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An approach to the synthesis of neoclovene Mar, Andrew 1974

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AN APPROACH TO THE SYNTHESIS OF NEOCLOVENE BY ANDREW MAR B.Sc. (Hons.), U n i v e r s i t y of B r i t i s h Columbia, 1971. A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of CHEMISTRY We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA August, 1974 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced degree at the U n i v e r s i t y o f B r i t i s h Co lumb ia , I a g ree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s tudy . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s . It i s u n d e r s t o o d tha t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i thou t my w r i t t e n p e r m i s s i o n . Department o f The U n i v e r s i t y o f B r i t i s h Co lumbia Vancouver 8, Canada D a t e flex:. <\ ABSTRACT , This thesis describes the i n v e s t i g a t i o n of two synthetic approaches to the keto t o s y l a t e 90_, a key intermediate i n a proposed synthesis of neoclovene. The f i r s t approach involved an e f f i c i e n t 9-step synthesis of the epoxy acetals 152 and 153 from indan-l-one 142. D i a l k y l a t i o n of 142 with methyl iodide followed by the r e a c t i o n of the dimethyl ketone 143 with d i e t h y l cyanomethylphosphorane gave the n i t r i l e s 144 and 145. Successive subjection of the n i t r i l e s to h y d r o l y s i s , hydrogenation, and reduction r e s u l t e d i n the formation of the aromatic alcohol 141. Treatment of the l a t t e r with l i t h i u m i n l i q u i d ammonia followed by r e g i o s e l e c t i v e hydrogenation of the di s u b s t i t u t e d double bond of 149 with the homogeneous c a t a l y s t t r i s ( t r i p h e n y l -phosphine)chlororhodium gave the o l e f i n alcohol 150. Epoxidation of the double bond o£ the o l e f i n acetal 151, corresponding to .the alcohol 150, with m-chloroperbenzoic acid gave a mixture of epoxy acetals 152 and 153 i n quantitative y i e l d . However, a l l attempts to obtain the keto t o s y l a t e 90 from the epoxy acetals f a i l e d to give s y n t h e t i c a l l y useful y i e l d s of the desired products. This precluded further use of t h i s approach. The second approach involved the synthesis of the o l e f i n alcohol 179, a proposed intermediate i n the synthesis of the keto t o s y l a t e 90_. Thus, a l k y l a t i o n of i s o b u t y r o n i t r i l e 165 with a l l y l bromide followed by ozonolysis of the a l k y l a t i o n product gave the aldehydic n i t r i l e 167. Successive treatment with cyclopentylidenetriphenylphosphorane, polyphosphoric acid, and a l c o h o l i c sodium hydroxide afforded the ketone 170. The ketone 170 was converted i n t o the epoxy ketone 171 and the l a t t e r was reacted with methylenetriphenylphosphorane to y i e l d the epoxy o l e f i n 173. The l a t t e r was subjected to hydroboration-oxidation to produce the epoxy alcohols 174 and 175. The a l c o h o l i c f u n c t i o n a l i t y was protected as the acetate and the epoxide was reduced with tungsten hexachloride-n-butyllithium to give the o l e f i n acetate 178 i n 90% y i e l d . Reduction of the o l e f i n acetate with l i t h i u m aluminum hydride y i e l d e d the o l e f i n alcohol 179. Unfortunately, due to the lack of time and m a t e r i a l , t h i s project was concluded at t h i s point. A p o s s i b l e synthetic route to the keto t o s y l a t e 90 from the o l e f i n alcohol 179 i s given. - i v -TABLE OF CONTENTS TITLE PAGE ABSTRACT . 1 . TABLE OF CONTENTS » ACKNOWLEDGEMENTS INTRODUCTION 1. Diorganocopper Reagents 2. Intramolecular A l k y l a t i o n 3. Or i g i n and S t r u c t u r a l E l u c i d a t i o n of Neoclovene . . . . o 4. Other Synthetic Approaches to Neoclovene ..... DISCUSSION 1. General 2. Attempted Synthesis of Keto Tosylate 90 ...... 3. Second Attempted Synthesis of Keto Tosylate 90 EXPERIMENTAL BIBLIOGRAPHY - V -ACKNOWLEDGEMENT I would like to express my thanks to Dr. Edward Piers for his encouragement, invaluable advice, and consistent interest during the course of this research and the preparation of this manuscript. I would also like to thank a l l the members of Dr. Piers' research group (past and present.) for their many helpful discussions and suggestions. Special thanks are to Mrs. Diane Gray for the very capable typing and to Mr. Marston Lee for drawing the many structural diagrams in this thesis. INTRODUCTION H 2 0 ' II 1. Diorganocopper Reagents The use of a catalytic amount of a copper salt in the reaction of an a,8-unsaturated carbonyl compound with an organometallic reagent o ' all H \ . _ / C C H , R V C = C A 4 R - M E T A L — — * - C H J C H C H = C - C H O C H 3 / \ H I 3 1 n C MLTAL -i—. . . . . j_ R o I II C H 3 C H C H 2 C C H 3 3. to achieve a Michael (1,4) addition has been known since 1941.* It was not until twenty-five years later that House, Respess, and 2 Whitesides experimentally showed that the reactive intermediate was in fact an organocopper derivative. This derivative, preformed from Cu(I) and an organometallic reagent or formed from the same reagents in situ gave the same product upon reaction with E-3-penten-2-one 1. 3 Since 1966, extensive research has shown that diorganocopper reagents can be used with a wide variety of substrates other than a,8-unsaturated carbonyl compounds. The coupling reaction of organo-4-8 9_11 cuprates with alkyl halides " and tosylates has been shown to H & U a CuLi 6,0% M 6.5 % 0 = c &/t 6 0 % s 9 15% 11 C H 2 = C K C H 2 0 T S ^ C " L V 12 89% C H 2 = C H C H 2 15 14 C u L i 4 C H 3 o T s 15 9 8 % 16 E ^ C H ^ C H o . 0 T « . IS 19 O O JL " M e o C u t i , II 9 C C H a C H ^ O T s — — — « ~ 9 C C H 2 C H 2 C H 3 2 0 21 - 3 -proceed not only i n high y i e l d but i n some cases with high stereo-s e l e c t i v i t y (see Chart 1). Other leaving groups have also been displaced by organocuprate reagents. In the case of ethynylcarbinol 12 acetates, allenes are formed. O l e f i n s are formed s t e r e o s e l e c t i v e l y 13 from a l l y l i c acetates and B-alkoxy- and 3-alkylthio-a,B-unsatur'ated 14 15 carbonyl compounds ' (see Chart 2) and ketones are formed from carboxylic a c i d c h l o r i d e s ' ^ (see Chart 3). Epoxide rings can al s o be 17-19 opened i n a n u c l e o p h i l i c manner by organocuprates. Although organocuprate reagents react with the aforementioned substrates, organic chemists have found these reagents to be most useful i n t h e i r - ' 2' unusually e f f e c t i v e conjugate addition to a , 8-unsaturated aldehydes, ketones,^' ^  e s t e r s , ^ ' ^  and n i t r i l e s ^ 3 ' ^  (see Charts 2 and 3). involves e i t h e r p a r t i a l or complete electron t r a n s f e r from organo-cuprate, [RCu(I)Y] , to unsaturated substrate forming e i t h e r a charge-tr a n s f e r complex or a r a d i c a l anion. Subsequent t r a n s f e r of an organic r a d i c a l from a t r a n s i e n t organocopper(II) species to the end of the conjugated anion r a d i c a l or collapse of the charge t r a n s f e r complex [R:Cu(I)Y] R:Cu(II)Y Cu(I)Y 0 R 0 I) -C=C-C-I I -C-C=C- -C-C=C-54 55 56 Y = R, halogen, CN would complete the addi t i o n sequence and generate enolate 56 which i s - 4 -24 2 5 CHART 2 - 5 -CN C C H o ) l o C o C l ' a ' 10 3£> R = 7lE>U 95% CN ( CH</)lo CoR. *7 -nC4Hcj 0 2 C C H 2 C H 1 C o C | •?8 I ( C H ^ l o CoCl 40 n So» R = nBu 93% PL-nE>u 93% * C 4 0aCCHaCH2CoR 1 CCH a ) 1 0 CoR • 41 M e 9 CuLi 8 8 % 42-O H 4 3 f> - C C H 2 ) 8 C o C H a C H 3 C H 2 C H CCH^g C0CH3 OH 4 4 45 • o 46 8 4 % yy 4_7_ 46 •5>7% 49 \ c = = c / MegCuLi, 50 cHo CH 3 ^ / C H 3 C = G C H C 0 2 C H 2 c H 3 CH CHART 3 - 6 -quenched on subsequent aqueous workup. The apparent requirements of a net negative charge on the copper complex f o r e f f i c i e n t conjugate ad d i t i o n has r e c e n t l y been confirmed. 26,27 Although enolates such as 56_ have been trapped as enol d e r i v a t i v e s 2 with acetyl c h l o r i d e , a c e t i c anhydride, and d i e t h y l phosphorochLori-28 date and have been found to give only one double bond isomer, few CH3 / \ H ccH, 5 7 3°) ccH3)2ca H / cH ( C 2 H 5 0 ) a P o II o researchers have,* u n t i l r e c e n t l y , a l k y l a t e d these enolates i n s i t u to f u r t h e r elaborate the carbonyl substrate. Last year, Boeckman and Coates independently showed that organo-copper enolates can be r e g i o s e l e c t i v e l y and, i n some cases, stereo-34 34-36 s e l e c t i v e l y a l k y l a t e d to y i e l d a - d i s u b s t i t u t e d and a,8-disubstituted carbonyl compounds. To date, the d i r e c t a l k y l a t i o n of the intermediate magnesium enolate formed from the copper-catalyzed conjugate addition of Grignard reagents to a,8-unsaturated ketones has been achieved by S t o r k 2 9 * 3 0 and Kretchmer. 3 1> 3 2 The a l k y l a t i o n of copper-lithium malonates has been reported by G r i e c o . 3 3 In his first' paper on this subject, BoeckmanJ'> was able to successfully react some regio-stable copper enolates with various a-trimethyl-s i l y l a,B-unsaturated ketones. It was found that in the case of cyclic a,B-unsaturated ketones, the incoming a-trimethylsilyl vinyl ketones add predominately anti to the previously introduced (from the cuprate addition) alkyl group and therefore the overall annelation reaction produces a highly stereoselective product. In the case of enolate 6_2, the cyclohexene skeleton assumes a half-chair conformation in which the allylic methyl group is in a pseudoaxial position to . fl 2) relieve A ' ' strain. In this conformation, the steric requirements favor alkylation on the a face. The resulting ratio (97:3) of the cis octalone 64 to the trans octalone 65_ respectively shows the potential of the conjugate addition-anneiation sequence in organic synthesis. Boeckman has also added an isopropenyl group via the cuprate as shown by his synthesis of hydrindenone 68_ (see Chart 4). In his second 36 paper on the alkylation of organocopper enolates, Boeckman turned his attention toward the use of alkyl halides as the alkylating agents (see Chart 4). This work showed that these metal enolates (formed in a regioselective manner), because of the covalent nature of the copper-37 oxygen bond, may be alkylated regiospecifically in unhindered cases without a significant amount of polyalkylation. If the B position of the carbonyl substrate is sterically hindered, as in ketone 71_ (see Chart 4),the metal enolates will undergo equilibration* at a significant _ Boeckman also proposed that reduction in the size of the alkyl halide would increase the ratio of alkylation to equilibration. - 9 -rate r e l a t i v e to the rate of a l k y l a t i o n r e s u l t i n g i n loss of r e g i o -* s p e c i f i c i t y , , 34 In a very s i m i l a r study, Coates investigated the conjugate a d d i t i o n - a l k y l a t i o n of 2-n-butylthiomethylehe ketones as well as other a,B-unsaturated ketones. Although the r e s u l t s obtained did not show as high a degree of s t e r e o s e l e c t i v i t y as Boeckman1s work, he has demonstrated a new method of acquiring a,a-disubstituted ketones. Thus, 37 double conjugate a d d i t i o n to 2-n-butylthiomethylene ketones (see for example ketone 7£, Chart 4 ) , followed by a l k y l a t i o n of the copper-li t h i u m enolate r e s u l t e d i n the formation.of cx-isopropyl-a-alkyl-d i s u b s t i t u t e d ketones. 2. Intramolecular A i k y l a t i o n s Intramolecular a l k y l a t i o n s play a very important r o l e i n synthetic 38 organic chemistry. With the advent and refinement of chromato-graphic techniques, p.m.r. spectrometers, and X-ray c r y s t a l l o g r a p h i c techniques chemists are now able to i s o l a t e and determine the structure of many natural products i n a r e l a t i v e l y short time. Most of these compounds have complex, p o l y c y c l i c s t r u c t u r e s . In order to synthesize these compounds from simpler mono-,.di-, or t r i - c y c l i c precursors, more and more chemists have used intramolecular c y c l i z a t i o n s as an i n t e g r a l step i n t h e i r synthetic sequence. This type of a l k y l a t i o n i s a t t r a c t i v e because of the f a c i l i t y of intramolecular r e a c t i o n s . Also, since i t i s k i n e t i c a l l y c o n t r o l l e d , t h i s process can lead to very _ It must be remembered that other s t e r i c f a c t ors i n the c i s - d e c a l i n system also contribute to the rate o f a l k y l a t i o n . - 10 -strained r i n g systems (vide i n f r a ) . In the synthesis of sesquiterpenes, the f i r s t good examples of intramolecular a l k y l a t i o n are to be found 39 40 41 i n McMurry's synthesis of ( i ) - s a t i v e n e and Heathcock's synthesis ' of (i)-copaene and (i)-ylangene. Intramolecular c y c l i z a t i o n s have been used not only i n the synthesis of sesquiterpenes but also i n the synthesis of s t e r o i d s , diterpene a l k a l o i d s , t r i t e r p e n e s , and a l k a l o i d s . 42 In P i e r s ' synthesis of (i)-seychellene 81_, the keto t o s y l a t e 79_ (see Chart 5), upon treatment with base, gave i n excellent y i e l d (±)-norseychellanone 80. This ketone was then converted by standard methods into (i)-seychellene 81_. In the f i e l d of diterpene a l k a l o i d s Nagata 43 and co-workers, i n the synthesis of the p e n t a c y c l i c compound a t i s i n e , employed an intramolecular a l k y l a t i o n of ketone 82^  to form the C-D 44 r i n g system of this complex compound. Piers and co-workers again demonstrated the use of t h i s type of a l k y l a t i o n i n the synthesis of (+)-copacamphor 85_ by base treatment of the keto-tosylate 84. The f i n a l 45 example i s taken from Corey's recent synthesis of (t)-q-copaene 88. The keto t o s y l a t e 8_6 was converted to the ketone 87^  thus e s t a b l i s h i n g the required t r i c y c l i c skeleton. The isopropyl substituent was then established to y i e l d (t)-q-copaene 88. In view of the p o t e n t i a l synthetic u t i l i t y of the"conjugate a d d i t i o n - a l k y l a t i o n r e a c t i o n and the importance of the intramolecular a l k y l a t i o n i n organic synthesis, we were in t e r e s t e d i n combining these two aspects i n one step. That i s to say, i t was proposed to "tr a p " an organocopper enolate formed from a cuprate a d d i t i o n v i a an intramolecular a l k y l a t i o n step. To demonstrate the a p p l i c a t i o n of t h i s r e a c t i o n , we proposed to synthesize neoclovene 89. The key -11 -- 12 -reaction f o r the proposed synthesis was the formation of the t r i c y c l i c skelton v i a the organocopper enolate 91_. The expected stereochemistry of the addition product, intermediate £1_ w i l l be discussed at a l a t e r time (see p. 23 ). 3. O r i g i n and S t r u c t u r a l E l u c i d a t i o n of Neoclovene Since t h i s t h e s i s i s p a r t i a l l y concerned with an approach to the synthesis of neoclovene, i t i s pertinent to discuss the o r i g i n and the work which led to the establishment of the structure and stereo-chemistry of t h i s compound. 46 Neoclovene was f i r s t i s o l a t e d by Parker, Raphael, and Roberts, ' when, i n an attempt to obtain a pure sample of (i)-clovene by the 48 well-known sulphuric acid-catalyzed rearrangement of caryophyllene, they discovered a then unknown hydrocarbon as one of the two main products i n t h i s r e a c t i o n . They subsequently characterized t h i s hydrocarbon and showed i t s structure and absolute stereochemistry to be as depicted i n structure 89_. This s t r u c t u r a l determination by IO II 8<3? Raphael and co-workers w i l l be summarized i n the following paragraphs. Neoclovene fC, „.H„ . ) was shown to be t r i c y c l i c by c a t a l y t i c hydrogenation over 10% palladium on charcoal to a f u l l y saturated dihydro d e r i v a t i v e , neoclovane 93. The p.m.r. spectrum of neoclovene indicated one v i n y l proton at x 4.19, three t e r t i a r y methyl groups at x 8.80(3H) and x 8.99 (6H) and a v i n y l i c methyl group at x 8.41 (J = 1.5 Hz). Hydroboration followed by Jones oxidation gave two epimeric ketones 9_4 whose carbonyl absorptions at 1712 cm * were i n d i c a t i v e of cyclohexanones (see Chart 6). , Treatment of neoclovene with osmium tetroxide followed by sodium metaperiodate cleavage of the d i o l resulted i n the keto-aldehyde 9_5, the p.m.r. spectrum of which showed a sharp s i n g l e t at x 7.98 (3H) confirming the presence of the v i n y l i c methyl group. Further, the aldehydic proton at x 0.2 appeared as a t r i p l e t (J =2.5 Hz) thus i n d i c a t i n g the presence of a neighbour-ing methylene group. - 14 -C H A R T £» - 15 -When the keto-aldehyde 95 was s e q u e n t i a l l y treated with chromium t r i o x i d e , diazomethane, and t r i f l u o r o p e r a c e t i c a c i d , the r e s u l t a n t acetoxy-methyl ester 9>6 was shown to possess a t e r t i a r y acetoxy group due to a lack of resonance i n the x 5-6 region. In a d d i t i o n , none of the three t e r t i a r y methyl groups showed any appreciable downfield s h i f t to be expected i f one or two of them were substituted on the carbon bearing the acetoxy-function. Treatment of the hydroxy-ester 97_ corresponding to 96^ with excess phenyl magnesium bromide, followed by a c e t i c anhydride dehydration gave the diphenylene acetate 98. The v i n y l i c proton s i g n a l at T 3.89 was c l e a r l y resolved i n t o a t r i p l e t ( J = 8 Hz) demonstrating the j u x t a p o s i t i o n of a methylene group. Treatment of 98_ with a c a t a l y t i c n « - , n ; „ i t r,f - . » , ) ! , . r . . i'i i.-.v. .14 * w 5 A~ n-r\A r, „ ,-, •• ,. .C .1 4 . .v. ,„.-.(-...-. ^  -«4 r. A ~ UlV/Ul ^  \J S- J. \A UlUlX L^ ill \_i JL \J S*. JL. \JL ^ ClWl Uil fA\.VJO \J JL. JUUXUil J1IV L.a^ .^i. t ^. followed by methanolic sodium hydroxide, hyd r o l y s i s and e s t e r i f i c a t i o n gave the nor-hydroxy-ester 99. 49 A second Barbier-Wieland sequence performed on 99_ afforded i n i t i a l l y the nor-diphenyleneacetate 100 the p.m.r. spectrum of which, revealed the v i n y l i c proton as a sharp s i n g l e t at T 3.62 i n d i c a t i v e of a neighbouring quaternary c e n t e r In a d d i t i o n , one of the t e r t i a r y methyl groups had moved downfield i n the conversion of 98_ to 100 suggesting that one of the substituents at t h i s quaternary center was probably a methyl group. Conversion of this.product to the hydroxy-ester 101 was achieved i n the same manner as f o r the higher homologue. Lithium aluminum hydride reduction of 101 led to a 1,3-diol which was transformed to the mono-tosylate 102. Base induced fragmentation of 102 y i e l d e d 4-isopropenyl-3,3-dimethylcyclohex-2-enone 103. This - 16 -established the t r i c y c l i c system of neoclovene. The assignment of the r e l a t i v e configuration of the t e r t i a r y methyl group at with respect to the gem-dimethyl group at C g was proven by the following method. Hydroboration of neoclovene gave two epimeric alcohols 104 and 105 which were shown by p.m.r. to have the structure shown. Jones oxidation of 104 gave ketone 106 the o.r.d. curve of which showed a marked negative Cotton e f f e c t which i s consistent with the p r e d i c t i o n of the octant r u l e . ' I f t h i s ketone had possessed a structure i n which the C^ methyl group were a n t i to the C c gem-dimethyl group then the Cotton curve would be expected to 8 show a p o s i t i v e e f f e c t . The mechanism p r o p o s e d ^ f o r the rearrangement of caryophyllene into neoclovene involves i n i t i a l l y the isomerization of the exo c y c l i c double-bond followed by an acid-catalyzed c y c l i z a t i o n to the t r i c y c l i c c a tion 109. A Wagner-Meerwein rearrangement of t h i s c a t i o n would produce the bridge-head cation 110. A f i n a l Wagner-Meerwein rearrange-ment and subsequent proton loss would then generate neoclovene. 108 lo9 t 89 89 4. Other Synthetic Approaches to Neoclovene There has been a number of approaches to the t o t a l synthesis of 52 53 neoclovene ' but, f o r the sake of b r e v i t y , the only successful one 53 w i l l be discussed. Parker and co-workers succeeded i n synthesizing neoclovene by u t i l i z i n g a synthetic scheme which also added support to h i s proposed mechanism f o r the rearrangement of caryophyllene i n t o neoclovene (vide supra). Thus, the t r i - s u b s t i t u t e d double bond of - 18 -caryophyllene 107 vv'as epoxidized with m-chloroperbenzoic acid followed by oxidative cleavage of the ex o c y c l i c double bond with osmium tetroxide-sodium periodate to give the epoxy-ketone 111 (see Chart 7). Treatment of the l a t t e r with potassium hydroxide produced the ket o l 112. The carbonate ester 113, formed from the re a c t i o n of the ketol 112 with ethyl chloroformate, was pyrolyzed at 350° to give a 3:1 mixture of ketones 114 and 115 r e s p e c t i v e l y . Hydrogenation of t h i s mixture over 10% palladium on charcoal y i e l d e d the saturated ketone 116. Treatment of the t r i c y c l i c ketone 116 with methylmagnesium iodide afforded the t e r t i a r y alcohol 117 which, when treated i n ether with concentrated sulphuric a c i d rearranged to neoclovene. JL l a V H ^ - 61 -DISCUSSION 1. General At the onset of t h i s p r o j e c t , we wished to apply the conjugate addition-intramolecular a l k y l a t i o n sequence to the synthesis of neoclovene. Because of the great d i v e r s i t y i n the number of t h e o r e t i c a l pathways in which t h i s complex molecule could be constructed, a b r i e f d iscussion of synthetic stratagem and methodology i s appropriate. The f i r s t order of business i n planning a synthesis of a complex molecule must be the reduction of the complex framework to simpler r a t i o n a l precursors. A less complex r i n g structure may be obtained by the t h e o r e t i c a l cleavage of a bond i n a complex bridged-ring s t r u c t u r e . The c y c l i z a t i o n of the appropriately f u n c t i o n a l i z e d intermediate would regenerate the desired p o l y c y c l i c skeleton. This 54 approach i s well i l l u s t r a t e d by Corey and co-workers, i n the synthesis of longifolene 118. The t h e o r e t i c a l cleavage of the C^-C^ bond i n longifolene 118 produced a s i m p l i f i e d structure. 119 as compared with 118. The appropriately f u n c t i o n a l i z e d intermediate 120 underwent an intramolecular Michael c y c l i z a t i o n to produce the t r i c y c l i c diketone 121. - 21 -This same basic approach was used by McMurry i n h i s synthesis 39 of (t)-sativene 122. The key step i n t h i s synthesis involved the intramolecular a l k y l a t i o n of an appropriately f u n c t i o n a l i z e d intermediate, the b i c y c l i c keto t o s y l a t e 123, to a f f o r d the t r i c y c l i c ketone 124. 123 111 - 22 -Following t h i s general o u t l i n e , the t h e o r e t i c a l cleavage of two .carbon-carbon bonds i n neoclovene 89_ were considered (see Chart 8). Cleavage of the C^-C.^ and C^-C^ bonds of neoclovene 89_ (see numbering below) would lead to the hypothetical intermediates 125 and 126 r e s p e c t i v e l y . Bearing i n mind that the conjugate a d d i t i o n - . c y c l i z a t i o n sequence involves, i n i t i a l l y , the addition of a methyl group by an organocuprate reagent, the appropriately f u n c t i o n a l i z e d intermediates that might be envisaged f o r the regeneration of the required t r i c y c l i c skeleton were 90, 127, 128, and 129. Upon analyzing the proposed intermediates, keto t o s y l a t e 127 was rejected f o r lack of a "handle" on f o r the intr o d u c t i o n of the C^^ v i n y l methyl group. The ester t o s y l a t e 128 was also rejected not only because of the- obvious d i f f i c u l t y i n •synthesizing t h i s complex intermediate but also of the uncertainty i n the decarboxylation of the c y c l i z e d product. Thus, our at t e n t i o n was focused on intermediates 90 and 129. There was an obvious l i m i t a t i o n i f 129 were to be the b i c y c l i c precursor to neoclovene, since conjugate addition could produce not only the desired trans hydrindenone 130 but also the c i s isomer 131. Therefore, we believed that the keto t o s y l a t e 9_0 should be our objective. In a search of the current l i t e r a t u r e , several examples were found, which led us to beli e v e that conjugate addition would occur a n t i to the two carbon chain. In an i n v e s t i g a t i o n on some approaches to the synthesis of cadinene sesquiterpenenes, P h i l l i p s found that, conjugate addition to the dienones 132 and 135 occurred a n t i to the a x i a l bridgehead substituents^^ to a f f o r d ketones 134 and 135. In a recent - 23 -130 131 paper, Zie g l e r and Wender° u reported that upon treatment of 3,4-dimethylcyclohex-2-en-l-one 136 with l i t h i u m d i v i n y l c u p r a t e - t r i - n -butylphosphine complex, the v i n y l ketone 137 was produced i n good y i e l d free of i t s diastereomer. The cuprate reagent was proposed to f l 2") have added apt! to the pxial (due to A v ' interaction") C, methyl 4 -group. An examination of molecular models of keto t o s y l a t e 9_0 c l e a r l y showed that, although the two carbon side chain i s i n a pseudo-axial and not a purely a x i a l o r i e n t a t i o n , approach o f the cuprate reagent from the 3 face would cause the reagent to be almost e c l i p s e d with the C^ Q methylene group. This s t e r i c i n t e r a c t i o n should be almost comparable i n magnitude to the i n t e r a c t i o n experienced by the cuprate reagent i n the above examples (see Chart 9) and thus, attack from the a face would be predicted. This would produce, a f t e r intramolecular a l k y l a t i o n of the i n i t i a l l y formed enolate, the required stereochemistry i n the product, ketone 97. The l a t t e r could be e a s i l y transformed v i a the a l c o h o l 138 to neoclovene. - 25 -CHART «D - 26 -2. Attempted Synthesis of Keto Tosylate 90 At the outset of t h i s work, we had a v a i l a b l e a sample* of the methoxy alcohol 139 which we attempted to reduce and hydrolyze to the keto alcohol 140. Unfortunately, the l i t h i u m - l i q u i d ammonia 57 5 8 " reduction, ' when attempted under a v a r i e t y of conditions (varying temperature, amount of l i t h i u m and inverse a d d i t i o n ) , e i t h e r gave no reduction products using mild r e a c t i o n conditions or a complex mixture of saturated and unsaturated products using a greater amount of l i t h i u m and a higher r e a c t i o n temperature. We therefore synthesized the aromatic alcohol 141, the demethoxy analogue of 139 in the hopes * We thank Dr. F. Kido f o r a generous sample of t h i s compound. - 27 -of introducing an oxygen functionality at the carbon atom of the indane system at a later stage in the synthesis. |39 UO \M We chose as our starting material, indan-l-one 142 which was alkylated with methyl iodide in the presence of potassium t-butoxide to give an 86% yield of 2,2-dimethylindan-l-one 143 (see Chart 10). The keto group of 145 was then used as a "handle" for the introduction of the two carbon side chain. Initially considered for this purpose was the reaction of 143 with the modified Wittig reagent, triethyl 59 phosphonoacetate. However, this reaction proved very sluggish and even when carried out at elevated temperatures, produced no syntheti-cally useful results. Since i t was felt that the failure of this reaction was due, at least in part, to the sterically hindered nature of the carbonyl group in 145, i t was decided to attempt the use of a reagent which was sterically less demanding, namely, diethyl cyano-methylphosphonate.^"^ This approach proved successful. Thus, reaction of ketone 143 with diethyl cyanomethylphosphonate in the 63 presence of methyl-sulfinyl carbanion in dimethyl sulfoxide at 105° for twenty hours produced a mixture* of Z and E isomers 144 and 145 _ A 65:35 mixture of the Z 144 and E 145 isomers was obtained as judged by g.l.c. analysis and by integration of the signals at T 4.36 and T 4.87 in the p.m.r. spectrum. - 29 -respectively in 93% yield. The physical and spectral properties of the nitriles were in agreement with structures 144 and 145. Thus the infrared spectrum showed a nitrile absorption at 2238 cm * and olefinic absorptions at 1615 and 1600 cm *. This mixture of isomers were partially separated by column chromatography to give a fraction that contained the major^* Z_ isomer in 96% purity. From the p.m.r. spectrum of this fraction, the proton resonances of the E isomer could be deduced. Of particular 64 interest was the anisotropic effect of the cyano group shown in the p.m.r. spectrum. The C.7 proton (see Chart 10) of the Z_ isomer was deshielded by the cyano group and appeared as a multiplet at x 1.53-1.83. The gem dimethyl group appeared as a singlet at T 8.73 in the isomer while i t appeared at lower field (T 8.54), due to the deshielding effect of the nitrile group, in the E isomer. The vinyl proton of the E_ isomer, deshielded by the aromatic ring,appeared as a singlet at T 4.36 while i t appeared at x 4.87 in the £_ isomer. The mixture of nitriles 144 and 145 was hydrolyzed^^ to a mixture of unsaturated acids 146 and 147 using a refluxing mixture of ethylene glycol, water, and sodium hydroxide. The white crystalline product exhibited physical properties in accord with those expected for a mixture of compounds 146 and 147. Of particular interest in the infrared spectrum was the absence of the nitrile absorption, the presence of the hydroxyl absorption at 3600-2400 cm and an unsaturated carbonyl absorption at 1690 cm-1. Again, the presence of the Z. 146 and 147 isomers were evident in the p.m.r. spectrum. The deshielding effect of the acid group and the aromatic ring system caused the resonances of the gem dimethyl group (x 8.45) and the vinyl proton (x 3.62) to appear - 30 -at lower field in the E_ isomer as compared to the corresponding signals (T 8.72 and 4.15 respectively) of the Z_ isomer. The proton of the Z isomer was also deshielded by the acid functionality and appeared as a multiplet at T 1.14-1.42. Hydrogenation of the mixture of acids (one equivalent of hydrogen) over palladium on charcoal gave a 94% yield of the saturated acid 148. The physical and spectral properties of the acid were in agreement with structure 148. Thus the infrared spectrum showed a hydroxyl absorption at 3500-2400 cm \ and a saturated carbonyl absorption at 1705 cm The presence of the acidic proton was evidenced in the p.m.r. spectrum by a broad singlet at T -1.08. The doublet of doublets at T 6.73 ( J = 6 Hz) was assigned to the benzylic methine proton and the unresolved multiplet (AB of ABM system) between T 7.16 and T 7.68 wa readily attributable to the methylene protons adjacent to the acid functionality. The magnetic nonequivalence of methylene protons found in an asymmetric environment is a well-established phenomenon,^ and this therefore deserves no further comment. The sharp singlets at x 9.08 and T 8.82 were attributed to the tertiary methyl groups. The reduction of the aromatic acid 148 to the aromatic alcohol 141 67 68 was achieved by the reaction of the former with diborane ' in tetrahydrofuran. The physical and spectral properties of the resulting product (93% yield) were in accord with structure 141. The hydroxyl group was evident due to an absorption at 3360 cm * in the infrared spectrum and an exchangeable hydroxyl proton (broad singlet, T 6.50-6.93) in the p.m.r. spectrum. The aromatic protons appeared as a singlet at T 2.98. The triplet at T 6.27 (J = 6 Hz) was assigned to the methylene protons a to the hydroxyl group. The geminal dimethyl - 31 -group appeared as singlets at x 8.89 and 9.05 while the singlet at T 7.38 was attributed to the C 3 methylene protons. With the achievement of our first synthetic objective, the next step involved the reduction of the aromatic system and hopefully the introduction of an oxygen functionality at the carbon atom 69 (vide supra). Since previous work in this laboratory showed that 70 'the allylic oxidation of the alcohol 154, under a variety of conditions, yielded a number of a,6-unsaturated carbonyl products, we decided to synthesize the epoxy ethers 152 and 153 (see Chart 10) and introduce + OTHER PRODUCT'S the oxygen functionality via an allyl i c alcohol (vide infra). Reaction of the aromatic alcohol 141 with lithium in liquid 72 ammonia afforded the diene alcohol 149 in 90% yield. This compound showed the expected spectral properties. The infrared spectrum showed a hydroxyl absorption at 3365 cm~* and an olefinic absorption at 1645 cm In the p.m.r. spectrum the vinyl protons were evident as a singlet at x 4.25. The C^  methylene protons appeared as a singlet at T 7.38 while the triplet* at x 6.33 (J = 7 Hz) was assigned to the methylene protons adjacent to the hydroxyl group. The exchangeable hydroxyl proton appeared as a singlet at x 7.05, and the geminal methyl group as singlets at T 8.92 and 9.03. v. - 32 -Regioselective hydrogenation of diene 149 was achieved by the use of the homogeneous c a t a l y s t t r i s (triphenylphosphine)chloro-72 rodiunu A f t e r the uptake of one equivalent of hydrogen, the o l e f i n i c alcohol 150 was i s o l a t e d i n 95% y i e l d . The s p e c t r a l properties of t h i s compound were i n complete agreement with the assigned s t r u c t u r e . There was an absence of o l e f i n i c absorptions due to the d i s u b s t i t u t e d double bond i n the i n f r a r e d spectrum. The hydroxyl absorption appeared at 3370 cm \ In the p.m.r. spectrum, the complete reduction of the d i s u b s t i t u t e d double bond was evident due to the lack of resonances i n the v i n y l proton region. The t r i p l e t at x 6.45 (J = 7 Hz) was assigned to the methylene protons adjacent to the hydroxyl group while the s i n g l e t s at x 8.95 and x 9.08 were a t t r i b u t e d to the gsminal methyl group. The exchangeable hydroxyl proton appeared as a . broad s i n g l e t at x 6.05 to x 6„28. The hydroxy f u n c t i o n a l i t y of 150 was protected as an a c e t a l . Thus treatment of the o l e f i n i c alcohol 150 with chloromethyl methyl 73 74 ether ' i n the presence of excess potassium t-butoxide afforded, in 92% y i e l d , the o l e f i n i c a c e t a l . The p h y s i c a l and s p e c t r a l properties of t h i s product were i n agreement with structure 151. Of i n t e r e s t was the absence of hydroxyl absorptions i n the i n f r a r e d spectrum. The p<,m0r. spectrum showed the methoxy group as a s i n g l e t at T 6.73 while the methylene protons adjacent to the methoxy group appeared as a s i n g l e t at x 5.48. The m u l t i p l e t at x 6.20 to x 6.66 was a t t r i b u t e d to the methylene protons. The two s i n g l e t s at x 8.95 and x 9.07 are due to the geminal methyl group. The epoxy acetals 152 and 153 were formed by treatment of the - 33 -76 77 o l e f i n i c acetal 151 with m-chloroperbenzoic a c i d . ' This mixture had s p e c t r a l properties that were almost i d e n t i c a l with those of the corresponding o l e f i n i c acetal 151, except for the presence of the epoxy absorption at 740 cm i n the i n f r a r e d spectrum. Gas-liquid chromatographic analysis of the product revealed an 80:20 mixture of the epimeric epoxy acetals 152 and 153 r e s p e c t i v e l y . This assignment was based on the s t e r i c approach control p r i n c i p l e . The epoxidizing reagent was assumed to have attacked from the less hindered side of the double bond, a n t i to the two carbon chain, thus forming the major isomer 152. R - - C H a O C H 3 - 34 -With the achievement of our second o b j e c t i v e , we now wished to introduce an oxygen substituent at the p o s i t i o n . We therefore 77-79 reacted the epoxy acetals 152 and 153 with l i t h i u m diethylamide i n tetrahydrofuran to produce a mixture of a l l y l i c alcohols 156 (two diastereomers) and 157 (two diastereomers). The above ten t a t i v e assignment was supported by a hydroxyl absorption at 3480 cm * i n the i n f r a r e d spectrum and a broad s i n g l e t , assigned to the v i n y l proton, at T 4.62 i n the p.m.r. spectrum. Although the four products, evidenced by g a s - l i q u i d chromatographic a n a l y s i s , showed that t h i s sequence would probably be s y n t h e t i c a l l y unproductive, we nevertheless decided to continue with the sequence. 80 Upon treatment of t h i s mixture with aqueous hydrochloric a c i d , a diastereomeric mixture of the rearranged a l l y l i c alcohols 158 (two diastereomers) and 159 (two diastereomers) were formed. This t e n t a t i v e assignment was based on the disappearance of the v i n y l proton resonance i n the p.m.r. spectrum and the presence of a m u l t i p l e t at x 5.84-6.17 which was assigned to the proton adjacent to the hydroxyl group. When the alcohols 158 and 159 were oxidized with C o l l i n s 8182 reagent, ' a mixture of ketones 160 and 161 were formed. This tentative assignment was sustained by the presence of an a,3-unsaturated ketone absorption at 1665 and 1630 cm - 1 i n the i n f r a r e d spectrum. The presence of two major products were evident by g a s - l i q u i d chromatographic a n a l y s i s . Although t h i s sequence produced the desired ketone 160, i t was not s y n t h e t i c a l l y useful due to the poor o v e r a l l y i e l d and the expectation that the desired ketone 160 was the minor component. The - 35 -77 above expectation was due to the f a c t , established by Rickborn, that the base induced rearrangement of epoxides occurs with the abstraction of a proton that i s a and syn to the epoxide. Abstraction of a proton at by the base would be s t e r i c a l l y hindered by the two carbon side chain but, since t h i s s t e r i c i n t e r a c t i o n i s more pronounced i n the minor epoxide, that i s epoxy a c e t a l 153, the attack by the base at the psotion i s h i g h l y favored f o r only t h i s compound. Therefore, the desired ketone 160 should be the minor isomer. Thus, we attempted to synthesize the keto t o s y l a t e 90_ by another synthetic sequence. 2. Second Attempted Synthesis of Keto Tosylate 90 The d i f f i c u l t i e s encountered i n the reduction of the methoxy alcohol 139 and i n the introduction of an oxygen-containing f u n c t i o n a l group at the p o s i t i o n of the epoxy acetals 152 and 153 led us to investigate a synthetic sequence i n which the i n t r o d u c t i o n of the oxygen containing substituent at C. and the formation of the desired b i c y c l i c system was r e a l i z e d i n the same r e a c t i o n . This could be achieved through the base-catalyzed A l d o l c y c l i z a t i o n of the diketone 162. Upon examination of the p o s s i b l e c y c l i z e d intermediates of the diketone 162, there are i n i t i a l l y four p o s s i b l e c y c l i z a t i o n products. Two of these products have a four membered r i n g incorporated i n t h e i r skeleton and the t h i r d product cannot be dehydrated to give an a,8-unsaturated ketone. Since only the k e t o l 163 can be dehydrated to the a,^-unsaturated ketone 164, the thermodynamically favored product, ketone 164, would be r e a l i z e d i f the c y c l i z a t i o n were c a r r i e d out under the proper conditions. f - 36 -163 I&4 We chose, as our first objective, the ketone 170, which would be an intermediate to the diketone 162. The starting material chosen was isobutyronitrile 165 which was alkylated with allyl bromide in the presence of lithium diisopropylamide to give a 83% yield of 2,2-dimethyl-4-pentenenitrile 166 (see Chart 11). The physical and spectral properties of the olefinic nitrile were in agreement with structure 166, and with the data reported in the 83 84 literature ' for this compound. Thus the infrared spectrum showed the presence of the terminal olefinic functionality as bands at 3090, 1640, and 920 cm * and a nitrile absorption at 2245 cm In the p.m.r. spectrum of 166, the vinyl group exhibited a multiplet at T 3.75-4.45 for the C 4 proton and a multiplet at x 4.63-5.06 for the C 5 protons. The doublet (J = 7 Hz) at x 7.72 was assigned to the ally l i c C, protons - 37 -- 38 -while, the s i n g l e t at T 8.67 was assigned to the t e r t i a r y methyl groups. Cleavage of the double bond of compound 166 was eff e c t e d by 85 ozonolysis i n 1% pyridine- dichloromethane s o l u t i o n at -78°, followed 8 6 by decomposition of the r e s u l t i n g ozonide with zinc and a c e t i c a c i d . The r e s u l t i n g crude aldehyde n i t r i l e 167 was somewhat unstable and prone to autoxidation and was therefore used i n the next r e a c t i o n without further p u r i f i c a t i o n . However, the s p e c t r a l data obtained from the crude product supported the assigned structure 167. The in f r a r e d spectrum showed the presence of the aldehydic carbonyl f u n c t i o n a l i t y with "absorptions at 2750 and 1720 cm ^ while the absorption band at 2250 cm * indicated the presence of the n i t r i l e group. A mul t i p l e t at T 0.10 i n the p.m.r. spectrum confirmed the presence of the aldehyde fu n c t i o n a l i t y . - The t e r t i a r y methyl groups appeared as a sharp s i n g l e t at T 8.50 while the methylene protons were evident as a mu l t i p l e t at x 7.26. The crude aldehyde n i t r i l e was then reacted with the W i t t i g 87 reagent cyclopentylidenetriphenylphosphorane i n dimethoxyethane to give, i n 87% y i e l d , the o l e f i n i c n i t r i l e 168.* This compound showed * We attempted to synthesize compound 168 by an alternate route. Unfortunately, even at low temperatures, the Wit t i g reagent acted o < T H 3 ^ 3 as a base causing the formation of the A l d o l condensation product 1-cyclopentylidenec.yclopentanone. - 39 -the expected s p e c t r a l p r o p e r t i e s . The n i t r i l e group was evidenced by the absorption at 2255 cm * i n the i n f r a r e d spectrum while the o l e f i n i c absorption appeared at 1680 cm The p.m.r. spectrum showed a sharp s i n g l e t at x 8.65 f o r the t e r t i a r y methyl groups while the v i n y l proton appeared as a m u l t i p l e t at T 4.37-4.90. 88 8! When the o l e f i n i c n i t r i l e was treated with polyphosphoric a c i d , ' i t underwent c y c l i z a t i o n and formed the b i c y c l i c imine 169.* The crude imine was immediately hydrolyzed using a methanolic sodium hydroxide s o l u t i o n to a f f o r d a 70% (overall) y i e l d of the desired product. The phy s i c a l and s p e c t r a l properties of t h i s compound were i n complete accord with structure 170. The u l t r a v i o l e t spectrum exhibited an absorption at 248 mu (e = 14,300) which i s t y p i c a l of a f u l l y substituted ft-unsaturated ketone. This was supported by the in f r a r e d spectrum with absorptions at 1660 and 1640 cm In the p.m.r. spectrum, the t e r t i a r y methyl groups appeared as a s i n g l e t at x 8.90. Having accomplished our f i r s t o b j ective, we next wished to introduce a two carbon chain at the carbonyl carbon. 'Die so l u t i o n to t h i s problem seemed to be the use of the modified W i t t i g reagent t r i e t h y l phosphonoacetate. Unfortunately, a l l attempts at the r e a c t i o n of the ketone 170 with t h i s reagent or the less s t e r i c a l l y demanding reagent d i e t h y l cyanomethylphosphonate f a i l e d due to the e n o l i z a t i o n In our hands, i t was found that the use of 10% phosphorous pentoxide-methanesulfonic acid^O was superior to that of polyphosphoric acid due to the d i f f i c u l t y i n s t i r r i n g a s o l u t i o n of the l a t t e r . The y i e l d s of ketone 170 was approximately the same i n both cases. - 40 -of the ketone. Various other attempts at the introduction of only one carbon atom at the carbonyl carbon also f a i l e d . We, therefore, decided to prevent the e n o l i z a t i o n of the ketone 170 by "blocking" the double bond. The blocking group chosen had to p r o h i b i t e n o l i z a t i o n and had to be susceptible to^removal to reform the double bond. -The epoxide moiety seemed to meet both requirements. Thus treatment of the 91 ketone 170 with a mixture of hydrogen peroxide and sodium hydroxide gave, i n 76% y i e l d , the epoxy ketone 171. An a n a l y t i c a l sample of t h i s material was obtained by preparative g . l . c . and exhibited s p e c t r a l data i n agreement with the assigned structure. Most notable i n the in f r a r e d spectrum was the carbonyl absorption at 1700 cm In the p.m.r..spectrum, the t e r t i a r y methyl groups now appeared as two s i n g l e t s at Y 9.07 and T 5.92. One of the methyl groups was apparently 92 shielded by the oxygen atom of the epoxide r i n g thus causing it. to resonate at a higher f i e l d . With the establishment of the blocking group, we again attempted to introduce the two carbon chain v i a the W i t t i g r e a c t i o n . Although the r eaction of the epoxy ketone with t r i e t h y l phosphonoacetate was unsuccessful, we were able to react the former with d i e t h y l cyano-methylphosphonate at an elevated temperature (see page 27). However, when we t r i e d to hydrogenate the double bond of the epoxy Q n i t r i l e 172 (see Chart 11) with a v a r i e t y of c a t a l y s t s , hydrogenolysis of the a l l y l i c C-0 bond occurred concurrently with the reduction of the double bond. We therefore decided to i n s e r t the two carbon chain v i a two one-carbon homologations. The f i r s t carbon atom was introduced by means of the Witt i g - 41 -reaction. Thus, reaction of the epoxy ketone 171 with methylenetri-phenylphosphorane resulted in an 88% yield of the epoxy olefin 173. The spectral properties of this product were consistant with the assigned structure. Of interest was the complete disappearance of the carbonyl absorption and the presences of olefinic absorptions at 3120, 1635, and 890 cm"1 in the infrared spectrum. The vinyl protons in the p.m.r; spectrum were evident as a singlet at x 4.73. The signals at x 9.05 and 8.87 were assigned to the tertiary methyl groups. In accord with our plans to convert this compound into the next higher homologue, i t was necessary at this stage of the synthesis to functionalize the terminal double bond into a primary alcohol functionality. This was achieved by subjecting the epoxy olefin 173 to hydroboration with diborane in tetrahydrofuran followed by decomposition of the intermediate alkylborane with alkaline hydrogen peroxide. The resultant ratio of the products (epoxy alcohols 174 and 175) varied somewhat.from reaction to reaction but the mixture of products, as judged by gas-liquid chromatographic analysis, never contained less than 75% of the major isomer,* epoxy alcohol 175. An analytical sample of this major isomer, collected by preparative g.l.c, exhibited spectral properties in accord with structure 175. Thus, the infrared spectrum showed a hydroxyl absorption at 3460 cm In the p.m.r. spectrum, the tertiary methyl groups were evident as sharp singlets at x 9.30 and 9.00. _ The assignment of the stereochemistry ot the two epimeric epoxy alcohols 174 and 175 is tentative and was based on examination of molecular models and the application of the steric approach control principle. v. - 42 -The p r o t o n s a d j a c e n t t o t h e h y d r o x y l g roup appeared as a m u l t i p l e t a t T 5 . 8 4 t o T 6 . 5 7 . The a l c o h o l f u n c t i o n a l i t y was p r o t e c t e d as an e s t e r by t r e a t m e n t o f t h e epoxy a l c o h o l s 174 and 175 w i t h a c e t i c a n h y d r i d e i n d r y p y r i d i n e t o g i v e , i n 92% y i e l d , a m i x t u r e o f epoxy a c e t a t e s 176 and 177o The r a t i o o f t h e e p i m e r i c a c e t a t e s was dependent on t h e r a t i o o f t h e m i x t u r e o f epoxy a l c o h o l s 174 and 175 u s e d . An a n a l y t i c a l sample o f t h e ma j o r i s o m e r 1 7 7 , o b t a i n e d by p r e p a r a t i v e g . l . c , e x h i b i t e d s p e c t r a l p r o p e r t i e s i n a c c o r d w i t h t h e a s s i g n e d s t r u c t u r e . The p r e s e n c e o f t h e a c e t a t e g r o u p was a p p a r e n t w i t h a b s o r p t i o n s a t 1740 and 1230 cm * . . i n t h e i n f r a r e d s p e c t r u m . I n t h e p.m.r. s p e c t r u m , t h e m u l t i p l e t a t T 5 . 4 7 - 6 . 4 0 was a s s i g n e d t o t h e p r o t o n s a d j a c e n t t o t h e a c e t a t e f u n c t i o n a l i t y . The t e r t i a r y m e t h y l groups a p p e a r e d as s i n g l e t s a t f 9 . 2 7 and T 8 . 9 7 w h i l e t h e a c e t o x y group a p p e a r e d as a s i n g l e t a t T 7 . 9 7 . A t t h i s t i m e , we f e l t t h a t i t would be a p p r o p r i a t e t o r e i n t r o d u c e t h e d o u b l e bond by t h e r e d u c t i o n o f t h e e p o x i d e f u n c t i o n a l i t y . A l t h o u g h t h e r e were many examples o f t h e r e d u c t i o n o f e p o x i d e s t o o l e f i n s i n t h e l i t e r a t u r e , t h e r e was, a p p a r e n t l y , no example o f t h e r e d u c t i o n o f a t e t r a s u b s t i t u t e d e p o x i d e . The a t t e m p t e d r e d u c t i o n o f t h e epoxy a c e t a t e 176 and 177 w i t h c h r o m i u m ( I I ) e t h y l e n e d i a m i n e 94 complex i n d i m e t h y l f o r i n a m i d e y i e l d e d o n l y s t a r t i n g m a t e r i a l . The 95 96 r e d u c t i o n o f t h e e p o x i d e w i t h z i n c - c o p p e r * ' o r z i n c - s i l v e r c o u p l e a t e l e v a t e d t e m p e r a t u r e s a l s o f a i l e d t o p r o d u c e any r e d u c t i o n p r o d u c t . We were f i n a l l y a b l e t o e f f e c t t h e r e d u c t i o n by t h e t r e a t m e n t o f t h e epoxy a c e t a t e s 176 and 177 w i t h t u n g s t e n h e x a c h l o r i d e and . n - b u t y l -l i t h i u m i n r e f l u x i n g t e t r a h y d r o f u r a n . J 1 The desired o l e f i n i c acetate 178 was thus obtained i n 90% y i e l d . The p h y s i c a l and s p e c t r a l properties were i n agreement with the assigned structure 178. Thus, the i n f r a r e d spectrum showed carbonyl absorptions at 1740 and 1230 cm *. Of p a r t i c u l a r i n t e r e s t was the p.m.r. spectrum i n which, due to the removal of the s h i e l d i n g e f f e c t of the oxygen atom of the epoxide r i n g , the t e r t i a r y methyl groups appeared as s i n g l e t s at x. 9.07 and 9.03. The acetoxy group was evident as a s i n g l e t at T 8.04 while the m u l t i p l e t at T 5.66-6.31 was assigned to the protons adjacent to acetate f u n c t i o n a l i t y . In order to add another carbon atom to the side chain, the acetate p r o t e c t i n g group was removed by the r e a c t i o n of the o l e f i n i c acetate with l i t h i u m aluminium hydride.. The product, obtained i n 97% y i e l d , exhibited s p e c t r a l properties in agreement with structure 179. Thus, the i n f r a r e d spectrum showed a hydroxyl absorption at 3410 cm In the p.m.r. spectrum,'the s i n g l e t s at x 9.14 and x 9.08 were assigned to the t e r t i a r y methyl grups while the doublet (J = 4 Hz) at x 6.40 was a t t r i b u t e d to the methylene protons adjacent to the hydroxyl group. At t h i s point i n the synthesis, we wished to homologate the o l e f i n i c alcohol 179 according to the scheme shown i n Chart 12. The proposed synthesis of the keto t o s y l a t e 90_ involved r e a c t i o n of the o l e f i n i c t o s y l a t e 180, corresponding to the o l e f i n i c alcohol 179, with sodium 99 cyanide i n dimethyl s u l f o x i d e to give the o l e f i n i c n i t r i l e 181. Base hydrolysis of the l a t t e r would a f f o r d the o l e f i n i c a c i d 182. Subjection of 182 to ozonolysis and base-catalyzed cyclization''' <^ , - 44 -would p r o d u c e t h e k e t o a c i d 184. S e l e c t i v e r e d u c t i o n o f t h e a c i d f u n c t i o n a l i t y w i t h d i b o r a n e f o l l o w e d by t o s y l a t i o n o f t h e r e s u l t a n t a l c o h o l would t h e n g i v e t h e d e s i r e d p r o d u c t , k e t o t o s y l a t e 90. U n f o r t u n a t e l y due t o t h e l a c k o f t i m e and s t a r t i n g m a t e r i a l , t h e o l e f a l c o h o l 179, t h e s y n t h e s i s o f t h e k e t o t o s y l a t e 90, as p r o p o s e d on C h a r t 12, was n o t c a r r i e d o u t . Thus, i n c o n c l u s i o n , an a t t r a c t i v e and q u i t e f e a s i b l e a p p r o a c h t o t h e s y n t h e s i s o f n e o c l o v e n e has been d e v e l o p e d w h i c h i n c l u d e d t h e a p p l i c a t i o n o f some r e c e n t s y n t h e t i c methods. The second and most s u c c e s s f u l a p p r o a c h d e s c r i b e d o f f e r s t h e p o s s i b i l i t y t h a t f u r t h e r development o f t h e s y n t h e t i c sequence c o u l d l e a d t o t h e s y n t h e s e s o f n e o c l o v e n e i n t h e n e a r f u t u r e . - 4 5 -C H A R T \Z EXPERIMENTAL G e n e r a l M e l t i n g p o i n t s , w h i c h were d e t e r m i n e d on a K o f l e r b l o c k , and b o i l i n g p o i n t s a r e u n c o r r e c t e d . U l t r a v i o l e t s p e c t r a were measured i n m e t h anol s o l u t i o n on e i t h e r a C a r y , model 14, o r a Unicam, model SP 800, s p e c t r o p h o t o m e t e r . R e f r a c t i v e i n d i c i e s were t a k e n on a O x j . J L C J . i i c : u a i j . i c u I v C x J . u u l i l c t C J . * J V U U L J . J J C i j i i i u i . U u I I ^ A V. r e c o r d e d on a P e r k i n - E l m e r model 710 s p e c t r o p h o t o m e t e r w h i l e c o m p a r i s o n s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r model 457 s p e c t r o p h o t o m e t e r . The p.m.r. s p e c t r a were t a k e n i n d e u t e r o c h l o r o f o r m o r c a r b o n t e t r a -c h l o r i d e s o l u t i o n on V a r i a n A s s o c i a t e s s p e c t r o m e t e r s models T-60 and/or HA-100, XL-100. L i n e p o s i t i o n s a r e g i v e n i n t h e T i e r s T s c a l e , w i t h t e t r a m e t h y l s i l a n e as i n t e r n a l s t a n d a r d ; t h e m u l t i p l i c i t y , i n t e g r a t e d peak a r e a s , and p r o t o n a s s i g n m e n t s a r e i n d i c a t e d i n p a r e n t h e s e s . G a s - l i q u i d c h r o m a t o g r a p h y ( g . I . e . ) was c a r r i e d o u t on e i t h e r an A e r o g r a p h A u t o p r e p model 700 o r a V a r i a n A e r o g r a p h , model 90-P. The f o l l o w i n g columns were employed: - 47 -Column Length S t a t i o n a r y Phase Support Mesh A 10 f t x 1/4 i n 20% SE 30 Chromosorb W 60/80 B 11 20% Carbowax 20 M 11 11 C " 10% SE 30 II . . II D " 10% FFAP " ' " E " 10% OV-210 11 ' " F 10 f t x 3/8 i n 20% SE 30 " 11 G 11 10% OV-210 " " H 5 f t x 1/4 i n 20% SE 30 " " The s p e c i f i c column used along with column temperature and c a r r i e r gas (helium) f l o w - r a t e ( i n ml/min), are i n d i c a t e d i n parentheses. Column chromatography was -performed us i n g f l o r i s i l ( F i s h e r S c i e n t i f i c Co.), n e u t r a l s i l i c a g e l (Camag or Macheray, Nagel and Co.) or n e u t r a l alumina (Ca map or Macher^yj Nagel and Co.) < The alumina was d e a c t i v a t e d as r e q u i r e d by a d d i t i o n o f the c o r r e c t amount of water. High r e s o l u t i o n mass s p e c t r a were recorded on an AEI type MS-9 mass spectrometer. M i c r o -analyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y o f B r i t i s h Columbia, Vancouver. P r e p a r a t i o n of 2,2-Dimethylindan-l-one 143 To an i c e - c o o l e d , s t i r r e d suspension of powdered potassium t -butoxide (156.8 g, 1.4 moles) i n 1 £ of dry dimethoxyethane, kept under an atmosphere of dry n i t r o g e n , was added a s o l u t i o n of 79.2 g (0.60 mole) of 1-indanone 142 i n 200 ml of dry dimethoxyethane. The r e s u l t i n g mixture was s t i r r e d f o r 10 min, and then a s o l u t i o n o f 426 g (3 moles) of methyl i o d i d e i n 300 ml of dry dimethoxyethane was added. The mixture was warmed to room temperature and allowed to s t i r f o r 3 h. The r e s u l t i n g mixture was d i l u t e d w i t h water and thoroughly e x t r a c t e d - 48 -with ether. The ethereal extracts were combined, washed with brine, and dried over anhydrous magnesium sulfate. Removal of the solvent gave an o i l which, upon d i s t i l l a t i o n under reduced pressure, afforded 78.2 g (86%) of the desired alkylated product 143, b.p. 47-49° at 0.2 mm [ l i t . b.p. 87-89° at 0.6 mm; n 1.5383]; m.p. 37-38°; n p 1.5442; u l t r a v i o l e t , X 246 my (e = 12,800); infrared ( f i l m ) , v max max 1706, 1610 cm \; p.m.r., T 8.80 (singlet, 6H, t e r t i a r y methyls), 7.OS (singlets, 2H, methylene protons), 2.17-2.85 (multiplet, 4H, aromatic protons). Anal. Calcd. for C 1 1 H 1 2 0 : C > 8 2- 4 6> H' 7' 5 5* F o u n d : c> 82.43; H, 7.56. Preparation of N i t r i l e s 144 and 14b A s t i r r e d suspension of sodium hydride (16.8 g, 0.35 mole) in 400 ml of dry dimethyl sulfoxide was slowly heated, under an atmosphere of dry nitrogen, to 75° and kept at t h i s temperature u n t i l frothing had ceased (approximately 30 min). The solution was cooled to room temperature and a solution of die t h y l cyanomethylphosphonate (67.5 g, 0.38 mole) i n 100 ml of dry dimethyl sulfoxide was added. The r e s u l t i n g solution was s t i r r e d for 15 min, and then a solution of the ketone 143 (11.2 g, 70 mmole) i n 50 ml of dimethyl sulfoxide was added. The reaction mixture was heated (bath temperature 105°) for 20 h, then cooled, d i l u t e d with water and thoroughly extracted with ether. The combined extracts were washed- with water, saturated brine, and then dried over anhydrous magnesium sulfate. Removal of the solvent, followed by d i s t i l l a t i o n of the residual o i l under reduced - 49 -pressure afforded 11.75 g (93%) of a 65:35 mixture of £ and E^  isomers respectively as judged by p.m.r. and gas-liquid chromatographic analysis (column E, 125°, 100). This mixture exhibited b.p. 96-98° at 0.25 mm; infrared (film) v 2238, 1615, 1600 cm \ A sample was subjected to J max r . column chromatography using Camag Kieselgel for TLC (without binder) and 98:2 petroleum ether (b.p. 68°)-ether as eluting solvent. A positive pressure (air) was required to maintain a reasonable flow rate. The ratio of compound to s i l i c a gel was 1:100. The major Z_ isomer was thus obtained in 96% purity. It exhibited p.m.r., T 8.73 (singlet, 6H, tertiary methyls), 7.13 (singlet, 2H, methylene protons), 4.87 (singlet, 1H, vinyl proton),-2.49-2.91 (multiplet, 3H, aromatic protons), 1.53-1.83 (multiplet, 1H, proton). From the above, the p.m.r. spectrum of the minor E^  isomer could be deduced. It showed p.ni.r.. 7 8.54 (singlet, 6H, tertiary methyls), 7.08 (singlet, 2H, methylene protons), 4.36 (singlet, 1H, vinyl proton), 2.43-2.90 (multiplet, 4H, aromatic protons). Anal. Calcd. for C^H^N: C, 85.21; H, 7.15; N, 7.64. Found: C, 84.90; H, 7.08; N, 7.51. Preparation of Acids 146 and 147 A mixture of nitriles 144 and 145 (24 g, 135 mmoles) was dissolved in 540 ml of 5:1 ethylene glycol-water containing 100 g (2.5 mole) of sodium hydroxide. The resulting solution was refluxed (bath temperature 140°) under an atmosphere of nitrogen for 20 h and then cooled to room temperature. This mixture was diluted with 600 ml of saturated brine and extracted with ether. The aqueous residue was acidified to pH 2 - 50 -with 6 N hydrochloric acid and the resulting mixture was thoroughly extracted with 600 ml of 1:1 petroleum ether (b.p. 68°)-ether. The combined extracts were washed twice with brine and then dried over anhydrous magnesium sulfate. Removal of the solvent gave 19 g (95%) of white crystals. An analytical sample, obtained by recrystallization from hexane, exhibited m.p. 114-115°; infrared (CHCl,), v 3600-2400, I960, 1625 cm"1; ultraviolet, A 276 my (e = 12,150), 286 (e = 11,660), 1H3-X 302 (e = 10,400). The p.m.r. spectrum showed a 81:19 ratio of Z to E isomers. The major 2_ isomer exhibited p.m.r., T 8.72 (singlet, 6H, tertiary methyls), 7.12 (singlet, 2H, methylene protons), 4.15 (singlet, IH, vinyl proton)2.35-2.85 (multiplet, 3H, aromatic protons), 1.14-1.42 (multiplet, IH, Cj proton). The E_ isomer had p.m.r., T 8.45 (singlet, 6H, tertiary methyls), 7.01 (singlet, 2H, methylene protons), 3.62 (singlet, IH, vinyl proton), 2.46-2.96 (multiplet, 4H, aromatic protons). Anal. Calcd. for C 1 3 H 1 4 0 2 : c» 77.20; H, 6.98. Found: C, 77.04; H, 7.20. Hydrogenation of Acids 146 and 147 The acids 146 and 147. (16 g, 0.89 mole) in 350 ml of ethyl acetate were hydrogenated over 2.0 g of 10% palladium on charcoal at room temperature until the uptake of hydrogen was complete (approximately 10 h). The reaction mixture was filtered through celite and the filtrate was evaporated to dryness to give a yellow o i l which was distilled under reduced pressure (b.p. 140-142° at 0.05 mm). The resulting pale yellow o i l (17.0 g, 94%) crystallized upon standing. v - 51 -An analytical sample, obtained by recrystallization from hexane, exhibited m.p. 74.5-75.5°; infrared (film) v 3500-2400, 1705 cm"1; r • ' *• 3 max ultraviolet X 260 my (e = 615), 267 my (e = 992), 273 my (e = 1145); nicLX p.m.r., x 9.08 (singlet, 3H, tertiary methyl), 8.82 (singlet, 3H, tertiary methyl), 7.32 (singlet, 2H, C 3 protons), 7.16-7.68 (multiplet, 2H, -CH2C02H), 6.73 (doublet of doublets, 1H, methine proton, J = 6.0 Hz), 2.88 (singlet, 4H, aromatic protons), -1.08 (broad singlet, 1H, -C00H). Anal. Calcd. for (L-H-.O.,: C, 76.44; H, 7.90. Found: C, 76.70; IS ID I H, 8.10. Preparation of Aromatic Alcohol 141 To a stirred solution cf acid 14S (16.2 g, 79 mmcles) in 30 ml of dry tetrahydrofuran, cooled to 0°, was added 75 ml (100 mmoles) of borane in tetrahydrofuran. The ice bath was removed and the resulting solution was stirred under nitrogen for 1 h.. The excess hydride was destroyed by careful addition of 50 ml of 1:1 tetrahydrofuran-water and the aqueous phase was saturated with 15 g of anhydrous potassium carbonate. The layers were separated and the aqueous phase was extracted four times with 50 ml portions of ether. The combined organic extracts were dried over anhydrous magnesium sulfate. The concentrated yellow o i l was distilled under reduced pressure to afford 20 14.0 g (93%) of the desired alcohol b.p. 106-108° at 0.55 mm; n Q I. 5318; ultraviolet A M A X 261 my (e = 668), 267 my (e = 1055), 274 my (e = 1270); infrared (film) v 3360, 3110, 3060, 1040, 1010 cm"1; 3 max p.m.r., T 9.05 (singlet, 3H, tertiary methyl), 8.89 (singlet, 3H, - 52 -t e r t i a r y methyl), 7.38 (singlet, 2H, methylene protons), 6.50-6.93 (broad s i n g l e t , IH, exchangeable, -OH), 6.27 ( t r i p l e t , 2H, -CH^OH, J = 6.0 Hz), 2.98 (singlet, 4H, aromatic protons). Anal. Calcd. f o r n H O : C, 82.06; H, 9.53. Found:- C, 81.95; IS l o H, 9.56. Preparation of Diene Alcohol 149 To a s t i r r e d solution of lithium (2.15 g, 310 mmoles) i n 350 ml of l i q u i d ammonia ( d i s t i l l e d from sodium metal) cooled to -78° was added a solution of 11.8 g (62 mmole) aromatic alcohol i n 20 ml of dry dimethyoxyethane and 8 ml of 95% ethanol. This solution was s t i r r e d at -78° for 45 min aid then at -33° for 30 min. The blue color was Hi scharged by the a d d i t i o n of 1 Q ml of 95% ethanol. The ammonia was allowed to evaporate and 360 ml of.water was added. This mixture was th r i c e extracted with ether. The combined organic extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. Removal of the solvent, followed by d i s t i l l a t i o n of the residue, gave 10.5 g (90%) of the diene alcohol 149_ as a colorless o i l , b.p. 92-94° at 0.2 mm. An a n a l y t i c a l sample, obtained by preparative g.l.c. (column A, 160°, 100) exhibited infrared (film) v m a x 3365, 3055, 1645, 1045, 1015 cm - 1; p.m.r., T 9.03 (singlet,- 3H, t e r t i a r y methyl), 8.92 (singlet, 3H, t e r t i a r y methyl), 7.38 (s i n g l e t , 2H, C„ methylene protons), 7.05 (singlet, III, exchangeable, -OH), 6.33 ( t r i p l e t , 2H, -CH_20H, J = 7.0 Hz), 4.25 (singlet, 2H, v i n y l protons). Anal. Calcd. f o r C jH^O: ' C, 81.20; H, 10.48. Found: .C, 81.27 H, 10.30. - 53 -Hydrogenation of Diene Alcohol 149 The hydrogenation of diene alcohol 149 (10.0 g, 52 mmoles) was carried out i n benzene (200 ml) at room temperature and atmospheric pressure using tris(triphenylphosphine)chlororhodium (2.0 g) as catalyst. One equivalent of hydrogen was consumed af t e r 11 h. The reaction mixture was f i l t e r e d through a column of Camag Kieselgel a c t i v i t y I I I neutral alumina (360 g) and eluted with 1 £ of ether. Removal of the solvent and d i s t i l l a t i o n under reduced pressure afforded 9.5 g (95%) of the o l e f i n i c alcohol as a colorless o i l , b.p. 94-96° at 0.5 mm. An a n a l y t i c a l sample obtained by preparative g'.l.c. (column B, 200°, 100) exhibited infrared"(film) v 3370, 1040, 1005 cm"1; p.m.r., x 9.08 max (singlet, 3H, t e r t i a r y methyl), 8.95 (singlet, 3H, t e r t i a r y methyl), 6.45 ( t r i p l e t , 2H, -Ch\,GH, J = 7.0 Hz), 6.05-G.28 (broad s i n g l e t , III, exchangeable, -OH). Mol. Wt. Calcd. for C 1 3 H 2 2 0 : 194.1670. Found (high resolution mass spectrometry):' 194.1614. Preparation of O l e f i n i c Acetal 151 To an ice bath cooled s t i r r e d s l u r r y of 8.27 g (72 mmoles) of powdered potassium t-butoxide i n 200 ml of a7.hydrous ether was added a solution of 7.4 g (38 mmoles) of o l e f i n i c alcohol 150 i n 50 ml of anhydrous ether. After s t i r r i n g i n the cold for 15 min, a solution of 6.45 g (80 mmoles) of chloromethyl methyl ether i n 30 ml of anhydrous ether was added. The ice water bath was removed and the reaction mixture was s t i r r e d under nitrogen for a further 15 min. Water was then added and this mixture was thoroughly extracted with ether. The - 54 -combined ethereal extracts were washed with saturated brine and dried over anhydrous magnesium s u l f a t e . The ether was removed in_ vacuo and the residue d i s t i l l e d to yield"8.3 g (92%) of the o l e f i n i c acetal 151 as a c o l o r l e s s o i l , b.p. 92-94° at 0.4 mm. An a n a l y t i c a l sample, 20 obtained by preparative g . l . c . (column D, 130°, 100) exhibited n^ 1.4820; i n f r a r e d (film) v 3060, 1140, 1100, 1025 cm"1; p.m.r., J max ' ' ' x 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.95 ( s i n g l e t , 3H, t e r t i a r y methyl), 6.73 ( s i n g l e t , 3H, -Ci^OCH.,), 6.29-6.66 (multiplet, 2H, -CH 2OCH 2OCH 3), 5.48 ( s i n g l e t , 2H, -Oq^OCIij). Anal. Calcd. f o r C , r H . , 0 _ : C, 75.58; H, 10.99. Found: C, 75.62; l b 26 2 H, 10.91. Preparation of Epoxy Acetals 152 and 153 To a cooled (0°) s t i r r e d s o l u t i o n of 500 mg (2„10 mmoles) o l e f i n i c a c e t a l 151 i n 5 ml of methylene c h l o r i d e was added a s o l u t i o n of 905 mg (5.25 mmoles) m~chloroperbenzoic acid i n 10 ml of methylene c h l o r i d e . This mixture was s t i r r e d under dry nitrogen at 0° for 0.5 h and then at room temperature f o r 2.5 h. The s o l u t i o n was poured onto 10 ml of 20% sodium hydroxide s o l u t i o n and the layers were separated. The organic extract was washed with a 10% sodium s u l f i t e s o l u t i o n , saturated brine and d r i e d over anhydrous magnesium s u l f a t e . D i s t i l l a t i o n of the concentrated o i l afforded a q u a n t i t a t i v e y i e l d of the desired compounds as a c o l o r l e s s o i l b.p. (hot box) 130-135° at 0.4 mm. Gas-l i q u i d chromatographic analysis (column E, 125°, 100) showed the product to be an 80:20 mixture of epimeric epoxy acetals 152 and 153 respectively*, An a n a l y t i c a l sample of t h i s mixture, obtained by - 55 -preparative g. I.e. (column G, 160°, 200), exhibited infrared (film) v 2990, 1140, 1100, 1030, 740 cm"1; p.m.r., T 9.02, 9.07 (singlet, J H c l X s i n g l e t , 6H, t e r t i a r y methyls), 6.70 (singlet, 3H, -CH2OCH_3), 6.17-6.59 (multiplet, 2H, -CH^OCH^Ciy, 5.47 (singlets, 2H, -OCH_2OCH3). Mol. Wt. calcd. for C H 0^: 2 3 8 • 1 9 3 2 • Found (high resolution mass spectrometry): 238.1937. Preparation of 2,2-Dimet.hyl-4-pentenenitrile 166 To an ice water bath cooled, s t i r r e d solution of diisopropylamine (45.5 g, 0.45 moles) i n 75 ml of dry benzene was added 150 ml (0.375 moles) n-butyllithium i n hexane. After s t i r r i n g i n an inert atmosphere for 5 min, a solution of 20.7 g (0.30 moles) of i s o b u t y r o n i t r i l e 165 in 45 ml of dry benzene was added dropwise. The cooling bath was removed and t h i s mixture was s t i r r e d at room temperature f o r 5 min. The reaction was again cooled to 0° and a solution of a l l y l bromide (72.6 g, 0.6 mole) i n 75 ml dry benzene was added. The r e s u l t i n g mixture was refluxed for 1.5 h and then cooled to room temperature. Water was added and the layers were separated. The aqueous layer was thoroughly extracted with ether. The organic extracts were combined, washed with water, saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue d i s t i l l e d to give 27.0 g (83%) of the desired product b.p. 147-148°; n£ 1.4191 [ l i t . b.p/ 147-148.5°, n D 1.4180]; infrared (film) V 3090, 2245, 1640, 920 cm"1; p.m.r., T 8.67 (singlet, 6H, IT13.X t e r t i a r y methyls), 7.72 (doublet, 2H, methylene protons, J = 7 Hz), 4.63-5.06 (multiplet, 2H, C 5 pi'otons), 3.75-4.45 (multiplet, 1H, C 4 proton)„ - 56 -Preparation of 3-Cyano-3,3-dimethyl propanal 1.67 A solution of 5 g (46 mmoles) of o l e f i n i c n i t r i l e 166 i n 80 ml of a 1% pyridine-dichloromethane solution was treated with ozone at -78° u n t i l the solution turned blue. The excess ozone was removed by bubbling dry nitrogen through the solution. This mixture was poured onto 24 g (370 mmoles) of zinc dust. Acetic acid (46 ml, 810 mmoles) was immediately added and the r e s u l t i n g s l u r r y was slowly warmed to room temperature. After the solution had been s t i r r e d for 1 h, i t was f i l t e r e d , d i l u t e d with brine and extracted with methylene chloride. The organic phase was washed with water, saturated sodium bicarbonate solution, saturated brine, and dried over anhydrous magnesium s u l f a t e . The solvent was removed to afford 3.5 g (70%) of the crude aldehyde n i t r i l e .167- Due to t h e i n s t a b i l i t y of t h i s compound, i t was used immediately i n the next reaction without further p u r i f i c a t i o n . A small sample of the aldehyde n i t r i l e 167 was d i s t i l l e d and exhibited b.p. 90-91° at 19 mm; infrared (film) v 2750,. 2250, 1720 cm"1; p.m.r., max x 8.50 (singlet, 6H, t e r t i a r y methyls), 7.26 (multiplet, 2H, methylene protons), 0.10 (multiplet, IH, -CHO). This compound was characterized as i t s 2,4-dinitrophenylhydrazone derivative, r e c r y s t a l l i z e d from ethanol, m.p. 153-154°. Anal. Calcd. for C 2-H N 0 : C, 49.48; H, 4.50; N, 24.04. Found: C, 49.66; H, 4.47; N, 23.85. - 57 -Preparation of Cycloperityltripheriylphdsphdriium Iodide To a solution of 13.6 g (70 mmoles) of cyclopentyl iodide i n 50 ml of xylene was added 39.3 g (150 mmole) of triphenylphosphine. This mixture was refluxed f o r 17 h and then cooled to room temperature. The precipitated s a l t was f i l t e r e d , washed with benzene, and dried under vacuum overnight to afford 28.6 g (90%) of the desired compound as a pale yellow c r y s t a l . It exhibited m.p„ 238-240°; infrared (CHCl^) V 1590, 1440, 1110 cm"1, max Anal. Calcd. for C H 2 4IP: C, 60.28; H, 5.28; I, 27.68. Found: C, 60.46; H, 5.55; I, 27.32. Preparation of O l e f i n i c N i t r i l e 168 To a cooled (0°), s t i r r e d s lurry of 45.8 g (100 mmoles) of cyclopentyltriphenylphosphonium iodide i n 250 ml of dry dimethoxy-ethane was added 48.2 ml (92 mmoles) of a 1.9 M solution of n-butyl-lithium i n hexane. The r e s u l t i n g blood red solution was s t i r r e d , under dry nitrognen, at room temperature for 15 min. A solution of 3.0 g (27 mmole) of crude aldehyde n i t r i l e 167 i n 20 ml of dimethoxy-ethane was added.— After s t i r r i n g for 30 min, the mixture was poured into 300 ml of water and thoroughly extracted with petroleum ether (b.p. 30-60°). The organic extracts were combined, washed with saturated brine, and dried over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue gave 3.8 g (87%) of the desired compound. An a n a l y t i c a l sample, obtained by preparative 2] ^ g.l.c. (column H, 135°, 100) exhibited b.p. 52-54° at 0.35 mm; n 1.4699; infrared (film) v 2255, 1680 cm ;^ p.m.r., T 8.65 (singlet, - 58 -6H, t e r t i a r y methyls), 4.37-4.90 (multiplet, 1H, v i n y l proton). Anal. Calcd. for C H^N: C, 80.93; H, 10.50. Found: C, 80.95; H, 10.72. Preparation of Ketone 170 A s t i r r e d solution of 5.0 g (30.5 mmoles) of the o l e f i n i c n i t r i l e and 75 g of polyphosphoric acid was heated, i n an inert atmosphere, at 125-130° for 30 min. This mixture was poured onto i c e , ba s i f i e d with a 20% sodium hydroxide solution, and extracted with chloroform.. The organic extract was washed with saturated brine and concentrated to y i e l d the crude imine 169 which exhibited infrared (film) v 1650, J J max ' 1600 cm ^. The imine 169 was immediately added to a solution of 184 ml of ^0% sodium hydroxide solution and 180 ml of methanol and refluxed. under a nitrogen atmosphere, for 2.5 h. The reaction mixture was cooled and the methanol was removed at aspirator pressure. The residue was dilu t e d with water and a c i d i f i e d with 6 N hydrochloric acid. This mixture was thoroughly extracted with ether, the ether layer was washed with saturated brine and dried over anhydrous magnesium su l f a t e . Removal of the solvent, f i l t r a t i o n through a column of Camag Kieselgel a c t i v i t y I I I neutral alumina (15 g), and elution with ether gave a yellow o i l . D i s t i l l a t i o n of this material under aspirator pressure gave 3.5 g (70%) of the ketone 170, b.p. 108-109° at 10 mm. An a n a l y t i c a l sample was obtained by preparative g.l.c. (column A, 155°, 120), and i t exhibited n 1 9 , 51.5079; u l t r a v i o l e t X 248 my (e = 14,300) J D max ^ ' J infrared (film) v 1660, 1640, 1390 cm"1; p.m.r., 8.90 (singlet, 611, t e r t i a r y methyls). - 59 -Anal. Calcd. f o r C -.H.' 0: C, 80.44; H, 9.82. Found: C, 80.19; 1116 H, 9.60. Preparation of Epoxy Ketone 171 To a s t i r r e d s o l u t i o n of 2.5 g (15.3 mmoles) of ketone 170 and 5 ml (45.8 mmoles) of 30% hydrogen peroxide s o l u t i o n i n 50 ml of methanol was added 15.3 ml (76.3 mmoles) of 20% sodium hydroxide s o l u t i o n . The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 2 h. Water was then added and the mixture was thoroughly extracted with ether. The organic layer was washed twice with saturated brine, d r i e d over anhydrous magnesium s u l f a t e , and concentrated in_ vacuo. D i s t i l l a t i o n of the residue under reduced pressure afforded 2.1 g (76%) of the epoxy ketone 17i, b.p. 6i>-67° at 1.2 mm. An a n a l y t i c a l sample obtained by preparative g . l . c . (column G, 130°, 200) exhibited i n f r a r e d (film) v 1700 cm"1; p.m.r., x 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.92 max ( s i n g l e t , 3H, t e r t i a r y methyl). Mol. Wt. Calcd. f o r C ^ H ^ C y 180.1149. Found (high r e s o l u t i o n mass spectrometry): 180.1140. Preparation of Epoxy O l e f i n 173 To a cooled (0°), s t i r r e d s l u r r y of 19.1 g (53.5 mmoles) of methyltriphenylphosphonium bromide i n 200 ml of anhydrous ether was added 20.8 ml (50 mmoles) of a 2.4 M s o l u t i o n of n - b u t y l l i t h i u m i n hexane. A f t e r the s o l u t i o n was s t i r r e d at room temperature, under an atmosphere of dry nitrogen, f o r 10 min, a s o l u t i o n of epoxy ketone 171 (3.0 g, 16.7 mmoles) i n 20 ml of dry ether was added. This mixture - 60 -was refluxed for 4 h, cooled, poured into water, and thoroughly extracted with ether. The ethereal extracts were combined, washed with saturated brine, and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent and d i s t i l l a t i o n of the residue gave 2.6 g (88%) of the epoxy o l e f i n 173. This sample was shown to be pure by g . l . c . analysis (column E, 115°, 110). It exhibited b.p. 105-108° (hot box) at 10 mm; i n f r a r e d (film) v _ 3120, 1635, 890 cm - 1; p.m.r., T 9.05 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl), 4.73 ( s i n g l e t , 2H, v i n y l protons). Anal. Calcd. f o r C 1 0 H 1 0 0 : C, 80.85; H, -10.18. Found: C, 80.68; 12 l o H, 10.33. Preparation of Epoxy Alcohols 174 and 175 To a s o l u t i o n of 2.3 g (12.9 mmoles) of epoxy o l e f i n 173 i n 80 ml of dry tetrahydrofuran at 0° and under an atmosphere of dry nitrogen was added 5.6 ml (7.4 mmoles) of 1.33 M borane i n tetrahydrofuran. This s o l u t i o n was then s t i r r e d at room temperature for 1.5 h. The r e a c t i o n mixture was again cooled to i c e temperature, and 16 ml of 20% sodium hydroxide s o l u t i o n was added slowly, followed by a d d i t i o n of 26.6 ml of 30% hydrogen peroxide. The r e a c t i o n mixture was warmed to room temperature and s t i r r e d f o r 1 h, then concentrated. The r e s u l t i n g material was d i l u t e d with water then thoroughly extracted with ether. The combined ether extracts were washed with a saturated brine s o l u t i o n , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent, followed by d i s t i l l a t i o n of the r e s i d u a l material under reduced pressure (b.p. 105-107° at 0.4 mm) afforded - 61 -2.6 g (93%) of the desired epoxy alcohols 174 and 175 as a c o l o r l e s s o i l . An a n a l y t i c a l sample of the major isomer was obtained by preparative g . l . c . (column G, 165°, 200) and exhibited i n f r a r e d ( f i l m ) , v 3460, 1035 cm"1; p.m.r., x 9.30 ( s i n g l e t , 3H, t e r t i a r y methyl), nicix 9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 5.84-6.57 (multiplet, 2H, -CH 20H). Mol. Wt. Calcd. f o r C 1 2 H 2 0 ° 2 : 1 9 6 - 1 4 6 3 - Found (high r e s o l u t i o n mass spectrometry): 196.1459. Preparation of Epoxy Acetates 176 and 177 To a s o l u t i o n of 2.1 g (10.7 mmoles) of epoxy alcohols 174 and 175 i n 14 ml dry p y r i d i n e was added 5.6 g (56 mmoles) of a c e t i c anhydride. This s o l u t i o n v:as i r r p r i i^- rp.nm i-p>m'nr'TT?i"iirf^  fcv* P. Ti ?rnd then d i l u t e d with water. The ethereal extracts of t h i s mixture were combined, washed with saturated brine, and dri e d over anhydrous magnesium s u l f a t e . The solvent was removed under reduced pressure and the residue was d i s t i l l e d at 99-101° at 0.5 mm to give 2.3 g (92%) of the desired products. An a n a l y t i c a l sample of the major isomer obtained by preparative g . l . c . (column G, 180°, 200) exhibited i n f r a r e d (film) v 1740, 1230, 1030 cm"1; p.m.r., x 9.27 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.97 ( s i n g l e t , 3H, -0C0CH 3), 5.47-6.40 (multiplet, 2H, -CH_20Ac). Anal. Calcd. f o r C H^o : C, 70.56; H, 9.30. Found: C, 70.43; H, 9.50. - 62 -Preparation of O l e f i n i c Acetate 178 To a s t i r r e d solution of 12.0 g (30 mmoles) of tungsten hexachlorid i n 40 ml of dry tetrahydrofuran, cooled to -78°, and under an atmosphere of nitrogen was added 25 ml (60 mmoles) of 2.4 M i i-butyl-lithium i n hexane. The solution was then warmed to room temperature over a 20 min period. A solution of 1.9 g (8 mmoles) of epoxy acetates 176 and 177 i n 5 ml of dry tetrahydrofuran was then added. This green solution was refluxed for 7 h, cooled to room temperature, and poured into 350 ml of a solution that was 1.5 M i n sodium t a r t r a t e and 2 M i n sodium hydroxide. This mixture was thoroughly extracted with ether and the ethereal extracts were combined. This organic extract was washed with saturated brine, dried over anhydrous magnesium sul f a t e , and then concentrated. The residue was d i s t i l J e d to afford 1.6 g (90%) of the o l e f i n i c acetate 178^ , b.p. 87-90° at 0.5 mm. An a n a l y t i c a l sample, obtained by preparative g.l.c. (column F, 180°, 200) exhibited infrared (film) v 1740, 1230, 1025 cm"1: p.m.r., T 9.07 and 9.03 v ; m a x (singlets, 6H, t e r t i a r y methyls), 8.04 (singlet, 3H, ~0C0CH3), 5.66-6.31 (multiplet, 2H, -CH_20Ac). Mol. Wt. calcd. for C ] 4 H 2 2 ° 2 : 2 2 2.1619. Found (high resolution mass spectrometry): 222.1583. Preparation of the O l e f i n i c Alcohol 179 To a s t i r r e d solution of 1.2 g (5.4 mmole) of o l e f i n i c acetate 178 i n 10 ml of dry ether was added 100 mg (2.6 mmole) lithium aluminum hydride. This mixture was refluxed, under an atmosphere of dry nitrogen, for 1 h then cooled to room temperature. The excess - 63 -hydride was destroyed by the addition of powdered sodium sulfate decahydrate and the reaction mixture was f i l t e r e d through c e l i t e . The f i l t r a t e was concentrated and d i s t i l l e d at reduced pressure to afford 900 mg (97%) of the o l e f i n alcohol 179, b.p. (hot-box) 82-85° at 0.3 mm. An a n a l y t i c a l sample, obtained by preparative g.l.c. (column G, 160°, 200) exhibited infrared (film) v 3410, 1025 cm"1 max p.m.r., x 9.14 and 9.08 (singlets, 6H, t e r t i a r y methyls), 6.40 (doublet, 2H, -CH^OH, J = 4 Hz). Mol. Wt. calcd. for C H Q0:. 180.1514. Found (high resolution mass spectrometry): 180.1511. - 64 -BIBLIOGRAPHY 1. M.S. Kharasch and P.O. Tawney, J . Amer. Chem. S o c , 63, 2508 (1941). 2. H.O. House, W.L. Respess, and G.M. Whitesides, J . Org. Chem., 31, 3128 (1966). 3. G.H. Posner, Organic Reactions, 19, 1 (1972), and references therein. ,4. E.J. Corey and G.H. Posner, J . Amer. Chem. S o c , 89, 3911 (1967). 5. E.J. Corey and G.H. Posner, i b i d . , 90, 5615 (1968). 6. G.M. Whitesides, W.P. Fisher, J r . , J . San F i l i p p o , J r . , R.W. 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