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Synthesis of jasmonoids : Synthesis of cyclic ketal-type insect pheromones Sum, Phaik-Eng 1979

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I. SYNTHESIS OF JASMONOIDS SYNTHESIS OF CYCLIC KETAL-TYPE INSECT PHEROMONES by PHAIK-ENG SUM B.Sc, Fu Jen University, Taiwan, 1972 M.Sc, University of B r i t i s h Columbia, 1976 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF July, © Phaik-Eng BRITISH COLUMBIA 19 7 9 Sum, 1979 In present ing t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree tha t 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 re fe rence and s tudy. I f u r t he r agree that permiss ion f o r ex tens ive copying of 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 granted by the Head of my Department or by h i s r e p r e s en t a t i v e s . I t i s understood tha t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l ga in s h a l l not be a l lowed wi thout my w r i t t e n pe rm iss i on . Department The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook P lace Vancouver, Canada V6T 1W5 Date 3P 75-5 1 1 E ABSTRACT T h i s t h e s i s c o n s i s t s o f two p a r t s . P a r t I d e s c r i b e s t h e p r e p a r a t i o n o f c y c l o p e n t e n o n e s u s i n g t r i m e t h y l s i l y l p r o p y n e as an a c e t o n y l u n i t , and i t s a p p l i c a t i o n t o t h e s y n t h e s i s o f c i s - j asmone (_1) and d i h y d r o j asmone (3_) . B-Keto e s t e r d i a n i o n s were a l k y l a t e d a t t h e Y _ c a r b o n w i t h 3 - b r o m o - l - t r i m e t h y l s i l y l -1 - propyne. The r e s u l t i n g a l k y n e s were h y d r a t e d t o g i v e t h e 1,4-d i k e t o compounds w h i c h were t h e n c y c l i z e d t o t h e c o r r e s p o n d i n g c y c l o p e n t e n o n e s , c i s - j asmone (1) and d i h y d r o j asmone (3_) . P a r t I I d e s c r i b e s t h e s y n t h e s i s o f v a r i o u s c y c l i c k e t a l i n s e c t pheromones, v i z . , f r o n t a l i n (1_7) , e n d o - b r e v i c o m i n (16_) , e x o - b r e v i c o m i n (1_5) , ( - ) - a - m u l t i s t r i a t i n (18a) and l i n e a -t i n (22_) , w h i c h have c o n s i d e r a b l e e c o n o m i c v a l u e s due t o t h e i r p o t e n t i a l u t i l i t y i n t h e c o n t r o l o f b e e t l e p o p u l a t i o n . The d i a n i o n o f m e t h y l a c e t o a c e t a t e was a l k y l a t e d w i t h h o m o a l l y l i c b r o m i d e s . The r e s u l t i n g a l k e n e s were e p o x i d i z e d and t h e n c y c l i -z e d w i t h a L e w i s a c i d t o p r o d u c e e s t e r s c o n t a i n i n g t h e 6 , 8 - d i o x a -b i c y c l o [ 3 . 2 . 1 ] o c t a n e s k e l e t o n . T h e s e e s t e r s were h y d r o l y z e d and d e c a r b o x y l a t e d . T h i s m e t h o d o l o g y was u t i l i z e d i n a s y n t h e s i s o f f r o n t a l i n (1_7) and s t e r e o s p e c i f i c s y n t h e s e s o f e n d o - b r e v i c o m i n ( 1 6 ) , and e x o - b r e v i c o m i n ( 1 5 ) . I n a d d i t i o n , one o f t h e i n t e r -m e d i a t e s i n t h e s y n t h e s i s o f 15 was p a r t i a l l y r e s o l v e d , l e a d i n g t o o p t i c a l l y a c t i v e - e x o - b r e v i c o m i n . A c h i r a l s y n t h e s i s o f ( - ) - a - m u l t i s t r i a t i n (18a) was accomplished u s i n g methyl a - D - g l u c o p y r a n o s i d e (7i) as s t a r t i n g m a t e r i a l . Methyl 4,6-0-benzylidene-2,3-dideoxy-2-C-methyl - a -D-arabino-hexopyranoside (197) was prepared i n s i x steps from methyl a-D-glucopyranoside (71) . The benzylidene 197 was con-v e r t e d i n t o the alkene 207. Then the methyl group a t C-4 i n the i n t e r m e d i a t e 201 was generated by a s t e r e o s e l e c t i v e hydro-genation of 207 u s i n g Wilkinson's c a t a l y s t . The d i t h i a n e d e r i -v a t i v e 219 was used to e f f e c t both i n t r o d u c t i o n of the e t h y l s i d e - c h a i n and the c y c l i z a t i o n to form the b i c y c l i c k e t a l s k e l e -ton. The s p e c t r a l data of the s y n t h e t i c ( - ) - a - m u l t i s t r i a t i n (18a) was found to be i d e n t i c a l with those f o r the n a t u r a l com-pound. A s y n t h e s i s of l i n e a t i n (2_2) i s a l s o d e s c r i b e d . The c i s fused b i c y c l o [ 4 . 2 . 0 ] r i n g system i n 22 was c o n s t r u c t e d v i a a p h o t o c y c l o a d d i t i o n r e a c t i o n i n v o l v i n g 3-methyl-5-hydroxy-2-pentenoic a c i d 6-lactone 119 and a l l e n e . A mixture o f r e g i o -isomers 2 33 and 234 was o b t a i n e d i n a r a t i o of 5:3. This mix-tu r e was used throughout the subsequent r e a c t i o n s and the f i n a l i s o m e r i c products l i n e a t i n (22) and 2 3 were separated by column chromatography. The p r e s e n t route to l i n e a t i n (22) r e p r e s e n t s a major improvement over the p r e v i o u s syntheses i n terms of e f f i c i e n c y and s t e r e o s e l e c t i v i t y . V TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF SCHEMES v i i LIST OF TABLES x i i LIST OF FIGURES x i i i LIST OF ABBREVIATIONS xiv ACKNOWLEDGMENTS xv PART I: SYNTHESIS OF CIS-JASMONE AND DIHYDROJASMONE 1 INTRODUCTION 2 RESULTS AND DISCUSSION 8 (i) Synthesis of Dihydrojasmone 12 (i i ) Synthesis of cis-Jasmone 22 EXPERIMENTAL 29 Synthesis of Dihydrojasmone 29 Synthesis of cis-Jasmone 37 BIBLIOGRAPHY 44 SPECTRAL APPENDIX 4 6 PART I I : SYNTHESIS OF CYCLIC KETAL-TYPE INSECT PHEROMONES 51 INTRODUCTION 51 (i) General 52 ( i i ) Source, Structure Elucidation and Synthesis of C y c l i c Ketal-type Beetle Pheromones 60 v i Table of Contents - continued Page ( i i ) a) exo- and endo-Brevicomin 60 b) Fron t a l i n 77 c) M u l t i s t r i a t i n 83 d) endo-1,3-Dimethyl-2,9-dioxabicyclo-[3•3.1]nonane 9 7 e) Lineatin 102 RESULTS AND DISCUSSION 113 (i) Synthesis of Front a l i n , endo- and exo-Brevicomin 113 ( i i ) Synthesis of (-)-a-Multistriatin 133 ( i i i ) Synthesis of Lineatin 161 EXPERIMENTAL 184 Synthesis of 5-Methyl-6,8-dioxabicyclo [3.3.1]octane 184 Synthesis of Frontalin 188 Synthesis of endo-Brevicomin 193 Synthesis of exo-Brevicomin 199 Synthesis (-)-a-Multistriatin 206 Synthesis of Lineatin 228 BIBLIOGRAPHY 241 SPECTRAL APPENDIX 24 8 v i i LIST OF SCHEMES Scheme T i t l e Page PART I I Buchi and Wuest's Syn t h e s i s o f c i s -Jasmone (1) 4 II Stork and Borch's Sy n t h e s i s o f c i s -Jasmone (1) 5 I I I Ho's Synt h e s i s o f Dihydro j asmone (_3) 6 IV Modes of C y c l i z a t i o n o f Enolate !L6 11 V S y n t h e s i s of 3 - B r o m o - l - t r i m e t h y l s i l y l -propyne (2_7) 14 VI S y n t h e s i s of Dihydro j asmone (_3) 15 VII Proposed Mechanism f o r the Hydration of Compound 10. 18 V I I I Proposed Mechanism f o r the Hydration of Compound 2_9 18 IX Proposed Mechanism f o r the Cleavage of T r i m e t h y l s i l y l Group of 29_ 19 X Cleavage of the T r i m e t h y l s i l y l Group of 3_2 20 XI Proposed Mechanism f o r the Cleavage of T r i m e t h y l s i l y l Group i n an a - T r i m e t h y l -s i l y l Ketone 20 v i i i L i s t of Schemes - continued Scheme T i t l e Page XII Proposed Mechanism for the Hydrolysis, Decarboxylation and C y c l i z a t i o n of 30 to 3 21 XIII Preparation of l-Bromo-2-pentyne (3_5) 22 XIV Synthesis of cis-Jasmone (1) 2 3 PART II I Synthesis of exo- and endo-7-Ethyl-5-methy1-6,8-dioxabicyclo[3.2.1]octane (15) and (16) 6 3 II Stereoselective Synthesis of exo-Brevicomin (15) 66 III Synthesis of Brevicomin from a Cyclo-hexenone 68 IV Synthesis of Acetylene Ketone _38_ 69 V Synthesis of exo-Brevicomin v i a Kolbe E l e c t r o l y s i s 70 VI Synthesis of endo-Brevicomin from 1,3-Butadiene (4_4) 71 VII Diels-Alder Route to exo- and endo-Brevicomin 72 VIII Mori's Synthesis of O p t i c a l l y Active exo-Brevicomin (15) from Ta r t a r i c Acid 74 ix L i s t of Schemes - continued Scheme T i t l e Page IX Meyer's Synthesis of O p t i c a l l y Active exo-Brevicomin from Diethyl (+)-(2R, 3R) Tartrate 7 6 X A One-step Synthesis of Frontalin (1_7) v i a Diels-Alder Reaction 78 XI Mundy's Synthesis of Fron t a l i n (IT) v i a Diels-Alder Reaction 79 XII Mori's Synthesis of O p t i c a l l y Active Frontalin (17) 80 XIII C h i r a l Synthesis of Frontalin v i a T r i -m e t h y l s i l y l Epoxide 82 XIV A Non-stereoselective Synthesis of Mul t i -s t r i a t i n 86 XV Stereospecific Synthesis of M u l t i s t r i a t i n 88 XVI C h i r a l Synthesis of a - M u l t i s t r i a t i n (18a) 91 XVII Ch i r a l Synthesis of M u l t i s t r i a t i n from D-Mannitol 93 XVIII C h i r a l Synthesis of M u l t i s t r i a t i n from (+)-Citronellol 95 XIX Synthesis of a- and y - M u l t i s t r i a t i n from (Z-)-2-Buten-l,4-diol 96 XX Synthesis of endo-1,3-Dimethyl-2,9-dioxa-bicyclo[3.3.1]nonane 99 X L i s t of Schemes - continued Scheme T i t l e Page XXI S y n t h e s i s of 21_ from Bromo K e t a l 116 101 X X I I MacGonnell's S y n t h e s i s of L i n e a t i n 106 X X I I I S y n t h e s i s of Proposed L i n e a t i n S t r u c t u r e 22^  108 XXIV S y n t h e s i s of 22 from 135 109 XXV Mori's S y n t h e s i s of L i n e a t i n (22) 111 XXVI S y n t h e s i s of Methyl 7,8-Epoxy-3-oxo-octanoate 114 XXVII Proposed Mechanism f o r the C y c l i z a t i o n of 153_ 116 X X V I I I C y c l i z a t i o n o f Epoxy Dihydropyran 157 117 XXIX Proposed Mechanism f o r the C y c l i z a t i o n of Epoxide 157 118 XXX S y n t h e s i s o f F r o n t a l i n (17) 120 XXXI Proposed Mechanism f o r the Decarboxyla-t i o n of 169 123 XXXII S y n t h e s i s of E-l-Bromo-3-hexene (176) 124 X X X I I I S y n t h e s i s of endo-Brevicomin (1_6) 125 XXXIV Mechanism f o r the C y c l i c a t i o n of 178 127 XXXV Synthesis of exo-Brevicomin (15) 13 0 XXXVI R e s o l u t i o n of C a r b o x y l i c A c i d 189 132 XXXVII P r e p a r a t i o n of Methyl 4,6-0-Benzylidene-2-deoxy-2-C-methyl-a-D-altropyranoside (195) 136 x i L i s t o f Schemes - c o n t i n u e d Scheme T i t l e Page X X X V I I I D e o x y g e n a t i o n o f 195 139 XXXIX P r o p o s e d M e c h a n i s m f o r D e o x y g e n a t i o n o f 196 w i t h T r i - n - b u t y l t i n ( I V ) h y d r i d e 140 XL A t t e m p t e d P r e p a r a t i o n o f Compound 201 141 X L I P r e p a r a t i o n o f Compound 201 14 7 X L I I A P o s s i b l e R o u t e t o ( - ) - a - M u l t i s t r i a t i n 151 X L I I I A l k y l a t i o n o f D i t h i o a c e t a l C a r b a n i o n s 151 X L I V A t t e m p t e d P r e p a r a t i o n o f Compound 217 15 3 XLV S y n t h e s i s o f ( - ) - a - M u l t i s t r i a t i n v i a A l k y l a t i o n a n d C y c l i z a t i o n o f D i t h i a n e D e r i v a t i v e s 155 X L V I S y n t h e s i s o f 3 - M e t h y l - 5 - h y d r o x y - 2 -p e n t e n o i c a c i d 6 - l a c t o n e (119) 164 X L V I I O z o n o l y s i s o f Compounds 227 and 228 170 X L V I I I A P o s s i b l e R o u t e t o L i n e a t i n (22) v i a O z o n o l y s i s o f 233 171 X L I X S y n t h e s i s o f L i n e a t i n (22) 172 x i i LIST OF TABLES Table T i t l e Page  PART II 1 NMR Chemical Shif t s for M u l t i s t r i a t i n Isomers 90 2 NMR Data for Compounds 201 and 202 14 9 3 Rates of Metallation of Dithiane 219 157 4 Some Characteristic IR and NMR Absorptions for 233 + 23_4, 239, 24_0 and 241 169 5 270 MHz NMR of Compounds 2_2 and 23_ 111 6 Spin Decoupling on 2 70 MHz NMR of Compound 22_ 178 7 Spin Decoupling on 2 70 MHz NMR of Compound 2_3 180 x i i i LIST OF FIGURES Figure T i t l e Page PART I 1 Stereoelectronic Effects for C- and 0-Alkylation of Enolates 10 PART II 1 General Synthetic Pathways to 6,8-Dioxabicyclo-[3.3.1]octane Systems 64 2 NMR Spectra of M u l t i s t r i a t i n Isomers 90 3 Unit Resolution Mass Spectrum of Lineatin 103 4 Infrared Spectrum of Lineatin 103 5 100 MHz NMR Spectrum of Lineatin 104 6 100 MHz En(fod)3-shifted NMR Spectrum of Lineatin 104 x i v LIST OF ABBREVIATIONS AcOH a c e t i c a c i d Ac 20 a c e t i c anhydride DIBAL di i s o b u t y l a l u m i n u m hydride DMF dimethylformamide GLC gas l i q u i d chromatography HMPA hexamethylphosphoramide IR i n f r a r e d LDA l i t h i u m d i i s o p r o p y l a m i d e MsCl methanesulfonyl c h l o r i d e NMR proton n u c l e a r magnetic resonance 1 3 C NMR carbon-13 n u c l e a r magnetic resonance Pyr p y r i d i n e L - S e l e c t r i d e l i t h i u m t r i - s e c - b u t y l b o r o h y d r i d e THF t e t r a h y d r o f u r a n THP 2 - t e t r a h y d r o p y r a n y l TLC t h i n l a y e r chromatography T r C l t r i p h e n y l c h l o r o methane T s C l p a r a - t o l u e n e s u l f o n y l c h l o r i d e TsOH p a r a - t o l u e n e s u l f o n i c a c i d XV ACKNOWLEDGMENTS I w i s h t o e x p r e s s my g r a t i t u d e t o P r o f e s s o r L a r r y W e i l e r f o r h i s e n c o u r a g e m e n t and g u i d a n c e t h r o u g h o u t t h e c o u r s e o f t h i s r e s e a r c h , and f o r h i s h e l p d u r i n g t h e p r e p a r a t i o n o f t h i s t h e s i s . I am i n d e b t e d t o P r o f e s s o r R. E. P i n c o c k and P r o -f e s s o r G. S. B a t e s f o r r e a d i n g t h r o u g h t h e m a n u s c r i p t o f t h i t h e s i s and p r o v i d i n g i n v a l u a b l e o p i n i o n s . F i n a l l y , I w i s h t o t h a n k my h u s b a n d , Fuk-Wah, whose i n f i n i t e p a t i e n c e , c o n s t a n t e n c o u r a g e m e n t , and h e l p f u l sugge t i o n s made t h i s t h e s i s p o s s i b l e . 1 PART I SYNTHESIS OF CIS-JASMONE AND DIHYDROJASMONE 2 INTRODUCTION cis-Jasmone (1) and methyl jasmonate (2) are c o n s t i -tuents of the essential o i l of jasmine flowers, Jasminum. Dihydro jasmone (3_) i s present i n bergamot o i l and i s c l o s e l y related to cis-jasmone (1) both i n structure and i n odor. A l l of these compounds are important substances i n the perfume industry. In the past two decades, there has been an increasing interest i n the synthesis of these jasmonoids. 1 Two reviews of these syntheses have also been p u b l i s h e d . 1 a ' b The most common strategy .among the documented syntheses i s v i a 1,4-diketone • intermediates 4_ and 5_, which upon treatment with base could be c y c l i z e d to cis-jasmone (1) and dihydro jasmone (3_) , respectively. Various methods for the preparation of these 1,4-diketone i n t e r -mediates 4_ and _5 have been reported. Among them, the acid hydrolysis of furan derivatives and the hydration of acetylenes represent two noteworthy approaches to these compounds. One of the examples i n v o l v i n g the use of furan d e r i v a t i v e s i s the s y n t h e s i s r e p o r t e d by Buchi and Wuest 2 (Scheme I ) . The anion of 2-methylfuran (_6) was generated u s i n g n - b u t y l l i t h i u m and a l k y l a t e d with l-bromo^3-hexene to g i v e compound Hydro-l y s i s t o the diketone 4_ was e f f e c t e d i n moderate y i e l d u s i n g aqueous s u l f u r i c a c i d i n g l a c i a l a c e t i c acid.. The r e s u l t i n g diketone was then c y c l i z e d i n aqueous sodium hydroxide to c i s -j asmone (1) . Two examples i n v o l v i n g the h y d r a t i o n of an a c e t y l e n i c compound have been r e p o r t e d . The f i r s t s y n t h e s i s was accom-4 Scheme I. Buchi and Wuest's S y n t h e s i s of cis-Jasmone (1) 2 p l i s h e d by Stork and B o r c h 3 (Scheme I I ) . The l i t h i u m a c e t y l i d e 8_ was a l k y l a t e d w i t h l-bromo-3-hexene to g i v e compound 9_ which was hydrolyzed to the corresponding ketone 1_0. Subsequent hy-d r a t i o n of the a c e t y l e n i c bond i n 10, f o l l o w e d by base c a t a -l y z e d i n t r a m o l e c u l a r condensation of the r e s u l t i n g diketone 4_, l e d to cis-jasmone {!) .• I t was suggested t h a t r e g i o s e l e c t i v e h y d r a t i o n of a c e t y l e n e 10_ to g i v e _4 i s . due to i n t r a m o l e c u l a r p a r t i c i p a t i o n of the c a r b o n y l group i n 10_. ( 1 ) Another s i m i l a r ^ The proposed mechanism i s shown i n Scheme V I I , p. 17. Scheme I I . Stork and Borch's S y n t h e s i s of cis-Jasmone 9 10 6 example was reported by Ho l b (Scheme III) . In t h i s synthesis, the acetylenic ketone intermediate 13_ was prepared i n three steps, s t a r t i n g with the reaction of lithium compound 11 with epoxide 12_. The diketone intermediate 5_ was then obtained by hydration of the terminal t r i p l e bond i n 13_. Conversion of 5_ into dihydro j asmone (3_) was accomplished by the usual base treatment. Although the jasmonoids have been synthesized by numer-ous workers, our intere s t i n exploiting the synthetic u t i l i t y of the dianion chemistry of 3-keto esters, developed e a r l i e r i n Scheme I I I . Ho's Synthesis of Dihydro j asmone (3_) l b Q 7 t h i s l a b o r a t o r y , 4 s t i m u l a t e d our i n t e r e s t i n d e v e l o p i n g a new and e f f i c i e n t route to these compounds u s i n g 6-keto e s t e r s as p r e c u r s o r s . Our approach i s d e s c r i b e d i n the f o l l o w i n g s e c t i o n . 8 RESULTS AND DISCUSSION For s e v e r a l y e a r s , we have been i n t e r e s t e d i n u t i l i z -i n g the d i a n i o n chemistry of 8-keto esters'* t o prepare 2 - c y c l o -pentenones which are u s e f u l s y n t h e t i c s u b s t r a t e s f o r many nat-u r a l products, e.g., jasmonoids, p r o s t a g l a n d i n s and r e t h r o -lones. In p r i n c i p l e , t h i s s t r a t e g y c o u l d be accomplished by us i n g methyl a c e t o a c e t a t e as a p r e c u r s o r , which possesses the chemical v e r s a t i l i t y to undergo a l k y l a t i o n a t both the y- and a - p o s i t i o n s (equation 1 ) . Process (A) i n equation 1 i n v o l v i n g X, Y = l e a v i n g groups the d i a n i o n of methyl a c e t o a c e t a t e , has been achieved e f f e c t -i v e l y f o r a wide range of a l k y l a t i n g agents. 4 I t was conceived t h a t , by employing an a l k y l a t i n g agent which would r e t a i n (or f a c i l i t a t e a f t e r simple t r a n s f o r m a t i o n s ) a s u i t a b l e l e a v i n g group Y a f t e r the d i a n i o n a l k y l a t i o n , formation of a f i v e -membered r i n g might be e f f e c t e d by i n t r a m o l e c u l a r a l k y l a t i o n at the a - p o s i t i o n of the 8-keto e s t e r . However, t h i s c y c l i z a -9 t i o n step (B) was u n s u c c e s s f u l under a v a r i e t y of a c i d and base c a t a l y z e d c o n d i t i o n s when the carbon b e a r i n g the l e a v i n g group was s p 3 h y b r i d i z e d . 5 For example, treatment o f 6-hydroxy-3-oxoheptanoate (14) with boron t r i f l u o r i d e gave the O - c y c l i z e d t e t r a h y d r o f u r y l i d e n e 15_ i n g r e a t e r than 80% y i e l d (equation 2) . No cyclopentanone product was observed. 6 I n t e r e s t i n g l y , e t h y l a c e t o a c e t a t e r e a c t e d w i t h 2-propanol to g i v e e t h y l a - i s o p r o p y l -a c e t o a c e t a t e i n 60-70% y i e l d under the same c o n d i t i o n s (equa-t i o n 3 ) . 7 F a i l u r e i n o b t a i n i n g the cyclopentanone product i n equation ,2 i s c o n s i s t e n t w i t h the r u l e s f o r r i n g c l o s u r e sug-gested by Baldwin, 8 and c o u l d be e x p l a i n e d by s t e r e o e l e c t r o n i c 10 considerations. In theory, the ambident enolate ion 1_6 may undergo intramolecular a l k y l a t i o n on carbon or oxygen. In the carbon a l k y l a t i o n , approach of the e l e c t r o p h i l e has to be perpendicular to the plane of the enolate, whereas i n the oxygen al k y l a t i o n , the e l e c t r o p h i l e may l i e i n the plane of the eno-late (Figure 1). .In the formation of a five-membered ri n g , Figure 1. Stereoelectronic Effects for C- and O-Alkylation of Enolates perpendicular approach of the carbon bearing the leaving group to the carbon s i t e i s s t e r i c a l l y d i f f i c u l t . On the other hand, the in-plane attack on oxygen to form 18^ i s s t e r i c a l l y f a c i l e (Scheme IV). c c 11 Scheme IV. Modes of Cy c l i z a t i o n of Enolate 16 17 18 When the e l e c t r o p h i l i c carbon i n 1_6 i s sp 2 hybridized, c y c l i z a t i o n analogous to the transformation of 16_ to 17_ appeared to be fe a s i b l e . A t y p i c a l example i s the intramolecular conden-sation of .19 to give cyclopentenones 20_ as shown i n equation 4. 1Since a 1,4-dicarbonyl intermediate would circumvent the d i f f i -c u l t i e s encountered i n e f f e c t i n g step (B) i n equation 1, we decided to develop an e f f i c i e n t synthesis of 1,4-dicarbonyl derivatives using the dianion of methyl acetoacetate. These 12 •R O H " R (4) 1 9 20 1,4-dicarbonyl compounds c o u l d then be c y c l i z e d to g i v e c y c l o -pentenones. T h i s approach i s demonstrated i n the s y n t h e s i s of cis-jasmone (1) and dihydro j asmone (_3) d e s c r i b e d below. wit h a l k y l a t i n g agents c o n t a i n i n g a masked c a r b o n y l f u n c t i o n adjacent to the l e a v i n g group were f i r s t i n v e s t i g a t e d f o r the s y n t h e s i s of 1,4-diketones. Reaction of the d i a n i o n of methyl a c e t o a c e t a t e w i t h a-halo ketones l e d to a mixture of products which were of no s y n t h e t i c v a l u e . No a l k y l a t i o n product was observed when the d i a n i o n of methyl a c e t o a c e t a t e was allowed to r e a c t w i t h the a-bromo k e t a l of acetone. Treatment of the d i a n i o n of 21 w i t h 2-methoxyallyl bromide 9 l e d to formation of the y-bromo B-keto e s t e r 2_2 (equation 5) . The outcome of t h i s r e a c t i o n was i n agreement with s e v e r a l other examples of bromine t r a n s f e r i n the r e a c t i o n of B - s u b s t i t u t e d bromoalkanes wit h r e a c t i v e n u c l e o p h i l e s . 1 0 (i) S y n t h e s i s of Dihydrojasmone (3) The r e a c t i o n s o f the d i a n i o n of methyl a c e t o a c e t a t e 13 ( 5) A r e c e n t r e p o r t by M i l l e r 1 1 r e g a r d i n g the s u c c e s s f u l use of 3 - b r o m o - l - t r i m e t h y l s i l y l - l - p r o p y n e (27) as an a l k y l a t i n g agent prompted our i n t e r e s t i n u t i l i z i n g t h i s reagent as a masked a c e t o n y l u n i t . As shown i n Scheme V, compound 2_7 was prepared i n fo u r steps s t a r t i n g from 2 - p r o p y n - l - o l (2_3_) . The a l c o h o l 2J3 was f i r s t p r o t e c t e d as i t s t e t r a h y d r o p y r a n y l d e r i -v a t i v e 2j4. The a c e t y l e n i c anion o f 24_ was generated with 1. 1 e q u i v a l e n t s of m e t h y l l i t h i u m and a l k y l a t e d with c h o r o t r i m e t h y l -s i l a n e to g i v e compound 2_5 i n 94% y i e l d . The a l c o h o l 26_ ob-t a i n e d a f t e r a c i d - c a t a l y z e d h y d r o l y s i s o f the t e t r a h y d r o p y r a n y l group i n 2_5 was t r e a t e d w i t h phosphorus t r i b r o m i d e and p y r i d i n e to g i v e the bromide 2_7 i n 8 0% y i e l d . The t r i m e t h y l s i l y l a c e t y -lene moiety i n 27_ can be e a s i l y converted i n t o an a c e t y l group as i l l u s t r a t e d by equation 6 . 1 2 b Me 3SiCEC-R Hg 2 + >• CH3-C-R II O; (6) 14 Scheme V. S y n t h e s i s of 3 - B r o m o - l - t r i m e t h y l s i l y l p r o p y n e (27) 1. M e L i 2. Me 3 S i C I M e 3 S i C = C C H 2 0 p-TsOH M e O H . A 25 M e 3 S i C = C C H 2 O H P B r 3 / Pyr -> M e 3 S i C = C C H 2 B r 26 27 I t was e n v i s i o n e d t h a t a l k y l a t i o n of the d i a n i o n of 8-keto e s t e r w i t h bromide 27_ f o l l o w e d by treatment w i t h Hg would p r o v i d e a convenient r o u t e to 1,4-dicarbonyl compounds Indeed we accomplished t h i s s y n t h e t i c sequence i n a s y n t h e s i of dihydro jasmone (_3) o u t l i n e d i n Scheme VI. 15 Scheme VI. Sy n t h e s i s of Dihydro j asmone (_3) 1. NaOM'e/MeOH C 0 2 M e ;» 2 . 1-Bromopentane 21 1. NaH 2. n-BuLi 3. B r C H 2 C = C S i M e 3 C 0 2 M e 29 16 The n - p e n t y l s i d e c h a i n i n the dihydro jasmone (3_) was in t r o d u c e d by the a l k y l a t i o n o f the monoanion o f methyl a c e t o -a c e t a t e (2_1) wit h 1-bromopentane. Compound 28 was thus o b t a i n e d i n 58% y i e l d . The d i a n i o n of 8-keto e s t e r 28^ prepared by suc-c e s s i v e treatment w i t h one e q u i v a l e n t of sodium h y d r i d e , and one e q u i v a l e n t of n - b u t y l i t h i u m , was a l k y l a t e d w i t h bromide 2_7 to g i v e the y - a l k y l a t e d product 29_ i n g r e a t e r than 9 0% crude y i e l d . Attempts t o p u r i f y the t r i m e t h y l s i l y l a l k y n e 29_ by pre -p a r a t i v e t h i n l a y e r chromatography (TLC) were u n s u c c e s s f u l . The proton n u c l e a r magnetic resonance (NMR) spectrum of crude com-pound 29_ showed a b s o r p t i o n s a t 6 0.25 (s, 9H, C ( C H 3 ) 3 ) , 0.8-1.2 (m, 3H, CH 3), 1.2-1.6 (m, 6H, CH2CH2CH2), 1.7-2.1 (m, 2H, O O fl - £ c H C H 2 ) , 2.5-3.0 (m, 4H, -C-CH2CH2C=.C) , 3.50 (m, IH, -CCHC0 2CH 3), and 3.73 (s, 3H, 0CH 3), which were c o n s i s t e n t w i t h s t r u c t u r e 29. The a b s o r p t i o n a t 2195 cm 1 i n the i n f r a r e d (IR) spectrum i n d i -c ated the presence of the C-C s t r e t c h i n g of the t r i p l e bond. Compound 29^  was f u r t h e r c h a r a c t e r i z e d by mass s p e c t r a . The t r i m e t h y l s i l y l a c e t y l e n e i n 29_ was hyd r o l y z e d and hydrated by aqueous a c i d i n the presence of a c a t a l y t i c amount of H g 2 + 1 2 to y i e l d the d e s i r e d 1,4-diketone 3_0. The formation of 3_0 was i n d i c a t e d by the appearance of a sharp three proton s i n g l e t at 6 2.15 i n the NMR spectrum f o r the methyl group ad-j a c e n t to the c a r b o n y l group, and a fo u r proton broad s i n g l e t a t 2.72 f o r the methylene protons between the two keto groups. The nine proton s i n g l e t a t 6 0.25 f o r the protons on the t r i -17 m e t h y l s i l y l group and the four proton multiplets at 2.5-3.0 for the methylene protons between the t r i p l e bond and the keto group observed i n compound 29_ were absent. The IR spectrum of 3_0 showed carbonyl absorption at 1715 and 1740 cm 1 . The stronger absorption at 1715 cm 1 indicated the presence of two ketones whereas the weaker absorption at 1740 was assigned to the ester group. The exact sequence of occurrence of cleavage of the t r i m e t h y l s i l y l group and hydration of the acetylenic bond during the transformation of 29^  to 3_0 i s not clear. In any case, the exclusive formation of the 1,4-diketone 3_0 could be explained i n terms of intramolecular p a r t i c i p a t i o n of the keto group i n 29 during the hydration step. This type of carbonyl assisted regioselective hydration of acetylenes was f i r s t reported by Stork and Borch. 3 I t was suggested that intramolecular carbonyl p a r t i c i p a t i o n goes through a k i n e t i c a l l y and geometrically fav-ored five-membered rin g intermediate 3_1 as shown i n Scheme VII. Apparently, a similar mechanism might be involved for the con-version of 29_ into 3_0 (Scheme VIII) . If cleavage of the t r i m e t h y l s i l y l group preceded the hydration step, the usual hydration of terminal acetylenes, following Markovnikov's rule, would also lead to the 1,4-dicarbonyl product 30. 18 Scheme V I I . Proposed Mechanism f o r the Hydration o f Compound 10, 3 R' Scheme V I I I . Proposed Mechanism f o r the Hyd r a t i o n of Compound 2_9 29 R = SiMe 3 or H 19 Cleavage of the s i l i c o n - c a r b o n bond p r i o r to h y d r a t i o n of the a c e t y l e n e would be a s s i s t e d by the H g 2 + i o n as i l l u s t r a -+ . -ted i n Scheme IX. The known Ag c a t a l y z e d cleavage of t r i m e t h y l -Scheme IX. Proposed Mechanism f o r the Cleavage of T r i m e t h y l -s i l y l Group of 29 -s i l y l a c e t y l e n e s 3_2 (Scheme X) supported t h i s mechanism. I t was suggested t h a t A g + formed a complex wi t h the a c e t y l e n e and thus a s s i s t e d the displacement a t s i l i c o n . The cyanide t r e a t -ment converted the s i l v e r a c e t y l i d e i n t o the a c e t y l e n e 33. I t i s a l s o p o s s i b l e to c l e a v e the t r i m e t h y l s i l y l moiety a f t e r 20 Scheme X. Cleavage of the T r i m e t h y l s i l y l Group of 3 2 1 3 AgNO-M e 35 i C=C—R H C=C—R KCN 32 33 QH 2 Me_li—C=C—F Ag + A g N 0 3 Ag—C=C—R KCN H 2 0 H—C=C—R 33 h y d r a t i o n of the a c e t y l e n e . T h i s process might be f a c i l i t a t e d by the a-carbonyl f u n c t i o n (Scheme X I ) . Scheme XI. Proposed Mechanism f o r the Cleavage of T r i m e t h y l -s i l y l Group.in an a - T r i m e t h y l s i l y l Ketone 21 F i n a l l y , t r e a t m e n t o f t h e d i k e t o n e 30_ w i t h aqueous b a s e a t 70° C e f f e c t e d h y d r o l y s i s , d e c a r b o x y l a t i o n , and c y c l i -z a t i o n i n one s t e p t o g i v e d i h y d r o j asmone (3_) i n 75% y i e l d . Scheme X I I shows a p r o p o s e d mechanism f o r t h e above c o n v e r s i o n . Scheme X I I . P r o p o s e d Mechanism f o r t h e H y d r o l y s i s , D e c a r b o x y -l a t i o n , and C y c l i z a t i o n o f 30 t o 3 Me 30 R = p e n t y l 22 ( i i ) Sy n t h e s i s of cis-Jasmone (1) We have a l s o s y n t h e s i z e d cis-jasmone (1_) u s i n g a route s i m i l a r to t h a t d e s c r i b e d above. The s i d e c h a i n p r e -c u r s o r 3_5 was prepared as shown i n Scheme X I I I . The d i a n i o n of 2 - p r o p y n - l - o l (23) was a l k y l a t e d w i t h 1-bromoethane to pro-duce 2 - p e n t y n - l - o l (34) i n 75% y i e l d . Treatment of a l c o h o l 3_4 wit h phosphorus t r i b r o m i d e gave l-bromo-2-pentyne (3_5) 14 i n 77% y i e l d . Scheme X I I I . P r e p a r a t i o n of l-Bromo-2-pentyne (35) 1. LiNH / NH H O C H p C = C H -—»• H O C H 2 C = C C H 2 C H 3 2. E t B r 23 34 P B r 3 / Pyr B r C H 2 C = C C H 2 C H 3 35 The s y n t h e s i s of cis-jasmone (1) i s i l l u s t r a t e d i n Scheme XIV. When the monoanion of methyl a c e t o a c e t a t e (21) was generated with sodium hydride i n t e t r a h y d r o f u r a n and a l k y l a -ted w i t h l-bromo-2-pentyne (35) a t room temperature, the d e s i r e d monoalkylated product 3_6 was obtained, along w i t h an equal amount of d i a l k y l a t e d product 37 (equation 7). A f t e r 23 Scheme XIV. S y n t h e s i s of cis-Jasmone (1) 24 f u r t h e r i n v e s t i g a t i o n , i t was found t h a t g e n e r a t i o n of the mono-anion u s i n g potassium hydride i n s t e a d o f sodium h y d r i d e , im-proved the y i e l d of the d e s i r e d monoalkylated product 3_6 from ( 7) 45 to 70%. A h i g h l y s e l e c t i v e m o n o a l k y l a t i o n of the potassium e n o l a t e o f 2, :4-dimethyl-3-pentanone has been r e p o r t e d p r e v i o u s l y by Brown. 1 6 Although the potassium e n o l a t e s of ketones and 1,3-dicarbonyl compounds are known to be more r e a c t i v e than, the corresponding sodium e n o l a t e s , i t i s not c l e a r what the exact reasons are f o r these observed s e l e c t i v e m onoalkylations i n c o n t r a s t t o the s i g n i f i c a n t d i a l k y l a t i o n t h a t o c c u r r e d w i t h sodium e n o l a t e s . 25 The NMR spectrum of methyl 2-acetyl-4-heptynoate (36) was f u l l y consistent with the proposed structure. Signals ob-served at 6 1.07 (t, J = 7 Hz, 3H), 1.8-2.3 (m, 2H), 2.4-2.8 (m, 2H), 2.27 (s, 3H), 3.60 (t, J = 7 Hz, IH), and 3.72 (s, 3H) were assigned to the C-l methyl group, the two methylenes at each end of the t r i p l e bond, the methyl group next to the car-bonyl, the methine proton and the 0-methoxy protons, respectively. TAbsorptions at 1715 and 1740 cm - 1 i n the IR spectrum indicated the presence of a saturated ketone, and an ester group. In ad-d i t i o n , there was a weak band at 227 5 cm 1 which was ascribable to the C-C stretching of the t r i p l e bond. Compound 3_6 was par-t i a l l y hydrogenated using palladium on barium s u l f a t e 1 5 as catalyst to give the c i s alkene 3_8 i n 8 9% y i e l d . The NMR spec-trum of t h i s hydrogenation product had an absorption at 6 4.9-5.6 (m, 2H) indicating the presence of two v i n y l protons. The dianion of the hydrogenated product 3_8 was generated i n the same manner as described above and was alkylated with 3-bromo-1-trimethylsilyl-l-propyne (27). Hydrolysis and hydration of the alkylated product 3_9 followed by c y c l i z a t i o n as before afforded cis-jasmone (1) i n greater than 4 0% o v e r a l l y i e l d from methyl acetoacetate. The above syntheses i l l u s t r a t e a f a c i l e and e f f i c i e n t route to 1,4-dicarbonyl compounds and cyclopentenones u t i l i z i n g the trimethylsilylpropyne group as a convenient precursor to the acetonyl unit. 26 EXPERIMENTAL General Unless otherwise stated the following are implied. Melting points (mp) were determined on a Kofler micro heating stage or a Thomas Hoover c a p i l l a r y melting point apparatus and are uncorrected. Gas-liquid chromatography (GLC) was performed on a Hewlett Packard Model 5831A gas chromatograph, using 6' x 1/8" columns and nitrogen as c a r r i e r gas. The following columns were employed: Column Stationary Phase Support Mesh A 3% OV 17 chromosorb W (HP) 80/100 B 3% OV 101 chromosorb W (HP) 80/100 C 10% DEGS chromosorb W (HP) 80/100 Carrier gas flow-rate for the column was about 35 mL/min. The 60 MHz nuclear magnetic resonance (NMR) spectra were recor-ded on a Varian Associates Model T-60, the 100 MHz spectra were recorded on Varian Associates Model HA-100 or Model XL-100, and the 270 MHz spectra were recorded on a homebuilt high reso-l u t i o n NMR spectrometer consisting of an Oxford Instruments' 6 3.4 KG magnet. Chemical s h i f t s i n ppm are reported using 6 scale with tetramethylsilane (TMS) as i n t e r n a l reference. Signal m u l t i p l i c i t y , integrated area and proton assignments are i n d i -cated i n parenthesis. Infrared spectra (IR) were recorded on 27 either a Perkin-Elmer model 700 or 710B spectrophotometer. Solution spectra were performed using a sodium chloride solu-tion c e l l of 0.2 mm thickness. Absorption positions are given i n cm 1 and are calibrated by means of the 16 01 cm 1 band of polystyrene. Optical rotations [ o t ] ^ were measured with a Perkin-Elmer model 241 MC polarimeter. Low resolution mass spectra were determined on a Varian/Mat model CH4B mass spectro-meter. High resolution mass measurements were obtained using Kratos-AEI model MS902 or model MS50 instrument. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of B r i t i s h Columbia, Vancouver. A l l solvents used for NMR, IR, and o p t i c a l rotations were of Spectral grade. A n a l y t i c a l thin layer chromatography (TLC) plates and preparative TLC plates were prepared from s i l i c a gel GF-254 from E. Merck Co. Preparative TLC plates were of about 1 mm i n thickness. Column chromatography was carried out i n 100-200 mesh ASTM s i l i c a gel from Davison Chemical. Plates were v i s u a l -ized under long and short wavelengths u l t r a v i o l e t radiation and were developed by iodine. Solvents and reagents used were of either Reagent grade or C e r t i f i e d grade. Solvents were d i s t i l l e d before use. The petroleum ether used was of b o i l i n g range ca. 30-60° C. Dry solvents or reagents, where indicated, were prepared as follows: 28 ethyl ether (ether) and tetrahydrofuran (THF) by refluxing over lithium aluminum hydride followed by d i s t i l l a t i o n ; chloro-form ( C H C I 3 ) , dichloromethane (CH2CI2) and carbon tetrachloride (CCI4) by d i s t i l l a t i o n from phosphorus pentaoxide; hexamethyl-phosphoramide (HMP'A) by d i s t i l l a t i o n from calcium hydride f o l -lowed by storage over molecular sieve (Type 4 A ) ; d i i s o p r o p y l -amine and triethylamine by d i s t i l l a t i o n from and storage over potassium hydroxide p e l l e t s ; pyridine by d i s t i l l a t i o n from barium oxide followed by storage over potassium hydroxide p e l l e t s ; acetone by d i s t i l l a t i o n from and storage over anhydrous magnes-ium sulfate; benzene, toluene and n-hexane by d i s t i l l a t i o n from calcium hydride, and methanol by refluxing over magnesium methox-ide followed by d i s t i l l a t i o n . Boron t r i f l u o r i d e etherate and phosphorus tribromide were d i s t i l l e d under nitrogen before use. Methyllithium (in ethyl ether) and n-butyllithium (in hexane) were obtained from A l d r i c h Chemical Company, Inc. te r t - B u t y l l i t h i u m (in pentane) was supplied by A l f a D i v i s i o n , . Ventron Corporation. The a l k y l l i t h i u m solutions were standard-ized by t i t r a t i o n against 1.0 M t e r t - b u t y l alcohol i n benzene using 1,10-phenanthroline as indicator. 29 S y n t h e s i s of Dihydrojasmone Methyl 2-acetylheptanoate (28) Approximately 125 mL of anhydrous methanol was added dropwise through an a d d i t i o n a l f u n n e l to a 3-necked f l a s k con-t a i n i n g 1.25 g (54.0 mmol) of sodium (washed o i l - f r e e w i t h dry benzene). When a l l of the sodium had r e a c t e d , 5.80 g (50.0 mmol) of methyl a c e t o a c e t a t e was added dropwise. The r e a c t i o n mixture was heated t o a g e n t l e r e f l u x and 8.15 g (54.0 mmol) of 1-bromopentane was added slowly. The r e a c t i o n mixture was r e f l u x e d f o r an a d d i t i o n a l 15 h. I t was allowed to c o o l to room temperaure and the methanol was removed under reduced pr e s s u r e . The r e s i d u e was d i l u t e d w i t h e t h y l ether and washed wit h d i l u t e h y d r o c h l o r i c a c i d and sodium b i c a r b o n a t e s o l u t i o n . The o r g a n i c l a y e r was d r i e d over anhydrous magnesium s u l f a t e and the s o l v e n t was removed by e v a p o r a t i o n under reduced p r e s -sure to g i v e 6.90 g (74%) of crude product. D i s t i l l a t i o n of the r e s u l t i n g o i l gave 5.40 g (58%) of methyl 2-acetylheptano-ate (28_) , bp 60-61° C/0.9 t o r r ; IR (CHC13) 1710 and 1740 cm" 1; NMR (CDC13) 6 0.7-1.1 (m, 3H), 1.1-1.5 (m, 6H), 1.6-2.1 (m, 2H), 2.18 (s, 3H), 3.37 ( t , J = 7 Hz, IH), and 3.7 (s, 3H) ; mass spectrum-.a) high r e s o l u t i o n c a l c d f o r CioHi 8 0 3 : 186.1244 amu; found: 186.1241; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 30 43 (96), 55 (28), 87 (90), 101 (58),. 116 (100), 117 (20), 129 (16), 144 (64), 155(12), and 186(8). Ana l . C a l c d f o r C i 0 H i 8 0 3 : C, 64.49; H, 9.74. Found: C, 64.38; H, 9.70. 3 - ( 2 - T e t r a h y d r o p y r a n y l o x y ) - l - t r i m e t h y l s i l y l - l - p r o p y n e ( 2 5 ) 1 1 Under a n i t r o g e n atmosphere, a c a t a l y t i c amount (ca. 0.40 g) of p - t o l u e n e s u l f o n i c a c i d monohydrate was added to a s t i r r e d s o l u t i o n of 8.40 g (150 mmol) of 2-pr o p y n - l - o l and 13.46 g (160 mmol) of dihydropyran i n ca. 130 mL of anhydrous dichloromethane a t 0° C. The r e a c t i o n temperature was r a i s e d to 25° C and s t i r r i n g was continued f o r 2 h... The r e a c t i o n mix-t u r e was then washed with d i l u t e aqueous sodium b i c a r b o n a t e , b r i n e and d r i e d over anhydrous sodium s u l f a t e . The s o l v e n t was removed under reduced p r e s s u r e . D i s t i l l a t i o n of the crude pro-duct gave 19.53 g (93%) of 1-(2-tetrahydropyranyloxy)-2-propyne ( 2 4 ) , bp 95-97° C/20 t o r r [ l i t . 1 7 bp 63-65° C/9 t o r r ] ; IR (CHC13) 2150 and 3350 cm" 1; NMR (CDC13) 6 1.2-1.9 (m, 6H), 2.2-2.4 (m, IH), 3.2-4.0 (m, 2H), 4.18 (d, J = 2.5 Hz, 2H), and 4.75 (br s, IH). Under a n i t r o g e n atmosphere, 48.54 mL (100 mmol, 2.06 M i n e t h y l ether) of m e t h y l l i t h i u m was added t o a s t i r r e d s o l u -t i o n of 14.0 g (100 mmol) of the t e t r a h y d r o p y r a n y l compound 24^  i n 120 mL of anhydrous e t h y l ether a t 0° C. A heavy white pre-c i p i t a t e was formed and the r e a c t i o n mixture was s t i r r e d f o r 31 15 min. Then 10.86 g (100 mmol) of chlorotrimethylsilane was added dropwise, the reaction mixture turned clear and a white pr e c i p i t a t e was observed again aft e r the addition of a l l the chlorotrimethylsilane. The reaction mixture was s t i r r e d at 0° C for 15 min, at room temperature for 10 min and then quen-ched with aqueous sodium bicarbonate, and the mixture diluted with pentane. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvents were removed under reduced pressure to give 21. 09 g (99%) of crude product. Kugel-rohr d i s t i l l a t i o n (bath temperature 56 -57° C/0.7 torr) gave 19.95 g (94%) of pure compound 2_5, IR (CHC13) 2205 cm"1; NMR (CDC13) 6 0.24 (s, 3H), 1.4-2.0 (m, 6H), 3.5-4.0 (m, 2H), 4.33 (s, 2H), and 4.8-5.0 (m, IH); mass spectrum m/e (rel intensity) 41(31), 43(31), 56 (65), 73 (55), 75 (35), 83 (55), 85 (100), 97(22), 101 (81), 103 (56), 111(69), 113(83), 128(21), 173(22), 197(10), and 212(5). 3-Hydroxy-l-trimethylsilyl-l-propyne ( 26) 1 1 To a solution of 21.'2, g (100.0 mmol) of compound 25 in 150 mL of anhydrous methanol was added a c a t a l y t i c amount of p-toluenesulfonic acid monohydrate (0.10 g). The reaction mix-, ture was refluxed under nitrogen for 2 h. I t was then allowed to cool to room temperature and methanol removed under reduced pressure. The yellow o i l was dil u t e d with ethyl ether, washed 32 with d i l u t e aqueous sodium bicarbonate, water and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure to give an o i l which was p u r i f i e d by d i s t i l l a -t i o n (Kugelrohr) to give 11.30 g (88%) of 3-hy d r o x y l - l - t r i -methylsilyl-l-propyne (2^6), bath temperature 48° C/0.6 t o r r ; IR (CHC13) 2200, 3300-3800 cm"1; NMR (CDC13) 6 0.28 (s, 9H), 2.2 (t, J = 6 Hz, IH), and 4.33 (d, J = 6 Hz, 2H); mass spectrum m/e (rel intensity) 43(23) , 45 (31) , 61 (31), 75 (33), 75 (46), 83 (23), 85 (100), 87(26), 113 (99), 114 (22), and 128 (17) . 3-Bromo-l-trimethylsilyl-l-propyne (27) To a solution of 9.98 g (78.0 mmol) of 3-hydroxy-l-trimethylsilyl-l-propyne, 0.16 g (2.0 mmol) of anhydrous p y r i -dine, and ca. 45 mL of anhydrous ethyl ether was added dropwise 8.66 g (32.0 mmol) of phosphorus tribromide. The reaction mix-ture was refluxed for 2 h, allowed to cool, and poured onto ice . The ether layer was washed with water, 5% aqueous sodium bicarbonate, and saturated ammonium chloride solution. I t was then dried over anhydrous magnesium sulfate and the solvent re-moved under reduced pressure. The crude product was p u r i f i e d by d i s t i l l a t i o n to give 11.93 g (80%) of 3-bromo-l-trimethyl-sily l - l - p r o p y n e (21_) , bp 75-78° C/20 tor r [ l i t . 1 1 bp 71-73° C/ -26 torr] and had the following spectral data; 33 IR (CHC13) 2200 cm"1; NMR (CDC13) 6 0.26 (s, 9H) and 3.92 (s, 2H); mass spectrum m/e (rel intensity) 43(36), 53(25), 55 (32), 83(37), 85(28), 96(31), 111(47), 113(33), 123(24), 125 (22), 137 (49), 139 (49), 147 (66), 149 (67), 175 (100), 177 (99), 190 (20) and 192 (19). 6-Carbomethoxy-l-trimethylsilyl-l-undecyn-5-one (29) A sample of 0.27 g (5.10 mmol) of sodium hydride, as a 50% mineral o i l dispersion was weighed into an oven dried flask. I t was washed with THF to remove the mineral o i l . About 50 mL of dry THF was d i s t i l l e d d i r e c t l y into the fla s k . The flask was then equipped with a magnetic s t i r r e r , septum cap, flushed with nitrogen, and cooled i n ic e . Then 0.93 g (5.0 mmol) of methyl 2-acetylheptanoate (28) was added dropwise to the cooled slurry and the reaction was s t i r r e d for 10 min, 3.13 mL (5.0 mmol, 1.6 M i n hexane) of n-butyllithium was added dropwise to the reaction mixture, and s t i r r e d for another 10 min. The r e s u l t i n g dianion was alkylated with 0.98 g (5.2 mmol) of 3-bromo-l-trimethylsilyl-l-propyne (27_) . After s t i r r i n g for 2 h at 0° C the reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl ether, washed with brine, and dried over anhydrous sodium sulfate. The s o l -vents were removed under reduced pressure to y i e l d 1.6 g of crude 2 9 which was .homogeneous by chromatography and spectro-34 scopy. T h i s crude compound 29_ was used d i r e c t l y i n the next step and the compound was c h a r a c t e r i z e d by the f o l l o w i n g data; IR (CHC13) 1715, 1740, and 2195 cm" 1; NMR (CDC13) 6 0.25 (s, 9H), 0.8-1.2 (m, 3H), 1.2-1.6 (m, 6H), 1.7-2.1 (m, 2H), 2.5-3.0 (m, 4H), 3.5 (m, IH) and 3. 73 (s, 3H) ; mass spectrum: a) h i g h r e s o l u t i o n c a l c d f o r C 1 6 H 2 8 0 3 S i : 296.1804 amu; found: 296.1803; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (20), 43 (28), 55 (24), 73 (96), 89 (42), 139 (30), 153 (100), 154 (15), 169 (18), 195 (14), 209 (10), 211(10), 221 (8), 223 (7), 225 (11), 236 (8), 237 (11), 249 (11), 265 (9), 281 (68), and 296 (3). 6-Carbomethoxy-2,5-undecanedione (30) A s o l u t i o n of 0.16 g of mercury (II) oxide i n 0.26 mL of concentrated s u l f u r i c a c i d and 6 mL of water was added t o 10 0 mL of THF and warmed to ca. 60° C. A s o l u t i o n of 2.96 g of crude a c e t y l e n e 29_ i n 10 mL of t e t r a h y d r o f uran was added to t h i s mercuric s u l f a t e s o l u t i o n . The r e s u l t i n g s o l u t i o n was c o o l e d to ca. 40° C and s t i r r e d a t t h a t temperature f o r 2 h. The r e a c t i o n mixture was quenched with v/ater and e x t r a c t e d with e t h y l ether. The e x t r a c t s were d r i e d over anhydrous sodium s u l f a t e and the s o l v e n t s were removed under reduced p r e s s u r e . The crude o i l was d i s t i l l e d a t 118° C/0.4 t o r r (Kugelrohr) to y i e l d 1.91 g (79% from 28) of 6-carbomethoxy-35 2,5-undecanedione (3_0) . A s m a l l amount of _30 was p u r i f i e d by TLC (using a mixture of CCl^ and E t 2 0 , \ 8 : l v / v ) , and was charac-t e r i z e d by; IR (CHC13) 1715 and 1740 cm" 1; NMR (CDC1 3) 6 0.7-1.0 (m, 3H), 1.1-1.5 (m, 6H), 1.7-2.0 (m, 2H), 2.15 (s, 3H), 2.72 (br s, 4H), 3.45 ( t , J = 7 Hz, IH), and 3.68 (s, 5H); mass spectrum: a) h i g h r e s o l u t i o n c a l c d f o r C i 3 H 2 2 0i+: 242.1503 amu; found: 242.1506; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 43 (50), 55 (14), 71 (10), 87 (10), 99 (100), 140 (11), 172 (20), 211 (5), and 242 (0.1). An a l . C a l c d f o r Ci3H2 2 0 i , : C, 64.44; H, 9.15. Found: C, 64.33; H, 9.25. Dihydro jasmone (3) A s o l u t i o n of 0.242 g (1.0 mmol) of d i k e t o e s t e r (30) i n 8 mL of 3% aqueous sodium hydroxide was s t i r r e d at ca. 7 0° C f o r 5h h. A f t e r c o o l i n g t o room temperature, the r e a c t i o n was a c i d i f i e d t o pH 4 w i t h 25% aqueous s u l f u r i c a c i d and e x t r a c t e d with ether. The e x t r a c t s were d r i e d over anhydrous magnesium s u l f a t e and the s o l v e n t s were removed under reduced p r e s s u r e . The crude y e l l o w o i l was d i s t i l l e d (Kugelrohr) a t 85° C/0.4 t o r r [ l i t . 1 9 bp 93° C/2.3 t o r r ] to y i e l d 0.12 g ( 7 2 % ) of d i h y d r o -jasmone (3_) . A TLC ( C C l l t : E t 2 0 8 : 1 v/v) p u r i f i e d sample of _3 had s p e c t r a l data i d e n t i c a l t o those r e p o r t e d and was charac-t e r i z e d by: 36 IR (CHC1 3) 1640 and 1690 c m " 1 ; NMR (CDC1 3) 6 - 0 . 6 - 0 . 9 (m, 3H) , 1 . 0 - 1 . 5 (m, 6H) , 2.03 (br s , 3H) , and 2 . 0 - 2 . 6 (m, 6H); mass spectrum m/e ( r e l i n t e n s i t y ) 41 (25 ) , 67 (17 ) , 95 (18) , 96 (18) , 109 (21) , 110(100) , 101 (26) , 123(23) , 137 (25) , 151 (56) , and 166 (45) . 37 Synthesis of cis-Jasmone 2-Pentyn-l-ol (34) 2 0 To 1 L of l i q u i d ammonia i n a 2 L three-necked flask f i t t e d with a mechanical s t i r r e r and a dry-ice condenser and a nitrogen outlet, was added a c a t a l y t i c amount of f e r r i c nitrate.and 12.1 g of lithium (washed o i l - f r e e with benzene) i n small portions. After the disappearance of the dark blue color, 52.5 mL of propargyl alcohol (50.56 g, 887 mmol) i n 100 mL of THF was added dropwise over 15 min. Another 150 mL of THF were added over 5 min and the reaction mixture was allowed to reflux (-33° C) for 1 h before a solution of 96.78 g (888 mmol) of 1-bromoethane i n 5 0 mL of THF was added over 10 min. The reaction was allowed to reflux for 3 0 min and l e f t overnight under a posi t i v e N 2 pressure to drive o f f the ammonia. The r e s i -due was poured into a beaker containing some ice and ammonium chloride solution and the aqueous layer was then extracted with (3 x 500 mL) ethyl ether. The ether extracts were combined, washed with saturated brine solution, dried over anhydrous so-dium sulfate, and the solvents were removed by evaporation at reduced pressure. The crude product was p u r i f i e d by d i s t i l l a -t i o n at reduced pressure to give 56.14 g (75%) of 2-pentyn-l-ol (34), bp 76-77° C/20 torr> [ l i t . 2 0 bp 61-62°/15 t o r r ] ; IR (CHC13) 2250 and 3500 cm"1; NMR (CDC13) 6 1.13 (t, J = 7 Hz, 3H), 1.17-2.5 (m, 3H) and 4.1-4.4 (m, 2H); 38 mass spectrum m/e (rel intensity) 41(80), 53(29), 55 (100), 56 (38), 83 (61), and 84 (28). 1-Bromo-2-pentyne (35) 1 To a solution of 19.69 g (235 mmol) of 3-pentyn-l-ol (34), 0.48 mL of dry pyridine and 120 mL of anhydrous ethyl ether was added dropwise 9 mL of phosphorus tribromide i n 3 0 mL of anhydrous ethyl ether. The mixture was refluxed for 2 hr and poured onto i c e . The ether layer was washed with water, 5% aqueous sodium bicarbonate solution, and saturated ammonium chloride solution. The etheral solution was dried over anhydrous sodium sulfate and the ether was removed under reduced pressure. The crude product was p u r i f i e d by d i s t i l l a t i o n to give 26.253 g (77%) of 1-bromo-2-pentyne (3_5) ; bp 60-64° C/20 tor r ; IR (CHC13) 2250 cm"1; NMR (CDC13) 6" 1.15 (t, J = 7 Hz, 3H), 2.0-2.5 (m, 2H), and 3.86 (t, J = 2.5Hz, 2H) ; mass spectrum m/e (rel intensity) 41(47), 50(5), 51 (10), 52(5), 65 (10), 67 (100), 68(8), 146 (27), and 148 (23). Methyl 2-acetyl-4-heptynoate (36) A sample of 1.8 0 g (ca. 10.0 mmol) of potassium hydride in mineral o i l was washed with dry THF and suspended i n 25 mL of dry THF. Then 1.16 g (10.0 mmol) of methyl acetoacetate was added at 0° C and the solution of the monoanion was s t i r r e d at 0° for 10 min before i t was alkylated with 1.75 g (12 mmol) of 39 l-bromo-2-pentyne (35). The reaction mixture was s t i r r e d at room temperature for 4 h, di l u t e d with ethyl ether, washed with water, and dried over anhydrous magnesium sulfat e . The solvents were removed under reduced pressure and the crude product d i s -t i l l e d at 75° C/0.1 t o r r to y i e l d 1.27 (70%) of methyl 2-acetyl-4-heptynoate (3_6) . A small sample of 3_6_ was p u r i f i e d by TLC (using a mixture of CC1 4 and E t 2 0 , 8:1 v/v) and had the following spectral data; IR (CHC13) 1715, 1740 and 2275 cm"1; NMR (CDC13) 6 1.07 (t, J = 7 Hz, 3H) , 1.8-2.3 (m, 2H) , 2.27 (s, 3H), 2.4-2.8 (m, 2H), 3.60 (t, J = 7 Hz, IH), and 3.72 (s, 3H) ; mass spectrum: a) high resolution calcd for Ci^H^O^: 182.0922 amu; found: 182.0918; b) low resolution m/e ( r e l intensity) 43(60), 79 (22), 106 (23), 123 (15), 139 (100), 140 (10), 151 (6), 167.(2) , and 182 (4) . Anal. Calcd for C 1 0 H 1 4 O 3 : C, 65.92, H, 7.74. Found: C, 66.21; H, 7.87. Methyl (Z)-2-acetyl-4-heptenoate (38) A mixture of 3.64 g (20.0 mmol)> of methyl 2-acetyl-4-heptynoate (3_6) , 0.12 g of 5% palladium on barium s u l f a t e 6 6 and 6 drops of d i s t i l l e d quinoline i n 125 ml of anhydrous methanol was hydrogenated at atmospheric pressure. After ca. 1 h one equivalent of hydrogen was absorbed, the mixture was f i l t e r e d , 40 and the methanol was removed, under reduced pressure. The crude product was dissolved i n ethyl ether, and washed with d i l u t e aqueous hydrochloric acid and brine. The etheral solu-tion was dried over anhydrous magnesium sulfate and solvent removed under reduced pressure. The crude product was d i s t i l l e d at 75° C/0.1 t o r r to y i e l d 3.26 g (89%) of methyl U ) - 2 - a c e t y l -4-heptenoate (3_8) . A small sample of 3_8_ was p u r i f i e d by TLC (CClit:Et20, 8:1 v/v) and was characterized by; IR (CHC13) 1710 and 1740 cm"1; NMR (CDC13.) 6 0.95 (t, J = 7 Hz, 3H) , 1.7-2.2 (m, 2H) , 2.22 (s,-*'3H), 2.57 (m, 2H) , 3.43 (t, J = 7 Hz, IH) , 3.70 (s, 3H) , and 4.9-5.6 (m, 2H); mass spectrum: a) high resolution calcd for C 1 0 H i 6 0 3 : 184.1096 amu; found: 184.1095; b) low resolution m/e ( r e l intensity) 43(100), 68(45), 81(33), 95(25), 109(30), 123(15), 137(7), 141 (85), 152 (10), 166 (5), and 184(10). Anal. Calcd for C i 0 H i 6 0 3 : C, 65.19; H, 8.75. Found: C, 65.37; H, 8.67. (Z)-6-Carbomethoxy-l-trimethylsilyl-8-undecen-l-yn-5-one (39) A solution of 1.84 g (10.0 mmol) of the ester 38 i n 5 mL of anhydrous THF was added dropwise to a suspension of o i l - f r e e sodium hydride (0.55 g) i n THF at 0° C under nitrogen. After s t i r -r ing for 10 min, 4.8 mL of 2.1 M n-butyllithium (10.1 mmol) was added , and" aft e r another 10 ;min , . the .resulting dianion was -alkyl a-41 ted with 2.28 g (12.0 mmol) of 3-bromo-l-trimethyl-l-propyne (27). The reaction mixture was then s t i r r e d at 0° C for 3 h and room temperature for 2 hr. I t was quenched with saturated ammonium chloride, extracted with ethyl ether, washed with brine and dried over anhydrous sodium su l f a t e . The solvents were removed under reduced pressure to y i e l d 3; 0 'g>( 99%) of crude 3_9 which was used d i r e c t l y i n the next step. The a l k y l a t i o n pro-duct 39 was homogeneous by chromatography and i t was character-ized by the following spectral data; IR (CHCl 3) 1720, 1745, and 2200 cm"1; NMR (CDC13) <5 0.20 (s, 9H), 1.00 (t, J = 7 Hz, 3H), 1.8-2.9 (m, 8H), 3.53 (t, J = 7 Hz, IH), 3.70 (s, 3H), and 5.1-5.7 (m, 2H); mass spectrum: a) high resolution calcd for Ci6H,2 6 0 3 S i : 294.1641 amu; found: 294.1636; b) low resolution m/e (rel intensity) 41 (40), 43 (40) , 73 (100) , 89 (26), 141 (35), 193 (11), 235 (22), 279 (10) , and 294 (3) . (Z)-6-Carbomethoxy-8-undecen-2,5-dione (40) The crude t r i m e t h y l s i l y l a l k y n e 3_9_ (1.47 g, 5.0 mmol) was hydrolyzed with 0.076.g of mercuric oxide i n s u l f u r i c acid, water and THF under the same conditions as those reported for hydrolysis of 29_. The crude product was d i s t i l l e d (Kugelrohr) at 125° C/0.5 to r r to give 1.20 g (80%) of dione 4_0. Further p u r i f i c a t i o n was achieved by TLC: 0.1 g of the d i s t i l l e d pro-42 duct was chromatographed u s i n g carbon t e t r a c h l o r i d e and e t h y l ether (4:1 v/v) as e l u e n t to y i e l d 0.075 g of pure dione 4_0 which had the f o l l o w i n g s p e c t r a l data; IR (CHC1 3) 1715 and 1745 cm" 1; NMR (CDC13) 6 0.93 ( t , J = 7 Hz, 3H), 1.7-2.2 (m, 2H), 2.17 (s, 3H), 2.57 (m, 2H), 2.73 (br s, 4H), 3.52 ( t , J = 7 Hz, IH), 3.70 (s, 3H), and 5.0-5.7 (m, 2H); mass spectrum: a) high r e s o l u t i o n c a l c d f o r C ^ ^ o O ^ : 240.1376 amu; found: 240.1373; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41(33), 43 (100), 81 (25), 99(90), 109 (50), 127(29), 129 (18), 141(71), 151 (21), 172 (10), 183 (15), 190 (13), 208 (10), 209°(H) , 222 (18) , and 240 (10). Anal, c a l c d f o r C 1 3 H 2 0 O 4 : C, 64.98; H, 8.39. Found: C, 64.70; H, 8.45. Cis-Jasmone (1) A sample of 0.48 g (2.0 mmol) of d i k e t o e s t e r 40_ was hydrolyzed and c y c l i z e d w i t h 16 mL of 3% aqueous sodium hydroxide u s i n g the same procedure as t h a t used i n the s y n t h e s i s of d i -hydro j asmone (2). The crude product was d i s t i l l e d (Kugelrohr) to y i e l d 0.28 g (85%) of cis-jasmone (1_) which was homogeneous by TLC a n a l y s i s and a TLC p u r i f i e d (CCli+:Et2 0, 4:1 v/v) sample of 1_ had s p e c t r a l data i d e n t i c a l t o those r e p o r t e d f o r c i s -jasmone ( 1 ) ; 1 8 43 IR ( C H C I 3 ) 1640 and 1690 cm 1 ; NMR ( C D C I 3 ) 6 0.97 ( t , J ~ 7 Hz , 3H) , 2.03 ( s , 3H), 1 .7 -2 .1 (m, 2H), 2 . 2 - 2 . 6 (m, 4H) , 2.9 (m, 2H) , and 5.25 (m, 2H) , mass spectrum m/e ( r e l i n t e n s i t y ) 41 (38 ) , 43 (41) , 55 (41 ) , 79 (35) , 109 (58) , 110 (53) , 122 (44) , 135 (45) , 149 (43) , and 164(100) . 44 BIBLIOGRAPHY 1 a. R. A. E l l i s o n , S y n t h e s i s , 397 (1973). b. T. L. Ho, Syn.. Commun. , 4, 265 (1974). c. T. L. Ho, Syn. Commun., 7, 351 (1977). d. A. E. Greene and P. CrabEe, Tetrahedron L e t t . , 4867 (1967). e. P. Bakuzis and M. L. F. Bakuzis, J . Org. Chem., 42, 2362 (1977). ~~ f. S. T o r i i , W. Tanaka, and Y. Kobayasi , J . Org. Chem., 42, 3473 (1977). ~~ g. W. J . Manteiro, J . Org. Chem., 42, 2324 (1977). h. S. Takano, T. Sugahara, M. I s h i g u r o , and K. Ogasawara, H e t e r o c y c l e s , 6, 1141 (1977). i . S. T o r i i , W. Tanaka, and Y. Tomotaki, B u l l . Chem. Soc. Jpn., 50, 537 (1977). j . E. Keinan and Y. Mazen, J . Amer. Chem. Soc., 99, 3861 (1977). — k. W. C. S t i l l , J . Amer. Chem. Soc., 99, 4836 (1977). 2. G. Buchi and H. Wuest, J . Org. Chem., 31, 977 (1966). 3. G. Stork and R. Borch, J . Amer. Chem. Soc., 86, 935, 936 (1964). 4 a. S. N. Huckin and L. W e i l e r , J . Amer. Chem. Soc., 96, 1082 (1974). b. L. W e i l e r , J . Amer. Chem. Soc. , 9_J, 6702 (1970). 5. S. N. Huckin, G. R. Ric k a r d s , F. W. Sum, and P. E. Sum, unpublished r e s u l t s , 1972-1976. 6 a. P. E. Sum, M.Sc. T h e s i s , U n i v e r s i t y of B r i t i s h Columbia, Vancouver, B.C., 1976. b. T. A. Bryson, J . Org. Chem. , 3_8, 3 4 2 8 d 9 7 3 ) • 7. J . T. Adams, R. Le v i n e , and C. R. Hauser, Organic Syntheses, C o l l . V o l . I l l , John Wiley and Sons, New York, N.Y. , 1955, p. 405. 8 a. J . E. Baldwin, J . Chem. Soc. Chem. Commun., 734 (1976). b. J . E. Baldwin and K. T. Kruse, J . Chem. Soc. Chem. Commun., 233 (1977). 9. R. M. Jacobson, R. A. Raths, and J . W. McDonald I I I , J . Org. Chem., 42, 2545 (1977). 10. A. E. Greene, J . C. M u l l e r , and G. Our i s s o n , J . Org. Chem., 3J, 186 (1974) . 45 11. R. B. M i l l e r , Syn. Commun. , 2_, 267 (1972). 12 a. A. G. W. Stacy and R. A. Mi k u l a c , Organic Syntheses, C o l l . V o l . IV, John Wiley and Sons, New York, N.Y., 1963, p. 13. b. D. A. McCrae and L. Dolby, J . Org. Chem., 42, 1607 (1977). 13 a. H. M. Schmidt and J . F. Arens, Rec. Trav. Chim., 86, 1138 (1967). b. J . F l a h a u t and P. M i g i n i a c , Helv. Chim. Ac t a , 60, 2275 (1978). "~ 14. K. E. S c h u l t e and W. Eng e l h a r d t , Arch. Pharm., 287, 495 (1954). 15 a. D. J . Cram and N. L. A l l i n g e r , J . Amer. Chem. Soc. , 78, 2518 (1956). b. R. Maringo, Organic Syntheses, C o l l . V o l . I l l , John Wiley and Sons, New York, N.Y., 1955, p. 685. 16 a. C. A. Brown, J . Org. Chem., 3J, 1324 (1974). b. C. A. Brown, J . Org. Chem. , 3J, 3913 (1974). 17. R. G. Jones and M. J . Mann, J . Amer. Chem. Soc., 75, 4048 (1953). 18. P. Dubs and R. S t u s s i , Helv. Chim. A c t a . , 61, 990 (1978). 19. R. T. D a h i l l , J r . , J . Org. Chem., 31, 2694 (1966). 20. J . M. Conia, B u l l . Soc. Chim. France, 1449 (1975). 46 SPECTRAL APPENDIX 4 7 48 49 bO 51 PART I I S Y N T H E S I S OF C Y C L I C K E T A L - T Y P E I N S E C T PHEROMONES 52 INTRODUCTION (:L) General Pheromones are highly active chemical messengers se-creted by an insect to influence the behavior of other insects of the same species. The term "Pheromone" i s derived from the Greek "pherein" (to carry, transmit) and "hormon" (to excite, stimulate). 1 Compounds which are involved i n the i n t e r n a l trans-port of information i n insects, for example, development, meta-morphosis and reproduction are c a l l e d "hormones," while those involved i n the external transport of information are c a l l e d "pheromones." Pheromones include sex attractants, alarm phero-mones, and aggregation pheromones whose names are self-explana-tory for t h e i r functions. Since pheromones are usually trans-mitted among insects through the atmosphere i n very minute quan-t i t i e s , insects can frequently be attracted by an active chemical to a trap for surveying purposes, to a toxic compound that des-troys them, or to substances that render them incapable of f e r -t i l e mating. Pheromones can also be used to i n t e r f e r e with normal insect behavior. Due to the environmental p o l l u t i o n and ecological imbalance caused by i n s e c t i c i d e s , insect pheromones may serve as an alternate method to coritrol pest insect popula-t i o n s . 2 In recent years, i n t e r e s t i n the chemical i d e n t i f i c a t i o n and synthesis of insect pheromones has greatly increased because of t h e i r s c i e n t i f i c and economic values. 53 The number of pheromones i s o l a t e d from v a r i o u s o r d e r s of i n s e c t s has been growing r a p i d l y i n the past decade. The s t r u c t u r e s of many i n s e c t pheromones have been found to be sim-p l e l o n g - c h a i n , s l i g h t l y branched o l e f i n i c hydrocarbons, or c y c l i c e t h e r s . Some of these pheromones are c h i r a l compounds. Unsaturated a l i p h i l i c a l c o h o l s , aldehydes, or a c e t a t e s are the most commonly o c c u r r i n g f e a t u r e s found i n the sex pheromones of L e p i d o p t e r a (moths and b u t t e r f l i e s ) species-. (E)-10-Propyl-5 , 9 - t r i d e c a d i e n y l a c e t a t e ( 1 ) 3 has been found to be the sex a t t r a c t a n t produced by the v i r g i n female pink bollworm moth. The sex a t t r a c t a n t produced by the female gypsy moth was Y 1 i d e n t i f i e d as (7R, 8S)-epoxy-2-methyl-octadecane (2). T h i s i s a l s o one of the few examples of c h i r a l compounds among the 54 Lepidopterous pheromones. M' 5 Another example i s (E)-3,7-d i m e t h y l - 2 - o c t e n - l , 8 - d i o l (3_) which i s one of the major compo-nents s e c r e t e d by the h a i r p e n c i l s of the A f r i c a n Monarch b u t t e r -f l y , Danaus c h r i s i p p u s . 6 Pheromonal communication has a l s o been found i n D i p t e r a n ( f l i e s ) s p e c i e s , but not many pheromones of t h i s s p e c i e s have been i d e n t i f i e d . One of the i d e n t i f i e d compounds i s the sex a t -t r a c t a n t of the. common h o u s e f l y , Musca domestica, which has been c h a r a c t e r i z e d as ( Z ) - 9 - t r i c o s e n e (4_) . 7 Jacobson e t a l . 8 i d e n t i -f i e d two components of the sex pheromone of the Mediterranean _£_ f r u i t f l y , C e r a t i t i s c a p i t a t a , as (E)-6-nonen-l-ol (5_) and methyl (E)-6-nonenoate (J5) . C o l e o p t e r a (beetles and weevils) i s the l a r g e s t order of i n s e c t s and u n l i k e L e p i d o p t e r a , the sex pheromones of b e e t l e s and w e e v i l s are s t r u c t u r a l l y d i v e r s e and.many of them are c h i r a l compounds. (-)-Methyl ( E ) - 2 , 4 , 5 - t e t r a d e c a t r i e n o a t e (7_) was i d e n t i f i e d as the pheromone produced by males of the bean w e e v i l •OMe A c a n t h o s e e l i d e s o b t e c t u s , t o a t t r a c t the v i r g i n female w e e v i l s . 9 ' T h i s was a l s o the f i r s t known a l l e n i c sex pheromone. The fo u r components ( c o l l e c t i v e l y c a l l e d "grandlure") produced by male b o l l w e e v i l s t o a t t r a c t the female have been i d e n t i f i e d as • ( + ) - 2 - ( c i s - i s o p r o p e n y l - l - m e t h y l c y c l o b u t y l ) e t h a n o l (8_) , (Z_)-2- (3 , 3-dimethylcyclohexylidene) - e t h a n o l (9_) , (Zj-2-(3,3-dimethylcyclohexylidene)acetaldehyde (10), and (E)-2-(3,3-d i m e t h y l c y c l o h e x y l i d e n e ) a c e t a l d e h y d e ( 1 1 ) . 1 1 — 1 4 8 9 10 11 56 Some other i n t e r e s t i n g pheromones are exc r e t e d by-bark b e e t l e s of the f a m i l y S c o l y t i d a e . (+)-cis-Verbenol ( 1 2 ) , ( - ) - 2 - m e t h y l - 6 - m e t h y l e n e - 7 - o c t e n - 4 - o l (13J (also named i p s e n o l ) , and ( - ) - 2 - m e t h y l - 6 - m e t h y l e n e - 2 , 7 - o c t a d i e n - 4 - o l (14) (or i p s -d i e n o l ) , are the p r i n c i p a l components of the a t t r a c t a n t phero-mone produced by the bark b e e t l e Ips p a r a c o n f u s u s . 1 5 ' 1 5 A l l of H OH 12 13 14 these compounds are o p t i c a l l y a c t i v e and none of the i n d i v i d u a l compounds i s a t t r a c t i v e to the b e e t l e by i t s e l f . However, a mixture of the three compounds a t t r a c t s the f l y i n g b e e t l e s r i n the f i e l d . 1 7 ~ 2 2 A group of pheromones having an unusual 6 , 8 - d i o x a -b i c y c l o [ 3 . 2 . 1 ] o c t a n e s k e l e t o n have been i s o l a t e d from bark b e e t l e s of the f a m i l y S c o l y t i d a e . The f i r s t i d e n t i f i e d phero-mone wit h t h i s b i c y c l i c k e t a l s k e l e t o n i s the a t t r a c t a n t phero-mone produced by western p i n e b e e t l e s , Dendroctonus b r e v i c o m i s . I t c o n s i s t s of exo- and e n d o - 7 - e t h y l - 5 - m e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] octane (15) and (_16) , which have been given the t r i v i a l 57 names exo-brevicomin and endo-brevicomin, r e s p e c t i v e l y . 2 3 ' 2 1 , 1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octane (17) ( f r o n t a l i n ) 2 5 i s another component of the aggregation pheromone is o l a t e d from the hindgut extracts of male western pine beetles and i t has also been detected i n the southern pine beetle Dendroctonus  f r o n t a l i s . 2 5 This unusual b i c y c l i c ketal skelton i s found in other sex pheromones as well. The aggregation pheromone for the European elm bark beetle, Scolytus m u l t i s t r i a t u s , has been characterized as a mixture of three components, 2 6 one of which i s 2,4-dimethyl-5-ethyl-6,8-dioxabicyclo[3.2.1]octane (18), 15 1 6 1 7 18 1 9 20 58 named a - m u l t i s t r i a t i n . The other two components are (-)-4-methyl-3-heptanol (19) and (-)-a-cubebene (20) . Compounds 1_8 and 19_ are produced by the beetles while compound 2_0 i s produced by the host elm tree. endo-1,3-Dimethyl-2,9-dioxabicyclo[3.3.1] nonane (21) , 2 7 ' 2 8 a hos t - s p e c i f i c substance found i n Norway spruce infested by Trypodendron lineatum OLIV i s another example of the b i c y c l i c ketal-type pheromones. 21 Very recently, a t r i c y c l i c ketal-type pheromone was isolated from the frass of Trypodendron lineatum female beetles. The structure of t h i s pheromone was f i r s t proposed to be one of the two isomeric compounds 22 or 23 shown below. 2 9 I t was 22 23 59 l a t e r confirmed to be 3 , 3 , 7 - t r i m e t h y l - 2 , 9 - d i o x a t r i c y c l o [ 3 . 3 .1. 0 4 ' 7 ] nonane (2_2) and l i n e a t i n i s the t r i v i a l name given to t h i s pheromone. 3 0 Since d e t a i l e d coverage of a d i v e r s e t o p i c such as "Ins e c t Pheromones" i s out of the scope of t h i s d i s s e r t a t i o n , the above d e s c r i p t i o n i s merely intended to pr o v i d e a ge n e r a l back-ground f o r our p r e s e n t work. As can be noted from t h i s b r i e f s u r -vey, the c y c l i c k e t a l - t y p e pheromones comprise a unique group of compounds, which are s t r u c t u r a l l y and f u n c t i o n a l l y s i m i l a r and are a l l e x c r e t e d by b e e t l e s . The economic i m p l i c a t i o n of these phero-mones i n connection w i t h the timber i n d u s t r y and the s y n t h e t i c c h a l l e n g e a r i s i n g from t h e i r unusual s t r u c t u r e s s t i m u l a t e d our i n t e r e s t i n t a c k l i n g the s y n t h e s i s of these compounds. In the f o l l o w i n g p a r t of t h i s t h e s i s , b r i e f reviews of the source, s t r u c -t ure e l u c i d a t i o n , and recorded syntheses of the i n d i v i d u a l c y c l i c k e t a l - t y p e pheromones are presented b e f o r e a d e t a i l e d d i s c u s s i o n of our syntheses of these compounds (except compound 21). 60 ( i i ) Source, Structure Elucidation and Synthesis of Cy c l i c  Ketal-type Beetle Pheromones (a) exo- and endo- Brevicomin Source: The western pine beetle Dendroctonus brevicomis, i s one of the most destructive bark beetle pests. The i n i t i a l attackers are the female bark beetles. They bore into the ponderosa pine to.construct a nuptial chamber, and expel frass -a mixture of wood fragments and f e c a l p e l l e t s . The frass con-tains the sex attractant which i n i t i a t e s the mass attack that usually k i l l s the tree. Each year, about f i v e b i l l i o n board-feet of timber are destroyed by these bark beetles, and so far there are no e f f e c t i v e methods to control t h i s pest. Structure Elucidation: In 1968, Sil v e r s t e i n . et a l . i s o l a t e d about 2 mg of the sex attractant produced by the v i r g i n female D. brevicomis by extracting a t o t a l of 1.6 kg of f r a s s . 2 3 High resolution mass, spectrometry established the molecular formula of the pheromone as C 9 H 1 6 O 2 . The infrared spectrum showed intense peaks between 1250-900 cm - 1 (8-11.7 u) i n d i c a t i n g the presence of an ether group. Neither hydroxy1 nor carbonyl peaks were observed. The NMR spectrum showed the methyl protons of an ethyl group (6 0. 87 , 3H, s l i g h t l y d i storted t r i p l e t ) , a methyl 61 group on a d e s h i e l d e d q u a r t e r n a r y carbon (6 1.3, 3H, s i n g l e t ) , a m u l t i p l e t from 6 1.1 to 1.9 (8H), and two s i n g l e protons at 6 3.7 8 and 3.9 8 which must be on carbon atoms adjacent to oxygens. No r e a c t i o n was observed when the pheromone was t r e a t e d w i t h e i t h e r diborane or l i t h i u m aluminum h y d r i d e . Since spec-t r a l evidence showed the absence of double or t r i p l e bonds i n the molecule,, a b i c y c l i c e ther s t r u c t u r e was thus suggested. C a t a l y t i c hydrogenation a t 250° C gave n-nonane as the major product. T h i s i n d i c a t e d t h a t the e t h y l and methyl groups must be at o p p o s i t e ends of the u n f o l d e d molecule. Since NMR showed t h a t the methyl group was attached to a q u a r t e r n a r y carbon 15 or 1 6 and was d e s h i e l d e d , a b i c y c l i c k e t a l s t r u c t u r e analogous to 1_5 or 16_, was proposed. Assuming t h a t the e t h y l group was a s i d e c h a i n on a r i n g , one oxygen must be j o i n e d to C-7, and the other oxygen was- attached to G-l i n o rder to account f o r the d o w n f i e l d t r i p l e t which was a t t r i b u t e d to the proton on C-7 (the protons 62 on C - l and C-7 have a d i h e d r a l angle of 90° i n the exo isomer 15, and t h e r e f o r e the c o u p l i n g constant i s c l o s e to z e r o ) . Since s e v e r a l b i c y c l i c k e t a l s t r u c t u r e s were p o s s i b l e from these data, a s y n t h e t i c route which would g i v e both exo-and endo-7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane (15 and 16) was designed (Scheme I ) . 2 3 The triphenylphosphonium bromide 24_ was t r e a t e d w i t h p h e n y l l i t h i u m and the r e s u l t i n g y l i d was allowed to r e a c t w i t h propanol to give a mixture of c i s and t r a n s o l e f i n s 2_5. A f t e r e p o x i d a t i o n , the i s o m e r i c epoxides were separated by gas l i q u i d chromatography (GLC)',. Upon h y d r o l y s i s , the c i s epoxide 26a c y c l i z e d t o g i v e the exo compound 15_ w h i l e the t r a n s epoxide 26b gave the endo compound 16. The s p e c t r a l data of the s y n t h e t i c exo compound 15_ matched those o f the a c t i v e i s o l a t e d compound d e s c r i b e d above, whereas the s p e c t r a of the s y n t h e t i c endo isomer 16_ matched those of an i n a c t i v e compound i s o l a t e d a l s o from the f r a s s . Thus, the s t r u c t u r e o f the a c t i v e n a t u r a l compound was a s s i g n e d as exo-7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane (15) and was given the t r i v i a l name exo-brevicomin. 15 63 Scheme I . S y n t h e s i s o f exo- and endo-7-Ethyl-5-methyl-6,8-d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n e (15) and ( 1 6 ) 2 3 1. PhLi 2. C H 3 C H 2 C H O 24 ( c is, trans mixture ) m - C I C 6 H 4 C 0 3 H 26 (c is trans mixture) GLC separation 26a (cis epoxide ) 26b ( trans epoxide) H 3 ° + H 3 G + 1 5 1 6 64 S y n t h e s i s : S h o r t l y a f t e r the r e p o r t on the s t r u c t u r e of brevicomin by S i l v e r s t e i n and coworkers, 2 3 a number of syntheses of t h i s compound were r e p o r t e d . In these syntheses, the two g e n e r a l methods l e a d i n g to the formation of the 6,8-dioxabicyclo[3.2.1] octane s k e l e t o n were (A) the thermal or a c i d c a t a l y z e d c y c l i z a -t i o n of keto epoxide 27_ to 2_9, and (B) the c y c l i z a t i o n of the dihydropyran 2_8 to 29. F i g u r e 1. General S y n t h e t i c Pathways to 6,8-Dioxabicyclo[3.2.1]-octane Systems S i l v e r s t e i n and coworkers have developed s e v e r a l syn-t h e t i c routes to brevicomin u t i l i z i n g method (A). Besides the aforementioned s y n t h e s i s which was designed to c o n f i r m the 6 5 structure of brevicomin (Scheme I ) , 2 3 a stereoselective syn-thesis involving the same intermediate 25a (cis isomer) was also achieved by these workers (Scheme I I ) . 3 1 The c i s alkene 25a was prepared i n a stereoselective manner from 2-acetyl-butyrolactone (30) . Hydrolysis of the lactone i n 30_ with con-comitant decarboxylation and bromination of the r e s u l t i n g hy-droxy acid was effected by treatment with 48% hydrobromic acid. The carbonyl group i n the bromo" ketone thus formed was protected as the ethylene ketal. to give 31. A l k y l a t i o n of sodio 1-butyne with bromide 3_1 afforded'the acetylene 32, which was p a r t i a l l y hydrogenated (H 2/Ni(0Ac)2-NaBH4) to furnish the c i s alkene 25a. exo-Brevieomin was f i n a l l y obtained by epoxidation of 25a, f o l -lowed by acid-catalyzed hydrolysis of the ketal group and cy-c l i z a t i o n of the resultant epoxy ketone. During a study of the rearrangement of epoxy carbonyl compounds, Wasserman.and Barber 3 2 noted the f a c i l e formation of b i c y c l i c compounds, exemplified by the conversion of 23_ into 34. This rearrangement was applied to the synthesis of exo-brevicomin. 3 2 The keto epoxide 35_ was synthesized, which upon thermal rearrangement gave the desired product 1J5 and 16^  i n the 3 3 3 4 66 Scheme I I . S t e r e o s e l e c t i v e S y n t h e s i s of exo-Brevicomin (15) 3 1 1. HBr , H 2 0 2, (HOCH 2) 2 ,p-TsOH 30 31 Na, C ^ C I - ^ C S E C H H 2 / N K O A c ^ -NaBH 4 32 1. m-CICgH 4CO H 2. HCIO„ A 25a 1 5 67 ( 9 1 ) r a t i o of 9:1. K o c i e n s k i and Ostrow 3 3 r e p o r t e d an i n t e r e s t i n g s y n t h e s i s of brevicomin, through an unusual method of g e n e r a t i n g the ace-t y l e n i c ketone 3_8, as shown i n Scheme I I I . The a c e t y l e n i c k e t a l 32 was prepared i n three steps from the cyclohexenone _36_. Eschen-moser fragmentation of the epoxy ketone 3_7 gave a c e t y l e n i c ketone 38 which was p r o t e c t e d as the corresponding ethylene k e t a l . S t e r e o s e l e c t i v e r e d u c t i o n s o f the a c e t y l e n i c k e t a l 32_ w i t h d i -borane or sodium i n ammonia gave the c i s or t r a n s o l e f i n s , 25a or 25b, r e s p e c t i v e l y . E p o x i d a t i o n of 25a f o l l o w e d by a c i d c a t a l y z e d c y c l i z a t i o n gave exo-brevicomin (15), w h i l e a s i m i l a r treatment on 25b l e d to endo-brevicomin (16). A new s y n t h e s i s of the a c e t y l e n i c ketone 3_8 was r e p o r t e d very r e c e n t l y by Cooke e t a l . 3 1 * T h i s sequence i n v o l v e d methyl-l i t h i u m a d d i t i o n to the c a r b o n y l group of the 8 - c h l o r o enone 40 and thermal cleavage o f the i n t e r m e d i a t e a l k o x i d e (Scheme IV). A p p l i c a t i o n to the s y n t h e s i s of exo-brevicomin (15) was a l s o r e p o r t e d . 6 8 Scheme I I I . S y n t h e s i s of Brevicomin from a Cyclohexenone:. 3 3 H 2 ° 2 O H TS NHNH-H O A c / C H g C l g 3 6 3 7 3 8 ( H O C H 2 ) 2 9 p - T s O H G 3 2 N a - N H . 1. B H 3 - M e 2 S 2 . H O A c , A 2 5 b 2 5 a 1. r r i - C I C 6 H 4 C 0 3 H 2 . 0 . 1 N HCIO„ 1. m -C I C g ^ G O ^ 2 . 0.1 "N H C I C L 1 6 1 5 69 Scheme IV. S y n t h e s i s of A c e t y l e n i c Ketone 3.8 -3 8 A t o t a l l y d i f f e r e n t approach was adopted by K n o l l e and S c h a f e r . 3 5 In t h e i r s y n t h e s i s , the o l e f i n i c ketone 4_3 was prepared by a Kolbe e l e c t r o l y s i s of trans-3-hexenoic a c i d (41) and l e v u l i n i c a c i d (4_2) . A mixture of dimers and trans-6-nonen-2-one (4_3) were thus obtained. Compound 4_3_ was then converted i n t o exo-brevicomin (15) by c i s h y d r o x y l a t i o n with osmium t e t r a -oxide, f o l l o w e d by acid-promoted c y c l i z a t i o n (Scheme V ) . endo-Brevicomin (16) has a l s o been prepared from 1,3-butadiene (44_) by a novel approach which may be c o n s i d e r e d as a v a r i a t i o n of method (A) i n F i g u r e 1 (Scheme V I ) . 3 6 P a l l a d i u m c a t a l y z e d d i m e r i z a t i o n of 1,3-butadiene (4_4) with concomitant c a r b o n y l a t i o n i n e t h a n o l gave the nonadienoate 4_5 which was 70 Scheme V. S y n t h e s i s of exo-Brevicomin v i a Kolbe E l e c t r o l y s i s 3 5 converted by a r e d u c t i o n - t o s y l a t i o n - r e d u c t i o n sequence i n t o the trans-nonadiene 46. S e l e c t i v e e p o x i d a t i o n of 4_6 f o l l o w e d by h y d r a t i o n gave d i o l 4_7_ which was c y c l i z e d d i r e c t l y to endo-brevicomin (16) u s i n g p a l l a d i u m (II) c h l o r i d e as c a t a l y s t i n 71 Scheme VI. Synthesis of endo-Brevicomin from 1,3-Butadiene (44) 3 6 the presence of excess copper (II) c h l o r i d e . The use of method (B) (Figure 1) to s y n t h e s i z e b r e v i -comin was f i r s t r e p o r t e d by Mundy and c o w o r k e r s 3 7 (Scheme V I I ) . 72 Scheme VII. Diels-Alder Route to exo- and endo-Brevicomin 3 This synthesis started with the Diels-Alder addition of methyl v i n y l ketone (4_8) to acrolein. The r e s u l t i n g dihydropyran 49_ was converted into alcohol 5_0 with methylmagnesium bromide. Hg 2 + catalyzed ring closure of 50 gave the desired products 15_ and 16_. Although the synthesis i s short, unfortunately, only a 9% y i e l d of the desired product was obtained. 3 8 ~ 4 0 This low y i e l d was l a t e r r a t i o n a l i z e d as follows. The Diels-Alder reaction i n i t i a l l y led to formation of the desired adduct 49, which could undergo Cope rearrangement to give the more stable and undesired product 51. **1 73 ) The e x o - b r e v i c o m i n (15) m o l e c u l e p o s s e s s e s two c h i r a l c e n t r e s . The f a c t t h a t a 0.05% h e x a n e s o l u t i o n o f t h e n a t u r a l compound showed no o p t i c a l r o t a t i o n 2 3 s u g g e s t e d t h a t t h e p h e r o -mone i s e i t h e r r a c e m i c o r h a s t o o s m a l l a r o t a t i o n t o be mea-s u r e d i n s u c h a d i l u t e s o l u t i o n . I n o r d e r t o e s t a b l i s h t h e a b s o l u t e c o n f i g u r a t i o n o f b o t h e n a n t i o m e r s o f e x o - b r e v i c o m i n (15) a n d t o c l a r i f y t h e r e l a t i o n s h i p b e t w e e n p h e r o m o n a l a c t i v i t y a n d c h i r a l i t y , t h e s y n t h e s i s o f o p t i c a l l y a c t i v e b r e v i c o m i n was n e c e s s a r y . The f i r s t s y n t h e s i s o f o p t i c a l l y a c t i v e , e x o - b r e v i c o m i n (15) o f known a b s o l u t e c o n f i g u r a t i o n was a c c o m p l i s h e d by M o r i i n 1974 1* 2 (Scheme V I I I ) . The r e a d i l y a v a i l a b l e D- ( - ) - t a r t a r i c a c i d (52) w i t h known a b s o l u t e c o n f i g u r a t i o n (2S, 3S) was 74 Scheme VIII. Mori's Synthesis of Op t i c a l l y Active exo-Brevicomin (15) from Ta r t a r i c Acid 1* 2 HO-H-C 0 2 H -H -OH C 0 2 H 1. esterif ication MeO-2. M e l , A g 2 0 H " C 0 2 E t - H 1. LiAIH -OMe C 0 2 E t 2. TsCI 4^ MeO-3»' H-„OTs -H -OMe "OTS 52 53 54 1. NaCN , DM SO MeO-2. HC I , MeOH /C0 2Me -H -OMe 1. KOH 2. B 2 Hg 3. TSCI MeO-- C 0 2 M e --H -OMe 1. L iAIH 4 2. TSCI 3. L iBr - C 0 2 M e 55 56 MeO-H-Br 57 1. > L ^ ° 2 M e M e O -OMe 2. Ba(OH) 2 H--H 5 8 1. C r O . 2. OH~ -OMe 3. H 3 O f (1 R ,5S ,7R )-V5 75 employed to synthesize (IR, 5S, 7R)-exo-brevicomin (15) while i t s antipode (IS, 5R, 7S)-15_ was prepared from (2R, 3R)-L-( + )-t a r t a r i c acid. The (3R, 4R)-l-bromo-3,4-dimethoxyhexane (57) prepared i n ten steps from diet h y l (2S, 3S)-tartrate was used to alkylate the monoanion of ethyl acetoacetate. The r e s u l t i n g product was then hydrolyzed to the (+)-dimethoxy ketone 58. Removal of the methoxy protecting groups was achieved i n low y i e l d by chromium t r i o x i d e oxidation of the methyl ether to give the corresponding formate ester. Base hydrolysis, f o l -lowed by acid-catalyzed c y c l i z a t i o n gave (IR, 5S, 7R)-15_, [ a ] ^ 4 + 84.1° (ethyl ether). A s i m i l a r reaction sequence was employed to prepare (IS, 5R, 7S)-15_, [ a ] 2 4 - 80.0° (ethyl ether), s t a r t -le ing from (2S, 3R)-tartaric acid. The entomological study of the synthetic compounds showed that only (IR, 5S, 7R)-1_5 was bio-if 3 l o g i c a l l y active. Meyer reported another synthesis of exo-brevicomm (15) i n i t s o p t i c a l l y active form as shown i n Scheme IX. The same s t a r t i n g material, d i e t h y l (+)-(2R, 3R)-tartrate, was used to prepare compound 5_9 which was allowed to react with lithium dimethylcuprate to give, after hydrolysis, alcohol 60a. The bromide 60b derived from 60a was alkylated with the anion of dithiane 61_ to give 6_2. The thioketal group was cleaved reduc-t i v e l y using Raney-Nickel. Subsequent acid-catalyzed c y c l i z a -t i o n led to the formation of the desired product (1S_, 5R, 7S)-15, [ a ] 2 4 - 67.5° (ethyl ether). 76 Scheme IX. Meyer's Synthesis of O p t i c a l l y A c t i v e exo-Brevicomin from D i e t h y l (+)-(2R, 3R) T a r t r a t e 4 4 1 . R a n e y — N i c k e l 2. p - T sOH ( 1 S , 5 R , 7 S ) - 1 5 77 (b) Frontalin Source: Frontalin (17_) was f i r s t detected i n the hindguts of females of the southern pine beetle, Dendroctonus f r o n t a l i s  Zimmerman, and was l a t e r found i n larger amount, i n the hindguts of emergent male D. brevicomis, 2 5 thus providing a better source for isolation.and i d e n t i f i c a t i o n . Structure Elucidation: About 0.3 mg of the active compound was i s o l a t e d from approximately 6500 hindguts of male D. brevicomis. The molecu-l a r formula as determined by high resolution mass spectrum was C 8H l l t0 3. The infrared spectrum showed no hydroxy 1 or carbonyl absorptions, while a strong absorption between 1115 and 1025 cm 1 indicated the presence of the C-O-C linkage. Two absorp-ti o n bands of unequal i n t e n s i t i e s at 1380 and 1390 cm - 1 were attributable to two d i f f e r e n t methyl groups. Two sets of three-proton singlets at 6 1.32 and 1.42 i n the NMR spectrum were consistent with two methyl groups attached to quaternary carbon atoms. A multiplet at 6 1.63 (6H), and two i n d i v i d u a l protons at 6 3.9 3 and 3.42 which must be on carbon atoms adjacent to the oxygens were also observed. From the above spectral data, the structure of the active compound was concluded to be 1,5-dimethyl-6,8-dioxa-bicyclo[3.2.1]octane (17). 2 5 78 1 7 Synthesis: The common strategies adopted i n the synthesis of f r o n t a l i n (1_7) were similar to those employed i n the synthesis of brevicomin (1_5) . Frontalin (17) was f i r s t prepared i n a one-step synthesis which involved the Diels-Alder reaction of 48 and 6_3, and the i n s i t u c y c l i z a t i o n of 6_4 as shown i n Scheme X.2 5'* 5 Scheme X. A One-step Synthesis of Frontalin (17_) v i a Di e l s -Alder Reaction 2 5 ' 4 5 Mundy et a l . - 3 7 reported a rather similar synthesis of f r o n t a l i n (17_) from methyl v i n y l ketone (48) and methyl meth-acrylate (6_5) as i l l u s t r a t e d i n Scheme XI. Lithium aluminum hydride reduction of the Diels-Alder adduct 6_6 gave alcohol 6_4 79 which was c y c l i z e d i n the presence, of mercuric a c e t a t e to 17, Scheme XI. Mundy' s Syn t h e s i s of F r o n t a l i n (17_) v i a D i e l s -A l d e r Reaction 3 7 OMe P h H 200° C 48 65 LiAIH, OH 66 64 H g ( O A c ) 2 2 . 0 H ~ , BH 1 7 Due to the s c a r c i t y of the pure n a t u r a l pheromone, i t has been impossible so f a r to e s t a b l i s h i f n a t u r a l l y occur-r i n g f r o n t a l i n (17_) i s o p t i c a l l y a c t i v e . However, s e v e r a l 80 syntheses of o p t i c a l l y active f r o n t a l i n (17) have been reported, In the synthesis reported by Mori 1* 6 (Scheme XII), the sta r t i n g material 61_ was f i r s t resolved and then reduced to the t r i o l 6_8. The acetonide 6_9 derived from.6_8 was tosylated and treated with sodium cyanide to afford compound 7_0. Subsequent Scheme XII. Mori's Synthesis of O p t i c a l l y Active Frontalin • (17) J-6 LiA IH 4 67 OH 81 reaction of 70_ with methylmagnesium iodide, followed by a c i d i -f i c a t i o n gave (IR, 5S)-frontalin (17_) , [ a ] 2 3 + 53.4 (ethyl ether). An analogous scheme was followed to prepare (IS, 5R)-17, t a l D 3 - 52.0 (ethyl ether) from (S)-67. Another synthesis of both enantiomers of f r o n t a l i n (17) made use of the ketone 12_ which was synthesized from methyl ,a-D-glucopyranoside (7_1) i n four steps. 1* 7 The synthesis was then completed i n seven steps from the keto compound 72_. This syn-thesis i s rather lengthy and i n e f f i c i e n t compared to Mori's. OMe L L I l -Very recently, Magnus and Roy1*8 reported a synthesis of ( + )-(lR, 5S_)-frontalin using an a, $-epoxysilane as the key-intermediate (Scheme XIII). In t h i s synthesis, (-) - ( 3R)-lina-l o o l (7_3) , a c h i r a l monoterpene having the c r u c i a l asymmetric centre at C-3, was chosen as the s t a r t i n g material. As shown in Scheme XIII, the t r i m e t h y l s i l y l ether 7_4 prepared from 73 82 Scheme XIII. Chiral Synthesis of Frontalin v i a T r i m e t h y l s i l y l Epoxide, 8 78 83 was s e l e c t i v e l y ozonized to give the aldehyde 75 which was allowed to react with reagent 79_ to give the a, 8-epoxysilane 76. Crude 76_ was ozonized and then reduced with sodium boro-hydride to give the d i o l Treatment of the crude d i o l 7_7 with boron t r i f l u o r i d e etherate afforded (+)-(lR, 5 S ) - f r o n t a l i n (17) i n an o v e r a l l y i e l d of 23-29% from (-)-(3R)-linalool (73). (c) M u l t i s t r i a t i n Source: The b i c y c l i c k e t a l , a - m u l t i s t r i a t i n (1.8a) , i s one of the three components of the aggregation pheromone for the Euro-pean elm bark beetle, Scolytus m u l t i s t r i a t u s , which i s the p r i n -pal vector of Dutch elm disease i n North /America.26 Structure elucidation: The i s o l a t i o n technique used here -was d i f ferehte from, that employed i n the i s o l a t i o n of other pheromones from Scolytids. The beetle and host-produced v o l a t i l e s were extracted from the a i r surrounding v i r g i n female beetles boring i n elm logs. P u r i -f i c a t i o n of the active fractions confirmed the attractant was a combination of three components, a-2,4-dimethyl-5-ethyl-6,8- , dioxabicyclo [3. 2 .1 ] octane (18a) , 4-methyl-3-heptanol (19_) , and a-cubebene (20) . Compounds 18a and 19_ were beetle-produced com-ponents, while 20 was a host-produced component. Besides these 84 a c t i v e compounds, t h e 8 - i s o m e r o f compound 1_8 was a l s o i s o l a t e d b u t f o u n d t o be b i o l o g i c a l l y i n a c t i v e . 2 6 The b i c y c l i c k e t a l s t r u c t u r e of.compound 18 was d e t e r -m i n e d on t h e b a s i s o f t h e s p e c t r a l d a t a , i t s h y d r o g e n o l y s i s p r o d u c t s , and p r e v i o u s e x p e r i e n c e w i t h a n a l o g o u s compounds i s o -l a t e d f r o m t h e S c o l y t i d b e e t l e s . 2 3 ~ 2 6 I n a d d i t i o n t o t h e two n a t u r a l l y o c c u r r i n g forms o f m u l t i s t r i a t i n , two o t h e r i s o m e r s 18y, and 185, a r e a l s o p o s s i b l e . The a - m u l t i s t r i a t i n i s o l a t e d f r o m n a t u r a l s o u r c e has b e e n shown t o be o p t i c a l l y a c t i v e , [ a ] ^ 5 - 47° ( h e x a n e ) , 2 6 a and f r o m now on, t h i s m a t e r i a l i s r e f e r -r e d t o as ( - ) - a - m u l t i s t r i a t i n o r (-)-18a. The a b s o l u t e c o n -f i g u r a t i o n o f (-)-18a has b e e n e s t a b l i s h e d as ( I S , 2R, 4S, 5R) by a c h i r a l s y n t h e s i s , 5 0 i n w h i c h t h e e n a n t i o m e r i c c o m p o s i t i o n o f a m i x t u r e o f (-)- and (+)-18a was d e t e r m i n e d by 1 3CNMR an a -l y s i s , u s i n g a c h i r a l s h i f t r e a g e n t (see d i s c u s s i o n u n d e r S y n -t h e s i s ) . 85 S y n t h e s i s : The r e p o r t e d approaches to the 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] -octane s k e l e t o n i n m u l t i s t r i a t i n were s i m i l a r to those used i n the s y n t h e s i s of f r o n t a l i n and brevicomin (see above). Pearce and c o w o r k e r s 2 6 ' 4 9 r e p o r t e d a n o n - s t e r e o s e l e c t i v e s y n t h e s i s of 86 Scheme X I V . A N o n - s t e r e o s e l e c t i v e S y n t h e s i s o f M u l t i s t r i a t i n 2 6 ' a:8:y:<5 (34 :1 : 7 :58) 87 m u l t i s t r i a t i n (18) which gave a l l f o u r isomers (Scheme XIV). The keto. o l e f i n 8_6 was the k e y - i n t e r m e d i a t e i n t h i s s y n t h e s i s . The t o s y l a t e 8_5 was prepared i n three steps from butenylmag-nesium bromide 80_. A l k y l a t i o n of the magnesium bromide d e r i -v a t i v e 8_4 of the ketimine 8_3 w i t h t o s y l a t e 85 gave, a f t e r a c i d h y d r o l y s i s , compound 8_6. E p o x i d a t i o n of alkene 8_6_, f o l l o w e d by Lewis a c i d - c a t a l y z e d c y c l i z a t i o n y i e l d e d a l l f o u r b i c y c l i c isomers. Only the a isomer i s b i o l o g i c a l l y a c t i v e . The r e l a t i v e s t e r e o c h e m i s t r y of a l l four isomers o f m u l t i s t r i a t i n were assigned on the b a s i s of t h e i r chemical and s p e c t r a l data. The f o l l o w i n g s t e r e o s p e c i f i c s y n t h e t i c approach (Scheme XV) p r o v i d e d d i r e c t chemical evidence for. the s t e r e o -chemistry a t C-2 r e l a t i v e to C - l and C-5.1*9 D i e l s - A l d e r a d d i -t i o n of c i s - 2 - b u t e n - l - o l (89a) to 2-methyl-l-penten-3-one (88) gave 18a and 18y w i t h the v i r t u a l e x c l u s i o n o f the 6 and 6 isomers. However, when 89a was r e p l a c e d by t r a n s - 2 - b u t e n - l - o l (89b), 185 was formed predominantly. Thus the C-2 methyl groups i n the a and y isomers must be i n the endo c o n f i g u r a t i o n w h i l e i n the B and 5 isomers, they are i n the exo c o n f i g u r a t i o n . A c i d - c a t a l y z e d h y d r o l y s i s of the m u l t i s t r i a t i n isomers r e s u l t e d i n i n t e r c o n v e r s i o n of the isomers w i t h the same con-f i g u r a t i o n a t C-2, i . e . , a y , B* > 5-. E p i m e r i z a t i o n occurs at 186 89 C-4 v i a the dihydropyran intermediates shown below. When the e q u i l i b r a t i o n was effected with trideuteriophosphoric acid, D-H exchange occurred at C^ '4 and on the methylene group of the ethyl side chain v e r i f y i n g the presence of the above interme-diates . The NMR spectra reported for the four isomers are summarized i n Table l . 1 * 9 As shown i n Figure 2, the isomer pair 18a and 18y c l e a r l y d i f f e r s from the 18B and 186 pair in the patterns observed for the G-7 methylene protons, and . In the 18g and 18y isomers, these two protons appear as two separ-ate signals at approximately 6 .3.7 (H ) and 3.9- (H„) , respec-D E t i v e l y , whereas i n 18B and 18 6 both signals are observed at 6 3.8-3.9. 90 F i g u r e 2. NMR S p e c t r a o f M u l t i s t r i a t i n I s o m e r s h 9 18Y 186 4 .20 3.89 3.68 4 .26 3.84 4.19 392 365 4.22 385 T a b l e 1. NMR Chemical Shifts (f>) for Multistriatin Isomers 4 9 Multistriatin pnxotu, chemical shifts0 Uomcr A B c 1 8 « 0.81 0.81 0.94 (3 H, d) (3 H, d) (3 H, t) 18J 1.24 1.10 0.93 (3 H, d) (3 H, d) (3 H, t) 18* 0.80 1.01 0.92 (3 H, d) (3 H, d) (3 H, I) 186 1.15 0.81 0.94 (3 H, d) (3 H, d) (3 H, t) 3.68 3.89 4.20 (1 H, ddd) (1 H, dd) (1 H, m) 3.85 4.26 (2 H, m) (1 H, m) 3.65 3.94 4.19 (1 H, ddd) (1 H, d) (1 H, m) 3.85 4.22 . (2 H, m) (1 H, m) " d = doublet, dd = doublet o f doublets, ddd «= doublet o f doublets of doublets, t = triplet, m = multiplet. 91 Pearce e t a l . 5 0 d e v i s e d a s y n t h e s i s to e s t a b l i s h the abs o l u t e c o n f i g u r a t i o n o f the m u l t i s t r i a t i n isomers. Racemic 2-methyl-3-butenoic a c i d ('81_)- used i n the pre v i o u s s y n t h e s i s (Scheme XIV) was p a r t i a l l y r e s o l v e d with (+)- and (-)-a-methyl-benzylamine t o gi v e ( + ) - ( S ) - and (-)-(R)-8JL (70 and 60% o p t i c a l p u r i t i e s , r e s p e c t i v e l y ) . Each of these o p t i c a l l y e n r i c h e d a c i d s was used i n the s y n t h e s i s o u t l i n e d : i n Scheme XVI. The synthe-Scheme XVI. C h i r a l S y n t h e s i s of a - M u l t i s t r i a t i n (18a) 5 0 ( ± ) - 8 1 6 - ( R ) - 8 7 SnCI 2 (R) -18a, 8,-y , 5 92 t i c sequence employed was the same as that"- shown i n Scheme XIV f o r the s y n t h e s i s of racemic 18. The (+)-(S)-2-methyl-3-bute-n o i c a c i d (8JL) gave r i s e to (-) - (2R) -18a, i n f e r r i n g the a b s o l u t e c o n f i g u r a t i o n (IS, 2R, 4S, 5R) f o r n a t u r a l (-)-18a. 5 0 (-) - (1S,2R,4S,5R) -18a The enantiomeric composition of s y n t h e t i c (-)- and (+)-18a, determined by 13CNMR with the c h i r a l s h i f t reagent t r i s -[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium ( I I I ) , was 56 and 47% r e s p e c t i v e l y . Comparison of the s p e c i f i c r o t a t i o n of the i s o l a t e d (-) enantiomer of 18a (-4 7°) with the value c a l c u l a t e d f o r the o p t i c a l l y pure enantiomers (-47° and +44°) i n d i c a t e s t h a t the n a t u r a l l y o c c u r r i n g ( - ) - a - m u l t i s t r i a t i n (18) i s . e n a n t i o m e r i c a l l y pure. Mori r e p o r t e d a c h i r a l s y n t h e s i s of m u l t i s t r i a t i n (18) s t a r t i n g from D-mannitol (Scheme X V I I ) . 5 1 The (+ ) - ( R ) - g l y c e r -aldehyde aeetonide (91) was prepared from D-mannitol and the 93 Scheme X V I I . C h i r a l S y n t h e s i s o f M u l t i s t r i a t i n f r o m D - M a n n i t o l 5 1 D-mannitol OHC MeMgBr OH C1-O3 91 92 93 P h 3 P C H 3 B r NaCH 2SOMe 94 1 B 2 H 6 2. H 2 0 2 , OH -3. TSCI / Pyr 4. Li I C H 2 X 95a X = OH 95b X = OTs 95c X = I N 83 EtMgBr / THF H 3 Q + 18 d'r'B : Y • 6 (33:2:11:53) 108b 94 c h i r a l i t y at C-2 i n 91_ was retained throughout the synthesis to give o p t i c a l l y active a-, 8-, y-, and 6 - m u l t i s t r i a t i n (18). Addition of methylmagnesium iodide to 9_1 gave an epimeric mix-ture of 9_2 which was then oxidized to ketone 9_3_. The Wittig reaction of 9_3 with methylenetriphenylphosphorane gave the alkene 9_4_. Hydroboration-oxidation of 9_4 afforded the alcohol 95a, which was converted into the iodide 95c v i a the correspond-ing tosylate 95b. Iodide 95c was alkylated with the magnesium s a l t of the eyelohexylimine 8_3 and the r e s u l t i n g crude product was heated with d i l u t e hydrochloric acid to y i e l d a mixture of the four possible m u l t i s t r i a t i n stereoisomers. a - M u l t i s t r i a t i n , having a s p e c i f i c rotation ( [ a ] ^ 5 ) of -17° (ether), was i s o l a t e d from the mixture using preparative GLC. Very recently, another asymmetric synthesis of multi-s t r i a t i n (18) was accomplished by Cernigliaro and K o c i e n s k i 5 2 (Scheme XVIII). (+)-(3R)-Citronellol, [a] + 1.98° (ca. 35% o p t i c a l purity) , was converted into diene 9_8_ by pyrolysis of the corresponding xanthate 9_7. Epoxidation of the t r i s u b s t i t u -ted o l e f i n 9_8_ afforded 99_ which was hydrated to the d i o l 100. Subsequent oxidation of 100 with lead tetraacetate gave the aldehyde 101 which was methylated i n a three-step sequence vi a the S c h i f f base 102 to give the aldehyde 103. Treatment of 103 with ethylmagnesium bromide followed by oxidation afforded 86. The rest of the reaction sequence was the same as those reported by S i l v e r s t e i n and coworkers 2 6(see Scheme XIV). The observed s p e c i f i c rotation of -18.7° for the synthetic (-)-18a 95 9 6 Scheme XIX. S y n t h e s i s o f a - and Y - M u l t i s t r i a t i n f r o m ( Z ) - 2 - B u t e n - l , 4 - d i o l 5 3 a 95a X= O H 95b X = OTS 95c X - I o LDA 97 obtained aft e r GLC separation, indicates an o p t i c a l purity of approximately 40%. The stereoselective synthesis of an 85:15 equilibrium mixture of a- and y - m u l t i s t r i a t i n (18) was reported by E l l i o t and.Fried (Scheme X I X ) . 5 3 a The dioxolane 95a, which had been employed i n Mori's s y n t h e s i s , 5 1 was prepared i n a t o t a l l y d i f -ferent route from (Z)-2-buten-l,4-diol (104). Compound 104 was f i r s t protected.as i t s isopropylidene.derivative.105. Epoxi-dation o f . o l e f i n 105 gave 106 which was treated with lithiu m dimethylcuprate to afford 107. The c r u c i a l a l k y l a t i o n step was effected by treating, an excess of the anion of 3-pentanone with the iodo compound 95c. Removal of the acetonide protect-ing group followed by acid-catalyzed c y c l i z a t i o n furnished the racemic m u l t i s t r i a t i n 18a, y i n 80% y i e l d from 95a. O p t i c a l l y active 95a could also be obtained by resolving 107. 5 3 b (d) endo-1,3-Dimethyl-2,9-dioxabicyclo[3.3.1]nonane endo-1, 3-Dimethyl-2., 9-dioxabicyclo [3.3.1] nonane (21) i s a ho s t - s p e c i f i c substance i n Norway spruce infested by Try-podendron. lineatum.OLIV. 2 7' 2 8 Unlike the previously described b i c y c l i c ketal pheromones which have the common 6,8-dioxabicyclo [ 3. 2 .1 ] octane (29) skeleton, 2 3 '°2 6 this compound contains the 2,9-dioxabicyclo[3.3.1]nonane structure (109). 98 l i 29 109 21 The synthesis of compound 21_ was reported by Gerlach and Kunzler i n 1977 (Scheme XX) . 5 Alkylation of the ac e t y l -acetone dianion 1_10 with 4-bromo-2-methy1-1-butene (111) a f f o r -ded compound 112. Reduction of 112 with sodium borohydride yielded erythro- and threo-8-methyl-8-nonen-2,4-diol, (113a) and (113b), which were then.separated by column chromatography. The configurations of these two diastereomers were established by converting them under equilibrium conditions into t h e i r benzal derivatives. Conversion of d i o l 113a into i t s benzal derivative gave only 115a, while d i o l 113b gave r i s e to both 115b and 115c (the phenyl group assumed an equatorial p o s i t i o n i n the most stable conformations of these benzal d e r i v a t i v e s ) . Oxidative cleavage.of the terminal double bond i n 113a with ozone gave ketone 114a which spontaneously c y c l i z e d to endo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane (21a). The 99 Scheme XX. Sy n t h e s i s of endo-1,3-Dimethyl-2,9-dioxabicyclo [3.3.1]nonane 5 k 114b exo- 21b 100 113b 115b 115c three- d i o l 113b was converted exclusively into exo-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane (21b) using the same, reaction se-quence. Comparison of. the NMR data of the two b i c y c l i c acetals, 21a and 21b, with that of the natural compound confirmed the endo configuration of the natural product. A second, more convenient route s t a r t i n g from the bromo ketal 116 was also reported by Gerlach and Kunzler (Scheme XXI). 5 The bromo ketal 116 was alkylated with the dianion of ace t y l -acetone to give compound 117. Reduction of 117 with sodium 101 Scheme XXI. Synthesis of 21 from Bromo K e t a l 116 5 "* 118a+118b borohydride a f f o r d e d a mixture of d i o l s 118a and 118b which were c y c l i z e d i n aqueous a c i d to y i e l d a mixture of 21a and 21b. 102 (e) Lineatin Source: Female beetles of Trypodendron lineatum produce an attractant compound while boring i n f a l l e n Douglas f i r l o g s . 2 9 About 200 micrograms of the pure attractant, c a l l e d l i n e a t i n , was obtained from 200 grams of frass. Structure Elucidation: The high resolution mass spectrum suggested C i 0 H 1 6 0 2 as the molecular formula and the low resolution mass spectrum (Figure 3) showed the f a c i l e loss of 15 mass unit (to m/e 153) which indicated methyl branching. The infrared spectrum (Figure 4) showed no absorptions due to hydroxyl or carbonyl groups and no reactions were observed when the compound was treated with a s i l y l a t i n g agent or lithium aluminum hydride. Since a l l the above data excluded hydroxyl, carbonyl, epoxy and peroxy groups, the ether linkage was obvious. The absorption i n the NMR spectrum (Figure 5) at 6 4.35 suggested a H-C-0 proton as i n exo-brevicomin. Since no o l e f i n i c double bond was indicated by infrared spectroscopy, the absorption at 6 4.85 was assigned to a proton deshielded by two oxygen atoms (0-CH-O), and a t r i c y c l i c ketal structure was thus suspected. The absorp-ti o n at 6 1.15 was assigned to two methyl groups, while the one at 6 1.09 represented a t h i r d methyl group. The signal at 6 1.05 was considered to be spurious. 103 100, % ss 1.1 •K.l *<>Y *9 i i j j i U il i n I S 135 J—li. 153 MS 411 60 80 100 120 F i g u r e 3 . Unit resolution mass spectrum of lineatin. 2 9 M« 160 104 4- 4- _u T A U V A I U I S Fio. 5 100-MHz NMR spectrum, recorded on about 200 ug of lineatin in CCI«.2 9 n 4- 4- 4- 4- 4-T A U V A I U I I Fio. 6 100-MHz Eu(fod)j-$hifted NMR spectrum or lineatin. Eu(fod),/substrate molar ratio - 1.3, in C C U . 2 9 1 0 5 One of the hydrogenolysis products of l i n e a t i n was 2,6-dimethyloctane. This established the basic carbon skeleton. From the information given by the Eu(fod) 3-shifted NMR spectrum of l i n e a t i n (Figure 6) and double i r r a d i a t i o n experiments on the shifted spectrum, the structure of l i n e a t i n was proposed to be one of the two isomeric t r i c y c l i c acetals 22 or 23. 22 23 An attempt to confirm the structure of l i n e a t i n using the synthetic sequence shown i n Scheme XXII was reported to be unsuccessful, 2 9 since the i n i t i a l photochemical addition gave a mixture of isomers which could not be separated or i d e n t i f i e d . The reaction sequence was carried through on the crude mixtures of isomers. Although these workers is o l a t e d a small amount of product indistinguishable i n chromatographic, spectral and b i o l o g i c a l properties from the natural compound, no d e f i n i t e proof of structure was concluded. The structure of l i n e a t i n 1 0 6 Scheme XXII. MacConnell"s Syn t h e s i s of L i n e a t i n 2 9 22 23 was f i n a l l y e s t a b l i s h e d as 22 by an unambiguous s y n t h e s i s 3 0 (see d e s c r i p t i o n under S y n t h e s i s ) . S y n t h e s i s : Since the s t r u c t u r e of n a t u r a l l i n e a t i n c o u l d not d e f i n i t e l y assigned from i t s s p e c t r a l data and the chemical 107 t e s t s , two d i f f e r e n t syntheses were designed by Borden e t a l . 3 0 a to e s t a b l i s h the s t r u c t u r e of n a t u r a l l i n e a t i n . Compound 2_2 was chosen as the i n i t i a l t a r g e t compound. T h e i r s y n t h e t i c route (Scheme X X I I I ) , though lengthy and low y i e l d i n g , p r o v i d e d an unambigous s y n t h e s i s of 3 , 3 , 7 - t r i m e t h y l -2 , 9 - d i o x a t r i c y c l o [ 3 . 3 . 1 . 0 k ' 7 ] n o n a n e (22). C y c l o a d d i t i o n of d i c h l o r o k e t e n e to compound 122 gave adduct 123 which was t r e a t e d with t r i - n - b u t y l t i n (IV) h y d r i d e to give the dehalogenated com-pound 124. The keto group i n 124 was p r o t e c t e d as i t s k e t a l . O z o n o l y s i s of the r e s u l t i n g compound 125 gave the keto aldehyde 126. W i t t i g r e a c t i o n of the methoxymethyltriphenylphosphorane with the aldehyde 126 gave compound 127 which was then reduced to i t s a l c o h o l . T h i s a l c o h o l was converted i n t o mesylate 128, which upon treatment w i t h potassium t e r t - b u t o x i d e gave compound 129. A c i d h y d r o l y s i s f o l l o w e d by l i t h i u m aluminum hy d r i d e r e d u c t i o n a f f q r d e d a l c o h o l 130. The k e t a l i n 130 was removed and the r e s u l t i n g ketone was reduced w i t h l i t h i u m t r i - t e r t -butoxyaluminum h y d r i d e t o g i v e 131. The a l c o h o l 131 was then c o n v e r t e d . i n t o d i a c e t a t e 132 which was t r e a t e d w i t h p e r i o d a t e -permanganate, f o l l o w e d by diazomethane to y i e l d compound 133. Reaction of 133 w i t h excess m e t h y l l i t h i u m gave t r i o l 134 and f i n a l l y , o x i d a t i o n of 134 w i t h p y r i d i n i u m chlorochromate f u r n i -shed the t r i c y c l i c k e t a l 22. ( 1 ) A l l these syntheses are o n l y b r i e f l y s t a t e d i n r e f e r e n c e 30a without experimental d e t a i l s . 108 Scheme XXIII. S y n t h e s i s of Proposed L i n e a t i n S t r u c t u r e 22 3 o a ;=c=o ci-A 1 2 2 H 1 2 4 . ( H O C H 2 ) 2 -O H 1 . Cy MeOH 2 . M e 2 S -CHO O k MeOCH 2 PPh,3CI PhLi H 1 2 5 1 2 6 l / ^ " 0 * " 8 1. LiAl H. O H 2 . MSCI, Pyr 1 2 7 0-)Me M s KO-t-Bu DMSO O H L ^ ^ O M e .O H 1 2 8 1 2 9 1 . 8 0 ° / o HOAc 2 . LiA I H, O-O H 1 . 8 8 8 / o HCOpH —, 2.LiAKO-t-Bu)3hl'1 HO Ac 2 0 Pyr AcO }Ac 1 3 0 1 3 1 1 3 2 1 . M n 0 4 - / I 0 4 _ 2 . C H 2 N 2 -OAc MeLi )Me AcO H •OH Pyr.HCI.CrO, 2 2 1 3 3 1 3 4 109 A second synthesis (Scheme XXIV), although shorter (disregarding the preparation of compound 135), suffered from the very low y i e l d (5%) i n the cycloaddition of 135 to dichloro-ketene. The cycloadduct 136 was reduced with sodium borohydride to give the alcohol 137. Acid c y c l i z a t i o n of 137 gave compound 138 which on treatment with sodium i n tert-butanol gave the t r i c y c l i c ketal 2_2 . Scheme XXIV. Synthesis of 22 from 135 3 °a 138 110 Since the spectral, chromatographic and b i o l o g i c a l properties of the synthetic compound 2J2 agreed with those of natural l i n e a t i n , the structure of the attractant compound was thus i d e n t i f i e d as 22. During the preparation of t h i s d i s s e r t a t i o n , Mori and Sasaki 3 °k reported another synthesis of l i n e a t i n (2^ 2) s t a r t i n g from the photocycloaddition reaction of enol acetate 120 with 3-methyl-2-cyclopentenone (139). Their route which i s consider-ably lengthy, i s described i n Scheme XXV. It should be pointed out that severely low y i e l d i n g and -low s t e r e o s e l e c t i v i t y steps were included i n t h i s synthesis. In fact a 60% y i e l d of a mix-ture of four stereoisomers of 140 was obtained i n the f i r s t reaction. The mixture of isomers 140 was converted into acetoxy acetals 141 and the acetate moiety was hydrolyzed to give alco-hols 14_2. Oxidation of 142 with pyridinium chlorochromate gave a mixture of two isomeric ketones 143 and 144 i n a r a t i o of 4:1 respectively. The two isomers 143 and 144 were separated by chromatography over s i l i c i c acid. It should be noted that only ketone 144, derived from the minor photoadduct, would lead to l i n e a t i n (_22) . The major isomer 14 3 was reduced with lithium tri-sec-butylborohydride (L-Selectride) to afford alcohol 142a which was protected as i t s acetate followed by regeneration of the ketone group to y i e l d 14 0a. This acetoxy ketone was con-verted into i t s t r i m e t h y l s i l y l enol ether 145 with lithium d i -isopropylamide and chlorotrimethylsilane. Ozonolysis of 145 and reductive work-up (triphenylphosphine) of the ozonide gave I l l Scheme XXV. Mori's S y n t h e s i s of L i n e a t i n (22)3 0 142b 22 1 1 2 an aldehyde a c i d . E s t e r i f i c a t i o n and a c e t a l i z a t i o n of t h i s compound gave 146 i n 11% y i e l d from 145. F i n a l l y , r e a c t i o n of compound 146 w i t h methylmagnesium i o d i d e and subsequent t r e a t -ment with d i l u t e a c i d a f f o r d e d 23_ i n 28% y i e l d . The s y n t h e s i s of l i n e a t i n (2_2) was c a r r i e d out i n the same manner as d e s c r i b e d above, s t a r t i n g from the minor ketone 144. Compound 142b and the corresponding hydroxy ketone were r e p o r t e d to be u n s t a b l e , s u f f e r i n g from cyclobutane cleavage. A l l of the s y n t h e t i c routes d e s c r i b e d above proceeded i n very low o v e r a l l y i e l d s and o f t e n mixtures of isomers were obtained. Consequently, o n l y very small q u a n t i t i e s of synthe-t i c l i n e a t i n were a v a i l a b l e f o r very l i m i t e d t e s t i n g . In the f o l l o w i n g s e c t i o n of t h i s t h e s i s , we r e p o r t the r e s u l t s from a study of the c y c l i z a t i o n of epoxy 8 - k e t o e s t e r s which l e d to e f f i c i e n t syntheses of f r o n t a l i n ; and endo- and exo-brevicomin. A s t e r e o s e l e c t i v e s y n t h e s i s of (-)-a-multi-s t r i a t i n along with an e f f i c i e n t , but n o n s t e r e o s e l e c t i v e , syn-t h e s i s of l i n e a t i n are a l s o presented. RESULTS AND DISCUSSION (i) Synthesis of Frontalin, endo-Brevicomin, and exo-Brevicomin In continuation of our studies on the c y c l i z a t i o n of 8-keto e s t e r s , 5 5 the c y c l i z a t i o n s o f a variety of substituted epoxy 8-keto esters were investigated. Results obtained e a r l i e r i n our laboratory indicated that p r o t i c or Lewis acids catalyzed reactions of methyl-6,7-epoxy-3-oxoheptanoate (147) , gave only the O-cyclized product 148. 5 6 To test the generality of t h i s type of c y c l i z a t i o n , the homologous epoxide 153 and i t s substituted derivatives were investigated. The epoxide 153 could be prepared i n two d i f f e r -ent ways as shown in Scheme XXVI. In the f i r s t method, the dianion of methyl acetoacetate 5 7 (149) was alkylated with 4-bromo-l-butene (150) to give the 114 Scheme XXVI. Syn t h e s i s of Methyl 7,8-Epoxy-3-oxooctanoate (153) y - a l k y l a t e d product 152. E p o x i d a t i o n of the r e s u l t i n g alkene gave methyl 7,8-epoxy-3-oxooctanoate (153). In the second method, 4-bromo-l-butene (15 0) was f i r s t converted i n t o i t s epoxide 151 and then t r e a t e d w i t h the d i a n i o n of methyl a c e t o -a c e t a t e . Besides the d e s i r e d a l k y l a t e d product 153, TLC a n a l y s i s a l s o showed s e v e r a l other s i d e products which were not i d e n t i f i e d . 115 The complication of t h i s l a t t e r reaction could r e s u l t from attack of the dianion on the epoxide group. We found that the y i e l d , of the second method was usually lower than the f i r s t method. Treatment of the epoxide 15 3 with boron t r i f l u o r i d e etherate i n dichloromethane at room temperature for two hours gave a cy c l i z e d product i n high y i e l d . The structure of t h i s product was readily i d e n t i f i e d from i t s spectral data. The sa l i e n t features were the lack of a saturated ketone absorp-t i o n and the presence of a single carbonyl band i n the infrared at 1740 cm - 1 which was assigned to an ester function. The NMR of t h i s product showed a three proton si n g l e t at 6 3.6 8 indicat ing the methoxy group of an ester, and a multiplet at 6 1.1-2.1 attributable to six methylene protons. The a-methylene of the 8-keto ester 153 was replaced by a two proton si n g l e t at 6 2.7 3 In addition, there were two low f i e l d multiplets at 6 3.8 and 6 4.5 ascribable to three protons on carbon atoms adjacent to 153 1 54 116 oxygen. The molecular formula of t h i s compound, determined by high resolution mass spectrometry, was C 9 H 1 4 O 4 . From these spectral data, the structure of the cy c l i z e d product was iden-t i f i e d as methyl a-(6 , 8-dioxabicyclo [ 3 . 2 .1 ] octan-5-yl):; acetate (154). The following mechanism (Scheme XXVII) was envisioned for the formation of t h i s b i c y c l i c k e t a l . Opening of the o x i -rane ring with intramolecular p a r t i c i p a t i o n of the keto group would lead to the c y c l i c enol ether intermediate 155. Further c y c l i z a t i o n involving the free hydroxyl group i n a Michael type addition to the unsaturated ester then furnished the b i c y c l i c ketal 154. The l a t t e r process might also occur v i a the i n t e r -Scheme XXVII. Proposed Mechanism for the C y c l i z a t i o n of 153 154 117 154 155 156 mediate 156. A s i m i l a r reaction has been reported recently by Boeckman and coworkers 5 8 (Scheme XXVIII). The c y c l i z a t i o n of epoxide 157 with boron t r i f l u o r i d e etherate i n dichloromethane Scheme XXVIII. C y c l i z a t i o n of Epoxy Dihydropyran 157 5 8 158 1 5 9 157 S n C I 4 yielded 158 and 159. A mechanism involving the intermediary oxonium ion 160 was proposed for the formation of 159 as shown 118 Compound 154 has a 6,8-dioxabicyclo[3.2.1]octane s k e l e t o n , 5 9 which i s the b a s i c framework of f o u r bark b e e t l e pheromones, exo-brevicomin (15_) , 2 3 endo-brevicomin (16) , 2 3 f r o n t a l i n (17_) , 2 5 and a - m u l t i s t r i a t i n ( 1 8 a ) . 2 6 I t i s apparent t h a t c y c l i z a t i o n s s i m i l a r to t h a t of 153 should p r o v i d e a f a c i l e and g e n e r a l route to these type of compounds. Because of t h e i r p o t e n t i a l u t i l i t y i n c o n t r o l l i n g the p o p u l a t i o n of bark b e e t l e s and t h e i r unique s t r u c t u r a l f e a t u r e , these compounds have been 119 1 7 18 g the o b j e c t of s e v e r a l s y n t h e t i c (see In t r o d u c t i o n ) and entomo-l o g i c a l s t u d i e s . 2 8 ' 6 0 With the same o b j e c t i v e , we i n v e s t i g a t e d the p r e p a r a t i o n of the f i r s t t h ree pheromones u s i n g the above epoxy 8-keto e s t e r c y c l i z a t i o n . The s y n t h e s i s o f f r o n t a l i n (17) i s o u t l i n e d i n Scheme XXX. In t h i s s y n t h e s i s , 4-bromo-2-methyl-l-butene (111) was prepared i n 42% y i e l d from the commercially a v a i l a b l e 3-methyl-3- b u t e n - l - o l (161) by t r e a t i n g the a l c o h o l 161 with phosphorus t r i b r o m i d e i n an e t h e r - p y r i d i n e m i x t u r e . 6 1 A l t e r n a t i v e l y , 120 165 121 bromide 111 could also be prepared by the reaction of 161 with triphenylphosphine and carbon tetrabromide 6 2 i n dichloro-methane. Although the alternate method gave high y i e l d (>90%), we found i t very d i f f i c u l t to separate the r e l a t i v e l y low b o i l -ing bromide 111 from the side product tribromomethane formed in the reaction. It was also found that when bromide 111, con-taminated with trace amounts of tribromomethane, was used i n the subsequent dianion reaction, unsatisfactory results were observed. The dianion of methyl acetoacetate was alkylated with 111 to give the y-alkylated product 162 i n good y i e l d . Compound 162 was epoxidized with m-chloroperbenzoic acid to produce 16 3 i n 73% y i e l d from methyl acetoacetate. Treatment of the epoxy compound 163 with boron t r i f l u o r i d e etherate afforded the b i c y c l i c compound 164 i n 95% y i e l d . The IR spectrum showed the c h a r a c t e r i s t i c absorption from an ester at 1740 cm 1. The NMR spectrum exhibited absorptions at 6 1.32 (s, 3H) for the bridge-head methyl group, 6 1.5-1..9 (m, 6H) for^the methylene protons in the ring, a two proton si n g l e t at 6 2.72 c h a r a c t e r i s t i c of the methylene protons adjacent to a carbonyl group, a three proton singlet at 6 3.66 for the methoxy group, and two low f i e l d absorptions at 6 3.40 and 3.88 for the methylene protons on the carbon next to oxygen. To convert compound 164 into f r o n t a l i n (1_7) , i t was necessary to develop a convenient method to remove the carbomethoxy group on the side chain at C-5. 122 This was f i r s t accomplished on the model compound 154. The ester 154 was hydrolyzed by aqueous alkaline to give the cor-responding carboxylic acid 166 i n good y i e l d . This carboxylic acid underwent a smooth thermal decarboxylation (Kugelrohr oven at 220° C, 5-8 min) to give 167 i n 84% y i e l d . A similar reac-154 166 167 tion sequence was employed to convert ester 164 into f r o n t a l i n (17) i n 85% y i e l d . The NMR, IR and mass spectral data of t h i s product were i d e n t i c a l with those reported for f r o n t a l i n (17). 2 5 The rather f a c i l e decarboxylation of acid 165 might be due to p a r t i c i p a t i o n of one of the ketal oxygens as shown i n equation 1. A similar mechanism involving the intermediates (1 ) 165 168 17 123 170 and 171 was proposed by Atkinson and M i l l e r 6 3 for the decarboxylation of acid 169 to form 172 (Scheme XXXI). Scheme XXXI. Proposed Mechanism for the Decarboxylation of endo-6-Isobutyl-l,4-dimethyl-2,7-dioxabicyclo [2.2.1]heptane-6-carboxylic acid (169) 6 3 172 171 124 The synthesis of endo-brevicomin (16) (Scheme XXXIII) was accomplished using the same methodology. (E)-l-Bromo-3-hexene (176) was prepared from 3-butyn-l-ol (17 3) as shown i n Scheme XXXII. The dianion of 3-butyn-l-ol (173) was generated Scheme XXXII. Synthesis of E-l-Bromo-3-hexene (176) 1. L i N h U / NH-, N a / N H o H O C H X H , C = C H § H O C H 2 C H 2 C = = C C H 2 C H 3 2_ ^ * 2. E t B r 173 174 HO = \ - : " B r / \ P B r o / P y r / > £ ». R  ^ 1 7 5 1 7 6 with lithium amide i n l i q u i d ammonia and then alkylated with 1-bromoethane to give the C-alkylated product 3-hexyn-l-ol (174) 6 4 i n 76% y i e l d . Birch r e d u c t i o n 6 5 of 174 gave (E)-3-hexen-l - o l (175) i n 87% y i e l d , which was converted into (E)-l-bromo-3-hexen (176). The dianion of methyl acetoacetate was alkylated with bromide 176 to give methyl (E)-3-oxo-7-decenoate (177) i n 83% y i e l d . Compound 17 7 was treated with m-chloroperbenzoic acid 125 Scheme XXXIII. Sy n t h e s i s of endo-Brevicomin 180 126 to a f f o r d the corresponding epoxide 17 8 which was c y c l i z e d to 179 i n 91% y i e l d . We c o u l d not d e t e c t from the NMR any exo isomer of 17 9 i n t h i s c y c l i z a t i o n . GLC a n a l y s i s of the c y c l i z e d product showed t h a t i t contained g r e a t e r than 99% of the endo isomer 179. A number of the e a r l i e r syntheses of endo- and exo-brevicomin i n v o l v e d a thermal, Lewis a c i d or p r o t i c a c i d c a t a l y z e d c y c l i z a t i o n of keto epoxides to generate the 6,8-d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n e s k e l e t o n 2 3 , 3 1 , 3 2 / 4 8 f 5 0 (see I n t r o -d u c t i o n ) . Our approach r e p r e s e n t s the f i r s t example.of a Lewis a c i d - c a t a l y z e d c y c l i z a t i o n of a 3-keto e s t e r epoxide. The high s t e r e o s p e c i f i c i t y i n the c y c l i z a t i o n of 8-keto e s t e r epoxide 178 i s b e l i e v e d to a r i s e from the anhydrous c o n d i -t i o n of the r e a c t i o n and the s i g n i f i c a n t l y h igher e n o l content of a 8-keto e s t e r r e l a t i v e t o a simple ketone. I t i s apparent from the observed r e s u l t s t h a t d u r i n g the c y c l i z a t i o n , the keto group of the 8-keto e s t e r a t t a c k e d the epoxide which underwent oxirane r i n g opening with i n v e r s i o n of c o n f i g u r a t i o n to give 181 as shown i n Scheme XXXIV. Most of the r e p o r t e d syntheses based on keto epoxides i n v o l v e d aqueous and c a t a l y z e d c y c l i z a -t i o n s i n which two r e a c t i o n mechanisms were p o s s i b l e . The f a c t t h a t the t r a n s epoxide 3_5 gave predominantly the endo isomer 16_ i n d i c a t e d t h a t the r e a c t i o n probably proceeded v i a a mechanism (equation 2a) which i n v o l v e d initial-,:• opening,-of the' epoxide 35 127 Scheme XXXIV. Mechanism for the C y c l i z a t i o n of Methyl-(E)-7,8-epoxy-3-oxodecanoate (178). — 7 9 to y i e l d d i o l 182. Attack of a hydroxy group of the d i o l on the ketone to form a six-membered ring hemiketal, followed by a second c y c l i z a t i o n furnished endo-brevicomin (16). Presence of the exo isomer 15_ obviously resulted from the second mecha-nism (equation 2b). Attack of the ketone on a hydroxy group of the d i o l i n 182 led to the c y c l i c enol ether 183 which then cyc l i z e d to exo-brevicomin (15). 128 H 1 " exo-1 5 E s t e r 17 9 was converted i n t o endo-brevicomin (16) by h y d r o l y s i s to the a c i d 18 0 (95%) and thermal, d e c a r b o x y l a t i o n (85%) as d e s c r i b e d above. There was no d e t e c t a b l e e p i m e r i z a t i o n d u r i n g the thermal d e c a r b o x y l a t i o n which i s c o n s i s t e n t with the mechanism proposed i n equation 1. 129 The s y n t h e s i s o f e x o - b r e v i c o m i n (15_) was c a r r i e d o u t as shown i n Scheme XXXV. {Z)-2-hexen-l-ol (184) was p r e p a r e d by h y d r o g e n a t i o n o f t h e a c e t y l e n e 174 u s i n g p a l l a d i u m on b a r i u m s u l f a t e as a c a t a l y s t and q u i n o l i n e as a p o i s o n . 6 6 C o n v e r s i o n o f t h e a l c o h o l 184 i n t o t h e c o r r e s p o n d i n g b r o m i d e 185 was e f -f e c t e d by p h o s p h o r u s t r i b r o m i d e and p y r i d i n e . A l k y l a t i o n o f t h e d i a n i o n o f m e t h y l a c e t o a c e t a t e w i t h b r o m i d e 185 gave 186, w h i c h was e p o x i d i z e d t o a f f o r d 187. T h i s c i s e p o x i d e was c o n -v e r t e d i n t o e x o - b r e v i c o m i n (15) v i a t h e e s t e r 188 and t h e a c i d 189, e m p l o y i n g a s i m i l a r r e a c t i o n s e q u e n c e as d e s c r i b e d i n Scheme X X X I I I . The o v e r a l l y i e l d o f 15_ f r o m m e t h y l a c e t o a c e t a t e and (Z)-l-bromo-3-hexene (185) was c a . 85%. I n a d d i t i o n t o the., o v e r a l l e f f i c i e n c y and h i g h s t e r e o s p e c i f i c i t y o f t h i s r o u t e , t h e c a r b o x y l i c a c i d f u n c t i o n i n compounds 165, 180 and 189 p r o -v i d e s a u s e f u l h a n d l e f o r t h e r e s o l u t i o n o f t h e s e i n t e r m e d i a t e s , f a c i l i t a t i n g t h e s y n t h e s i s o f b o t h e n a n t i o m e r s o f f r o n t a l i n (17), e n d o - b r e v i c o m i n (16) and e x o - b r e v i c o m i n (15) . C o m p a r i s o n o f t h e b i o l o g i c a l a c t i v i t y o f a r a c e m i c m i x t u r e r e l a t i v e t o t h a t o f t h e i n d i v i d u a l e n a n t i o m e r s c an sometimes p r o v i d e f a s c i n a t i n g i n s i g h t i n t o t h e i n s e c t ' s r e c e p -t o r s i t e ( s ) . 6 7 ' 6 8 F o r example, i t was f o u n d t h a t r e s p o n s e was g r e a t e r t o r a c e m i c s u l c a t o l (190) t h a n t o a m i x t u r e (65:35) o f 1 9 0 130 Scheme XXXV. Sy n t h e s i s of exo-Brevicomin (15) 1 5 131 ( + )-(S_) and (-)-(R) enantiomers, the naturally occurring i s o -meric r a t i o . 6 8 Since both enantiomers of a pheromone are usually needed for b i o l o g i c a l testing, a common synthesis leading to both i s o -mers would be most convenient. This can be achieved by resolv-ing a racemic intermediate at a late;; stage of the synthesis. Although a number of syntheses of o p t i c a l l y active exo-brevi-comin1* 2 ' k 4 and fr o n t a l i n 1 * 6 r h 7 r6 9 have been reported, the synthesis of these compounds vi a the resolution approach i s so far severely limited by the lack of a useful handle i n the common synthetic intermediates that would allow resolution. To our knowledge, the synthesis of (+)-exo-brevicomin (15) by the resolution of an intermediate has not been recorded. Thus we investigated the p o s s i b i l i t y of resolving the carboxylic acid 189. We chose to resolve 189 via formation of the a-methylbenzylammonium s a l t s (Scheme XXXVI) since both enantiomers of t h i s resolving agent are readily a v a i l a b l e . 7 0 ' 7 1 Two r e c r y s t a l l i z a t i o n s of the (+)-a-methylbenzylammonium s a l t of 189 gave a 4 0% y i e l d of a salt (mp 110-115° C). This s a l t was hydrolyzed i n aqueous acid to lib e r a t e the free acid which was then thermally decarboxylated to y i e l d an o p t i c a l l y active exo-brevicomin (15_), [ a l D 5 + 51.8° (c. = 0.12 g/mL, E t 2 0 ) . In comparison with the reported [ct]^ 6 + 81.1 °(c = 2.2, Et? 0) '' 2 for ( + ) -exo-brevicomin (15) ,: -the observed rotation of the resolved material indicated a maximum of 62% resolution of 15. 132 Scheme XXXVI. R e s o l u t i o n o f . C a r b o x y l i c A c i d 189. ( + ) - l 8 9 ( + )-15 ( i i ) S y n t h e s i s of ( - ) - a - M u l t i s t r i a t i n Despite the i n t e n s e s t u d i e s conducted on m u l t i s t r i a t i n (.18_) , 2 6 an e f f i c i e n t and s t e r e o s e l e c t i v e route to the pure n a t u r a l compound has not been achieved. Owing to the b i o l o g i c a l a c t i v i t y of t h i s compound and the e c o l o g i c a l advantages of i t s use i n i n s e c t c o n t r o l , a s y n t h e s i s which would p r o v i d e conven-i e n t access t o the n a t u r a l ( - ) - a - m u l t i s t r i a t i n seems necessary. In c o n t i n u a t i o n of our work on exo-brevicomin (15), endo-brevi-comin (16) and f r o n t a l i n (1J7_) , we accomplished a s t e r e o s e l e c t i v e s y n t h e s i s of ( - ) - a - m u l t i s t r i a t i n (-)- (18a) with the r e l a t i v e and absolute c o n f i g u r a t i o n as shown below. 7 6 ( - ) - ( l S , 2R, 4S, 5R)-18a Since chemoreceptors are o f t e n capable of d i s t i n g u i s h i n g enantiomeric s u b s t r a t e s , the b i o l o g i c a l a c t i v i t i e s of pheromones may be a f f e c t e d by the o p t i c a l p u r i t y o f these compounds. To study the b i o l o g i c a l a c t i v i t y of the enantiomers of a pheromone r e q u i r e s access to o p t i c a l l y pure forms of such m a t e r i a l . The t r a d i t i o n a l approach t o e n a n t i o m e r i c a l l y pure compounds by r e s o l v i n g racemic i n t e r m e d i a t e s i s not always f e a s i b l e . Use of an a p p r o p r i a t e c h i r a l s t a r t i n g m a t e r i a l i n an asymmetric s y n t h e s i s 134 would avoid the sometimes tedious resolution procedures. For t h i s purpose, carbohydrates that are cheap, read i l y available, and o p t i c a l l y pure provide a useful source of s t a r t i n g mater-i a l s for the stereospecific synthesis of many o p t i c a l l y pure, non-carbobydrate natural products. A b r i e f examination of the a - m u l t i s t r i a t i n (18a) mole-cule reveals that the i S i c y c l i c ketal skeleton could be prepared from a sugar moiety. After s e a r c h i n g through the readily a v a i l -able sugars, we found methyl a-D-glucopyranoside (71_) to be a suitable s t a r t i n g material for two reasons. F i r s t , i t has the desired absolute configuration at C - 5 , and secondly, i t already contains most of the desired carbon skeleton. In our synthetic plan, the asymmetric centre at C-5 i s retained throughout the entire synthesis. Three synthetic objectives are apparent i n 18a 135 the transformation of 71. into a - m u l t i s t r i a t i n (18a) , v i z . , (a) to introduce the two methyl groups at C-2 and C-4 with the correct stereochemistry, (b) to remove the three hydroxyl groups at C -2 , C - 3 , and C -4 , and (c) to introduce the ethyl side chain at C - l . To achieve goals (a) and (b) we decided to proceed v i a the known compound 195 which already had the methyl 201 OH OMe 195 group at C-2 with the desired stereochemistry. The preparation of compound 195 i s shown i n Scheme XXXVII. Methyl a-D-glucopyranoside (71_) was f i r s t protected as i t s benzyl-idene derivative 191 which was subsequently converted into the d i t o s y l compound 192 by treatment with excess p-toluenesulfonyl chloride i n anhydrous pyridine for 7 days at room temperature. Treatment of 192 with sodium methoxide i n dichloromethane a f f o r -ded the epoxy compound 194 . 7 3 The mechanism of t h i s reaction has been suggested to involve displacement of the C-3 sulfonyloxy group by backside attack of the adjacent oxide anion, leading to inversion of configuration at C - 3 . 7 5 It has also been 136 Scheme XXXVII. Preparation of Methyl 4,6-0-Benzylidene-2-deoxy-2-C_-methyl-a-D_-altropyranoside (195) 7 3 ' 7 "* 1 9 4 1 9 5 137 , 0 S O o R - C — c — A R S O RSO: — c — c -/ \ RSO„ suggested that the ease of hydrolysis of the C-2 tosylate was due to the inductive e f f e c t of the adjacent sulfonyloxy group. 7 6 I O I — C — O — S O _ R — C — O " + R O S O o R I J I 2 " O R The formation of the epoxy compound 194 i s believed to go through a skew conformation i n the t r a n s i t i o n state which would f a c i l i -tate an S N2 displacement of the tosylate at C-3 by the adjacent oxide anion. 194 138 An alternate way to synthesize the epoxide 194 v i a dimesylate 193 was also developed. Treatment of 191 with methane-sulfonyl chloride i n pyridine for 24 h at room temperature gave the dimesylate 193 i n 81% y i e l d . Conversion of the dimesylate 193 into the epoxide 194 was effected i n 91% y i e l d by treating 193, with sodium hydroxide i n dichloromethane at 0° C for 3 days and then at room temperature for 10 h. The dimesylate route appeared to be more e f f i c i e n t than the ditosylate method described e a r l i e r . Reaction of the epoxide 194 with lithium dimethylcuprate i n ether at 0° C, afforded 19_5 7 4 i n 75% y i e l d . The attack of the lithium dimethylcuprate reagent at C-2 instead of C-3 could be explained by stereoelectronic considerations. Presumably, t h i s reaction involved a trans d i a x i a l opening of the epoxide, which could only be achieved by a nucleophilic attack at C-2. Deoxygenation of the C-3 hydroxyl group i n 195 was accomplished using the method reported by Barton and McCombie. 7 7 As shown in Scheme XXXVIII, the alcohol 195 was f i r s t converted into the xanthate ester 196 by treatment with one equivalent of sodium hydride followed by excess amounts of carbon d i s u l f i d e and iodo-methane. The xanthate ester 196 was then heated under reflux with an excess of t r i - n - b u t y l t i n (IV) hydride 7 8=in toluene to y i e l d the deoxygenated product 197, the structure of which was corroborated by spectral evidence. It was suggested by Barton and McCombie7 7 that the reduction of the thiocarbonate 139 Scheme XXXVIII. Deoxygenation of 195 compound by t r i - n - b u t y l t i n (IV) hydride i n v o l v e s a f r e e r a d i c a l mechanism, as d e s c r i b e d i n Scheme XXXIX. The next step i n the s y n t h e t i c scheme was to remove the benzylidene p r o t e c t i n g group and s e l e c t i v e l y p r o t e c t the primary a l c o h o l . Subsequent c o n v e r s i o n of the hydroxyl group at C-4 i n t o a l e a v i n g group and displacement w i t h l i t h i u m dimethylcup-r a t e or methylmagnesium h a l i d e would l e a d to the d e s i r e d i n t e r -mediate 201 (Scheme XL). S e v e r a l methods f o r the removal of the benzylidene group were attempted. Hanessian and L a v a l l e e 7 9 r e p o r t e d a procedure u s i n g hydrogen and a Pd(OH) 2/C c a t a l y s t 140 Scheme XXXIX. Proposed Mechanism f o r Deoxygenation of 196 with T r i - n - b u t y l t i n (IV) h y d r i d e 7 7 R O - C + (n-Bu) 3SnH * RH + COS + (n-Bu) 3SnMe ^ S M e 1 9 6 RO — C + ( n - B u L S n i , • RO — C . \ ~ 3 \ SMe SSn(n-Bu) . S M e , .SMe R O — C - R- + 0 = C ^ S S r U n - B u ^ ^ S S n C n - B u ^ R- 4- (a -Bu) 3 SnH »- RH 4- (_n-Bu) 3Sn. SMe 0=C^ a- COS 4- (rv-Bu) 3SHSMe ^SSnCn-Bu). 3 to hydrogenolyze benzylidene groups. Using the same c a t a l y s t , we were unable to hydrogenolyze compound 197. Only s t a r t i n g m a t e r i a l was recovered. S i m i l a r l y , no r e a c t i o n s were observed when oth e r c a t a l y s t s such as Pd/C and Pt/C were used. The 142 f a i l u r e of these reactions could be due to the presence of trace amounts of t i n - s u l f u r by-products derived from the previous stannane reduction. Although p u r i f i c a t i o n of compound 197 could be achieved by column chromatography, we found the product i s o -lated from the column was s t i l l contaminated with trace amounts of by-products which could be detected e a s i l y from the character-i s t i c stench of these by-products. The p u r i f i e d 197 was shown to be homogeneous by spectral and TLC analyses. I t was decided at t h i s point to investigate other procedures to cleave the benzylidene group. We found that treatment of compound 197 with a c a t a l y t i c amount of p_-toluenesulfonic acid i n methanol at room temperature cleanly gave the desired product 19 8. I f the reac-ti o n was worked up c a r e f u l l y as described below, no p u r i f i c a t i o n was necessary for 198. The reaction mixture was neutralized with sodium carbonate and the concentrated under reduced pressure. The residue was partitioned between ether and water to get r i d of organic impurities. Pure 198 was i s o l a t e d from the aqueous phase as - a.colorless syrup i n good y i e l d . Compound 19 8 was readily i d e n t i f i e d from i t s spectral data. The IR spectrum showed absorptions for the hydroxyl groups at 3500 and 3650 cm 1 and no aromatic protons were observed i n the NMR spectrum. The mole-cular formula was confirmed by mass spectroscopy. Several reagents are known for the selec t i v e protection of the primary hydroxyl group i n 19.8. For example, Hanessian 14 j and L a v a l l e e 8 0 u s e d t e r t - b u t y l d i p h e n y l c h l o r o s i l a n e w h i c h p r e -f e r e n t i a l l y s i l y l a t e d p r i m a r y h y d r o x y l g r o u p s i n t h e p r e s e n c e o f s e c o n d a r y o n e s a s i n d i c a t e d by t h e f o l l o w i n g e x a m p l e . T r e a t -ment o f m e t h y l a - D - g l u c o p y r a n o s i d e ( 71) w i t h 1.1 e q u i v a l e n t s o f t e r t - b u t y l d i p h e n y l c h l o r o s i l a n e • i n N , N - d i m e t h y l f o r m a m i d e c o n -t a i n i n g 2.2 e q u i v a l e n t s o f i m i d a z o l e a f f o r d e d 203 i n 7 0 - 8 0 % y i e l d . However, we d e c i d e d t o u s e t r i p h e n y l c h l o r o m e t h a n e - 8 1 i n s t e a d o f t e r t - b u t y l d i p h e n y l c h l o r o s i l a n e f o r two r e a s o n s . F i r s t , t h e f o r m e r r e a g e n t i s c h e a p e r and was f o u n d t o g i v e h i g h y i e l d s o f 1 9 9 , and s e c o n d l y , a l e a v i n g g r o u p s u c h a s a m e s y l a t e c o u l d be i n t r o d u c e d a t C-4 w i t h o u t i s o l a t i n g t h e t r i t y l i n t e r m e d i a t e 199. T h i s was done i n t h e f o l l o w i n g manner. The d i o l 198 was f i r s t t r e a t e d w i t h t r i p h e n y l c h l o r o m e t h a n e ~ i n , a n h y d r o u s p y r i d i n e a t room t e m p e r a t u r e f o r 4 8 h>. W i t h o u t i s o -l a t i n g t h e p r o d u c t 199, more p y r i d i n e was a d d e d and t h e m i x t u r e was t r e a t e d w i t h m e t h a n e s u l f o n y l c h l o r i d e t o g i v e compound 200 i n g o od y i e l d . M e s y l a t e 200 was i d e n t i f i e d b y i t s NMR s p e c t r u m w h i c h showed an a b s o r p t i o n a t 6 2.8 c h a r a c t e r i s t i c o f t h e t h r e e OMe 71 203 144 protons on the mesyl group, and low f i e l d a b s o r p t i o n s at 6 7.0-7.6 a t t r i b u t a b l e t o the f i f t e e n protons o f the t r i t y l p r o t e c t i n g group. S e v e r a l attempts were made to d i s p l a c e the 0-mesylate at C-4. Johnson and D u t r a 8 2 developed a procedure i n which the a l k y l group of a l i t h i u m diorganocuprate d i s p l a c e d a t o s y l a t e w i t h 100% i n v e r s i o n of c o n f i g u r a t i o n . For example, when (+)-2-b u t y l t o s y l a t e (204) was allowed to r e a c t with a s o l u t i o n o f l i t h i u m d i p h e n y l c u p r a t e , the product was (-)-2-phenylbutane. (205). When compound 200 was t r e a t e d with l i t h i u m d i m e t h y l -O T S CH. -CH 2 C H 3 P h 2 C u L i 100 °/o inversion CH. - C ^ C H j H Ph 204 205 cuprate, we obtained the a l c o h o l 199 i n s t e a d of the d e s i r e d d i s -placement product. A s i m i l a r r e s u l t was observed when methyl-magnesium i o d i d e was used. Presumably, the 1 , 3 - d i a x i a l i n t e r -a c t i o n a r i s i n g from the C-2 methyl group and the approaching o r g a n o m e t a l l i c reagent p r o h i b i t e d these reagents from approach-i n g the top of the molecule t o achieve an S N2 displacement r e a c t i o n . Hence, i n s t e a d o f undergoing the d e s i r e d displacement 145 OMe 201 r e a c t i o n , the cuprate or the methylmagnesium reagent probably a b s t r a c t e d a proton from the mesylate moiety and regenerated a l c o h o l 199 as shown below. 200 146 C l e a r l y , we had to search f o r an al t e r n a t e : approach to 201. The p r e p a r a t i o n of compound 201 was e v e n t u a l l y accom-p l i s h e d by the route shown i n Scheme XLI. The a l c o h o l 199 was prepared from d i o l 198 by treatment w i t h 1.5 eq of t r i p h e n y l -chloromethane i n anhydrous p y r i d i n e . 8 1 The y i e l d o b t a i n e d a f t e r chromatographic p u r i f i c a t i o n was 86%. The IR spectrum of 199 showed an a b s o r p t i o n at 3570" 1 i n d i c a t i n g the presence of a h y d r o x y l group. Presence of the t r i t y l group was shown by a b s o r p t i o n s f o r the aromatic protons a t 6 6.7-7.4 (m, 15) -in the NMR spectrum. O x i d a t i o n of a l c o h o l 199 w i t h chromium t r i o x i d e -p y r i d i n e complex 8 3 gave ketone 206 i n good y i e l d . A W i t t i g r e a c t i o n of ketone 206 with m e t h y l e n e t r i p h e n y l p h o s p h o r a n e 8 h i n e t h e y l e t h e r a f f o r d e d 207 i n 82% y i e l d . Absence of the c a r b o n y l a b s o r p t i o n and appearance of an o l e f i n i c a b s o r p t i o n at 1660 cm - 1 i n the IR spectrum i n d i c a t e d a s u c c e s s f u l W i t t i g r e a c t i o n . The a b s o r p t i o n at 6: 4.62 a s c r i b a b l e to t e r m i n a l v i n y l protons i n the NMR spectrum of 207 confirmed the presence of the •.terminal--.methylene group. In the next c r u c i a l step the a x i a l methyl group at C-4 i n 201 was generated by s t e r e o s e l e c t i v e hydrogenation of 207 using W i l k i n s o n ' s c a t a l y s t . 8 5 When t h i s r e a c t i o n was run a t low temperature (0° C or lower) on a 0.065 mmol s c a l e , the s t e r e o s e l e c t i v i t y was very high. In f a c t , we d i d not d e t e c t 147 Scheme XLI. P r e p a r a t i o n of Compound 2 0 1 148 any of the C-4 epimer. However, when the same.reaction was run at room temperature on larger scales, lower s e l e c t i v i t y was observed. Along with the desired compound 201, a small quantity of the C-4 epimer 202 was also obtained. The NMR spectrum of the crude product showed a 9:1 r a t i o of the two compounds 201 and 202, which could be separated by column chro-matography on s i l i c a g el. The NMR spectral data of the p u r i f i e d isomers are l i s t e d i n Table 2. The structure of 201, with an a x i a l methyl group at C-4, was deduced both on mechanistic grounds and from spectroscopic analysis. The one-proton doublet at 6 4.2 assigned to H-l clo s e l y resembled H-l i n 207 both i n coupling pattern and chemical s h i f t , i n d i c a t i n g retention of the same chair conformation. The lower f i e l d absorption (6 0.70) for the methyl protons at C-4 i n 201 than that (6 0.58) i n 202 i s probably due to van der Waals deshielding of the 1,3-diaxial methyl groups i n 201. The 1 3C NMR spectrum of 201 also provided evidence for the st r u c t u r a l assignments. It has been established that a x i a l methyl groups i n cyclohexane rings normally have 1 3C NMR signals at 6 15-18 whereas the corresponding equatorial methyl groups are usually found at 6 18-25. 8 6 The 1 3C NMR spectrum of 201 showed only two signals above 6 30 at 15.93 and 18.30 respectively. This suggested that the methyl groups i n 201 are both a x i a l . The predominant formation of 201 i s probably due to the s t e r i c hindrance caused by the C-2 methyl group and the t r i t y l protecting group on the top face of the molecule 149 Table 2. NMR Data f o r Compounds 201 and 202 6M e OMe 201 202 Compound 2 01 202 <5, Chemical s h i f t s i n ppm (TMS, CDC1 3) CH 3 a t C-2 0.95 (d, J = 7 Hz, 3H) 1.05 (d, J = 7 Hz, 3H) CH 3 at C-4 0.70 (d, J = 7 Hz, 3H) 0.58 (d, J = 6 Hz, 3H) H-l 4.2 (d, J = 5 Hz, IH) 4.4 (br s, IH) OMe at C - l 3.45 (s, 3H) 3.38 (s, 3H) H-2, H-3, H-4 1.3-2.0 (m, 4H) 1.3-2.0 (m, 4H) H-5 3.8-4.1 (m, IH) 2.9-3.6 (m, 3H) H-6 3.0-3.3 (m, 2H) Ph 3 6.9-7.6 (m, 15H) 6.9-7.6 (m, 15H) 150 i n the favored conformation 207. Hence, hydrogen i s p r e f e r -e n t i a l l y d e l i v e r e d from the bottom face t o . g i v e the d e s i r e d 1 , 3 - d i a x i a l compound 201. O M e 207 I n t r o d u c t i o n of the e t h y l s i d e - c h a i n was f i r s t planned as shown i n Scheme XLII. H y d r o l y s i s o f compound 201 would g i v e 208 which c o u l d be p r o t e c t e d as i t s i s o p r o p y l i d e n e d e r i v a t i v e 209. The e t h y l group c o u l d then be i n t r o d u c e d v i a a Gri g n a r d r e a c t i o n a f f o r d i n g a l c o h o l 210. O x i d a t i o n of 210 to i t s k e -tone 1 f o l l o w e d by treatment with a c i d would l e a d t o the f i n a l product 18_. However, attempts t o hyd r o l y z e the t r i t y l and the methyl ether groups were u n s u c c e s s f u l . When compound 201 was hydrolyzed with a c a t i o n exchange r e s i n (Dowex 50 [H ] ) , s e r i o u s d i f f i c u l t i e s were encountered i n the i s o l a t i o n o f the water s o l u b l e h y d r o l y s i s product. Due to t h i s d i f f i c u l t y , we under-took a search f o r a more e f f i c i e n t route to i n t r o d u c e the e t h y l group. We were i n t r i g u e d by the p o s s i b i l i t y o f a p p l y i n g the method of Corey and Seebach u s i n g the a l k y l a t i o n -of d i t h i o a c e t a l ca-rbanions: to c h a i n extend carbohydrates. In t h i s method, 151 Scheme X L I I . A P o s s i b l e R o u t e t o ( - ) - a - M u l t i s t r i a t i n - : 209 210 a l d e h y d e s w e re c o n v e r t e d i n t o t h e c o r r e s p o n d i n g t h i o a c e t a l s 2 1 1 8 7 i 8 8 o r d i t h i a n e d e r i v a t i v e s 2 1 3 8 8 ' 8 9 w i t h a c i d c a t a l y s t s , (Scheme X L I I I ) . T h e s e t h i o a c e t a l s c o u l d be d e p r o t o n a t e d by Scheme X L I I I . A l k y l a t i o n o f D i t h i o a c e t a l C a r b a n i o n s R = a l k y l , H 2i3_ 2J_4 R 1 = C H 3 , C H 2 C H 3 R 2 = a l k y l E •>:= e l e c t r o p h i l e 152 al k y l l i t h i u m reagents to generate the sulfu r s t a b i l i z e d car-banions which undergo various reactions with electrophiles to furnish products of type 212 or 214.9 0 Since regeneration of the carbonyl function i n 212 and 214 can be achieved by mercuric chloride catalyzed hydrolysis, the thioacetal carbanions are equivalent to acyl anions and can be used e f f e c t i v e l y to reverse the c h a r a c t e r i s t i c e l e c t r o p h i l i c i t y of a carbonyl carbon. This approach appeared p a r t i c u l a r l y a t t r a c t i v e i n our synthesis. Two major advantages might arise from adopting the above reac-tions i n our synthetic scheme. F i r s t , hydrolysis of the ..tr i t y l protecting group, l i b e r a t i o n of the aldehyde and formation of the thioacetal might a l l be accomplished i n one step. Further-more, aprotic solvents might be used which would a l l e v i a t e the water s o l u b i l i t y problem encountered before. Secondly, the thioacetal function might f a c i l i t a t e the f i n a l c y c l i z a t i o n step in our synthetic plan without going through a carbonyl i n t e r -mediate which could cause epimerization of C-2. We f i r s t investigated the dieth y l thioacetal route as shown i n Scheme XLIV. Compound 201 was smoothly converted into d i e t h y l thioacetal 215 with concomitant cleavage of the t r i t y l group by treatment with concentrated hydrochloric acid and e t h a n e t h i o l . 9 1 The r e s u l t i n g thioacetal d i o l 215 was then pro-, tected as i t s isopropylidene derivative 216 using a c a t a l y t i c amount of p-toluenesulfonic acid and 2,2-dimethoxypropane. 9 2 153 Scheme XLIV. ' Attempted P r e p a r a t i o n of Compound 217 SEt 216 217 U n f o r t u n a t e l y , attempts to a l k y l a t e the d i e t h y l t h i o a c e t a l 216 were u n s u c c e s s f u l . The f a i l u r e of t h i s r e a c t i o n was found t o a r i s e from d i f f i c u l t i e s i n g e n e r a t i n g the anion of 216. T r e a t -ment of 216 wit h s t r o n g bases under v a r i o u s c o n d i t i o n s f a i l e d to e f f e c t carbanion formation. We f i r s t i n v e s t i g a t e d the use of n - b u t y l l i t h i u m as base. Quenching the mixture w i t h i o d o -ethane gave no d e t e c t a b l e amount of the d e s i r e d product 217. Only s t a r t i n g m a t e r i a l was recovered. D i f f e r e n t temperatures, r e a c t i o n times and bases (e.g., t e r t - b u t y l l i t h i u m ) were a l s o employed without success. Deuterium oxide quenching experiments i n v a r i a b l y showed no s i g n i f i c a n t i n c o r p o r a t i o n of deuterium, 154 r e v e a l i n g f a i l u r e i n the g e n e r a t i o n of the s u l f u r s t a b i l i z e d carbanion. I t has been shown t h a t u n s u b s t i t u t e d d i e t h y l t h i o -a c e t a l 211a was m e t a l l a t e d w i t h n - b u t y l l i t h i u m i n about 90% y i e l d w h ile under s i m i l a r c o n d i t i o n s the s u b s t i t u t e d dimethyl t h i o a c e t a l 211b was onl y 50% m e t a l l a t e d . 8 8 The r e l u c t a n c e o f Et C E t S ^ 211a n. -BuLi , - 2 0 ° C EtSv. J\r\ •-as* C 90 °/o T H F E t s / \ L J MeS. JE\ MeS H 211 b n.-BuLi , - 2 0 ° C MeS- -Et T H F C M e S ^ " L i 50 "lo 216 to form the carbanion was suspected to a r i s e from s t e r i c hindrance of the methyl group adjacent t o C-2 of the d i t h i o -a c e t a l group. In f a c t , d i f f i c u l t i e s i n a l k y l a t i n g s i m i l a r a-s u b s t i t u t e d d i e t h y l t h i o a c e t a l s have a l s o been r e p o r t e d . 8 8 S e v e r a l r e p o r t s have i n d i c a t e d t h a t the d i t h i a n e d e r i -v a t i v e of aldehydes are l e s s s u s c e p t i b l e to the s t e r i c e f f e c t s of an a - s u b s t i t u e n t i n c a r b a n i o n i c a l k y l a t i o n than the c o r r e s -ponding d i e t h y l t h i o a c e t a l s . Indeed, we were able to e f f e c t the d e s i r e d a l k y l a t i o n v i a the d i t h i a n e d e r i v a t i v e 219 as shown i n Scheme XLV. Compound 201 was t r e a t e d with 2 e q u i v a l e n t s 155 Scheme XLV. S y n t h e s i s of ( - ) - a - M u l t i s t r i a t i n v i a A l k y l a t i o n and C y c l i z a t i o n of D i t h i a n e D e r i v a t i v e s 221 156 of 1,3-dithiopropane and a c a t a l y t i c amount of boron t r i f l u o r i d e etherate to give 218 i n 80% y i e l d . This d i o l was then protected as i t s isopropylidene derivative 219 using the method described above. It i s known that the ease of metallation of dithiane derivatives varies with the s t e r i c and electronic character of the group R i n the 2-position of the dithiane compound (Scheme XLIV). 9 0 For example, metallation of the phenyl derivative -(R = C 6H 5) - occurred within a few minutes,.while the t e r t - b u t y l derivative - (R = t-Bu) - required about 5 h for complete metal-l a t i o n . An investigation was therefore conducted to develop suitable conditions for the generation of the anion of the d i -thiane derivative 219. The res u l t s obtained were summarized i n Table 3. Various bases and solvents were used to deprotonate 219 at d i f f e r e n t temperatures and for varied periods of time. The extent of anion formation was determined either by D20 quench-ing or by iodoethane a l k y l a t i o n . The most s a t i s f a c t o r y r e s u l t was obtained by treating compound 219 with 1.1 equivalents of te r t - b u t y l l i t h i u m i n n-hexane at -20° C for 2 h and then at -10° C for 6 h, followed by the addition of a solution of iodo-methane i n hexamethylphosphoramide. Progress of the a l k y l a t i o n was monitored by TLC analysis. The occurrence of a white pre-c i p i t a t e (presumably lithium iodide) could also be used as an indicatio n of a l k y l a t i o n . The alkylated product 220 was re a d i l y 157 Table 3. Rates of Metallation of Dithiane 219 Base-Solvent m o Temp C, Time Q. "O Deuterium incorporated (D.I.) or a l k y l a t i o n (EtI) n-BuLi-THF -20 , 10 min; 0 0 , lk h n-BuLi-THF -20 , 0 , 15 min; 2 h 45 (D.I.) n-BuLi-THF -20 , 15 min; 0 , 4 h 50 (D.I.) n-BuLi-THF -20 , 0 , 1 h; 3 3/4 h 40 (alkylated) tert-BuLi-n-Hexane -20 , -10 , 1 h 1 h 50 (alkylated) tert-BuLi-n-Hexane -20 , -10 , 1 h; 18 h >90 (alkylated) tert-BuLi-n-Hexane -20 , -10 , 2 h; 6 h >90 (alkylated) characterized by i t s NMR spectrum. No absorption correspond-ing to the methine proton of the d i t h i o a c e t a l was observed. Appearance of a new t r i p l e t at 6 0.98 (J = 7 Hz, 3H), ascrib-able to a primary methyl group confirmed the presence of the ethyl side-chain. 158 H y d r o l y s i s o f 22 0 with a c a t a l y t i c , amount, of p-to l u e n e -s u l f o n i c a c i d i n methanol a f f o r d e d the corresponding d i o l 221 i n 90% y i e l d . Many of the p r e v i o u s l y r e p o r t e d syntheses of m u l t i s t r i a t i n (18_) i n v o l v e d a c i d c a t a l y z e d c y c l i z a t i o n of the e pox y ketone .8_7 or keto d i o l 222. These c o n d i t i o n s u s u a l l y r e s u l t i n e p i m e r i z a t i o n of the methyl group adjacent to the carb o n y l f u n c t i o n . Since h y d r o l y s i s o f the t h i o k e t a l 221 to a 87 222 ketone under h y d r o l y t i c c o n d i t i o n s may cause e p i m e r i z a t i o n o f the C-2 methyl group, an attempt was made to c l e a v e the t h i o -k e t a l i n 221 with concomitant c y c l i z a t i o n , without going through the ketone. Mercuric s a l t c a t a l y z e d h y d r o l y s i s o f t h i o k e t a l i s b e l i e v e d to i n v o l v e i n t e r m e d i a t e s such as 2 23. 8 8 I n t r a -159 molecular p a r t i c i p a t i o n of the d i o l group d u r i n g the h y d r o l y s i s of 221 should l e a d d i r e c t l y to a - m u l t i s t r i a t i n (equation 3). C H. . 2*. pHgX O- / H 9 X +S SHgX >• 18a (3) 2 2 1 Indeed, when 221 was t r e a t e d w i t h a mixture of mer c u r i c c h l o r i d e and mercuric oxide i n anhydrous a c e t o n i t r i l e , 9 3 ' 9 4 the b i c y c l i c k e t a l 18a was formed i n 80% y i e l d . As p r e c a u t i o n s were taken to exclude water from the r e a c t i o n mixture, the mechanism shown by equation 3 was presumably i n v o l v e d i n t h i s p r o c e s s . The s t r u c t u r e of the f i n a l product was confirmed by comparison of i t s s p e c t r a l data with those r e p o r t e d f o r a - m u l t i -s t r i a t i n ( 1 8 a ) . 2 6 ' 9 5 The NMR spectrum o f the s y n t h e t i c m a t e r i a l showed one s e t of o v e r l a p p i n g doublets at 6 0.81 f o r the methyl groups at C-2 and C-4, i d e n t i c a l w i t h t h a t recorded f o r the a isomer. A b s o r p t i o n p a t t e r n s o f these methyl groups i n the diastereomers 188, 18y and 186 are s i g n i f i c a n t l y d i f f e r e n t from the above (see F i g u r e 2). Other NMR s i g n a l s c h a r a c t e r i s t i c of 18a were a l s o p r e s e n t : 6 3.68 (m, IH) and 3.89 (m, IH) f o r the methylene protons on C-7, and. 6 4.20 (m, IH) f o r the methine proton on C - l . The IR spectrum was i d e n t i c a l with t h a t r e p o r t e d 160 for natural a - m u l t i s t r i a t i n . 2 6 That our synthetic product was 18a was further ascertained by a combined GLC analysis with an authentic sample. ( 2 ) An o p t i c a l rotation of [ a ]^ 5 - 4 6 ° (10 mg/ mL, hexane) was observed for the synthetic compound, which i s i n good agreement with the measurement [ a]p 5 - 4 7 ° (1.9 mg/mL, hexane) reported for the natural compound. 2 6' 5 0 18a A sample of m u l t i s t r i a t i n with known composition was obtained from Dr. J. W. Peacock, of the Forest Service, United States Department, of Agriculture, Delaware, U.S.A. 161 ( i i i ) , Synthesis „of Lineatin (22) In continuation of our work on the synthesis of c y c l i c ketal insect pheromones, we also investigated the synthesis of l i n e a t i n (2_2_) . 2 9 ' 3 0 The major synthetic challenge represented 8 i i 2 2 224 by the l i n e a t i n molecule i s the construction of the unusual t r i -c y c l i c acetal skeleton with proper stereochemical control. A n t i -t h e t i c dissection of compound 2_2 at the C - l , 0-9 bond gave the obvious precursor 224. Our approach centred on the synthesis of 224 with reasonable control over stereochemistry. A convenient way to construct the four-membered ring i n 224 i s v i a a [ 2 + 2 ] cycloaddition reaction. It has been shown that the photocycloaddition reaction of a,8-unsaturated lactones with o l e f i n s gave mainly cis-fused adducts. For exam-ple, photocycloaddition of the lactone 119 with ethylene gave the cycloadduct 225. 9 6 The cycloaddition of a,8-unsaturated ketones or aldehydes with allene has also been re p o r t e d . 9 7 162 119 225 A d d i t i o n of 2-cyclopentenone (226) to a l l e n e gave a mixture of adducts 227 and 228, with 227 as the major p r o d u c t . 9 7 3 S i m i -l a r l y , i r r a d i a t i o n of a mixture of 2-cyclohexenone (229) and a l l e n e gave predominantly compound 230 . 9 7 b Z i e g l e r and K l o e k 9 7 e 229 230 r e p o r t e d the formation of 232 i n 42% y i e l d by i r r a d i a t i n g an ether s o l u t i o n of 231 i n the presence of a l l e n e . Only 3% of an isomer of 232 was i s o l a t e d . Although both a , 8 - u n s a t u r a t e d l a c t o n e s and a l l e n e s have been i n v e s t i g a t e d i n [2 + 2] c y c l o -a d d i t i o n r e a c t i o n s , 9 7 -.such a - r e a c t i o n - of-- an va -, 8 - u n s a t u r a t e d 163 231 232 l a c t o n e with a l l e n e has not been recorded. We chose to adopt t h i s type of photochemical c y c l o a d d i t i o n r e a c t i o n i n our syn-t h e t i c p l a n because the r e s u l t i n g photoadduct c o u l d be r e a d i l y transformed i n t o the p r e c u r s o r 224. The p r e p a r a t i o n of l a c t o n e 119 was c a r r i e d out as shown i n Scheme XLVI. l-Acetoxy-3-butanone (235) was prepared accord-i n g t o the procedure of C o r n f o r t h et a l . 9 8 from methyl v i n y l ketone 48_. Condensation of e t h y l l i t h i o a c e t a t e with 235 i n ether at -78° C a f f o r d e d 236 i n 88% y i e l d . 9 9 The d i e s t e r 236 was hydrolyzed i n methanolic potassium hydroxide and then c y c l i -zed i n methanolic h y d r o c h l o r i c a c i d to give mevalonolactone ( 2 3 7 ) 9 8 i n good y i e l d . Dehydration of 237 was e f f e c t e d by heat-i n g w i t h potassium hydrogen s u l f a t e , 9 6 ' 3 f o l l o w e d by d i s t i l -l a t i o n of the product. I t was found t h a t the i n i t i a l d i s t i l l a -164 Scheme XLVI. Sy n t h e s i s of 3-Methyl-5-hydroxy-2-pentenoic a c i d 6-lactone (119) 236 237 1 1 9 t i o n product contained a mixture of a , 8 - u n s a t u r a t e d and 8,Y~ unsaturated l a c t o n e s , 119 and 238. By r e d i s t i l l a t i o n of t h i s mixture i n the presence of potassium hydrogen s u l f a t e at a bath temperature of 190° C, we were ab l e to o b t a i n predominantly the conjugated isomer 119 i n 83% y i e l d . 237 238 165 The c y c l o a d d i t i o n r e a c t i o n of l a c t o n e 119 with a l l e n e was accomplished photochemically. I r r a d i a t i o n of a s o l u t i o n of 119 i n acetone a t room temperature through a Vycor f i l t e r w i th a moderate r a t e of i n t r o d u c t i o n of a l l e n e gave a mixture of c y c l o a d d u c t s i n 80% y i e l d . GLC a n a l y s i s of the product showed the presence of two b a r e l y separable components i n a r a t i o of ca. v.,5:3;. Attempts to separate the mixture were unsuc-c e s s f u l . The IR spectrum of the cycloadduct showed a b s o r p t i o n s at 1725 and 1680 cm 1 , a t t r i b u t a b l e t o the S-lactone and the .terminal' double' bond, r e s p e c t i v e l y . • The 27 0 MHz NMR .spectrum -had a b s o r p t i o n s at 6 4.8-5.2 corresponding to two v i n y l protons, and two methyl s i n g l e t s w i t h d i f f e r e n t i n t e n s i t i e s (ca. 5:3) at 6 1.26 and 1.24 r e s p e c t i v e l y . The high r e s o l u t i o n mass mea-surement gave C 9 H 1 2 0 2 as the molecular formula of the product. F u r t h e r evidence f o r the a d d i t i o n product was o b t a i n e d from the low r e s o l u t i o n mass spectrum and elemental a n a l y s i s . We were able to a s s i g n s t r u c t u r e s 2 33 and 234 (5:3) to the two p o s i t i o n a l isomers i n the photoadduct mixture from the r e s u l t s of subsequent 166 o z o n o l y s i s s t u d i e s d e s c r i b e d b e l o w . The c i s r i n g - f u s i o n i n t h e s e a d d u c t s was a s c e r t a i n e d b y a n a l o g y w i t h t h e r e s u l t s r e p o r t e d p r e v i o u s l y on s i m i l a r p h o t o c y c l o a d d i t i o n r e a c t i o n s ( v i d e s u p r a ) . F u r t h e r m o r e , t h e p h o t o a d d u c t s 233 and 234 w e r e n o t e p i m e r i z e d b y b a s e t r e a t m e n t w h i c h i s i n a g r e e m e n t w i t h a c i s f u s e d s k e l e t o n . To d e t e r m i n e t h e s t r u c t u r e s o f t h e p h o t o l y s i s p r o d u c t s , we c o n d u c t e d s e v e r a l o z o n o l y s i s e x p e r i m e n t s . When t h e m i x t u r e o f p h o t o a d d u c t s was o z o n i z e d i n m e t h a n o l a t -78° C, a n d w o r k e d up w i t h d i m e t h y l s u l f i d e , 1 0 0 - t h e NMR s p e c t r u m o f t h e c r u d e p r o -d u c t showed a m i x t u r e o f e s t e r 239 a n d k e t o n e 240 i n a r a t i o o f 5:3. Compound 239 was i d e n t i f i e d b y t h e c h a r a c t e r i s t i c a b s o r p -1. 0 3 / MeOH, - 7 8 ° a-f 2 3 3 + 2 3 4 2 3 9 2 4 0 t i o n s i n i t s NMR s p e c t r u m a t 6 3.6 3 ( s , 3H), f o r t h e t h r e e p r o t o n s o f t h e m e t h o x y g r o u p , and 6 1.18 ( s , 3H) f o r t h e m e t h y l g r o u p . The l o w r e s o l u t i o n mass s p e c t r u m showed a p a r e n t mass a t m/e 186. The I R s p e c t r u m h a d an a b s o r p t i o n a t 1740 c m - 1 f o r t h e c a r b o n y l g r o u p o f an e s t e r . The f o r m a t i o n o f compound 239 167 probably arose from n u c l e o p h i l i c a t t a c k o f methanol on the ketone 241 to gi v e an i n t e r m e d i a t e 242 which then underwent 241 242 239 a retro-Dieckmann r e a c t i o n t o produce e s t e r 239. Compound 240 was r e a d i l y i d e n t i f i e d by the c h a r a c t e r i s t i c I R a b s o r p t i o n of the four-membered r i n g ketone at 1790 cm" 1. The s t r u c t u r e of 240 was f u r t h e r c o r r o b o r a t e d by i t s . NMR and mass s p e c t r a l data. Since 239 was ap p a r e n t l y d e r i v e d from the i n t e r m e d i a r y ketone 241 which i n t u r n arose from compound 233, and 239 was the major o z o n o l y s i s product, the major photoadduct o b t a i n e d above must be 233. Ozo n o l y s i s of the photoadducts 233 and 234 i n d i c h l o r o -methane c o n t a i n i n g 1 eq of methanol gave a mixture of 240 and 241 i n a r a t i o of 3:5 a c c o r d i n g t o NMR a n a l y s i s . Compound 241 was i d e n t i f i e d by the three proton s i n g l e t a t 6 1.53 f o r the angular methyl group i n i t s NMR spectrum and by i t s I R absorp-t i o n s at 1720 (6-lactone) and 1790 cm - 1 (four-membered r i n g ketone). The NMR spectrum of compound 240 had a three proton 168 •O 240 241 singlet at 6 1.33 due to the angular methyl group and the IR spectrum showed the cyclobutanone absorption at 1790 cm 1. Attempts to separate the mixture 240 and 241 by TLC were unsuc-ce s s f u l . Only compound 240 was i s o l a t e d and compound 241 seemed to decompose upon chromatography. A similar mixture of 240 and 241 was obtained when the ozonolysis was car r i e d out i n dichloro-methane i n the absence of methanol. From the above r e s u l t s , i t was clear that the photochemical cycloaddition gave a mixture of adducts 233 and 234 i n a r a t i o of 5:3. The c h a r a c t e r i s t i c absorptions i n the IR and NMR spectra of compounds 233, 234, 2 39, 240, and 241 are summarized i n Table 4. ti o n of allene with an a ,8-unsaturated ketone which led to two regioisomers. The structures of the regioisomers 227 and 228 were also determined by ozonolysis of the photoadducts. Treat-ment of the ozonolysis products with base produced a mixture of 244 and 245. Of the ozonolysis products 243 and 244, only 243 would be expected to undergo retro-Dieckmann ring opening to Eaton 9 7 a has reported an example of cycloaddition reac-169 Table 4. Some Characteristic IR and NMR Absorptions for 233+234, 239, 240 and 241. NMR (6) IR (cm- ) 1. 31 (CH3) 1725 (6-lactone) 233 + 234 OMe 239 1.18 (CH3) 3.6 3 (OCH3) 1720 (6-lactone) 1740 (ester) 240 1.33 (CH3) 1720 (6-lactone) 1790 (C=0, cyclobutanone) 24 1 1.53 (CH3) 172 0 (6-lactone) 1790 (C=0*> cyclobutanone) 170 giv e 245 (Scheme XLVII). Scheme XLVII. Oz o n o l y s i s of Compounds 227 and 228 96 a 245 244 244 Our i n i t i a l s y n t h e t i c s t r a t e g y , as d e p i c t e d i n Scheme XLVIII, i n v o l v e d o z o n o l y s i s o f the photoadduct 2 33 to gi v e 241 which c o u l d be s e l e c t i v e l y reduced to hydroxy l a c t o n e 24 6. Subsequent r e a c t i o n o f 246 wit h m e t h y l l i t h i u m , f o l l o w e d by o x i -d a t i o n of the primary a l c o h o l i n the r e s u l t i n g t r i o l 134 wit h concomitant i n t r a m o l e c u l a r a c e t a l formation would h o p e f u l l y g i v e the d e s i r e d t r i c y c l i c compound 22^ . Although t h i s route appeared a t t r a c t i v e i n terms of number of r e a c t i o n s t e p s , i t was aban-doned due to the l a b i l i t y of the 8-keto l a c t o n e moiety i n 241 and the d i f f i c u l t i e s encountered i n the i s o l a t i o n of 241. 171 Scheme XLVTII. A Possible Route to Lineatin (22). v i a Ozonolysis of 233 134 22 An alternative approach was then conceived as shown i n Scheme XLIX, which consisted of one step more than the o r i g i n a l plan. Nevertheless, a l l the reactions i n t h i s sequence were accomplished e f f i c i e n t l y to furnish the f i n a l product 2_2. As can be noticed i n t h i s modified scheme, the methylidene group was ozonized at a l a t e r stage of the synthesis (compounds 249 and 250) , where the problem of retro-Dieckmann ring opening was avoided. Since separation of the two photoadducts was very d i f f i -c u l t , we decided to carry through the subsequent steps of the sequence on the isomeric mixture (Scheme XLIX). Addition of the 172 22 173 photoadduct mixture 233 and 234 to an excess of methyllithium at 0° C i n ethyl ether resulted i n the formation of the two d i o l s 247 and 248. The IR spectrum had absorption for the hydroxyl group and no carbonyl absorptions were observed. The NMR spectrum showed several methyl singlets from 6 1.1 to 1.4 for the two isomers, a multiplet at 6 3.5-3.9 for the methylene protons adjacent to a hydroxy group, and a multiplet at 6 4.6-5.0 for the v i n y l protons. Again, t h i s mixture of isomers (247 and 248) was homogeneous by TLC analysis. In fact, we have been unable to separate chromatographically the mixtures of isomers for any of' the intermediates on a preparative scale u n t i l the f i n a l stage of the synthesis. The rest of the reaction sequence was therefore conducted on isomeric mixtures. The NMR and IR spectra of a l l the intermediate mixtures are :showh :;in' • the spectral index. Oxidation of the d i o l s 247 and 248 with chromium t r i -oxide-pyridine complex 8 3 gave a mixture of lactones 249 and 250 i n 72% y i e l d . The products were readi l y recognized from the IR spectrum which, exhibited an absorption at 1725 cm - 1 due to the carbonyl function of the lactone. The NMR showed more than three singlets for the protons of the methyl groups i n the region 6 1.2-1.4. A multiplet around 5 1.8-2.0 (total 3H) and a broad singlet at 6 2.37 (total 2H) accounted for the protons on the four-membered ring and the methylene protons next to the car-bonyl group, respectively. In addition, there was a multiplet 174 for the v i n y l protons at 6 4.8-5.0. Further evidence for the molecular formula and structure was obtained from mass spec-t r a l data and elemental analysis. The mixture of the lactones 249 and 250 was ozonized i n dichloromethane at -78° C, followed by dimethyl s u l f i d e work-up to afford a mixture of keto lactones 251 and 252. Presence of the four-membered ring ketone and the 6-lactone was indicated by the IR absorptions at 1780 and 1730 cm - 1 , respectively. No v i n y l proton signals were observed i n the NMR spectrum of t h i s mixture. Selective reduction of the cyclobutanone carbonyl to an alcohol was achieved by treating the mixture of 251 and 252 with 1.2 eq of lithium tri-sec-butylborohydride (L-Selectride) . 1 0 This reagent was f i r s t studied by Brown and Krishnamur-t h y 1 0 2 and was shown to be a highly stereoselective reducing agent for c y c l i c ketones. It s e l e c t i v e l y reduces ketones i n the presence of esters, and owing to i t s s t e r i c bulk, delivers hydride from the less hindered side of the ketone plane. In the reduction of 251 and 252 with L-Selectride, i t i s believed that 251 253 175 delivery of the hydride from the less hindered, convex face of the cyclobutanone should give predominantly the alcohols 253 and 254 with the stereochemistry as indicated. In fact, the eventual successful transformation of these alcohols into 22 and 23^  proved the high s t e r e o s e l e c t i v i t y i n t h i s reduction. The IR spectrum of these alcohols showed absorptions at 3600 (free -OH) and 3450 cm - 1 (hydrogen bonded -OH). In addition, an absorption due to the carbonyl of the 6-lactone was observed at 1720 cm - 1. The NMR and mass spectral data were consistent with the assigned structures. F i n a l l y , the mixture of lactones 253 and 254 was reduced with diisobutylaluminum hydride (DIBAL) , 1 0 3 "' followed by treatment of the re s u l t i n g reaction mixture with aqueous acid to afford the cy c l i z e d products 22_ and 2_3.' Separation of these two isomers was achieved by column chromatography, giving each compound i n 29% y i e l d . Although the i s o l a t e d y i e l d of 22_ and 23_ was i n a 1:1 r a t i o , the NMR of the crude mixture showed that the r a t i o of 2_2 to _23_ was ca. 2:1. The' IR, NMR, high and low resolution mass spectra of the synthetic product 22_ were i d e n t i c a l with those reported by S i l v e r s t e i n and coworkers 2 9 for natural l i n e a t i n . In addition, elemental analysis of compound 2_2 was consistent with i t s mole-cular formula. The IR spectrum of compound 2_3 showed intense absorptions at 800-1400 cm - 1 i n d i c a t i n g the presence of C-0-C linkages, and neither carbonyl nor hydroxyl groups were present. It i s int e r e s t i n g to note that the NMR spectra of the two isomers 176 22 and 23_ showed s i g n i f i c a n t differences. A comparison of the NMR spectral data of these isomers are summarized i n Table 5. Assignment of the signals for the protons i n 2_2 and 2_3 was assisted by the use of spin decoupling experiments. Results from the decoupling experiments conducted on the 270 MHz NMR of l i n e a t i n (_2_2) are l i s t e d i n Table 6. The lowest f i e l d signal at 6 4.93 (d, J = 4 Hz) was assigned to the acetal proton H^. From a molecular model of 2_2, the dihedral angle between U1 and H 3 i s estimated to be about 9 0°, therefore we expect the coupling constant J i , 3 to be small or zero. This explains the observation of a doublet for Hx instead of a more complex signal. The doublet would be due to the coupling between Hi and H 2 which have a dihedral angle of about 30°. When H\i was irr a d i a t e d , the signal at 6 2.04 (dd, J = 12, 4 Hz) collapsed to a doublet (J = 12 Hz). Hence we assign the signal at 6 2.04 to H 2. The second low f i e l d signal at 6 4.38 (t, J = 4 Hz) i s assigned to H 6. Irr a d i a t i o n at 6 4.38 (H 6), showed a change i n the signals at <5 1.83 (d, J = 4 Hz) and at 6 1.69 (dt, J = 10.5, 4 Hz). The doublet at 6 1.83 i s assigned to the t e r t i a r y H 7 which i s only coupled to H 6. The fact that J 6 7 = 4 Hz instead of a normal v i c i n a l cyclobutane coupling of ca. 10 H z 1 0 4 may be due to the electronegative oxygen on the carbon bearing H 6 . 1 0 5 177 Table_5. 2 70 MHz NMR of Compounds 2_2 and 2 3 H3 22 23 22 23 Chemical s h i f t i n ppm (6) from TMS i n CC1 4 Hi 4.93 (d, J — 4 Hz) Hi 5.32 (d, J = 4 Hz) H 2 2.04 (dd, J = 12, 4 Hz) H 2 1.33 (dd, J = 12, 4 Hz) H 3 1.91 (dd, J = 12, 4 Hz) H 3 2.09 (d, J = 12 Hz) Hi* 1.61: (d, J = 10.5 Hz) Hu 2.35 (ddd, J = 13, 9,4 Hz) Hs 1.69 (dt, J = 10.5, 4 Hz) H 5 1.9 (m) H 6 4.38 (t, J = 4 Hz) He 3.93 (t, J = 4 Hz) H 7 1.83 (d, J = 4 Hz) H 7 1.9 (m) Me(a) 1.12 (s) Me(a) 1.08 (s) Me(b) 1.17 (s) Me(b) 1.39 (s) Me(c) 1.16 (s) Me(c) 1.2 3 (s) These assignments may be reversed. 1 7 8 Table 6. Spin Decoupling on 2 70 MHz NMR of Compound 22 (see spectral appendix, p., 270) Irradiated Signal Decoupled Signal 6 ( m u l t i p l i c i t y ) A s s i -gned • II 6 ( m u l t i p l i c i t y ) 8(multiplicity) Assi (before decoupl- (after . ? n^ d ing) decoupling) 4.93 (d, J=4 Hz) Hj 2.04 (dd, J=12f (d, J = 12) H 2 4 Hz) 4.38 (t, J=4 Hz) H 6 1.83 (d, J=4 Hz) (s) H 7 1.69 (ddd, J = (dd = 10.5, 10.5, 4 Hz) 4 Hz) H 5 1.83 (d, J=4 Hz) H 7 4.38 (t, J=4 Hz) (d, J = 4 Hz) H 6 1 The signal at 6 1.69 i s a doublet of t r i p l e t s which would arise from three couplings as shown. We assign t h i s s i g -nal to H 5. Irra d i a t i o n at 6 4.38 (H6) led to s i m p l i f i c a t i o n 179 of the doublet of t r i p l e t s at 1.69 to a doublet of doublets (J = 10.5, 4 Hz); thus J s f 6 = 4 Hz. The geminal hydrogens Hit and H 5 are coupled with 5 = 10.5 Hz, and f i n a l l y H 5 experien-ces long range coupling with H 3 ; J 3 j 5 = 4 Hz. A study of mole-cular models indicate that H 3-C 8-C7-C 6-H 5 can adopt the "W" configuration. The doublet at 6 1.61 (J = 10.5 Hz) then was assigned to H i , . The lack of coupling between H^ and H 6 may again be due to the electronegative substituent on the cyclo-butane ring. The remaining doublet of doublets at 6 1.91 (J = 12, 4 Hz) i s assigned to H 3. This signal was unaltered by i r r a d i a -t i o n at H i . Thus the couplings are assigned to J 2 / 3 = 12 Hz, a t y p i c a l value for a geminal' coupling, and J 3 ^ 5 = 4 Hz due to the long range coupling described above. The three methyl singlets at 6 1.12, 1.16 and 1.17 are tenta t i v e l y assigned as follows. The high f i e l d s i n g l e t at 6 1.12 i s assigned to Me(a) and the two lower f i e l d signals to Me(b) and Me(c). The assignment of the signals for the protons in l i n e a t i n {22) from the spin decoupling experiments i s con-sistent with the assignment made by S i l v e r s t e i n et a l . 2 9 from the s h i f t e d NMR spectrum of natural l i n e a t i n (2_2) . Results from the decoupling experiments performed on the 270 MHz NMR of 23. are given i n Table 7. As before, the lowest f i e l d signal at 6 .5.32 (d, J = 4 Hz) i s assigned to the 1 8 0 Table 7 . Spin Decoupling on 2 7 0 MHz NMR of Compound 2 J 3 (see spectral appendix, p. 2 7 1 ) Irradiated Signal 6 ( m u l t i p l i - A s s i -c i t y j gned H Decoupled Signal 6 ( m u l t i p l i c i t y ) 5 ( m u l t i p l i - Assi-(before decoupl- city) gned • i n r r i (after., de-. H mg; coupling) 5 . 3 2 (d, J = 4 Hi Hz) 1 . 3 3 (dd, J = 1 2 , (d, J = H 2 4 Hz) 1 2 Hz) 3 . 9 3 (t, J = H 6 4 Hz) 2 . 3 5 (ddd, J = (dd, J = H ^  1 3 , 9 , 4 Hz) 1 3 , 9 Hz) 1 . 9 (m) (simplified) 1 . 3 3 (dd, J = H 2 1 2 , 4 Hz) 5 . 3 2 (d, J = 4 Hz) (s) '• )•;\ H : 2 . 0 9 (d, J = ( S) 1 2 Hz) 2 . 0 9 (d, J = H 3 1 2 Hz) 1 . 3 3 (dd, J - 1 2 , (d, J = H 2 4 Hz) 4 Hz) 2 . 3 5 (ddd, H 4 J = 1 3 , 9 , 4 Hz) 3 . 9 3 (t, J = 4 Hz) (d, J = H 6 4 Hz) 1 . 9 (m) (simplified) ^ H 7 1 . 9 (m) H 5 V H 7 3 . 9 3 (t, J = 4 Hz) (d, J = H 6 4 Hz) 2 . 3 5 (ddd, J = 1 3 , (d, J = H, 9 , 4 Hz) 4 Hz) 181 acetal proton Hi. The dihedral angle between Hi and H 2 i s estimated to be about 30° whereas that between Ha and H 3 i s about 90°. Thus the observed doublet at 5 5.32 i s consistent with the lack of coupling between Hi and H 3 . I r r a d i a t i o n of Hi produced a collapse of the d o u b l e doublet (J = 12, 4 Hz) at 6 1.33 to a doublet (J = 12 Hz). Hence t h i s double doublet i s assigned to H 2 which i s expected to show a v i c i n a l coupling, J i ^ 2 = 4 Hz, and a geminal coupling, J 2 ^ 3 = 12 Hz. I r r a d i a t i o n of the signal at 6 1.33 led to a collapse of the doublet at 6 2.09 (J = 12 Hz) to a s i n g l e t . Hence t h i s doublet i s assigned to H 3. Incidently, the i r r a d i a t i o n at 6 1.33 also collapsed the doublet at 6 5.32 to a s i n g l e t . These assignments were cross-checked by an i r r a d i a t i o n at 6 2.09 which collapsed the signal at 6 1.33 to a doublet (J = 4 Hz). The second lowest f i e l d signal at 6 3.93 (t, J = 4 Hz) i s assigned to H 6. Irr a d i a t i o n of H 6 produced a s i m p l i f i c a t i o n of the multiplet at 6 2.35 to a double doublet (J = 13, 9 Hz) and a s i m p l i f i c a t i o n of the two proton multiplet at 6 1.9. The multiplet at 6 2.35 can arise as shown and the observed 1 8 2 coupling constants are J, , = 1 3 Hz, j = 9 Hz, and j , = ab' • ac .. • cd 4 Hz. I r r a d i a t i o n of the signal, at <5 1 . 9 collapsed the multi-pl e t at 6 2 . 3 5 to a doublet (J = 4 Hz). From these decoupling results and the magnitudes of the coupling constants we suggest that the multiplet at 6 2 . 3 5 be assigned to H 4. Thus the c i s v i c i n a l coupling has the value JV 6 = 4 Hz. The geminal coupling, J i* 5 = 1 3 Hz, i s consistent with l i n e a t i n [22) and other cyclo-butanes. The trans v i c i n a l coupling J 4 7 = 9 Hz i s t y p i c a l of value observed i n many cyclobutyl compounds . 1 0 ** »1 0 5 F i n a l l y , the multiplet at 6 1 . 9 i s assigned to H 5 and H 7 . The low f i e l d s h i f t of H 4 r e l a t i v e to the other cyclobutane protons i n 22/and 2^ 3 i s attributed to van der Waals deshielding of Hi, i n 2_3 by Me (b) and 0 - 9 . The signal at 6 1 . 0 8 i s assigned to Me(a) and the remaining two singlets at 6 1 . 3 9 and 1 . 2 3 are assigned to Me(b) and Me(c) respectively. The low f i e l d s h i f t of Me(b) r e l a t i v e to Me(c) might be due to the van der Waals deshielding of Me(b) by H 4. The previous syntheses of l i n e a t i n 2 9 ' 3 0 were of very low o v e r a l l y i e l d and often complex mixtures of isomers were obtained. Hence, only very minute quantities of pure l i n e a t i n (22) were available for testing. Our synthesis of l i n e a t i n ( 2 2 ) represents a major improvement over the previous methods i n terms of both e f f i c i e n c y and s t e r e o s e l e c t i v i t y . The intermediate 3 -methyl-5-hydroxy-2-pentenoic acid 6-lactone ( 1 1 9 ) could be 183 e a s i l y s y n t h e s i z e d on a l a r g e s c a l e . The photochemical c y c l o -a d d i t i o n r e a c t i o n of 119 with a l l e n e , although not h i g h l y r e g i o -s e l e c t i v e , l e d to predominant formation of the d e s i r e d adduct 233. T h i s mixture of r e g i o i s o m e r s c o u l d be c o n v e n i e n t l y c a r r i e d through the subsequent steps to the f i n a l product which was r e a d i l y p u r i f i e d by column chromatography. T h i s sequence has a l r e a d y been u t i l i z e d to generate gram q u a n t i t i e s of 2_2 and 23, and i t should be f e a s i b l e t o s y n t h e s i z e even l a r g e r q u a n t i t i e s of 2_2_ f o r e x t e n s i v e b i o l o g i c a l s t u d i e s . 184 EXPERIMENTAL General: see p. 26. Synthesis of 5-Methyl-6,8-dioxabicyclo[3.2.1]octane (167) Methyl 3-oxo-7-octenoate (152) Sodium hydride, as a 57% mineral o i l dispersion, (5.45 g, 100 mmol) was weighed into an oven dried flask. It was washed o i l - f r e e with THF and after decantation of the THF, fresh THF (ca. 250 mL) was d i s t i l l e d d i r e c t l y into the fla s k . The flask was then equipped with a magnetic s t i r r e r , septum cap, cooled i n ice and flushed with nitrogen. Methyl aceto-acetate (11.60 g, 100 mmol) was added dropwise to the cooled slurry, and after the addition, the reaction mixture was allowed to s t i r for 10 min. n-Butyllithium, as a 2.1 M solution i n hexane (48 mL, .101 mmol) was added dropwise to the reaction mixture and i t was allowed to s t i r for another 10 min. To the resu l t i n g dianion was added 14.85 g (110 mmol) of 4-bromo-l-butene. The yellow reaction mixture was s t i r r e d for 2 h at 0° C a n: d • i t was quenched with d i l u t e hydrochloric acid solution u n t i l s l i g h t l y acid. Ethyl:ether'(2 x 400 mL)- was used to extract the reaction mixture. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over anhydrous magnesium sulfat e . The solvents were removed 185 under reduced pressure. P u r i f i c a t i o n was achieved by d i s t i l -l a t i o n to give 13.43 g (79%) of methyl 3-oxo-7-octenoate (152) , bp 62° C/0.1 to r r ; IR (CHC13) 920, 1650, 1720, and 1745 cm"1; NMR (CDC13) 6 1.5-2.3 (m, 4H), 2.51 (t, J = 7 Hz, 2H), 3.38 (s, 2H), 3.68 (s, 3H), 4.7-5.2 (m, 2H), and 5.3-6.1 (m, 1H) ; mass spectrum m/e (rel intensity) 41(57), 43(45), 55(32), 59 (37), 69 (43), 74 (60), 84 (32), 97(53), 101 (54), 116 (100), 129 (13), 138(16), and 170 (29). Anal. Calcd for C 9 H 1 4 O : , : C, 63.51; H, 8.29. Found: C, 63.51; H, 8.37. Methyl 7,8-epoxy-3-oxooctanoate (153) A sample of 1.01 g (5.50 mmol) of 85% m-chloroperbenzoic acid was added to a solution of 0.85 g (5.0 mmol) of methyl 3-oxo-7-octenoate (152) i n ca. 20 mL dry dichloromethane at 0° C. The reaction mixture was s t i r r e d at 0° C for 0.5 h and at room temperature for an additional 20 h. It was quenched with sat-urated aqueous sodium b i s u l f i t e and the aqueous layer was ex-tracted with 2 x 50 mL ethyl ether. The extracts were combined, washed with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvents were removed under reduced pressure. The re s u l t i n g o i l was d i s t i l l e d (Kugel-rohr, bath temperature 90° C/0.7 torr) to y i e l d 0.70 g (75%) of epoxide 153; IR ( C H C I 3 ) 1720 and 1745 cm"1; 186 NMR (CDCl 3) 6 1.1-2.0 (m, 4H) , 2.3-3.0 (m, 5H). , 3.4 (s, 2H), and 3.68 (s, 3H); mass spectrum: a) high r e s o l u t i o n c a l c d f o r CgHm'Oif : 186.0892 amu; found: 186.0912; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41(71), 43(57), 55(61), 59 (57), 69 (50), 74 (28), 101(100), 113 (25), 116(21), 117(15), 124 (15), 155 (21), and 186(15). Methyl a-(6,8-dioxabicyclo[3.2.1]octan-5-yl) a c e t a t e (154) A s o l u t i o n of 0.09 g (0.50 mmol) of epoxy e s t e r 153 i n 12 mL of dry dichloromethane was t r e a t e d w i t h 0.1 mL of d i s t i l l e d boron t r i f l u o r i d e e t h e r a t e under n i t r o g e n and the r e s u l t i n g s o l u -t i o n was s t i r r e d at room temperature f o r 2 h.. The r e a c t i o n was quenched wi t h water and the aqueous l a y e r was e x t r a c t e d s e v e r a l times with e t h y l e t h e r . The e x t r a c t s were combined, d r i e d over anhydrous magnesium s u l f a t e , and the s o l v e n t s were removed under reduced p r e s s u r e t o y i e l d an o i l which was d i s t i l l e d (Kugelrohr) at 93° C/0.5 t o r r to y i e l d 0.08 g (85%) of c y c l i c k e t a l 154, IR (CHC1 3) 1740 cm" 1; NMR (CDCl3 ) 6 1.1-2.1 (m, 6H), 2.73 (s, 2H), 3.68 (s, 3H), 3.8 (m, 2H), and 4.5 (m, I H ) ; mass spectrum: a) high r e s o l u t i o n c a l c d f o r Cc jH iuOu: 189.0908 amu; found: 186.0889; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41(11), 57 (13), 59 (16), 74 (15), 87 (23), 101 (100), 113 (13) , 155 (23), and 186 (32). 187 g-(6,8-Dioxabicyclo[3.2.1]octan-5-yl)acetic acid (166) A solution of 0.0 93 g (0.50 mmol) of ester 154 i n 5 mL of methanol and 3 mL of 50% aqueous potassium hydroxide was refluxed for 3 h. The methanol was removed under reduced pressure; the solution was then a c i d i f i e d with d i l u t e hydro-c h l o r i c acid and extracted several times with ethyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, and solvents were removed under reduced pressure to give 0.075 g (87%) of the acid 166. P u r i f i c a t i o n was achieved by TLC (carbon tetrachloride:ethyl ether 2:1 v/v) to give a white s o l i d , mp 77-79° C; IR (CHC13) 1715, 1760, and 2700-3300 cm"1; NMR (CDC13) 6 1.0-2.0 (m, 6H), 2.78 (s, 2H), 3.8-3.95 (m, 2H), 4.35-4.6 (m, IH), and 9.87 (b s, 1H) ; mass spectrum: a) high resolution calcd for CsH^Oi,:. 172.0736 amu; found: 172.0731; b) low resolution m/e ( r e l . intensity) 41 (57), 43 (62), 55(28), 57 (66), 58 (43), 67(32), 68(37), 86 (100), 87(27), 98 (30), and 172(60). 5-Methyl-6 ,.8-dioxabicyclo [3.2.1] octane (167) A sample of 0.026 g (0.15 mmol) of acid 166 was placed in a small Kugelrohr tube which was then inserted into a pre-heated (220° C) Kugelrohr oven. The decarboxylated product was d i s t i l l e d within 8 min at that temperature at 1 atm. A t o t a l of 0.0192 g (84%) of 5-methyl-6,8-dioxabicyclo[3.2.1]octane (167) 188 was obtained. Compound 167 was c h a r a c t e r i z e d by; IR (CHC1 3) 840, 1015, 1390, and 2990 cm" 1; NMR (CDCl 3) 6 1.41 (s, 3H), 1.3-2.0 (m, 6H), 3.8 (m, 2H), and 4.5 (m, IH); mass spectrum: a) high r e s o l u t i o n c a l c d f o r C 7 H 1 2 0 2 : 128.0837 amu; found: 128.0837; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (16), 43 (100), 47 (14), 58 (18) , 68 (12) , 86 (24), 100 (15), and 128 (30). S y n t h e s i s of F r o n t a l i n (17) 4-Bromo-2-methyl-i-butene ( 1 1 1 ) 6 l b 3-Methyl-3-buten-l-ol (161) (1.4 g, 16.0 mmol) was weighed i n t o a 25 mL of R-B f l a s k and 10 mL of anhydrous e t h y l e ther was added. The f l a s k was then f i t t e d with an a d d i t i o n a l f u n n e l and a n i t r o g e n o u t l e t . Anhydrous p y r i d i n e (0.045 g) was added and the mixture was c o o l e d to -5° C and allowed to s t i r f o r 15 min. A s o l u t i o n of 2.07 g of phosphorus t r i b r o m i d e i n 5 mL of anhydrous e t h y l e ther was added dropwise through the a d d i t i o n a l f u n n e l to the r e a c t i o n mixture. The r e a c t i o n mixture was allowed to s t i r at -5 to 0° C f o r an a d d i t i o n a l 4 h. I t was then poured onto i c e , and the mixture was e x t r a c t e d s e v e r a l times w i t h e t h y l e t h e r . The e t h e r a l l a y e r was washed wi t h aqueous sodium bicar b o n a t e s o l u t i o n , d r i e d over anhydrous mag-189 nesium sulfate and ethyl ether was removed by simple d i s t i l l a -t i o n (at 1 atm). Kugelrohr d i s t i l l a t i o n at 105° C/760 t o r r gave 1.002 g of 4-bromo-2-methyl-l-butene (111) , [ l i t . 6 l b bp 105-107° C/760 t o r r ] ; NMR (CDCl 3) 6 1.76 (br s, 3H), 2.53 (t, J = 7 Hz, 2H), 3.43 (t, J = 7 Hz, 2H), and 4.7-5.0 (m, 2H). Methyl 7-methyl-3-oxo-7-octenoate (162) This compound was prepared by the same procedure as that employed i n the preparation of methyl 3-oxo-7-octenoate (152). The reagents used were: 0.464 g (4.0 mmol) of methyl acetoace-tate, 0.22 g of sodium hydride (as a 57% mineral o i l dispersion), 2.5 mL (1.6 M i n hexane) of n-butyllithium, and.0.61 g (4.10 mmol) of 4-bromo-2-methyl-l-butene (111). The crude product was d i s t i l l e d at 75° C/0.3 t o r r to give 1.33 g (80%) of methyl 7-methyl-3-oxo-7-octenoate (162) which had the following spectral data ; IR (CHC13) 890, 1635, 1650, 1715, and 1745 cm"1; NMR (CDCl3) <5 1.69. (s, 3H) , 1.6-2.1 (m, 4H) , 2.49 (t, 3 = 1 Hz, 2H), 3.40 (s, 2H), 3.70 (s, 3H), and 4.65 (m, 2H) ; mass spectrum m/e (rel intensity) 41(57), 43(87), 55(77), 59 (42) , 68 (56) , 69 (58), 74 (100), 101(37), 111 (35), 116(75), 117 (34), 129(37), 166 (18), and 184 (24). Anal. Calcd for C 1 0 H 1 6 0 3 : C, 65.19; H, 8.75. Found: C, 65.20; H, 8.75. 1 9 0 Methyl 7,8-epoxy-7-methyl-3-oxooctanoate (163) A solution of 0.184 g (1.0 mmol) of methyl 7-methyl-3-oxo-7-octenoate (162) i n 6 mL of anhydrous dichloromethane was cooled to 0° C and treated with 0.24 g (1.30 mmol) of 95% m-chloroperbenzoic acid and 0.21 g (1.50 mmol) of anhydrous sod-ium monohydrogen phosphate. The reaction mixture was raised to room temperature and s t i r r e d for 4 h. It was quenched with saturated aqueous sodium b i s u l f a t e , and the aqueous layer was extracted several times with ethyl ether. The extracts were combined, washed with aqueous sodium bicarbonate.solution, and dried over anhydrous magnesium sulfat e . The solvents were removed under reduced pressure. Kugelrohr d i s t i l l a t i o n at 95° C/ 0.7 tor r gave 0.172 g (86%) of epoxide 163. A small sample of 163 was p u r i f i e d by TLC (carbon tetrachloride:ethyl ether 8:1 v/v) and was characterized by; IR (CHC13) 1720 and 1745 cm"1; NMR (CDC13) 6 1.30 (s, 3H), 1.5-1.8 (m, 4H), 2.53 (s, 2H), 2.55 (t, J = 7 Hz, 2H), 3.39 (s, 2H), and 3.68 (s, 3H); mass spectrum: a) high resolution calcd for CioHi 6 Oi+: 200.1042 amu; found: 200.1035; b) low resolution m/e (rel intensity) 41 (50), 43 (100), 55 (68), 59(44), 69(40), 72(47), 81 (42), 85 (49), 101 (65), 111 (54), 127 (30), 129 (28), 164(20), 169(25), 170(17), and 200 (13) . 191 Methyl a-(l-methyl-6,8-dioxabicyclo[3.2. 1]octan-5-yl)acetate (164) The epoxide 163 was cy c l i z e d to the bicyclo ketal 164 by the same procedure as that employed i n the preparation of compound 154. The reagents used were 0.08 g (0.4 mmol) of epo-xide 163 and 5 drops of d i s t i l l e d boron t r i f l u o r i d e etherate. The crude product was homogeneous for TLC and d i s t i l l e d (Kugel-o rohr) at 90 C/0.1 tor r to y i e l d 0.076 g (95%) of ketal 164. A small sample of 164 was p u r i f i e d by TLC (carbon t e t r a c h l o r i d e : ethyl ether 4:1 v/v) and was characterized by; IR (CHC13) 1740 cm"1; NMR (CDCl3) 6 1.32 (s, 3H), 1.5-1.9 (m, 6H), 2.72 (s, 2H) , 3.66 (s, 3H), 3.40 and 3.88 (dd, J = 7 Hz, 2H); mass spectrum m/e (rel intensity) 43(59), 72(70), 100 (100), 101 (59), 111(15), 169 (29), and 200(32). ' ' . Anal. Calcd for CioHigO^: C, 59.98; H, 8.05. Found: C, 59.86; H, 7.96. a-(l-Methyl-6,8-dioxabicyclo[3.2.1]octan-5-yl)acetic acid (165) The ester 164 (0.03 g, 0.15 mmol) was hydrolyzed i n the same fashion as that employed i n the hydrolysis of compound 154 to y i e l d 0.025 g (88%) of acid 165 which was homogeneous by TLC analysis. A small sample of 165 was p u r i f i e d by TLC (carbon tetrachloride:ethyl ether 2:1 v/v) and had the following data; 192 IR (CHC13) 1715, 1755, and 2400-3600 cm"1; NMR (CDC1 3) 6 1.34 (s, 3H), 1.5-1.9 (m, 6H), 2.78 (s, 2H), 3.48 and 3.95 (dd, J = 7 Hz, 2H), and 9.52 (br s, 1H) ; mass spectrum: a) high resolution calcd for C^H^O^: 186.0892 amu; found: 186.0895; b) low resolution m/e (rel intensity) 43 (42), 72 (79), 87(23), 100 (100), 111(24), 156 (13), and 186(10). Frontalin (17) The crude acid 165 (0.019 g, 0.10 mmol) was decarboxy-lated by the same procedure as that employed i n the preparation of 5-methyl-6,8-dioxabicyclo[3.2.1Joctane (167) to y i e l d 0.012 g (85%) of f r o n t a l i n (17) which had spectral data i d e n t i c a l to that reported for. natural f r o n t a l i n (17). 2 5 IR (CHC13) 815, 840, 865, 890, 905, 980, 1020, 1060, 1118, 1170, 1240, 1260, 1285, 1350, 1380, 1390, 1455, 2920, and 2980 cm"1; NMR (CDC13) 6 1.32 (s, 3H) , 1.43 (s, 3H) , 1.5-1.8 (m, 6H) , 3.40 and 3.88 (dd, J = 7 Hz, 2H) ; mass spectrum m/e (rel intensity) 41(15), 43(100), 71(22), 72 (77) , 100 (37) , 112 (17), 114 (13), and 142(40). 193 Synthesis of Endo-Brevicomin (16) 3-Hexyne-l-ol (174) To 250 mL of l i q u i d ammonia i n a 500 mL 3-necked flask f i t t e d with a mechanical s t i r r e r and dry-ice condenser was added a c a t a l y t i c amount of Fe(NO 3) 3 *9H20 and 2.21 g (320 mmol) of lithium i n portions. After the disappearance of the blue color, 10.51 g (150 mmol) of 3-butyn-l-ol (173) i n ca. 20 mL of dry THF was added dropwise over 10 min. Another 20 mL of dry THF was added and the reaction mixture was allowed to reflux (-33° C) for 1 h. A solution of 16.88 g (155 mmol) of 1-bromoethane i n 10 mL of dry THF was added. The reaction was then continued to reflux for another 1 hr. I t was quenched with saturated aqueous ammonium chloride solution and the am-monia w,as allowed to evaporate. The aqueous layer was extracted several times with ethyl ether, the extracts were combined, dried over anhydrous magnesium su l f a t e , and solvents were removed under reduced pressure. The crude product was d i s t i l l e d at 80° C/14 t o r r to y i e l d 11.2 g (76%) of 3-hexyn-l-ol (174) , [ l i t . 6 " bp 64° C/7 t o r r ] ; IR ( C H C I 3 ) 3630 and 3460 cm"1; NMR ( C D C I 3 ) 6 1.28 (t, J - 7 Hz, 3H), 1.8-2.6 (m, 5H), and .3.4-3.9 (m, 2H) ; 194 mass spectrum m/e_ (rel intensity) 40 (41), 41(67), 53 (66), 67 (88), 68 (100), and '9-8 (56) . (E)-3-Hexen-l-ol (175) A solution of 9.80 g (100 mmol) of 3-hexen-l-ol (174), i n 50 mL of anhydrous ethyl ether was added dropwise to a solu-tion of 8.81 g of sodium i n 500 mL of ammonia. The reaction was s t i r r e d at -35° C for 4 hr, quenched with 12 g of ammonia chloride, and the ammonia was allowed to evaporate. The r e s i -due was treated with 250 mL of i c e - c o l d water and the aqueous layer, was extracted with 4 x 300 mL ethyl ether. The extracts were combined and worked up to y i e l d 8.70 g (87%) of (E)-3-hexen-l-ol (175) which d i s t i l l e d at 72-74° C/20 t o r r , [ l i t . 7 2 b 80-85° C/22 t o r r ] , and was characterized by; IR (CHC13) 970 and 3200-3600 cm"1; NMR (CDCl3) 6 0.98 (t, J = 7 Hz, 3H), 1.7-2.4 (m, 4H), 3.67 (t, J = 7 Hz, 2H) , and 5.0-5.2 (m, 2H) ; mass.spectrum m/e ( r e l intensity) 41(100), 42(27), 53 (15), 55 (41), 57(17), 67 (60), 68 (15), 69 (47), 70 (19), 82 (47), and 100(15). (E)-l-Bromo-3-hexene (176) 7 2 C This compound was prepared by the same procedure as that employed i n the preparation of 4-bromo-2-methyl-l-butene (111). The reagents used were: 6.0 g (60.0 mmol) of (E)-3-hexen-l-ol 195 (175), 4.34 g (16.0.mmol) of phosphorus tribromide, and 0.30 g of anhydrous pyridine. The crude product was d i s t i l l e d to give 5.40 g (56%) of (E)-l-bromo-3-hexene (176), bp 78-80° C/ 2 0 t o r r ; IR (CHC13) 970, 2925, and 3000 cm"1; NMR (GDC13 ) 6 0. 98 (t, J = 7 Hz, 3H) , 1.7-2.7 (m, 4H) , 3.2-3.7 (m, 2H), and 5.0-5.8 (m, 2H); mass spectrum m/e (rel intensity) 41(100), 55(81), 67 (38), 69 (28), 82 (38), 83 (77), 162 (22), and 164(21). Methyl (E)-3-oxo-7-decenoate (177) This compound was prepared by the same procedure as that employed i n the preparation of methyl 3-oxo-7-octenoate (152). The reagents used were: 2.32 g (20.0 mmol) of methyl acetoacetate, 1.10 g of sodium hydride (as a 57% mineral o i l dispersion), 9.6 mL (2.0 M.in hexane) of n-butyllithium and 4.05 g (25.0 mmol) of (E)-l-bromo-3-hexene (176). Kugelrohr d i s t i l l a t i o n of the crude product at 81° C/0.1 tor r gave 3.2 7 g (83%) of methyl (E)-3-oxo-7-decenoate (177). Further p u r i -f i c a t i o n was achieved by preparative TLC (carbon te t r a c h l o r i d e : ethyl ether 8:1 v/v) and r e d i s t i l l a t i o n (Kugelrohr) to give pure 177 which was characterized by the following data; IR (CHC13) 970 , 1630,, 1660, 1720, and 1745 cm"1; NMR (CDGl3) 6 0.94 (t, J = 7 Hz, 3H), 1.2-2.1 (m, 6H), 2.48 (t, J = 7 Hz, 2H) , 3.39 (s, 2H) , 3.70 (s, 3H) , and .5.2-5.4 (m, 2H); 196 mass spectrum m/e ( r e l intensity) 51(21), 67(55), 82 (83), 101(30), 116 (100), 117 (21), 125 (21), 180 (32), and 198 (32) . 7Anal. Calcd for C n H i 8 0 3 : C, 66.64; H, 9.15. Found: C, 66.65; H, 9.05. Methyl (E)-7,8-epoxy-3-oxodecanoate (178) The procedure used i n this reaction was the same as that employed i n the preparation of compound 163. The reagents used were: 1.78 g (9.0 mmol) of methyl (E)-3-oxo-7-decenoate,(177), 2.16 g of 90% m-chloroperbenzoic acid, and 1.59 g of anhydrous sodium monohydrogen phosphate; 1.68 g (87%) of crude epoxide 178 was obtained. P u r i f i c a t i o n was achieved by TLC: 0.2 g of the crude product 178 was chromatographed, using a mixture of carbon tetrachloride and ethyl ether. (7:3 v/v) as eluent. Pure epoxide (0.165 g, 72%) was i s o l a t e d and d i s t i l l e d (Kugelrohr) at 96° C/0.1 t o r r . This epoxide 178 was characterized by the following spectral data; IR (CHC13) 1720 and 1745 cm"1; . NMR ( C D C I 3 ) <5 0.98 (t, J = 7 Hz, 3H) , 1.2-2.0 (m, 6H) , 2.35-2.7 (m, 4H), 3.43 (s, 2H), and 3.72 (s, 3H); mass spectrum m/e ( r e l intensity) 41(66), 43(66), 55(67), 57 (51), 59 (51), 96 (76), 97 (68), 101(91), 113 (44), 114 (45), 116 (59), 124(100), 141(22), 156(56), 184(20), and 214(16). Anal. Calcd for C n H i 8 0 4 : C, 61.66; H, 8.47. Found: C, 61.38; H, 8.57. 197 Methyl a - ( e n d o - 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n - 5 - y l a c e t a t e  (179) In a s i m i l a r f a s h i o n as t h a t employed i n the p r e p a r a t i o n of compound 154, 1.28 g (6.0 mmol) of epoxide 17 8 was c y c l i z e d t o g i v e 1.71 g (91%) of b i c y c l i c k e t a l 179. P u r i f i c a t i o n was achieved by p r e p a r a t i v e TLC: about 0.15 g of the crude product was chromatographed u s i n g carbon t e t r a c h l o r i d e and e t h y l e t h e r (8:1 v/v) as e l u e n t t o g i v e 0.112 g of c y c l i z e d k e t a l 179 which was d i s t i l l e d (Kugelrohr) a t 95° C/0.1 t o r r . T h i s compound was c h a r a c t e r i z e d by the f o l l o w i n g s p e c t r a l data; IR (CHC1 3) 1740 cm"i; NMR (CDCl3 ) <5 0.97 ( t , J = 7 Hz, 3H) , 1.2-2.0 (m, 8H) , 2.73 (s, 2H), 3.68 (s, 3H), 3.7-4.1 (m, IH), and 4.1-4.3 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 41(51), 59(54), 68(59), 85 (55), 96 (61), 101 (100), 113 (53), 114 (61), 124 (66), 141 (33), 156(75), 184(47), 196(31), and 214(26). A n a l . C a l c d f o r C n H i 8 0 ^ : C, 61.66; H, 8.47. Found: C, 61.36; H, 8.29.. g- ( e n d o - 7 - E t h y 1 - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n - 5 - y l ) a c e t i c a c i d  (180) A sample of 0.107 g (0.5 mmol) of e s t e r 174 was hydro-l y z e d u s i n g the same procedure as t h a t employed i n the prepara-t i o n of compound 166 to g i v e 0.095 g (95%) of a c i d 180. The 198 crude m a t e r i a l was homogeneous by TLC and had the f o l l o w i n g data; IR (CHC13) 1715, 1765 and 2400-3500 cm" 1; NMR (CDC1 3) <5 0.98 ( t , J = 7 Hz, 3H), 1.2-2.1 (m, 8H), 2.77 (s, 2H), 3.8-4.15 (m, IH), 4.26 (br s, IH), and 8.6 (br s, IH) ; mass spectrum: a) hi g h r e s o l u t i o n c a l c d f o r doH^O.,: 200.1049 amu; found: 200.1045; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (29), 43 (100), 44 (47), 57 (25), 71 (26), 98 (45), 114 (36), 124 (12), 142(14), 149 (14), 156 (21), 192(14), and 200 (3). endo-Brevicomin (16) In a s i m i l a r f a s h i o n as t h a t employed i n the p r e p a r a t i o n of 5-methyl-6,8-dioxabicyclo[3.2.1]octane (167), 0.06 g (0.30 mmol) of c a r b o x y l i c a c i d 180 was decarboxylated to y i e l d 0.04 g (85%) of endo-brevicomin (16) which had s p e c t r a l data i d e n t i c a l to t h a t r e p o r t e d f o r n a t u r a l endo-brevicomin (16) . 2 ** IR (CHC1 3) 840, 865, 900, 962, 995, 1025, 1100, 1170, 1200, 1230, 12.60, 1310, 1330, 1350, 1380, 1462,. 2905, and 2975 cm" 1; NMR (CDC13) S 0.98 ( t , J = 7 Hz, 3H), 2.1 (s, 3H), 1.2-2.0 (m, 8H), 3.7-4.05 (m, IH), and 4.08 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 41(17), 43(100), 57 (15), 67 (13), 68 (24), 71(22), 81 (16) , 86 (22) , 98 (50), 99 (17), 113(17), 114(41), and 156 (22). 199 Synthesis of exo-Brevicomin (15) (Z)-l-Bromo-3-hexene ( 1 8 5 ) 7 2 a A mixture of 4.16 g (41.0 mmol) of 3-hexyn-l-ol, 0.20 g of 5% palladium on barium su l f a t e , and 3 drops of freshly d i s t i l l e d quinoline i n 50 mL of methanol, was hydrogenated at atmospheric pressure. After 2 h, the hydrogenation was stopped and the methanol was removed under reduced pressure. The crude product was dissolved i n ethyl ether, washed with d i l u t e aqueous hydrochloric acid, dried over anhydrous magnesium sul f a t e , and d i s t i l l e d to y i e l d 3.40 g (82%) of (Z)-3-hexen-l-ol (184) by 74° C/20 torr , [ l i t . 7 2 b bp 59-61° C/12.5 t o r r ] . A solution of 8.50 g (85.0 mmol) of (Z_)-3-hexen-l-ol (184) in. .10 mL of anhydrous ethyl ether was added dropwise to a cooled (-30° C) mixture of 7.6 g (28 mmol) of phosphorus tribromide and 0.43 g of anhydrous pyridine i n 40 mL of ethyl ether. The reaction mixture was s t i r r e d at -30° C for 1 hr, and then at room temperature for 5 h. The reaction was quenched with ice and water, and the aqueous layer was extracted several times with ethyl ether. The extracts were combined, washed with 5% aqueous sodium bicarbonate and brine, dried over anhydrous mag-nesium sulfate, and the solvent was removed under reduced pres-sure. The preduct was d i s t i l l e d at 65° C/20 t o r r to y i e l d 6.30 g (46%) of (Z)-l-bromo-3-hexene (185); [ l i t . 7 2 3 bp 40-48° C/7 t o r r ] ; 200 IR (CHCl3) 1265, 2910, and 3000 cm"1; NMR (CDC13) 6. 0.98 (t, J = 7 Hz, 3H) , 2.03 (qn, J = 7 Hz, 2H), 2.6 3 (q, J = 7 Hz, 2H), 3.32 (t, J = 7 Hz, 2H), and 5.0-5.75 (m, 2H); mass spectrum m/e (rel intensity) 41(89), 55(100), 67 (33), 68 (55), 82 (31), 83 (88), 162 (25), and 164 (25). Methyl (Z)-3-oxo-7-decenoate (186) A solution of the dianion of 3.48 g (30 mmol) of methyl acetoacetate was generated using the same procedure as that employed i n the preparation of compound 152. The dianion was alkylated with a solution of 5.82 g (35 mmol) of (Z)-1-bromo-3-hexene (185) i n 5 mL of dry THF at 0° C. The reaction mixture was s t i r r e d at 0° C for 2 h and at room temperature for an addi-t i o n a l 3 h. It was then quenched with d i l u t e hydrochloric acid and extracted several times with ethyl ether. The extracts were combined, washed with sodium bicarbonate and brine, and dried over anhydrous magnesium sulfat e . The solvents were removed under reduced pressure to give 5.23 g (88%) of crude o i l which was d i s t i l l e d as 82-84° C/0.1 t o r r to give 4.2 g (71%) of pure methyl (Z)-3-oxo-7-decenoate (186); IR (CHCl 3) 1630, 1650, 1715, and 1745 cm"1; NMR (CDC13) •6 0.96 (t, J = 7 Hz, 3H), 1.4-2.2 (m, 6H), 2.53 (t, J = 7 Hz, 2H), 3.41 (s, 2H), 3.72 (s, 3H), and 4.9-5.5 (m, 2H); 201 mass spectrum m/e (rel intensity) 41(46), 55(41), 67(68), 82(84), 101 (22), 116 (100), 117 (22), 129 (22), 180 (25), and 198 (10). Anal. Calcd for C i 0 H i 8 0 3 : C, 66.64; H, 9.15. Found: C, 66.56; H, 9.24. Methyl (Z)-7,8-epoxy-3-oxodeanoate (187) A solution of 2.97 g (15 mmol) of methyl (Z)-3-oxo-7-decenoate (186) i n 10 mL of dry dichloromethane was cooled to 0° C and treated with 3.147 g (15.5 mmol) of 85% m-chloroper-benzoic acid and 3.179 g (22.3 mmol) of anhydrous sodium mono-hydrogen phosphate. The reaction mixture was raised to room temperature and s t i r r e d for 4 h. It was quenched with saturated sodium b i s u l f i t e , and the aqueous layer was extracted several times with ethyl ether. The extracts were combined, washed with aqueous sodium bicarbonate, and worked up to y i e l d 2.88 g (90%) of crude epoxide 187. P u r i f i c a t i o n was achieved by pre-parative TLC: 0.1 g of the crude product was chromatographed using a mixture of carbon tetrachloride and ethyl ether (8:1, v/v) as eluent. In t h i s way, 0.078 g of pure epoxide 187 was isolat e d and d i s t i l l e d (Kugelrohr) at 90° C/0.15 t o r r . Epoxide 187 was characterized by the following spectral data; IR (CHCl3) 1715 and 1745 cm"1; NMR (CDC13) 6 1.02 (t, J = 7 Hz, 3H) , 1.3-2.0 (m, 6H), 2.5-3.1 (m, 4H), 3.42 (s, 2H), and 3.70 (s, 3H); 202 mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 4 1 ( 7 7 ) , 4 3 ( 7 8 ) , 5 5 ( 7 2 ) 57 ( 6 0 ) , 59 ( 5 2 ) , 69 ( 5 2 ) , 83 ( 5 5 ) , 96 ( 6 9 ) , 97 ( 7 1 ) , 101 ( 5 5 ) , 116 ( 3 7 ) , 124 (100) , 139 (41) , 1 4 1 ( 2 5 ) , 156 ( 5 7 ) , 1 5 9 ( 2 1 ) , a nd 2 1 4 ( 1 5 ) . /Anal. C a l c d f o r C i i H 1 8 0 4 : C, 61.66; H, 8.47. F o u n d : C, 61.38; H, 8.25. M e t h y l g - ( e x o - 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n - 5 - y l ) a c e t a t e  (188) T h i s compound was p r e p a r e d by t h e same p r o c e d u r e as t h a t e m p l o y e d i n t h e p r e p a r a t i o n o f compound 154. The r e a g e n t s u s e d w e r e : 0.10 mL o f d i s t i l l e d b o r o n - t r i f l u o r i d e e t h e r a t e a n d 0.30 (1.40 mmol) o f e p o x i d e 187 i n 5 mL o f a n h y d r o u s d i c h l o r o m e t h a n e . The c y c l i z e d c r u d e p r o d u c t (0.277 g) was d i s t i l l e d ( K u g e l r o h r ) a t 90° C/0.15 t o r r t o y i e l d 0.25 g (82%) o f p r o d u c t 188. The e x o compound 188 t h u s o b t a i n e d was c o n t a m i n a t e d w i t h <1% o f t h e endo i s o m e r 179 by GLC ( c o l u m n A) a n a l y s i s . F u r t h e r p u r i f i c a -t i o n was a c h i e v e d b y TLC ( c a r b o n t e t r a c h l o r i d e : e t h y l e t h e r 8:1, v / v ) t o g i v e p u r e 188 w h i c h was c h a r a c t e r i z e d by t h e f o l -l o w i n g d a t a ; I R (CHC13) 1740 cm" 1; NMR ( C D C l 3 ) 6 0.89 ( t , J = 7 Hz, 3 H ) , 1.3-2.0 (m, 8 H ) , 2.71 ( s , 2 H ) , 3.67 ( s , 3 H ) , 3.91 ( t , J = 6 Hz, I H ) , a n d 4.15 ( b r s, I H ) ; mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 4 1 ( 1 8 ) , 5 7 ( 1 5 ) , 5 9 ( 1 7 ) 68 ( 1 9 ) , 8 5 ( 5 0 ) , 1 0 1 ( 3 1 ) , 114 ( 1 0 0 ) , 115 (10), 1 2 4 ( 1 0 ) , 141 ( 9 ) , 203 183 (15) , and 214.(10) . A n a l . C a l c d f o r C n H u O i , : C, 61.66; H, 8.47. F o u n d : C, 61.54; H, 8.35. a - ( e x o - 7 - E t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n - 5 - y l ) a c e t i c a c i d  (189) T h i s compound was p r e p a r e d by t h e same p r o c e d u r e a s t h a t e m p l o y e d i n t h e p r e p a r a t i o n o f compound 166. The r e a g e n t s u s e d w e r e : 0.214 g (1.0 mmol) o f e s t e r 188 i n 5 mL o f m e t h a n o l a nd 6 mL o f 50% a q u e o u s p o t a s s i u m h y d r o x i d e . The c r u d e a c i d 189 (0.189 g, 95%) was o b t a i n e d a n d u s e d d i r e c t l y i n t h e d e c a r b o x y l a -t i o n . P u r i f i c a t i o n was a c h i e v e d b y p r e p a r a t i v e TLC ( c a r b o n t e -t r a c h l o r i d e : e t h y l e t h e r 2:1, v / v ) and t h i s a c i d was c h a r a c t e r i z e d by t h e f o l l o w i n g d a t a ; I R (CHCI3) 1 7 1 5 , 1 7 5 0 , and 2400-3400 cm' 1; NMR ( C D C l 3 ) 6 0.90 ( t , J = 7 Hz, 3H) , 1.3-2.2 (m, 8H) , 2.77 ( s , 2 H ) , 3.97 ( t , J = 6 Hz, I H ) , 4.18 ( b r s, I H ) , and 9.72 ( b r s, I H ) ; mass s p e c t r u m : a) h i g h r e s o l u t i o n c a l c d f o r CaoHieOi*: 200.1049 amu; f o u n d : 2 0 0 . 1 0 4 9 ; b) l o w r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 43 ( 2 5 ) , 57 ( 2 5 ) , 6 8 ( 2 8 ) , 85 ( 8 2 ) , 8 7 ( 2 6 ) , 1 1 4 ( 1 0 0 ) , 124 ( 1 1 ) , a n d 200 ( 3 ) . e x o - B r e v i c o m i n (15) A s a m p l e o f 0.10 g (0.50 mmol) o f t h e c r u d e a c i d (189) 204 was p l a c e d i n a Kugelrohr tube and i n s e r t e d i n t o a preheated (200° C) Kugelrohr oven. A c o l o r l e s s o i l d i s t i l l e d w i t h i n 8 min at atm pressure to y i e l d 0.068 g (87%) of exo-brevicomin (15) which had s p e c t r a l data i d e n t i c a l t o t h a t r e p o r t e d f o r n a t u r a l exo-brevicomin (15) . 2 ** IR (CHCl3) 840, 875, 925, 965, 1000, 1015, 1030, 1080, 1105, 1140, 1170, 1190, 1200, 1240, 1335, 1355, 1385, 1470, 2900, and 299 0 cm" 1; NMR (CDC1 3) 6 0.9 ( t , J = 7 Hz, 3H), 1.4 (s, 3H), 1.3-2.1 (m, 8H) , 3.9 ( t , J = 7 Hz, lH),and 4 ..1 (br s, IH) ; mass spectrum m/e ( r e l i n t e n s i t y ) 41(16), 43(100), 57(16), 67(16), 68 (19), 71 (16), 85 (52), 86 (25), 88 (36), 89 (17), 114 (82), 127 (15) , and 156 (30). R e s o l u t i o n o f a - ( e x o - 7 - e t h y 1 - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . l ] o c t a n - 5 - y l ) a c e t i c a c i d (189) A s o l u t i o n of 0.40 g (2.0 mmol) of c a r b o x y l i c a c i d 189 i n 10 mL of dry dichloromethane was t r e a t e d w i t h 0 ;242 g (2.0 mmol) of (+)-a-methyl-benzylamine. The mixture was s t i r r e d a t room temperature f o r 2 h and the s o l v e n t was removed. The r e s u l t i n g s o l i d was c r y s t a l l i z e d from ether-hexane. A f t e r two such r e c r y s t a l l i z a t i o n s 0.18 g of s a l t , mp 110-115° C, was o b t a i n e d . T h i s s a l t was d i s s o l v e d i n 10% h y d r o c h l o r i c a c i d and e x t r a c t e d s e v e r a l times with e t h y l ether. The e x t r a c t s were combined and and worked up to y i e l d 0.100 g of p a r t i a l l y r e s o l v e d c a r b o x y l i c 205 a c i d 189, I 5 + 3 9 - 8 ° (0.20 g/mL, E t 2 0 ) ? T h i s a c i d (0.100 g) was decarboxylated as d e s c r i b e d b e f o r e t o y i e l d 0.06 g of (+)-exo-brevicomin (15), [ a ] 2 6 + 51.8° (0.12 g/mL, E t 2 0 ) [ l i t . " 2 [ a ] 2 4 = + 84.1° ( e t h e r ) ] . 206 Synthesis of .(-)-g-Multistriatin (18a) Methyl 4,6-0-benzylidene-a-D-glucopyranoside (191) A mixture of 120 g (618.5 mmol) of methyl a-D-gluco-pyranoside (7JJ , 90 g of anhydrous zinc chloride, and 300 mL of benzaldehyde was s t i r r e d i n a 1 L flask for 18 h. The mix-ture was poured slowly, with s t i r r i n g into 2 L of cold water, whereupon the product c r y s t a l l i z e d readily.' The s o l i d was sus-pended i n 150 mL of petroleum ether and t h i s mixture was s t i r r e d for 30 min to aid i n removing the excess benzaldehyde. The product was f i l t e r e d , washed twice with 200 mL of cold water, twice with petroleum ether, and again with 200 mL of cold water. The product was dried overnight i n a i r and then i n a vacuum oven at 70° C; crude y i e l d of benzylidene compound, s a t i s f a c t o r y for the next step, was about 120 g (70%), mp 161-163° C. A small amount of the crude product was p u r i f i e d by r e c r y s t a l l i z a -t i o n from chloroform-ethyl ether to give pure methyl 4,6-0-benzylidene-a-D-glucopyranoside (191), mp 162-164° C [ l i t . 7 3 mp 163-164° C]. This compound was characterized by; IR (CHCl 3) 3500 and 3630 cm - 1; NMR (CDC13) 6 3.33 (s, 3H), 3.0-4.3 (m, 8H), 4.6 (d, J = 3 Hz, IH), 5.40 (s, IH), and 7.1 and 7.65 (m, 5H); mass spectrum m/e (rel intensity) 45(34), 47(38), 49(41), 105 (95), 107 (100), 133 (48), 162 (34), 179 (55), and 282 (73). 207 Methyl 4,6-0-benzylidene-2,3-di-O-p-tolylsulfonyl-g-D-gluco- pyranoside (192) To a solution of 60 g (213 mmol) of methyl 4,6-0-benzyli-dene-a-D-glucopyranoside i n 420 mL of pyridine was added 50% excess of p-toluenesulfonyl chloride (120 g) and the mixture was allowed to stand at room temperature for 7 days. The mix-ture was poured onto cracked i c e , whereupon the d i t o s y l compound c r y s t a l l i z e d r e a d i l y . The solution was decanted and extracted with 3 x 300 mL portions of dichloromethane. The dichlorome-thane extracts were used to dissolve the crude s o l i d and the solution washed several times with d i l u t e hydrochloric acid at 0° C u n t i l no trace of pyridine could be detected. It was then washed with water and aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfat e . Solvents were removed under reduced pressure and ethyl ether was added to the r e s u l t -ing thin syrup to e f f e c t c r y s t a l l i z a t i o n . The y i e l d of the material, pure enough for the next step was 100 g (80%) •  -Methyl 4,6-0-benzylidene-2,3-di-O-p-tolylsulfonyl - a-D-glucopyranoside (192) was r e c r y s t a l l i z e d from chloroform-ethyl ether, needles, mp 148-149° C [ l i t . 7 3 mp 147-148° C]. This compound was charac-terized by; IR (CHCl 3) 1180 and 1605 cm"1; NMR (CDC13) 6 2.33 (s, 3H), 2.42 (s, 3H), 3.35(2, 3H), 3.5-4.4 (m, 4H), 4.47 (d, J = 3 Hz, IH), 4.8-5.1 (m, 2H), 5.23 (br s, IH), and 6.6-7.8 (m, 13H) ; 208 mass spectrum m/e (rel intensity) 69(13), 91(70), 105 (21), 121(18), 139(17), 149 (15), 155 (100), 156 (14), 157 (30), 203 (8), 261 (9) , 269 (10) , 375 (37), 381 (25), 435 (26), and 590 (8). Methyl 4,6-0-benzylidene-2,3-di-0-methanesulfonyl-g-D-gluco- pyranoside (193) Benzylidene d i o l 191 (20.0 g, 70.90 mmole) was dissolved in ca. 125 mL of dry pyridine. The solution was cooled i n ice and 19.95 g (175 mmol) of methanesulfonyl chloride was added. White heavy p r e c i p i t a t i o n was observed. The reaction was s t i r r e d at room temperature for 24 h. The mixture was then poured onto ice and extracted several times with dichloromethane. The com-bined extracts were washed several times with d i l u t e hydrochloric acid u n t i l no trace of pyridine could be detected. It was then washed once with water, once with sodium bicarbonate and water, dried over anhydrous magnesium sulfat e . The solvent was removed under reduced pressure to ca. 150 mL and ethyl ether was added to induce c r y s t a l l i z a t i o n . The y i e l d of the r e c r y s t a l l i z e d methyl 4,6-0-benzylidene-2,3-di-0-methanesulfonyl-a-D-glucopyra-noside (193) was 25.0 g (81%); mp 186-188° C. This compound was characterized by; IR (CHC13) 1100, 1130, 1180 and 1420 cm"1; NMR (CDCl3) 6 2.87 (s, 3H), 3.17 (s, 3H), 3.48 (s, 3H), 3.6-4.8 (m, 5H), 4.8-5.2 (m, 2H), 5.51 (s, IH), and 7.1-7.6 (m, 5H); 209 mass spectrum: a) high resolution calcd for C 1 6 H 2 2 O 1 0 S 2 : 438.0655 amu; found: 438.0655; b) low resolution m/e ( r e l intensity) 47(13), 49 (100), 69 (4), 79(4-), 107 (8), 116 (6), 121 (4) , 149 (3) , 157 (4), 185 (4), 193 (7), 229(3), 289 (3), 299 (8), 359 (3), 437(11), and 438 (7). Methyl 2,3-anhydro-4,6-0-benzylidene-a-D-allopyranoside (194) A solution of 100 g (169 mmol) of the d i t o s y l compound 192 i n 1.5 L of anhydrous dichloromethane was cooled i n ice and a cold solution containing 19.60 g (852 mmol) sodium i n 450 mL of anhydrous methanol was added. The mixture was kept i n the ref r i g e r a t o r for 4 days with occasional shaking and then at room temperature for 2 days. The reaction mixture was dil u t e d with water and the dichloromethane layer separated. The aqueous layer was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sul f a t e , and solvents were removed under reduced pressure. The product c r y s t a l l i z e d r e a d i l y , and was f i l t e r e d and washed with ether. The crude product was recrys-t a l l i z e d from chloroform-ethyl ether to y i e l d 38.25 g (85%) of pure methyl 2,3-anhydro-4,6-0-benzylidene-a-D-allopyrano-side (194), needle, mp 198-200° C [ l i t . 7 3 mp 200° C]. This compound was characterized by; IR (CHCl3) 900, 970, 1060, 1090, 1105, 1140, 1390, 2900, and 2950 cm - 1; 210 NMR (CDCl 3) <5 3.43 (s, 3H), 3.5-4.4 (m, 6H), 4.8 (d, J = 2Hz, IH) , 5.48 (br s, 1H) , and 7.1-7.6 (m, 5H) ; mass spectrum m/e (rel intensity) 45(17), 58(19), 59 (18), 77(17), 91 (16), 105 (31), 115 (100), 127(33), 221 (35), and 264(72) . Methyl 2,3-anhydro-4,6-0-benzylidene-a-D-allopyranoside (194) was also prepared from dimesylate 193. A solution of sodium methoxide was prepared using 12.7 g (552 mmol) of sodium and 188 mL of dry methanol. Methyl 4,6-0-benzylidene-2,3-di-0-methanesulfonyl-a-D-glucopyranoside (193) (48.18 g, 110 mmol) in 780 mL of dichloromethane was added to the sodium methoxide solution at 0° C. The reaction mixture was kept at 0° C for 3 days and s t i r r e d at room temperature for 10 h. Work-up pro-cedure was the same as above. The crude product was r e c r y s t a l -l i z e d from a mixture of dichloromethane and ethyl ether to give 26.40 g (91%) of pure epoxide 194. The spectral data were the same as l i s t e d above. Methyl 4,6-0-benzylidene-2-deoxy-2-C-methyl-a-D-altropyranoside  (195) Cuprous iodide (15.2. g, . 80'..0' mmol) in-90 mL of anhy-drous ethyl ether was s t i r r e d under nitrogen at 0° C. Then 120 mL (1.7 M) of methyllithium was added to the suspension and a l i g h t clear yellow solution was formed. Epoxy compound 194 (10.56 g, 4 0 mmol) was added to the res u l t i n g lithium dimethyl-211 cuprate reagent and the reaction was s t i r r e d at 0 C for 4 h. The reaction mixture was dil u t e d with ethyl ether, washed with d i l u t e ammonium chloride and saturated sodium bicarbonate solu-t i o n , and dried over anhydrous magnesium sulfat e . The ether was removed under reduced pressure and the crude product r e c r y s t a l -l i z e d from ethyl ether-n-hexane to y i e l d 8.44 g (75%) of methyl 4,6-0-benzylidene-2-deoxy-2-C-methyl-a-D-altropyranoside (195), chunky prisms, mp 112-113° C ( l i t . 7 1 * mp 110-111° C) . This com-pound was characterized by; IR (CHCl3) 3450-3750 cm"1; NMR (CDC13) 6 1.09 (d, J = 7 Hz, 3H), 2.0-2.6 (m, IH) , 3.0 (d, J = 7 Hz, IH), 3.33 (s, 3H), 3.4-4.5 (m, 6H), 5.53 (br s, IH), and 7.0-7.6 (m, 5H); mass spectrum m/e (rel intensity) 45(41), 71(43), 72(38), 91 (47), 105 (100), 106 (38), 107 (94), 113 (66), 131 (70), 162(27), 179 (97)., and 280 (88) . Methyl 4,6-0-benzylidene-2-deoxy-2-C-methyl-3-0-[(thiomethyl)- thiocarbonyl]-g-D-altropyranoside (196) Sodium hydride 1.52 g (31.80 mmol), as a 50% mineral o i l dispersion (washed o i l - f r e e with ethyl ether), was placed in a 250 mL dry round bottom flask f i t t e d with a magnetic s t i r -rer, reflux condenser, and drying tube. Thirty mL of anhydrous ethyl ether was added to the sodium hydride, then 7.2 0 g (25.70 mmol) of methyl 4,6-0-benzylidene-2-deoxy-2-C-methyl-212 a-D - a l t r o p y r a n o s i d e (195) was d i s s o l v e d i n ca. 150 mL of e t h y l e ther and added dropwise t o the sodium hydride suspension. The r e a c t i o n mixture was r e f l u x e d f o r 3 h, then 3.18 mL of carbon d i s u l f i d e and 3.24 mL of iodomethane were added to the s o l u t i o n a f t e r 3 hr and 6 h r e s p e c t i v e l y . The r e a c t i o n was r e f l u x e d f o r another 3 h and water was added to d e s t r o y the excess sodium hy d r i d e . The r e a c t i o n mixture was d i l u t e d with e t h y l e t h e r , washed twice w i t h water, d r i e d over anhydrous magnesium s u l f a t e , and the s o l v e n t s were removed under reduced pressure to g i v e 9.18 g (96%) of crude product which was used d i r e c t l y i n the next step. A small amount of compound 196 was p u r i f i e d by pre-p a r a t i v e TLC ( C C l i i : E t 2 0 , 4:1 v/v) and c h a r a c t e r i z e d by the f o l l o w i n g s p e c t r a l data, a l l of which were the same as those • r e p o r t e d ; 7 4 IR (CHC1 3) 950, 1005, 1040, 1060, 1100, 1140, and 2950 cm" 1; NMR (CDCl3) 6 1.18 (d, J = 7 Hz, 3H), 2.55 (s, 3H), 2.4-2.8 (m, IH), 3.33 (s, 3H), 3.5-4.5 (m, 5H), 5.55 (br s, IH), 5.75 (m, IH), and 7.1-7.6 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 41(29), 43(30), 55(21), 57 (29), 69 (23), 85(44), 91 ( 3 8 ) 1 0 5 (56) , 113(44), 121 (32), 125 (25), 131(29), 149(100), 150 (14), 231 (20), 262(47), 263 (24), and 370 (11). 213 Methyl 4,6-0-benzylidene-2,3-dideoxy-2-C-methyl-a-D-arabino  hexopyranoside (197) A s o l u t i o n of 22.2 g (60.0 mmol) of the S-methyl d i t h i o -carbonate compound 196 i n 260 mL of dry tol u e n e was added over 1.5 h to 34.92 g (120.0 mmol) of t r i - n - b u t y l s t a n n a n e i n 240 mL r e f l u x i n g dry toluene under dry n i t r o g e n . R e f l u x i n g was con-t i n u e d o v e r n i g h t , and the s o l v e n t was removed under reduced p r e s -sure. P u r i f i c a t i o n was achieved by column chromatography u s i n g s i l i c a g e l (100-200 mesh), and a mixture of petroleum e t h e r and e t h y l e t h e r (9.5:1, v/v, then 1:1, v/v) to y i e l d 14.30 g (90%) of pure compound 197, [ a ] 2 8 .+- 82.7° (142 mg/mL, e t h y l e t h e r ) . T h i s compound was c h a r a c t e r i z e d by; IR (CHC1 3) 930, 950, 1005, 1050, 1100, 1120, 1140, 1380, and 146 0 cm - 1; NMR (CDCl3) 6 k.13 (d, J = 7 Hz, 3H), 1.4-2.3 (m, 3H), 3.33 (s, 3H), 3.5-4.3 (m, 4H), 4.33 (s, IH), 5.50 (s, IH), and 7.0-7.5 (m, 5H); mass spectrum: a) h i g h r e s o l u t i o n c a l c d f o r C 1 5 H 2 0 O 4 : 264.1362 amu; found: 264.1374; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 55 (15), 73 (12), 83 (19), 105(21), 115 (100), 116 (11), 149 (11), 221(10), and 264 (22). 214 Methyl 2,3-dideoxy-2-C-methyl-g-D-arabino-hexopyranoside (198) To a solution of 12.41 g (47.0 mmol) of compound 197 in ca. 30 mL of methanol was.added 0.40 g of p-toluenesulfonic acid monohydrate. The reaction mixture was s t i r r e d at room temperature and followed by TLC. After the reaction was com-plete (2.5 h) , s o l i d sodium carbonate was added to neutralize the acid. The reaction mixture was f i l t e r e d , and the methanol was removed under reduced pressure. The residue was dissolved in water and ethyl ether, and extracted several times with water. The combined aqueous extracts were concentrated under reduced pressure and the residue dissolved i n dichloromethane and dried over anhydrous magnesium sulfat e . The dichloromethane was re-moved under reduced pressure to give a thick o i l , 6.81 g (82%) which was pure enough for the next step. Compound 198 was char- . acterized by the following spectral data; IR (CHCl 3) 960, 1050, 1100, 1150, 2975, 3500, and 3650 cm"1; NMR (CDC13) 6 1.03 (d, J = 7 Hz, 3H) , 1.5-2.2 (m, 3H) , 2.83 (br s, 2H), 3.33 (s, 3H), 3.6-4.2 (m, 4H) , and 4.3 (br s, IH) ; mass spectrum: a) high resolution calcd. for C 8H 1 60 4: 176.1049 amu, found: 176.1047; b) low resolution m/e (rel intensity) 41(24), 43(27), 55 (28), 56 (29), 57 (27), 72(100), 74 (55), 83 (23), 113 (26), 115(27), 145.(33), and 176(1). 215 Methyl 2,3-dideoxy-2-C-methyl-6-0-triphenylmethyl-a-D-arabino- hexopyranoside (199) Compound 198 (3.16 8 g, 18 mmol) was t r e a t e d with 7.5 g (27 mmol) of t r i t y l c h l o r i d e i n 30 mL of anhydrous p y r i d i n e . The r e a c t i o n mixture was s t i r r e d a t room temperature f o r 3 days. I t was then poured onto i c e c o l d water, a c i d i f i e d and e x t r a c t e d s e v e r a l times w i t h dichloromethane. The combined e x t r a c t s were washed with d i l u t e sodium b i c a r b o n a t e and b r i n e , d r i e d over an-hydrous magnesium s u l f a t e , and s o l v e n t s removed under reduced p r e s s u r e . P u r i f i c a t i o n was achieved by column chromatography u s i n g s i l i c a g e l (100-200 mesh) and a mixture of carbon t e t r a -c h l o r i d e and e t h y l e ther (4:1, v/v) as e l u e n t . The y i e l d o f compound 199 was 6.465 g (86%) and i t had mp 147-149° C, [ a ] 2 6 + 26° (200 mg/mL, c h l o r o f o r m ) . T h i s compound was c h a r a c t e r i z e d by; IR (CHCl 3) 1600 and 3570 cm" 1; NMR (CDC1 3) 6 0.99 (d, J = 7 Hz, 3H), 1.4-2.1 (m, 3H), 2.39 (br s, IH), 3.31 (s, 3H), 3.0-3.7 (m, 4H), 4.26 (s, IH), and 6.7-7.4 (m, 15H); mass spectrum m/e ( r e l i n t e n s i t y ) 43(4), 55(5), 72(4), 77 (6), 83 (6), 105 (13), 113(13), 127(5), 165 (27), 175(21), 183 (15), 243 (100), 244 (27), 258 (4) , 259 (7) , 260 (5), 309 (5), 386 (4), and 418 (3) . A n a l . C a l c d f o r C j 7 H 3 0 0 4 : C, 77.48; H, 7.22. Found: C, 77.61; H, 7.21. 216 Methyl 2,3-Dideoxy-2-C-methyl-6-0-triphenylmethyl-a-D-threo- hexopyranosid - 4-ulose (206) A sample of 6 g (60 mmol) of chromium t r i o x i d e was added to a m a g n e t i c a l l y s t i r r e d s o l u t i o n of 9.5 g (120 mmol) of an-hydrous p y r i d i n e i n ca. 150 mL anhydrous dichloromethane. The f l a s k was stopped with a d r y i n g tube, and the deep burgundy s o l u t i o n s t i r r e d f o r 15 min at room temperature. At the end of t h i s p e r i o d , a s o l u t i o n of 4.18 g (10 mmol) of compound 199 i n 5 mL of dry dichloromethane was added i n one p o r t i o n . A t a r r y , b l a c k d e p o s i t separated immediately. A f t e r s t i r r i n g f o r 18 h at room temperature, the s o l u t i o n was decanted and the dichloromethane removed under reduced p r e s s u r e . The r e s i d u e was d i s s o l v e d i n e t h y l e t h e r and the r e a c t i o n f l a s k was r i n s e d s e v e r a l times w i t h e t h y l e t h e r . The ether l a y e r s were combined and f i l t e r e d through a bed of c e l i t e . The s l i g h t y e l l o w f i l t r a t e was washed with d i l u t e h y d r o c h l o r i c a c i d and aqueous sodium b i -carbonate s o l u t i o n , d r i e d over anhydrous magnesium s u l f a t e , and the s o l v e n t s were removed under reduced pressure t o g i v e 3.99 g (96%) o f compound 206 which was homogeneous from TLC. The crude product was p u r i f i e d by column chromatography u s i n g s i l i c a g e l (100-200 mesh), and a mixture of carbon t e t r a c h l o r i d e and e t h y l e t h e r (8:1, v/v) as e l u e n t t o g i v e 3.35 g (81%) of compound 206, mp 88-89° C; [ a ] 2 8 + 98.8° (200 mg/mL, c h l o r o f o r m ) , which was c h a r a c t e r i z e d by; 217 IR (CHC13) 1600, 1730, and 2960 cm" 1; NMR (CDCl 3) 6 1.14 (d, J = 7 Hz, 3H), 1.9-2.6 (m, 3H) , 3.2-3.6 (m, 2H), 3.5 (s, 3H), 3.83 (m, IH), 4.6 (d, J = 4 Hz, IH), and 7.0-7.7 (m, 15H); mass spectrum: a) high r e s o l u t i o n c a l c d f o r C 2 7 H 2 8 O 4 : 416.1988 amu; found: 416.1989; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 43 (4), 45 (6), 55 (4), 59(7), 71 (6), 72 (8), 105 (7), 157 (6), 165 (20), 173 (5), 183 (5), 243 (100), 244 (24), 259 (6), 339 (4), and 416 (4) . Methyl 2,3, 4-trideoxy-2-C-me.thyl-4-methylene-6-0-triphenylmethyl- g-b-threo-hexopyranoside (207) A 250 mL 3-necked round-bottom f l a s k c o n t a i n i n g ca. 120 mL of anhydrous e t h y l e t h e r was f i t t e d w i t h a r e f l u x condenser, an a d d i t i o n f u n n e l , a septum stopper and a n i t r o g e n o u t l e t . n - B u t y l l i t h i u m (8.86 mL of 1.58 M, 14 mmol) was added t o the f l a s k and 5.00 g (14 mmol) of triphenylmethylphosphonium bromide was added i n p o r t i o n s to the n - b u t y l l i t h i u m s o l u t i o n . The orange r e a c t i o n mixture was r e f l u x e d f o r 4 h and 5.82 g (14 mmol) of keto compound 206 i n 30 mL of e t h y l e ther was added slowly. The orange c o l o r d i s c h a r g e d and a white p r e c i p i t a t e was observed. The r e a c t i o n mixture was then r e f l u x e d f o r 24 h, c o o l e d , and the p r e c i p i t a t e was f i l t e r e d o f f . The ether f i l t r a t e was washed with water and b r i n e , d r i e d , and the s o l v e n t s were evaporated under reduced p r e s s u r e . P u r i f i c a t i o n of the crude product was 218 achieved by column chromatography using s i l i c a gel (100-200 mesh) and a mixture of carbon tetrachloride and ethyl ether (10:1, v/v) as eluent to y i e l d 4.53 g (78%) of compound 207, mp 153-154° C; [ a ] ^ 2 + 45.4° (74 mg/mL, chloroform) and 0.5 g of compound 206. Thus, the y i e l d was 82% based on recovered sta r t i n g material 206. This product 2 0 7 was characterized by the following spectral data; IR (CHCl 3) 1600, 1660, 2960, 3040, and 3100 cm"1; NMR (CDC13) <5 0.93 (d, J = 7 Hz, 3H) , 1.6-2.8 (m, 3H) , 3.30 (d, J = 6 Hz, 2H), 3.43 (s, 3H), 4.2-4.4 (m, 2H), 4.62 (m, 2H), and 6.8-7.6 (m, 15H); mass spectrum: a) high resolution calcd for C2 8 H 3 o 0 3 : 414.2195 amu; found: 414.2214; b) low resolution m/e (rel intensity) 41 (2), 43 (2), 77 (2), 81 (4), 105 (5), 109(14), 139 (2), 141 (50), 142 (5), 165 (21), 166 (4), 183 (2), 215 (2), 228 (3), 241 (3), 243 (100), 244 (21) , and 414 (1). Hydrogenation of compound 2 07 A 100 mL round bottom flask containing 50 mL of anhydrous benzene, 0.7 g of tris(triphenylphosphine)rhodium chloride 8 5•and 3.31 g (8.0 mmol) of compound 207, was f i t t e d with a magnetic s t i r r e r and connected to an atmospheric pressure hydrogenation apparatus equipped with a graduated burette to measure the uptake of hydrogen. The system was evacuated and f i l l e d with hydrogen. 219 After 24 h, about 1 eq of hydrogen was absorbed. The solvent was removed under reduced pressure and the product was p u r i f i e d by column chromatography using s i l i c a , gel (100-200 mesh) and a mixture of ethyl acetate and petroleum ether (10:1, v/v) as eluent. Two components were is o l a t e d from t h i s chromatography, and these were, i n order of elu t i o n : methyl 2,3,4-trideoxy-2 , 4-di-C-methyl-a-D-arabino-hexopyranoside (202'); (0.29 g, 9%), and methyl 2,3,4-trideoxy-2,4-di-C-methyl-g-D-lyxo-hexopyrano-side (201) (2.74 g, 80%). Methyl 2,3,4-trideoxy-2,4-di-C-methyl-g-D-arabino-hexo-pyranoside (202) was characterized by; IR (CHCl 3) 1600 cm"1; NMR (CDC13) 6 0.58 (d, J = 6 Hz, 3H), 1.05 (d, J.= 7 Hz, 3H), 13.-2.0 (m, 4H), 2.9-3.6 (m, 3H), 3.38 (s, 3H), 4.4 (br s, IH), and 6.9-7.6 (m, 15H); mass spectrum: a) high resolution calcd for C 2 8 H 3 2 O 3 : 416.2351 amu; found: 416.2328; b) low resolution m/e (rel intensity) 83 (10), 85 (25), 105 (15), 111(17), 141 (9) , 143 (60) , 165(40), 173 (48), 243 (100), 244 (31), 258 (8) , and 416(5). Methyl 2,3,4-trideoxy-2,4-di-C-methyl-g-D-lyxo-hexo-2 4 o pyranoside (201) had [ a ] D +27 (66 mg/mL, chloroform) and was characterized by; IR (CHCl 3) 1600 cm - 1; 220 NMR (CDC1 3) <5 0.70 (d, J = .7 Hz, 3H) , 0.95 (d, J = 7 Hz, 3H) , 1.3-2.0 (m, 4H) , 3.0-3.3 (m, 2H.) , 3.45 (s, 3H) , 3.8-4.1 (m, IH), 4.2 (d, J = 5 Hz, IH), and 6.9-7.6 (m, 15H); 1 3CNMR (CDC1 3) 6 15.93, 18.3, 30.61, 33.75, 34.73, 55.35, 63.10, 71.96, 104.34, 126.98, 127.77, 128.83, and 144.21.;-raass spectrum: low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 55(7), 72 (7), 83 (8), 85 (20), 105(13), 111 (16), 115 (4), 141 (8), 143 (65), 144 (7), 165 (25), 166(6), 173(63), 174 (9), 183(7), 229 (5), 243 (100), 244 (36), 258(3), and 416 (1). Anal. C a l c d f o r C 2 8 H 3 2 O 3 : C, 80.73; H, 7.74. Found: C, 80.51; H, 7.55. (2S, 4S, 4 ' S ) - l , l - D i e t h y l t h i o - 2 - m e t h y l - 4 - ( 2 ' , 2 ' - d i m e t h y l - 1 ' , 3 ' - d i o x a c y c l o p e n t - 4 ' - y l ) p e n t a n e (217) To a mixture of 0.83 g of 201 and 1.80 mL of co n c e n t r a t e d h y d r o c h l o r i c a c i d at 0° C was added.1.80 mL of e t h a n e t h i o l . The r e a c t i o n mixture was s t i r r e d f o r 24 h at 0° C. Ice and water were added to the r e a c t i o n mixture and the mixture e x t r a c t e d s e v e r a l times with e t h y l a c e t a t e . The o r g a n i c e x t r a c t was washed with b r i n e and s a t u r a t e d aqueous sodium b i c a r b o n a t e , d r i e d over anhydrous sodium s u l f a t e and the s o l v e n t was removed under reduced p r e s s u r e . The crude product was p u r i f i e d by column chromato-graphy, ( s i l i c a g e l 100-200 mesh) u s i n g a mixture of petroleum ether and e t h y l ether (3:1, v / v ) ; a f t e r the s i d e - p r o d u c t had completely e l u t e d , the s o l v e n t was changed to e t h y l e t h e r . The y i e l d of compound 215 from t h i s chromatography was 0.44 g (83%). 221 The NMR (CDC13) of compound 215 had absorptions at 6 0.92 (d, J = 7 Hz, 3H), 1.16 (d, J = 7 Hz, 3H), 1.25 (t, J = 7 Hz, 6H), 1.4-2.3 (m, 4H), 2.2-3.0 (m, 4H), 3.26 (br s, 2H), 3.4-3.7 (m, 3H), and 3.75 (d, J = 3 Hz, IH). Compound 215 was characterized as i t s isopropylidene derivative. To a solution of compound 215 (0.43 g, 1.60 mmol) i n 9 mL of 2,2-dimethoxypropane was added ca. 2 0 mg of p-toluene-sulfonic acid. After s t i r r i n g at room temperature for 2 h, the reaction mixture was diluted with chloroform, washed with 5% aqueous sodium bicarbonate, dried over anhydrous magnesium s u l -fate, and solvents were removed under reduced pressure. The crude product was d i s t i l l e d (Kugelrohr, bath temperature 100° C/0.2 torr) to give 0.40 g (82%) of 217. A small sample was p u r i f i e d by TLC using a mixture of petroleum ether and ethyl ether (4:1, v/v) to give compound 217 and was characterized by; IR (CHC13) 860, 1060, 1160, 1260, 1280, 1380, and 1460 cm 1 ; 270 MHz NMR (CDC13) 6 0.98 (d, J = 6 Hz, 3H), 1.04 (d, J = 6 Hz, 3H), 1.25 (t, J = 7 Hz, 3H), 1.35 (s, 3H), 1.40 (s, 3H), 1.5-1.7 (m, 3H), 2.0-2.2 (m, 1H) , 2.5-2.8 (m, 4H), and 3.6-4.2 (m, 4H); mass spectrum: a) high resolution calcd for C 1 5 H 3 0 O 2 O 2 : 306.1687 amu; found: 306.1690; b) low resolution m/e (rel intensity) 43 (38), 55 (18), 75(27), 103 (19), 107 (55), 115 (56), 125 (29), 135(30), 169 (19), 187 (100), and 306 (30). 222 (2 ' S, 4 ' R, 5 ' S) -2- (2' ,4 ' -D-imethyl-5 ' ,6 ' -dihydroxyhex-2,'-yl) - 1,3-dithiane (218) To a solution of 2.08 g (5.0 mmol) of hydrogenated com-pound 201 i n ca. 40 mL of dry dichloromethane was added 1.63 g (15 mmol) of 1,3-dithiolpropane and 1.4 mL of d i s t i l l e d boron t r i f l u o r i d e etherate at 0° C. The reaction was s t i r r e d at 0° C for 18 h. It was then d i l u t e d with ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous magnesium s u l -fate, and the solvents were removed under reduced pressure. P u r i f i c a t i o n of the crude product was achieved by column chro-matography using s i l i c a gel (100-200 mesh), and a mixture of petroleum ether and ethyl ether (9:1, v/v) as eluent. After the side product had completely eluted, the eluting solvent was changed to ethyl acetate. The y i e l d of compound 218 from this, chromatography was 1.0 g (80%) and t h i s product was character-ized by; IR (CHC13) 3500 and 3660 cm"1; NMR (CDCl3) 6 0.98 (d, J = 6 Hz, 3H), 1.1 (d, J = 6 Hz, 3H), 1.5-2.5 (m, 8H), 2.7-3.1 (m, 4H), 3.4-3.7 (m, 3H), and 4.12 (d, J = 4 Hz, IH); mass spectrum: a) high resolution calcd for C i aH 22 02S2: 250.1061 amu; found: 250.1085; b) low resolution m/e (rel intensity) 41 (10), 43 (7), 55 (6), 73 (5), 119 (100), 120 (8), 121(10), 143 (5), 219 (5) , and 250 (16). 223 (2 'S, 4 'R, 4"S)-2- [4 '- (2" , 2 "-Dime thy 1-1',' , 3"-dioxacyclopent-4"- y l ) p e n t - 2 ' . - y l ] - l , 3 - d i t h i a n e (219) To a s o l u t i o n of 1.0 g (4.0 mmol) of d i o l d i t h i a n e 218 i n 20 mL of 2,2-dimethoxypropane was added a c a t a l y t i c amount of p_-toluenesulfonic a c i d (0.10 g) . The r e a c t i o n was s t i r r e d at room -temperature f o r 1.5 h. I t was then d i l u t e d w i t h c h l o r o -form, washed with aqueous sodium b i c a r b o n a t e , d r i e d over anhydrous magnesium s u l f a t e , and the s o l v e n t s were removed under reduced p r e s s u r e . The crude product was p u r i f i e d by column chromato-graphy u s i n g s i l i c a g e l (100-200 mesh) and a mixture of p e t r o -leum e t h e r and e t h y l e t h e r (9:1, v/v) as e l u e n t . From t h i s chro-matography 1.02 g (88%) of compound 219 was i s o l a t e d . Kugel-rohr d i s t i l l a t i o n (bath temperature 120° C/0.1 t o r r ) of 219 i s o l a t e d from t h i s column had [ c t ] ^ 5 - 6.2° (150 mg/mL, e t h y l e t h e r ) , and was c h a r a c t e r i z e d by; IR (CHCl3) 920, 1070, 1380, 1390, and 2975 cm" 1; 270 MHz NMR (CDC1 3) 6 0.98 (d, J = 7 Hz, 3H), 1.07 (d, J = 7 Hz, 3H), 1.35 (s, 3H), 1.41 (s, 3H), 1.5-1.9 (m, 4H), 1.95-2.2 (m, 2H), 2.75-3.0 (m, 4H), 3.65 ( t , J = 7 Hz, IH), 3.85 (q, J = 7 Hz, IH), 4.01 ( t , J = 7 Hz, IH), and 4.16 (d, J = 4 Hz, IH) ; mass spectrum m/e ( r e l i n t e n s i t y ) 41(22), 43(38), 72(21), 119(100), 159 (31), 161 (18), 232 (24), 275(44), and 290(58). A n a l . C a l c d f o r C l l tH 2 6 0 2 S 2 : C, 57.89; H, 9.02. Found: C, 57.70; H, 9.00. 224 (2 'S, 4 'R, 4"S.) - 2 - E t h y l - 2 - [4 '- (2" , 2 "-dimethyl-1"', 3 " - d i o x a c y c l o - p e n t - 4 " - y l ) p e n t - 2 ' - y l ] - l , 3 - d i t h i a n e (220) A s o l u t i o n of 0.58 g (2.0 mmol) of compound 219 i n ca. 8 mL of dry n-hexane ( d i s t i l l e d over c a l c i u m hydride) was p l a c e d i n a 25 mL round bottom f l a s k f i t t e d w ith a magnetic s t i r r e r and n i t r o g e n o u t l e t . The f l a s k was co o l e d t o . c a . -20° C (dry i c e and carbon t e t r a c h l o r i d e ) and 1.5 mL (2.0 M i n pentane, 3 mmol) of t - b u t y l l i t h i u m was added dropwise. The r e a c t i o n was s t i r r e d at ca. -20° C f o r 2 h, then kept i n the f r e e z e r (ca. -10° C) f o r 16 h. The temperature of the r e a c t i o n mixture was then r a i s e d t o 0° C and 0.4 mL (.7 8 g, 5 mmol) of iodoethane i n 1.74 mL (5 eq) of hexamethylphosphoramide was added and a white p r e c i p i -t a t e formed immediately. The r e a c t i o n was s t i r r e d f o r 5 hr, d i l u t e d w i t h e t h y l e t h e r , washed with i c e c o l d d i l u t e hydro-c h l o r i c a c i d , sodium b i c a r b o n a t e s o l u t i o n , and b r i n e , d r i e d over anhydrous sodium s u l f a t e , and the s o l v e n t s were removed under reduced p r e s s u r e . The crude product was p u r i f i e d by column chromatography u s i n g s i l i c a g e l (100-200 mesh) and a mixture o f r petroleum ether and e t h y l e t h e r (9:1, v/v) as e l u e n t t o y i e l d 0.506 g (80%) o f compound 220. Kugelrohr d i s t i l l a t i o n - ( b a t h tem-per a t u r e .  12 8° G/0.1 t o r r ) . of :'2 2Q- i s o l a t e d from t h i s " column had [o. ] 2 ? -2.8° (50 mg/mL, e t h y l ether) ; and was c h a r a c t e r i z e d by: IR (CHCl3) 860, 1060, 1160, 1380, 1480, and 2970 cm" 1; 270 MHz NMR (CDC1 3) 6 0.98 ( t , J = 7 Hz, 3H), 1.01 (d, J = 7 Hz, 3H), 1.1 (d, J = 7 Hz, 3H), 1.34 (s, 3H), 1.41 (s, 3H), 225 1.5-2.2 (m, 8H), 2.6-3.0 (m, 2H), 3.7 (t, J = 7 Hz, 3H), and 3.9-4.1 (m, 2H); mass spectrum m/e ( r e l intensity) 41(12), 43(16), 134(15), 147(100), 148(13), 149(15), 303(18), and 320(16). Anal, calcd for C i 6 H 3 o 0 2 S 2 : C, 60.30; H, 9.49. Found: C,60.20; H,9.53 (2'S, 4'R, 5'S)-2-ethyl-2-(2',4'-dimethyl-5 1,6'-dihydroxyhex- 2-yl)-1,3-dithiane (221) To a solution of 0.35 g (1.1. mmol) of compound 220 i n ca. 15 mL of methanol was added.a c a t a l y t i c amount of p-toluene-sulfonic acid monohydrate (0.02 g). The reaction mixture was s t i r r e d at room temperature for 24 h. S o l i d sodium carbonate was added to neutralize the acid. The mixture was f i l t e r e d and the f i l t r a t e concentrated under reduced pressure. The residue was dissolved i n ethyl acetate, dried over anhydrous magnesium sulf a t e , and the solvents were removed under reduced pressure. P u r i f i c a t i o n was achieved by column chromatography using s i l i c a gel (100-200 mesh) and a mixture of petroleum ether and ethyl ether (9:1, v/v) as eluent to y i e l d 0.20 g (90%) of compound 221, [COQ'1' - 42.6° (50 mg/mL, ethyl ether). This compound was characterized by the following spectral data; IR (CHCl3) 900, 1005, 1050, 1280, 1380, 1460, 2970, 3500, and 365 0 cm - 1; NMR (CDC13) 6 0.87 (d, J = 7 Hz, 3H), 1.08 (d, J = 7 Hz, 3H), 1.02 (t, J = 7 Hz, 3H), 1.7-2.3 (m, 8H), 2.38 (br s, 2H), 226 2.6-3.0 (m, 4H), and 3.4-3.8 (m, 3H) ; mass spectrum: a) hig h r e s o l u t i o n c a l c d f o r C 1 3 H 2 6 O 2 S 2 : 278.1374 amu; found: 278.1358; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (8), 47(11), 83 (36), 85(23), 147(100), 148 (12), 149 (13), and 278 (12). g - M u l t i s t r i a t i n (18a) To a s t i r r e d s o l u t i o n o f 0.43 g (1.6. mmol) of mercuric c h l o r i d e and 0.17 g (0.80 mmol) of mercuric oxide i n ca. 5 mL of dry a c e t o n i t r i l e was added a s o l u t i o n of 0.1974 g (0.71 mmol) of compound 221 i n 5 mL of anhydrous a c e t o n i t r i l e under n i t r o g e n . The r e a c t i o n mixture was r e f l u x e d f o r 4 h with s t i r r i n g . A f t e r c o o l i n g , the r e a c t i o n mixture was f i l t e r e d and the s o l i d washed wit h pentane. An equal amount of s a t u r a t e d b r i n e s o l u t i o n was added to the f i l t r a t e and t h i s s o l u t i o n was e x t r a c t e d s e v e r a l times w i t h pentane. The o r g a n i c e x t r a c t s were washed with aqu-eous ammonium a c e t a t e , d r i e d over anhydrous sodium s u l f a t e and the s o l v e n t s were removed under reduced p r e s s u r e . Kugelrohr d i s t i l l a t i o n (bath temperature 110° C/20 t o r r ) of the crude pro-duce gave 0.096 g (80%) of a - m u l t i s t r i a t i n (18a) , [ a ] 2 1 * - 46° (10 mg/mL, hexane); [ l i t . 2 6 bp 90° C/20 t o r r , bath temperature], and a l l the s p e c t r a l data were i d e n t i c a l t o those r e p o r t e d . 2 6 ' 1 * 9 GLC a n a l y s i s (column C, 100° C) showed a major component (>90%). T h i s was f u r t h e r i d e n t i f i e d by comparison with a sample of (±)-g-m u l t i s . t r i a t i n k i n d l y - p r o v i d e d by Dr. .J;.• W.; Peacock ;;; 18g was c h a r a c t e r i z e d by; 22? IR (CHCl 3) 895, 920, 1035, 1130, 1180, 1255, 1460, 2925, and 29 8 0 cm - 1; NMR (CDCl 3) <5 0.81 (d, J = 7 Hz, 3H) , 0.81 (d, J = 7 Hz, 3H)., 0.93 ( t , J = 7 Hz, 3H) , 1.4-2.2 (m, 6H) , 3.68 (m, IH) , 3.89 (m, IH), and 4.20 (m, IH); mass spectrum: a) high r e s o l u t i o n c a l c d f o r C 1 0 H 1 8 0 2 : 170.1307 amu; found: 170.1298; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41(8), 43 (6), 54(9), 55 (22), 57 (100), 71(20), 81 (16), 96(25), 99 (11), 128 (25), and 170(19). 228 Synthesis of Lineatin or 3, 3,7-trimethyl-2,9-dioxatricyclo  [3. 3.1.0'* i 1 ]nonane (22) l-Acetoxybutan-3-one (235) 9 8 A mixture of 35 g (500 mmol) of methyl v i n y l ketone, 150 mL of g l a c i a l acetic acid, and a c a t a l y t i c amount of water was heated under reflux and under nitrogen for 24 h. P u r i f i -cation of the crude product was achieved by f r a c t i o n a l d i s t i l -l a t i o n to give 26.0 g (40%) of l-acetoxybutan-3-one (135), bp 92-95° C/20 to r r [ l i t . 9 8 bp 78-84° C/14 t o r r ] . This compound was further characterized by; IR (CHC13) 1720 and 1735 cm"1; NMR (CDCl3) 6 2.07 (s, 3H), 2.18 (s, 3H), 2.73 (t, J = 7 Hz, 2H), and 4.28 (t, J = 7 Hz, 2H); mass spectrum m/e (rel intensity) 42(8), 43(100), 55(13), 61 (10), 70 (10), 71 (9), 87 (8), 88 (17), 115 (3), and 130(3). Ethyl 5-acetoxy-3-hydroxy-3-methylpentanoate (236) 9 9 To a solution of 14.9 , g (148 mmol) of diisopropylamine i n 250 mL of anhydrous ethyl ether, was added v i a a syringe a solution of 91.6 . mL of 1.6 M (147 mmol) n-butyllithium i n hexane at 0° C under nitrogen. After s t i r r i n g for ^  hr at 0° C, the reaction was cooled to -78° C (dry ice plus acetone) and 12.18 g (138 mmol) of anhydrous ethyl acetate was added slowly. The reaction mixture was s t i r r e d for 15 min and 17.32 g (133 mmol) 229 of l-acetoxybutan-3-one (235) was added. After 15 min ca. 10 mL of d i l u t e hydrochloric acid was added slowly. The temperature of the reaction mixture was then raised to room temperature. The reaction mixture was di l u t e d with water and extracted several times with ethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate, and the solvents were removed under reduced pressure to give 25.52 g (88%) of ethyl 5-acetoxy-3-hydroxy-3-methyl>pentanoate • (236). P u r i f i c a t i o n was achieved by column chromatography using a mixture of ethyl ^acetate and petroleum ether (3:7 v/v) as eluent to give 23.6 g (81%) of compound 236 which had spectral data i d e n t i c a l to that r e p o r t e d ; 9 9 IR (CHCl 3) 1730 and 3560 cm - 1; NMR (CDCl3) 6 1.3 (s, 3H), 1.27 (t, J = 7 Hz, 3H), 1.86 (t, J = 7 Hz, 2H), 2.03 (s, 3H), 2.50 (br s, 2H), 3.52 (br s, IH), 4.12 (q, J = 7 Hz, 2H), and 4.20 (t, J = 7 Hz, 3H); mass spectrum: m/e (rel intensity) 43(100), 55(11), 71(36), 85 (24), 103 (12), 112(9), 113 (21), 115 (8), 132(88), 143 (25) , 173 (2) , and 218 (0.1) . Mevalonolactone (237) 9 8 A sample of 28.34 g (130 mmol) of ethyl 5-acetoxy-3-hydroxy-3-methylpentanoate-; (236) was weighed into a 2 L round bottom flask and the flask cooled to ca. -10° C. Then 600 mL of ice cold 1 N methanolic potassium hydroxide was added slowly. The reaction mixture was s t i r r e d at room temperature for 24 h. 230 A 10% solution of concentrated hydrochloric acid i n methanol was added u n t i l the reaction mixture was a c i d i c . S t i r r i n g was continued for another 1 h, and methanol removed under reduced pressure. The residue was di l u t e d with ethyl acetate and the s o l i d f i l t e r e d o f f . The s o l i d was washed several times with ethyl acetate and the combined f i l t r a t e s washed once with sat-urated brine solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 13.10 g (78%) of crude mevalonolactone (237). The crude mevalonolac-tone (237) was used d i r e c t l y i n the next step. A small sample, was p u r i f i e d by TLC and Kugelrohr d i s t i l l a t i o n at 130° C/0.9 t o r r [ l i t . 9 8 bp 114° C/0. 01 t o r r ] . Thi-s. compound, was, characterized by ,• IR (CHC13) 1730 and 3375 cm"1; NMR (CDCl3) 6 1.37 (s, 3H), 1.8-2.1 (m, 2H), 2.5-2.7 (m, 2H), 3.52 (br s, IH), and 4.1-4.9 (m, 2H); mass spectrum m/e (rel intensity) 43(100), 53(10), 58(23), 71 (77), 85 (6), 102(7), 103(8), 112 (5), 115 (4), and 130(4). 3-Methyl-5-hydroxy-2-pentenoic acid 6-lactone ( 1 1 9 ) 1 0 0 A mixture of 10.4 g (80 mmol) of mevalonolactone (237) and 13.6 g of potassium hydrogen sulfate was heated under vacuum for 1 h and d i s t i l l e d at 72-78° C/0.9 t o r r to give 8.0 g of color-less l i q u i d . The NMR of the d i s t i l l e d l i q u i d showed i t to be a mixture of compounds 238 and 119. The mixture of products was heated again with 3 g of potassium b i s u l f a t e to ca. 190° for 0.5 h, allowed to cool, and r e d i s t i l l e d at 72-74° C/0.9 t o r r 231 to give 7.4 g (83%) of 3-methyl-5-hydroxy-2-pentenoic acid S-lactone (119). The spectral data below were the same as those reported for t h i s compound: 1 0 0 IR (CHC13) 1650 and 1725 cm"1; NMR (CDCl 3) 6 2.01 (br s, 3H), 2.37 (t, J = 6 Hz, 2H), 4.33 (t, J = 6 Hz, 2H), and 5.73 (m, IH); mass spectrum m/e (rel intensity) 41(10), 53(12), 54(44), 55 (11), 82 (100), and 112(59). Photoaddition of 3-methyl-5-hydroxy-2-pentenoic acid 5-lactone  (119) to allene A solution of 1.57 g (14.0 mmol) of 3-methyl-5-hydroxy-2-pentenoic acid 6-lactone (119), i n 600 mL of acetone was i r r a -diated with a 450-watt Hanovia high pressure mercury arc at room temperature for 4 h through Vycor f i l t e r with continual i n t r o -duction of allene. At the end of the i r r a d i a t i o n the solvent was removed by d i s t i l l a t i o n under reduced pressure to give 2.0 g (90%) of a mixture of photoadducts; l-methyl-7-methylene-4-oxa-cis-bicyclo T 4.2.01octan-5-one (233) and l-methyl-8-methyl-ene-4-oxa-cis-bicyclo T 4.2.01octan-5-one (234). The crude pro-duct was p u r i f i e d by column chromatography using s i l i c a gel (100-200 mesh) and a mixture of petroleum ether and ethyl acetate (2:3, v/v) as eluent to give 1.67 g (82%) of a mixture of 233 and 234 which could not be separated by TLC. The material was shown to be a 3:2 mixture of 23 3 and 234 respectively by 270 MHz 232 NMR and by GLC (using a 23.2 m x 0.28 mm ID whisker-walled column coated with Carbowax 2 0 M) . ( 3 ) Since separation of the i n d i v i d u a l components of the photoadduct mixture was very d i f f i c u l t , the sequence was carr i e d through on the mixture. The f r a c t i o n i s o l a t e d by the above chromatography was further d i s t i l l e d at 120° C/0.8 t o r r (Kugelrohr) and was characterized by; IR (CHCl 3) 1725 cm"1; NMR (CDC13) - see spectral appendix p. 267 mass spectrum: a) high resolution calcd for C 9H 1 20 2: 152.0838 amu; found: 152.0845; b) low resolution m/e (rel intensity) 41 (13), 67 (10), 77 (27), 79(39), 91(20), 93 (100), 94 (24), 95(10), 107 (21), 109 (22), 124(15), 137(30), and 152 (40). Anal, calcd for C 9H 1 20 2: C, 71.03; H, 7.95. Found: C, 70.77; H, 8.16. Addition of methyllithium to photoadducts 233 and 234 A solution of 8.0 g (52.60 mmol) of photoadducts 247 and 248 i n ca. 2 0 mL of anhydrous ethyl ether was added dropwise to an ice-cooled flask containing 120 mL (210 mmol) of 1.75 M methyllithium i n ethyl ether. The mixture was s t i r r e d at 0° C ( 3 ) We wish to thank Dr. H. Pierce, J r . , Department of Chemistry, Simon Fraser University, Burnaby, B.C., Canada, for the GLC analysis of t h i s compound. 233 for 2 h and the excess methyllithium was decomposed with a saturated aqueous solution of ammonium chloride. The ether layer was separated and the aqueous layer extracted several times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, and the solvents were removed under reduced pressure to give 9.35 g (97%) of a mixture of diols 24 7 and 24 8 which could not be separated by TLC. The crude mixture was pure enough for the next reaction. A small sample of the mixture of products was chromatographed on a 20 x 20 cm s i l i c a gel coated plate, thickness 1 mm, using a mixture of ethyl acetate and petroleum ether (7:1, v/v) as eluent. A thick colorless o i l was isola t e d and characterized by the following data; IR (CHCl 3) 1680, 3420, and 3620 cm"1; NMR (CDC13) - see spectral appendix p. 2 67 mass spectrum: a) high resolution calcd for C i i H 2 0 0 2 : 184.1463 amu; found: 184.1462; b) low resolution m/e (rel intensity) 41 ( 4 5 ) , 43 ( 1 0 0 ) , 53 ( 1 3 ) , 55 ( 3 3 ) , 59 ( 9 5 ) , 67 ( 2 4 ) , 7 9 ( 2 7 ) , 83 ( 7 2 ) , 85 (36), 86 (32), 105 (19), 107 (34), 111(59), 121 (49), 123 (30), 135(60), 151(34), and 166(15) (P-H 20). Oxidation on mixture of d i o l s 247 and 248 A sample of 31.2 g (312 mmol) of chromium t r i o x i d e was added to a s t i r r e d solution of 49.32 g (624 mmol) of anhydrous 234 p y r i d i n e 8 3 i n ca. 30 mL of anhydrous dichloromethane. The chromium t r i o x i d e - p y r i d i n e complex was s t i r r e d at room temper-ature f o r 25 min. Then a s o l u t i o n of 9.20 g (50 mmol) of the mixture d i o l s 247 and 248 i n ca. 5 mL of anhydrous dichlormethane was added i n one p o r t i o n . A t a r r y , b l a c k p r e c i p i t a t e separated immediately. A f t e r s t i r r i n g f o r 4.5 h at room temperature, the s o l u t i o n was decanted from the r e a c t i o n , and the dichloromethane removed under reduced p r e s s u r e . The r e s i d u e was d i l u t e d with e t h y l e t h e r and the r e a c t i o n f l a s k r i n s e d s e v e r a l times w i t h e t h y l e t h e r . The combined ether l a y e r s were f i l t e r e d through a bed o f c e l i t e , washed w i t h i c e - c o l d d i l u t e h y d r o c h l o r i c a c i d , aqueous sodium bicar b o n a t e s o l u t i o n , b r i n e , and d r i e d over anhy-drous magnesium s u l f a t e . The s o l v e n t s were removed under reduced pressure to g i v e 7.60 g (84%) of a mixture of 2 , 2 , 6 - t r i m e t h y l -8-methylene-3-oxa-cis-bicyclo[4.2.0]octan-4-one (249) and 2,2,6-trimethyl-7-methylene-3-oxa-cis-bicyclo[4.2.0]octan-4-one (250). The crude products were p u r i f i e d by column chromatography u s i n g s i l i c a g e l (100-200 mesh) and a mixture of petroleum e t h e r and e t h y l a c e t a t e (2:3, v/v) as e l u e n t . The f r a c t i o n i s o l a t e d from t h i s chromatography was homogeneous by TLC a n a l y s i s , and shown to be a 3:2 mixture of 249 and 250 by NMR and GLC (using a 23.4 m x 0.28 mm ID whisker-walled column coated with s i l a r -10 C at 180° C) ^ Since s e p a r a t i o n of the i n d i v i d u a l components See f o o t - n o t e (3) on p. 232. 235 from the mixture was very d i f f i c u l t , the next sequence of steps was car r i e d through on the mixture. The mixture from the chroma-tography was further d i s t i l l e d at 100° C/1.0 t o r r (Kugelrohr) to afford 6.5 g (72%) of a mixture of 249 and 250 which was characterized by; IR (CHC13) 1680 and 1725 cm"1; NMR (CDCl 3) - see spectral appendix p. 268 mass spectrum: a) high resolution calcd for C ! i H 1 6 0 2 : 180.1150 amu; found: 180.1158; b) low resolution m/e ( r e l intensity) 41 (33), 43 (69), 79 (77). 80(90), 93 (32), 109 (24), 121 (20), 123 (31), 125 (31), 139 (14), 165 (10), and 180(17). Anal, calcd for d i H 1 6 0 2 : C, 73.30; H, 8.95. Found: C, 73.10; H, 8.95. Ozonolysis of alkenes 249 and 250 A stream of ozone and oxygen was bubbled through a solu-tion of 6.93 g (38.50 mmol) of a mixture of compounds 249 and 250 i n ca. 25 0 mL of anhydrous dichloromethane at -7 8° C u n t i l the solution turned blue. Excess dimethylsulfide was added slowly. The reaction mixture was allowed to s t i r at -78° C for 20 min, warmed slowly to room temperature, washed with water, and dried over anhydrous magnesium sulfat e . The solvents were removed under reduced pressure to give 6.27 g (89%) of crude product which was p u r i f i e d by column chromatography using s i l i c a 2 3 6 g e l ( 1 0 0 - 2 0 0 mesh) and a mixture o f petroleum ether and e t h y l a c e t a t e ( 1 : 1 , v/v) as e l u e n t . The f r a c t i o n i s o l a t e d from t h i s chromatography gave 4 . 8 g (6 9%) of a mixture of 2 , 2 , 6 - t r i m e t h y l -3 - o x a - c i s - b i c y c l o [ 4 . 2 . 0 ] o c t a n - 4 , 8-dione (2.51), and 2 , 2 , 6 - t r i m e t h y l -3 - o x a - c i s - b i c y c l o [ 4 . 2 . 0 ] o c t a n - 4 , 7 - d i o n e ( 2 5 2 ) . The mixture of products c o u l d not be separated by TLC and was c h a r a c t e r i z e d by the f o l l o w i n g s p e c t r a l data; IR (CHCl 3) 1 7 3 0 and 1 7 8 5 cm" 1; NMR ( C D C 1 3 ) - see s p e c t r a l appendix p. 2 6 8 mass spectrum: a) high r e s o l u t i o n c a l c d f o r C i o H i i t 0 3 : 1 8 2 . 0 9 4 3 amu; found: 1 8 2 . 0 9 5 3 ; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 40 ( 2 7 ) , 4 1 ( 6 0 ) , 4 2 ( 2 0 ) , 4 3 ( 7 8 ) , 44 ( 3 8 ) , 5 1 ( 1 0 ) , 5 3 ( 3 2 ) , 54 ( 1 7 ) , 5 5 ( 3 3 ) , 59 ( 1 0 ) , 6 7 ( 3 5 ) , 6 8 ( 4 7 ) , 6 9 ( 3 0 ) , 7 0 ( 1 4 ) , 7 7 ( 1 4 ) , 79 ( 3 0 ) , 8 1 ( 5 3 ) , 8 2 ( 2 6 ) , 8 3 ( 2 8 ) , 95 ( 2 5 ) , 9 6 ( 1 0 0 ) , 9 7 ( 7 9 ) , 98 ( 4 2 ) , 1 2 3 ( 4 6 ) , 1 2 5 ( 8 9 ) , 1 2 6 ( 2 3 ) , 1 4 1 ( 1 9 ) , 1 6 7 ( 8 ) , and 1 8 2 ( 6 ) . Reduction of compounds 2 5 1 and 2 5 2 w i t h L - S e l e c t r i d e A s o l u t i o n o f 3 . 1 9 g ( 1 7 . 5 mmol) of a mixture of 2 5 1 and 2 5 2 i n ca. 20 mL of anhydrous THF was co o l e d to - 7 8 ° C and 2 1 mL ( 1 . 0 M i n THF, 2 1 mmol) of L - S e l e c t r i d e 1 0 2 was added a t - 7 8 ° C under n i t r o g e n . The r e a c t i o n was s t i r r e d at t h a t temper-ature f o r 3 h, and 1 0 mL of 10% sodium hydroxide and 1 0 mL of 30% hydrogen peroxide were added sl o w l y . The temperature was then r a i s e d t o 0° and the r e a c t i o n was s t i r r e d f o r 1 h. I t was 237 then a c i d i f i e d with d i l u t e h y d r o c h l o r i c a c i d and the aqueous l a y e r e x t r a c t e d s e v e r a l times with e t h y l a c e t a t e . The e x t r a c t s were washed with an equal volume of s a t u r a t e d b r i n e s o l u t i o n , then w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e , and f i n a l l y d r i e d over anhydrous magnesium s u l f a t e . The s o l v e n t s were removed under reduced pressure to g i v e 3.01 g (94%) of crude product. A small amount of crude product (140 mg) was chroma-tographed u s i n g a mixture of e t h y l a c e t a t e and petroleum ether (7:3, v/v) as e l u e n t . The f r a c t i o n i s o l a t e d from t h i s chroma-tography gave 0.102 g (73%) of a mixture of 8-hydroxy-3,2,6-t r i m e t h y l - 3 - o x a - c i s - b i c y c l o [ 4 . 2 . 0 ] o c t a n - 4 - o n e (253) and 7-hydroxy-2, 2 , 6 - t r i m e t h y l - 3 - o x a - c i s - b i c y c l o [ 4 . 2 . 0 ] o c t a n - 4 - o n e (254). The mixture of products was homogeneous by TLC a n a l y s i s and attempts t o separate the i n d i v i d u a l isomers were not s u c c e s s f u l . The mixture of products was c h a r a c t e r i z e d by the f o l l o w i n g s p e c t r a l data ; IR (CHC1 3) 1720, 3450 and 3600 cm" 1; NMR (CDCl 3) - see s p e c t r a l appendix p. 269 mass spectrum: a) high r e s o l u t i o n c a l c d f o r C 9 H 1 3 O 3 : 184.1099 amu; found: 184.1118; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (28), 43(56), 55(23), 56 (17), 59 (15), 81 (17), 83 (15), 85 (13), 95 (51), 96 (29), 97 (36), 99 (41), 107 (20), 123(34), 125(100), 127 (14), 141(78), 167 (13}, and 184(1). 238 Lineatin (22) and 3,3,7-trimethyl-2,9-dioxatricyclo[4.2.1.0 h ' 7] nonane (23) A solution of 2.355 g (12.8 mmol) of a mixture of 253 and 254 i n ca. 2 0 mL of anhydrous toluene was cooled to -6 0° C (chloroform and dry ice) and a solution of 32 mL (1.0 M i n hex-ane, 32 mmol) of diisobutylaluminum h y d r i d e 1 0 3 i n hexane was added dropwise under nitrogen. The reaction mixture was s t i r r e d at -6 0° C for 1 h, and saturated ammonium chloride solution was added. The reaction mixture was warmed to 0° C and a c i d i f i e d by d i l u t e hydrochloric acid. S t i r r i n g was continued for an additional 1 h and the mixture was extracted several times with ethyl acetate. The extracts were combined, washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvents removed under reduced pressure to give 1.786 g (83%) of crude product. The material was shown to be an 3:2 mixture of 3,3,7-trimethyl-2,9-dioxatricyclo[3.3.1.0 4' 7] nonane (2_2) (lineatin) and 3 , 3 , 7-trimethyl-2 , 9-dioxatricyclo [ 4 . 2 .1. 01*' 7 ] nonane (2_3) by NMR. P u r i f i c a t i o n was achieved by column chromatography using s i l i c a gel (100-200 mesh) and a mix-ture of petroleum ether and ethyl ether (3:2, v/v) as eluent. Two components were is o l a t e d from t h i s chromatography, and these were, i n order of eluti o n , l i n e a t i n (2_2) (0.619 g, 29%) and 3 , 3 ,7-trimethyl-2 , 9-dioxatricyclo [4 . 2 .1. 0h ' 7 Jnonane (_23) (0.616 g, 29%) . A l l the spectral data of compound 22_ were the same as those published by S i l v e r s t e i n et a l . for l i n e a t i n (22). 2 9 239 Th i s s y n t h e t i c l i n e a t i n (_22) was d i s t i l l e d at 110° C/20 t o r r (Kugelrohr) and was c h a r a c t e r i z e d by; IR (CClit.) 838, 875, 905, 920, 960, 1000, 1020, 1078, 1100, 1125, 1170, 1185, 1210, 1225, 1245, 1318, 1345, 1365, 1380, 1385, 1455, 1470, 2880, 2940, and 2975 cm - 1; NMR (100 MHz, CCU) <$ 1.08 (s, 3H) , 1.12 (s, 3H) , 1.14 (s, 3H) , 1.55-2.1 (m, 5H) , 4.34 ( t , J = 4 Hz, IH) , and 4.86 (d, J = 3.5 Hz, IH); (270 MHz, CCli,) 6 1.12 (s, 3H) , 1.16 (s, 3H) , 1.17 (s, 3H) , 1.61 (d, J = 10.5 Hz, IH), 1.69 (dt, J = 10.5, 4 Hz, IH), 1.83 (d, J = 4 Hz, IH), 1.91 (dd, J = 12, 4 Hz), 2.04 (dd, J = 12, 4 Hz, IH), 4.38 ( t , J = 4 Hz, IH), and 4.93 (d, J = 4 Hz, IH); mass spectrum: a) high r e s o l u t i o n c a l c d f o r C i 0 H 1 6 0 2 : 168.1150 amu; found: 168.1148; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (44) , 43 (43) , 55 (64), 55(44), 69 (34), 83 (58), 85 (100), 96 (84), 97 (47), 107(68), 109(51), 111 (85), 125 (56), 140 (12), 153(8), and 168 (10). A n a l . C a l c d f o r C i 0 H 1 6 0 2 : C, 71.39; H, 9.59. Found: C, 71.52; H, 9.76. 3 , 3 , 7 - T r i m e t h y l - 2 , 9 - d i o x a t r i c y c l o [ 4 . 2 . 1 . 0 h ' 7]nonane (23) was d i s t i l l e d (Kugelrohr) at 110° C/20 t o r r and was c h a r a c t e r i z e d by the f o l l o w i n g s p e c t r a l data; IR (CC1 4) 660, 700, 850, 895, 905, 925, 938, 960, 970, 240 980, 990, 1000, 1018, 1040, 1050, 1080, 1100, 1115, 1140, 1160, 1178, 1195, 1205, 1220, 1238, 1255, 1295, 1300, 1325, 1345, 1360, 1365, 1382, 1435, 1455, 1470, 2875, 2950, and 2980 cm" 1; NMR (100 MHz, C C l i j 6 1,03 (s, 3H) , 1.19 (s, 3H) , 1.34 (s, 3H), 1.7-2.45 (m, 5H), 3.86 ( t , J = 4 Hz, IH), and 5.23 (d, J = 4 Hz, IH); (270 MHz, CCU) 6 1.08 (s, 3H) , 1.23 (s, 3H) , 1.39 (s, 3H), 1.33 (dd, J = 12, 4 Hz, IH), 1.9 (m, 2H), 2.09 (d, J = 12 Hz, 1 H ) , 2.35 (ddd, J = 13, 9, 4 Hz, IH), 3.93 ( t , J = 4 Hz,.1H), and 5.32 (d, J = 4 Hz, IH); mass spectrum: a) hi g h r e s o l u t i o n c a l c d f o r C 1 0 H 1 6 0 2 : 168.1150 amu; found: 168.1152; b) low r e s o l u t i o n m/e ( r e l i n t e n s i t y ) 41 (37), 43 (30), 55 (23), 67 (13), 69 (37), 71(17), 79 (14), 81(18), 83 (14), 91 (45), 92 (29), 93 (13), 95 (22), 97(16), 105 (16), 107 (22), 109 (100), 120 (15), 125(15), 124(60), 125 (20), 130 (16), 166 (6) , and 168 (1). 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Soc., 94, 8616 (1972). 102. H. C. Brown and S. Krishnamurthy, J . Amer. Chem. Soc., 94, 7195 (1972) . = 247 103. J. Schmidlin and A. Wettstein, Helv. Chem. Acta, 46, 2799 (1963). 104. L. M. Jackman and S. Sternhell, " Application of Nuclear Magnetic Resonance i n Organic Chemistry ", 2 n c^ ed. , Pergamon Press, Oxford, 1969. 105. D. H. Williams and I. Fleming, " Spectroscopic Methods i n Organic Chemistry ", McGraw-Hill Publishing Co. Limited, Maidenhead, Bershire, 19 66. 248 SPECTRAL APPENDIX 249 250 252 2 5 3 254 255 —c7 ,£,1 8 g S S s g ; 1*1 J 3 M V l l l » f NVW 256 257 • 258' 260 261 262 263 2 6 4 265 266 l*J aOMVil lMSMWl 267 269 270 2 70 MHz NMR of 23 and Decoupling Experiments " 1 ' 1 '<] h — 1 — 1 — 1 — ' — 1 1 1 r 271 272 1 3 C NMR of compound 201 iJLo 4c • 1 . 1 , 1 , 1 , ! O T r I ' I 1 1 1 I 1 I ' I ' I I I I I I T i o n 7*** - i — 1 —^ 1 L 1 8 0 i*« MO 120 100 ib~^ to 40 T 1 I ' I i | i | i i - r - r-20 0 

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