (t), 28.95 (t), 30.31 (t), 35.40 (d), 39.33 (t), 42.64 (d), 60.06 (t), 173.85 (s); exact mass calcd for C12H22O2 m/e 198.1620, found m/e 198.1603.

Diethyl 2-Cyclohexylsuccinate (236). A solution of

0.21 g (1.0 mmol) of cyclohexyl iodide, 0.26 g (1.5 mmol) of

diethyl fumerate 0.14 g (0.20 C mmol) bis(trimethyl-

stannyl)benzopinacolate (1) and 0.37 g (1.0 mmol) of

benzopinacol 234 in 30 mL of anhydrous toluene was

placed in an oil bath which had been preheated to 105°C.

The reaction mixture was heated 105-107°C for 13 h, cooled to room temperature, and

25 mL of saturated aqueous potassium fluoride was added. The resulting slurry was extracted by 75 mL diethyl ether. The organic extract was dried (MgSO4), and concentrated in vacuo. The resulting oil (0.81 g) was subjected to medium pressure liquid chromatography (Lobar size B; hexane-ethyl acetate, 10:1) to produce 173 mg

-1 1 (61%) of the desired ester 236 as a colorIess oil: IR (neat) 1745 cm ; H NMR (CDCI3) 

0.9-1.3 (broad multiplet with a overlapping triplets centered at 1.18, J = 8 Hz, 11 H, aliphatic CH), 1.70 (m, 6 H, aliphatic CH), 2.37 (m, 1 H, CHCO2), 2.65 (m, 2 H, CHCO2),

13 4.08 (m, 4 H, OCH2); C NMR (CDCl3)  14.00 (q), 14.10 (q), 26.07 (t), 26.21 (t, two carbons), 30.02 (t), 30.47 (t), 33.42 (t), 39.87 (d), 46.97 (d), 60.15 (t), 60.32 (t), 172.30

(s), 174.24 (s); exact mass calcd for C14H2404 m/e 256.1674, found m/e 256.1653. This material contained some 234 and possibly benzophenone by 13C and 1H NMR.

160

(2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-(3-

ethoxy-3-oxopropyl)tetrahydro-2H-pyran-3,4,

5-triyl triacetate (237). A solution of 0.48 g (1.3

mmol) of benzopinacol 234 and 0.87 g (2.6

mmol) of dimethylaminotri-n-butylstannane152 in

2 mL anhydrous benzene was stirred at room temperature for 15 min. A solution of 0.15 g (1.5 mmol) of ethyl acrylate, and 0.41 g (1.0 mmol) of 35 in 1 mL anhydrous benzene was added and the reaction mixture was warmed at 70°C for 5 h. The reaction mixture was cooled to room temperature and 25 mL of a saturated aqueous potassium fluoride solution was added. The resulting suspension was extracted by 75 mL of ether. The organic solution was dried (MgSO4), and concentrated in vacuo. The residual oil (1.09 g) was subjected to flash chromatography over 100 g of silica gel (hexane-ethyl acetate,

3:1) to produce 0.34 g (78%) of 237 as an 8:1 mixture of isomers: IR (neat) 1735 cm-1;

1 H NMR (C6D6)  0.93 (t, J = 7 Hz, 3 H, CH3), 1.59 (s, 3 H, CH3), 1.65 (m, 2 H, CH2), 1.69

(s, 3 H, CH3), 1.70 (s, 3 H, CH3), 1.73 (s, 3 H, CH3), 2.14 (m, 2 H, CH2CO), 3.62 (ddd, J

= 9, 5, 3 Hz, 1 H, OCH), 3.93 (q, J = 7 Hz, 2 H, OCH2), 4.01 (dd, J = 12, 3 Hz, 1 H,

OCH), 4.09 (m, 1 H, OCH), 4.19 (dd, J = 12, 5 Hz, 1 H, OCH), 5.12 (t, J = 9 Hz, 1 H,

13 OCH), 5.18 (dd, J = 9, 6 Hz, 1 H, OCH), 5.45 (t, J = 9 Hz, 1 H, OCH); C NMR (CDCI3) 

14.19 (q), 20.10 (q), 20.21 (q), 20.29 (q; two carbons), 20.88 (t), 29.82 (t), 60.41 (t),

62.25 (t), 69.15 (d), 69.26 (d), 70.63 (d), 70.80 (d), 72.22 (d), 169.14 (s), 169.22 (s),

169.74 (s), 170.07 (s), 172.34 (s).

161

1,1,2,2-tetrakis(4-(dimethylamino)-

phenyl)ethane-1,2-diol (239).154 To a

solution of 10.0 g (37 mmol) of ketone

238 in 50 mL of tetrahydrofuran was

added 0.52 g (75 mmol) of lithium wire

in several small portions. The mixture

was stirred overnight. The tetrahydrofuran was removed in vacuo, and the residue was diluted with 300 mL of a 3 N aqueous hydrochloric acid solution. The aqueous solution was washed by 300 mL of ether and poured onto 100 g of sodium bicarbonate. The resulting suspension was extracted by three 200 mL portion of methylene chloride. The combined organics were dried

o (MgSO4), and concentrated in vacuo. The residual brown solid (9.34 g; mp 132-135 C) was subjected to crystallization from a chloroform-hexane mixture to give 5.42 g (51%)

1 of 239 as a solid: mp 191-195°C; H NMR (CDCI3)  2.79 (s, 24 H, CH3) , 2.90 (s, 2 H,

13 OH), 6.48 (m, 8 H, ArH), 7.15 (m, 8 H, ArH); C NMR (CDCI3)  40.51 (q), 82.31 (s),

111.20 (d), 129.52 (d), 133.10 (s), 148.79 (s). This material contained trace impurities by 13C NMR.

162

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