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UBC Theses and Dissertations

Studies in Marine Natural Products : Onchidoris bilamellata, Nanaimoal and Capnellene Hellou, Jocelyne 1985

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S t u d i e s i n M a r i n e N a t u r a l P r o d u c t s : O n c h i d o r i s b i l a m e l l a t a , N a n a i m o a l a n d C a p n e l l e n e b y JOCELYNE HELLOU B . S c , U n i v e r s i t y de M o n t r e a l , 1 9 7 8 M . S c , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 980 A T H E S I S SUBMITTED IN P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES ( D e p a r t m e n t o f C h e m i s t r y ) We a c c e p t t h i s t h e s i s a s c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE U N I V E R S I T Y OF B R I T I S H COLUMBIA J a n u a r y 1985 © J o c e l y n e H e l l o u , 1985 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 requirements for an advanced degree at the University DE-6 (3/81) - i i -Abstract The following thesis is divided into three chapters. The first describes the isolation and identification of a sphingol ipid 1_ from the methanol ic "skin extract of the British Columbia nudibranch Onchidoris bilamellata. The long chain base has been identified as (E)-l,3-dihydroxy-2-amino-16-methyl-4-octadecene (1_3) and the fatty acid moiety as palmitic acid (12J. This ceramide possesses antibacterial activity towards the microorganisms Bacillus subtilis and Staphylococcus aureus. The second chapter presents our attempt to synthesize a hypothetical structure of nanaimoal (24), a marine sesquiterpenoid, isolated from the British Columbia nudibranch Acanthadoris nanaimoensis. The proposed route envisaged photolysis of a 2,2,10,10-tetrasubstituted cyclodecanone. This work lend to a study of the solution photochemistry of 2,2,10-trimethyl-cyclodecanone (35). CH,(CH 2 ) u C00H 12 2 4 H 35 H H 51 The last chapter outlines studies directed toward the synthesis of capnellene (51_), a tricyclopentanoid obtained by Djerassi and co-workers - i i i -f r o m t h e s o f t c o r a l C a p n e l l a i m b r i c a t a . S t a r t i n g w i t h an i m p r o v e d s y n t h e s i s o f t h e known k e t o n e A1'5- b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 3 8 ) , a n a c y l a t i o n 1 5 m e t h o d was d e v e l o p e d f o r t h e p r e p a r a t i o n o f A ' - 3 - c a r b o e t h o x y b i c y c l o -[ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 6 0 ) . The p r o c e d u r e i s o f g e n e r a l u t i l i t y a n d h a s b e e n e x t e n d e d t b r e l a t e d k e t o n e s . T h i s u n s a t u r a t e d k e t o - e s t e r u n d e r w e n t a M i c h a e l a d d i t i o n w i t h m e t h y l v i n y l k e t o n e t o g i v e . 1 7 8 . S e l e c t i v e K n o e v e n a g a l 1 5 c o n d e n s a t i o n o f t h e m e t h y l k e t o n e p r o d u c e d A ' - 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l -3 - m e t h y l - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e ) - b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 9 ) . R e d u c t i o n o f t h e u n s a t u r a t e d k e t o n e a n d d e h y d r a t i o n o f t h e a l l y l i c a l c o h o l p r o d u c e d a 1 , 1 , 3 , 4 - t e t r a s u b s t i t u t e d c y c l o p e n t a d i e n e d e r i v a t i v e 1 8 1 . I n t r a m o l e c u l a r D i e l s - A l d e r c y c l i z a t i o n o f t h e l a t t e r a f f o r d e d t h e t e t r a c y c l i c t r i c a r b o x y l i c e s t e r 1 8 2 . S e l e c t i v e h y d r o l y s i s o f t h e m a l o n i c e s t e r f u n c t i o n a l i t y o f 182 f o l l o w e d b y d e c a r b o x y l a t i o n l e d t o 1 8 3 , a k e y i n t e r m e d i a t e f o r t h e u l t i m a t e c o n s t r u c t i o n o f t h e c a p n e l l a n e r i n g s y s t e m . 160 H 9 o 138 173 0 \ ,9 o COOMe C O O M e 182 183 - i v -T a b l e o f C o n t e n t s p a g e T i t l e P a g e i • A b s t r a c t i i T a b l e o f C o n t e n t s i v L i s t o f F i g u r e s v L i s t o f Schemes v i i L i s t o f T a b l e s i x L i s t o f A b b r e v i a t i o n s x A c k n o w l e d g e m e n t s x i C h a p t e r 1: O n c h i d o r i s b i l a m e l l a t a 1.1 I n t r o d u c t i o n 1 1.2 R e s u l t s 9 1.3 D i s c u s s i o n 18 C h a p t e r 2 : N a n a i m o a l I I . 1 I n t r o d u c t i o n 27 1 1 . 2 R e s u l t s 33 1 1 . 3 D i s c u s s i o n 38 C h a p t e r 3 : C a p n e l l e n e 111.1 I n t r o d u c t i o n 49 1 1 1 . 2 R e s u l t s a n d D i s c u s s i o n . . 59 - A p p r o a c h t o 138 70 - A p p r o a c h U s i n g 1 3 8 a n d D i e t h y l O x a l a t e 74 - A p p r o a c h U s i n g 1_38 a n d E t h y l C h i o r o f o r n a t e 78 - The U s e o f DEPC 80 - A p p r o a c h U s i n g DEPC 83 - S u c c e s s f u l C y c l o p e n t a d i e n e A p p r o a c h 87 - C o n c l u s i o n 99 E x p e r i m e n t a l 121 B i b l i o g r a p h y . . . . . 177 - v -L i s t o f F i g u r e s page 1. D o r s a l V i e w o f a D o r i d N u d i b r a n c h 3 2 . 4 0 0 MHz 'H NMR S p e c t r u m o f C e r a m i d e 1 23 3 . IR S p e c t r u m o f C e r a m i d e 1_ 24 4 . 4 0 0 MHz 'H NMR S p e c t r u m o f D i a c e t y l a t e d D e r i v a t i v e 9 . . . . 25 5 . IR S p e c t r u m o f D i a c e t y l a t e d D e r i v a t i v e 9_ 26 6. Some C o n f o r m a t i o n s o f C y c l o d e c a n e 39 7. Some C o n f o r m a t i o n s o f C y c l o d e c a n o n e 4 0 8 . IR S p e c t r u m o f 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e (35_) 47 9 . 8 0 MHz 'H NMR S p e c t r u m o f 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( 3 5 ) . 48 1 0 . IR S p e c t r u m o f A1'5- b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 3 8 ) 100 1 1 . 60 MHz 'H NMR S p e c t r u m o f A1'5- b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 3 8 ) 101 1 2 . IR S p e c t r u m o f A ' - 3 - c a r b o e t h o x y b i c y c l o [ 3 . 3 . 0 ] -o c t e n - 2 - o n e ( 1 6 0 ) 102 1 3 . 60 MHz 'H NMR S p e c t r u m o f A1'5- 3 - c a r b o e t h o x y b i c y c l o [ 3 . 3 . 0 ] -o c t e n - 2 - o n e ( 1 6 0 ) 103 1 5 1 4 . IR S p e c t r u m o f A ' - 3 - ( b u t a n - 3 - o n e ) - 3 - c a r b o e t h o x y b i c y c l o -[ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 8 ) 104 1 5 . 8 0 MHz 'H NMR S p e c t r u m o f A1'5- 3 - ( b u t a n - 3 - o n e ) - 3 -c a r b o e t h o x y b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 8 ) 105 1 6 . 8 0 MHz 'H NMR S p e c t r u m o f A1 , 5- 3 - c a r b o e t h o x y - 3 - d i m e t h y l 2 - m e t h y l - 1 - b u t e n y l - 1 , 1 - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 9 ) 106 1 5 1 7 . IR S p e c t r u m o f A - 3 - c a r b o e t h o x y - 3 - d i m e t h y l 2 - m e t h y l - 1 - b u t e n y l - 1 , l - d i c a r b o x y ! a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 9 ) 106 1 8 . 6 0 MHz 'H NMR S p e c t r u m o f A1'5- 3 - c a r b o e t h o x y - 3 -( d i m e t h y l 2 - m e t h y l - 1 - b u t e n y l - 1 , 1 - d i c a r b o x y l a t e ) b i c y d o [ 3 . 3 . 0 ] o c t e n - 2 - o l ( 1 8 0 ) 107 1 5 1 9 . IR S p e c t r u m o f A ' - 3 - c a r b o e t h o x y - 3 -( d i m e t h y l 2 - m e t h y l - 1 - b u t e n y l - 1 , 1 - d i c a r b o x y l a t e ) b i c y c 1 o [ 3 . 3 . 0 ] o c t e n - 2 - o 1 ( 1 8 0 ) 107 2 0 . IR S p e c t r u m o f 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 2 - m e t h y l - 1 -b u t e n y l - 1 , 1 - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t a - 1 , 4 - d i e n e ( 1 8 1 ) 108 2 1 . 8 0 MHz 'H NMR S p e c t r u m o f 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 2 - m e t h y l - 1 - b u t e n y l - 1 , 1 - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t a - 1 , 4 - d i e n e ( 1 8 1 ) 1 0 9 - v i -page 8 12 2 2 . IR S p e c t r u m o f A - 6 - c a r b o e t h o x y - 2 - d i c a r b o m e t h o x y - 3 -m e t h y l t e t r a c y c l o [ 6 . 4 . 01 , 6. 03'7. 08'1 2] - d o d e c e n e ( 1 8 2 ) . . . 110 2 3 . 4 0 0 MHz 'H NMR S p e c t r u m o f A8'1 2- 6 - c a r b o e t h o x y - 2 - d i c a r b o -m e t h o x y - 3 - m e t h y l t e t r a c y c l o [ 6 . 4 . 01'6. 03 , 7, 08'1 2] -d o d e c e n e ( 1 8 2 ) I l l 2 4 . IR S p e c t r u m o f e n d o - 1 - c a r b o e t h o x y - 4 - m e t h y l - 5 a c e t y l b i c y c l o [ 2 . 2 . 1 ] h e p t a n - 2 - o n e ( 1 7 1 ) 1 1 2 2 5 . 4 0 0 MHz 'H NMR S p e c t r u m o f e n d o - 1 - c a r b o e t h o x y - 4 - m e t h y l - 5 a c e t y l b i c y c l o [ 2 . 2 . 1 ] h e p t a n - 2 - o n e ( 1 7 1 ) 1 1 3 2 6 . IR S p e c t r u m o f 6 - c a r b o e t h o x y - 8 - m e t h y l - 3 - d i m e t h y l m e t h y l e n e d i c a r b o x y l a t e b i c y c l o [ 4 . 3 . 01'6] n o n a - 1 , 8 - d i e n e ( 1 7 3 ) 114 2 7 . 60 MHz 'H NMR S p e c t r u m o f 6 - c a r b o e t h o x y - 8 - m e t h y l - 3 - d i m e t h y l m e t h y l e n e d i c a r b o x y l a t e b i c y c l o [ 4 . 3 . 0 ^ ' ^ ] n o n a - 1 , 8 - d i e n e ( 1 7 3 ) 115 2 8 . 80 MHz 'H NMR S p e c t r u m o f A1 1 , ] 2- 6 - c a r b o e t h o x y - 2 -d i c a r b o x y l i c a c i d 3 - m e t h y l t e t r a c y c l o [ 6 . 4 . 01 , 6. 03'7. 08'1 2] -d i d e c e n e 116 11 12 2 9 . IR S p e c t r u m o f A ' - 6 - c a r b o e t h o x y - 2 - d i c a r b o x y l i c a c i d S - m e t h y l t e t r a c y c l o t e ^ . O1'6. 03 , 7. 08'1 2] - d o d e c e n e 116 Q i n 3 0 . 80 HMz 'H NMR S p e c t r u m o f A - 6 - c a r b o e t h o x y - 2 -c a r b o x y l i c a c i d S - m e t h y l t e t r a c y c l o t e ^ . O1'6. 03'7. 08 , 1 2] -d o d e c e n e ( 1 8 3 ) 117 9 10 3 1 . IR S p e c t r u m o f A ' - 6 - c a r b o e t h o x y - 2 - c a r b o x y l i c a c i d S - m e t h y l t e t r a c y c l o t S ^ . O1'6. 03'7. 08 , 1 2] - d o d e c e n e ( 1 8 3 ) . . . . 118 9 10 3 2 . IR S p e c t r u m o f A 2 , 6 - d i c a r b o x y l i c a c i d 3 - m e t h y l -t e t r a c y c l o [ 6 . 4 . 01 , 6. 03'7. 08'1 2] d o d e c e n e 119 3 3 . 60 MHz 'H NMR S p e c t r u m o f A ' 2 , 6 - d i c a r b o x y l i c a c i d 3 - m e t h y l t e t r a c y c l o [ 6 . 4 . 01'6. 03'7. 08'1 2] d o d e c e n e 120 - v i i -L i s t o f Schemes pag e 1. C l a s s i f i c a t i o n o f t h e P h y l l u m M o l l u s c a 2 2 . R e a c t i o n s P e r f o r m e d on C e r a m i d e 1_ 16 3 . B i o s y n t h e s i s o f S p h i n g o l i p i d s 21 4 . P o s s i b l e B i o s y n t h e s i s o f t h e N a n a i m o a n e C S k e l e t o n 28 5 . P o s s i b l e R o b i n s o n A n n u l a t i o n o r D i e l s - A l d e r A p p r o a c h t o N a n a i m o a l ( 2 4 ) 30 6 . P o s s i b l e P h o t o c h e m i c a l A p p r o a c h t o N a n a i m o a l ( 2 4 ) 32 7. R e a c t i o n s P e r f o r m e d on 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e (35_) . . . 34 8 . P h o t o c h e m i c a l B e h a v i o u r o f 2 , 6 , 6 - t e t r a m e t h y l -c y c l o h e x a n o n e (45_) 44 9 . P h o t o c h e m i c a l B e h a v i o u r o f 2 , 2 , 1 0 - t r i m e t h y l -c y c l o d e c a n o n e ( 3 5 ) 43 1 0 . S y n t h e s i s o f 5 J j , a D e r i v a t i v e o f N a n a i m o a l (26_) 46 1 1 . B i o g e n e t i c R e l a t i o n s h i p o f t h e C a p n e l l a n e s 49 1 2 . S y n t h e s i s o f 51_, b y R.D. L i t t l e a n d G.L. C a r o l l 51 1 3 . S y n t h e s i s o f 5J_, b y L . A . P a q u e t t e a n d K.E. S t e v e n s 51 1 4 . S y n t h e s i s o f 5J_, b y L . H u g u e t , M. K a r p f a n d A . S . D r i e d i n g . . . 52 1 5 . S y n t h e s i s o f 51_, by T. F u j i t a , T. O h t s u k a , H. S h i r a h a m a a n d T. M a t s u m o t o 52 1 6 . S y n t h e s i s o f 5J_, b y W. O p p o l z e r a n d K. B a t t i g 53 1 7 . S y n t h e s i s o f 5J_, by A.M. B i r c h a n d G. P a t t e n d e n 53 1 8 . S y n t h e s i s o f 51_, by G. M e h t a , D.R. R e d d y a n d A.N. M u r t y . . . . 54 1 9 . S y n t h e s i s o f 5J_, b y E. P i e r s a n d V. K a r u m a r a t n e 55 2 0 . S y n t h e s i s o f a C S k e l e t o n R e l a t e d t o 51_, by J . E . Paw a n d A . C . Weddon 56 2 1 . S y n t h e s i s o f 5 3 , by G. P a t t e n d e n a n d S . J . T e a g u e 57 2 2 . E n o l E t h e r A p p r o a c h t o 5J_ 59 2 3 . S y n t h e s i s o f 108 60 2 4 . C y c l o p e n t a d i e n e A p p r o a c h t o 5_1 62 2 5 . A l k y l a t i o n C y c l o p e n t a d i e n e 116 63 2 6 . S y n t h e s i s o f 120 by M.S. B a i r d a n d C.B. R e e s e 66 2 7 . S y n t h e s i s o f 1_20 b y A . De M e i j e r e a n d L . M e y e r 66 2 8 . R e a c t i o n s o f 8 - d i k e t o n e 1 J 8 67 2 9 . Known A l k y l a t i o n o f 1 2 1 68 3 0 . 0 - a l k y l a t i o n o f 1 2 1 6 9 - v i i i -page 31. Synthesis of 138 72 32. Known Reaction of Cyclohexanone 74 33. Reactions Performed on 145 75 34. Reactions Performed on 150 79 35. The Use of DEPC 81 36. Reactions Performed on 160 84 37. Isomerization of 166 86 38. Diels-Alder Approach to 176, 177 88 39. Formation of Side Product U l 89 40. Possible Rearrangement Reaction 90 41. Formation of Side Product 17_3_ . , 91 42. Diels-Alder Reaction of 175 92 43. Diels-Alder Approach to 182 95 44. Diels-Alder Reaction of 181 96 45. Model Studies of Oxidative Decarboxylation 98 - i x -L i s t o f T a b l e s p a g e 1. 4 0 0 MHz 'H NMR S p e c t r a l D a t a 13 2 . P r o t o n - P r o t o n S p i n D e c o u p l i n g E x p e r i m e n t P e r f o r m e d on D i a c e t y l a t e d D e r i v a t i v e 9 14 3 . 100.1 MHz 1 3C NMR S p e c t r a l D a t a f o r C e r a m i d e 1 15 4 . C o n d i t i o n s f o r t h e A l k y l a t i o n o f 1_1_6 64 5 . A c y l a t i o n R e a g e n t s 80 6 . P r e p a r a t i o n o f C y c l i c £ k e t o - e s t e r s 82 7 . Y i e l d s O b t a i n e d i n V a r i o u s A l k y l a t i o n s o f 189 a n d 190 149 8 . 60 MHz 'H NMR S p e c t r a l D a t a R e l a t e d t o 192 150 9 . IR S p e c t r a l D a t a R e l a t e d t o 192 151 1 0 . MS R e s u l t s R e l a t e d t o 192 152 1 1 . 60 MHz 'H NMR S p e c t r a l D a t a R e l a t e d t o 19J_ 153 1 2 . IR S p e c t r a l D a t a R e l a t e d t o 19J_ 154 1 3 . MS R e s u l t s R e l a t e d t o 19J_ 154 1 4 . 60 MHz 1H NMR S p e c t r a l D a t a R e l a t e d t o 193 157 1 5 . IR S p e c t r a l D a t a R e l a t e d t o 193_ 158 1 6 . MS R e s u l t s R e l a t e d t o 193 158 1 7 . 8 0 MHz h" NMR S p e c t r a l D a t a R e l a t e d t o 194 164 1 8 . IR S p e c t r a l D a t a R e l a t e d t o 194 . . 165 1 9 . MS R e s u l t s R e l a t e d t o 194 165 - X -L i s t o f A b b r e v i a t i o n s mCPBA: m e t a - c h l o r o p e r b e n z o i c a c i d DEPC: d i e t h y l p y r o c a r b o n a t e DMAP: 4 - d i m e t h y l a m i h o p y r i d i n e DME: d i m e t h o x y e t h a n e DMF: N , N - d i m e t h y l f o r m a m i d e DMSO: d i m e t h y l s u l f o x i d e DNPH: 2 , 4 - d i n i t r o p h e n y l h y d r a z i n e E t : e t h y l E u C f o d ) ^ : 1 , 1 , 1 , 2 , 2 , 3 , 3 - h e p t a f l u o r o - 7 , 7 - d i m e t h y l o c t a n e d i o n a t o e u r o p i u m ( I I I ) GLC: g a s - l i q u i d c h r o m a t o g r a p h y HMPA: h e x a m e t h y l p h o s p h o r a m i d e HPLC: h i g h p r e s s u r e l i q u i d c h r o m a t o g r a p h y I R : 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 n e Me: m e t h y l MP: m e l t i n g p o i n t MS: mass s p e c t r u m M s C l : m e t h a n e s u l f o n y l c h l o r i d e NMR: n u c l e a r m a g n e t i c r e s o n a n c e P T LC: p r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y RT: room t e m p e r a t u r e SFORD: s i n g l e f r e q u e n c y o f f r e s o n a n c e d e c o u p l i n g THF: t e t r a h y d r o f u r a n T L C : t h i n l a y e r c h r o m a t o g r a p h y TMS: t e t r a m e t h y l s i l a n e pTsOH: p a r a - t o l u e n e s u l f o n i c a c i d UV: u l t r a v i o l e t - x i -A c k n o w l e d g e m e n t s The r e s e a r c h p r e s e n t e d i n t h i s t h e s i s was c o n d u c t e d a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a a n d a t M e m o r i a l U n i v e r s i t y o f N e w f o u n d l a n d . I am i n d e b t e d t o t w i c e t h e number o f p e o p l e a g r a d u a t e s t u d e n t u s u a l l y i s : t h e members o f t h e two MS a n d NMR l a b o r a t o r i e s , a n d i n a d d i t i o n t h e U n i v e r s i t y o f A l b e r t a f o r t w o NMR s p e c t r a . I t h a n k t h e p o s t - d o c t o r a l f e l l o w s , g r a d u a t e s t u d e n t s , D r s . S . J . A l w a r d a n d J . F . K i n g s t o n f o r t h e i r own s p e c i a l human a n d s c i e n t i f i c " c o n t r i b u t i o n s " d u r i n g t h i s t h e s i s . D r s . C. B a y l y a n d P. D e s l o n g c h a m p s f r o m t h e U n i v e r s i t y d e S h e r b r o o k e f o r m o l e c u l a r m e c h a n i c s c a l c u l a t i o n s . I w o u l d e s p e c i a l l y l i k e t o t h a n k my t w o s u p e r v i s o r s , D r . R . J . A n d e r s e n a t UBC, a n d D r . A.G. F a l l i s a t MUN, who a l l o w e d s u c h a n i n c o n v e n i e n t a r r a n g e m e n t t o t a k e p l a c e , f o r t h e i r u n d e r s t a n d i n g , a d v i c e a n d h e l p t h r o u g h o u t t h i s w o r k . W i t h o u t t h e s u p p o r t o f my h u s b a n d who knew how t o p u t p r o b l e m s b a c k i n t o p e r s p e c t i v e , t h i s r e s e a r c h w o u l d n o t h a v e t a k e n p l a c e . L a s t a n d c e r t a i n l y n o t l e a s t , M i s s T e r e s a B a r k e r f o r h e r c o n t i n u o u s h e l p w i t h t y p i n g t h i s t h e s i s o v e r a n d o v e r a g a i n ! - 1 -Chapter 1  Onchidoris bilamellata 1.1. Introduction^ This chapter describes the isolation and identification of a sphingolipid 1_ from Onchidoris bilamellata, a nudibranch collected in British Columbia. A short introduction to the biology of nudibranchs, preceeds an outline of the chemical aspects in the study of opisthobranch molluscs. Some examples of metabolites isolated from opisthobranch molluscs with novel structures and interesting biological properties are included. The work related to the identification of sphingolipid 1_ obtained from methanolic skin extracts of 0. bilamellata is then presented. This is followed by a discussion of the chemistry, biochemistry and biology of molecules related to 1. The phyllum Mollusca contains the second largest number of invertebrate species. Gastropoda represents its major class (see Scheme 1), with specimens found in a large variety of marine and terrestrial habitats. Members of this class have an asymmetric body and only one shell (univalve). Scheme 1 C l a s s i f i c a t i o n o f t h e P h y l l u m M o l l u s c a P h y l l u m M o l l u s c a C l a s s A m p h i n e u r a B i v a l v i a G a s t r o p o d a C e p h a l a s p i d e a S c a p h o p o d a S u b c l a s s O p i s t h o b r a n c h i a P r o s o b r a n c h i a P u l m o n a t a -I T~ - T 1 1 1 O r d e r S a c o g l o s s a N u d i b r a n c h i a C e p h a l o s p i d e a S u b o r d e r A r m i n a c e a D e n d r o n o t a c e a D o r i d a c e a E o l i d a c e a ( G e n u s ) ro N.B. O r g a n i s m s a r e c l a s s i f i e d a c c o r d i n g t o K o z l o f f - 3 -One o f t h e t h r e e s u b c l a s s e s o f g a s t r o p o d s i s t h e O p i s t h o b r a n c h i a , w i t h m a i n l y m a r i n e members c h a r a c t e r i z e d b y a s h e l l a n d m a n t l e c a v i t y r e d u c e d i n s i z e o r a b s e n t . T h e O p i s t h o b r a n c h i a c a n be f u r t h e r s u b d i v i d e d i n t o e i g h t o r d e r s , , i n c l u d i n g : S a c o g l o s s a , N u d i b r a n c h i a a n d C e p h a l o s p i d e a . I n t h e o r d e r N u d i b r a n c h i a ( n u d i b r a n c h s a r e a l s o known a s s e a s l u g s o r n a k e d s h e l l f i s h ) t h e a n i m a l s h a v e no s h e l l o r m a n t l e c a v i t y a n d a s i n d i c a t e d by t h e i r name, do n o t h a v e i n t e r n a l g i l l s . T h e i r b o d y a s s u m e s a n e l o n g a t e d f o r m w i t h a b i l a t e r a l s y m m e t r y . Among t h e N u d i b r a n c h i a , members o f t h e s u b o r d e r D o r i d a c e a e a r e c h a r a c t e r i z e d b y t h e p r e s e n c e o f a s e c o n d a r y g i l l r i n g e n c i r c l i n g t h e d o r s a l a n u s . F i g u r e 1 s h o w s a d o r s a l v i e w o f a d o r i d n u d i b r a n c h . Members o f t h i s s u b o r d e r v a r y f r o m 1 t o 12 cm i n l e n g t h a n d f r o m 0.5 t o 3 cm i n t h i c k n e s s . T h e i r c o l o r r a n g e s f r o m w h i t e t o n u m e r o u s s h a d e s o f y e l l o w a n d o r a n g e , o f t e n w i t h some p a r t i c u l a r c o l o r p a t t e r n ( " s p o t s " ) on t h e i r m a n t l e . T h e y a r e f o u n d on r o c k y s u r f a c e s f r o m t h e s h o r e l i n e up t o d e p t h s o f m o r e t h a n 18 m. A s p e c i a l m o r p h o l o g i c a l f e a t u r e w o r t h m e n t i o n i n g i s t h e two r h i n o p h o r e s , w h i c h r e p r e s e n t m o d i f i e d t e n t a c l e s u s e d a s s e n s e o r g a n s . E x p e r i m e n t s h a v e shown t h a t r h i n o p h o r e s a r e t h e m o s t l i k e l y s i t e f o r c h e m o r e c e p t i o n i n 3 n u d i b r a n c h s . tubercules mantle gills rhinophores F i g u r e 1 D o r s a l V i e w o f a D o r i d N u d i b r a n c h - 4 -N u d i b r a n c h s a r e s l o w - m o v i n g o r g a n i s m s w i t h o u t a n e x t e r i o r s h e l l a n d w i t h no o t h e r o b v i o u s p r o t e c t i v e f e a t u r e . F o u r g r o u p s o f a n i m a l s h a v e b e e n 5 s u g g e s t e d a s p o s s i b l e p r e d a t o r s : o t h e r o p i s t h o b r a n c h s , c r u s t a c e a n s , s e a s t a r s a n d f i s h . The f a c t t h a t n u d i b r a n c h s a v o i d d i r e c t p r e d a t i o n has r a i s e d i n t e r e s t among b i o l o g i s t s . 5 L.G. H a r r i s h a s r e v i e w e d t h e r e s u l t s o f s e v e r a l s t u d i e s c o n c e r n i n g n u d i b r a n c h d e f e n s i v e m e c h a n i s m s . He g r o u p e d them i n t o f i v e c a t e g o r i e s , as f o l l o w s : 1) B e h a v i o r a l r e s p o n s e 2) S p i c u l e s 3) N e m a t o c y s t s 4) C o l o r c a m o u f l a g e 5) C h e m i c a l s e c r e t i o n s E x p e r i m e n t s h a v e shown t h a t u p o n d i s t u r b a n c e , t h e b e h a v i o r o f n u d i b r a n c h s i s a l t e r e d . I m m e d i a t e r e t r a c t i o n o f r h i n o p h o r e s a n d g i l l s a n d s o m e t i m e s s w i m m i n g c a n be o b s e r v e d ^ . A l t h o u g h t h i s i s a r e s p o n s e t o b e i n g a t t a c k e d , i t d o e s n o t e x p l a i n t h e a b i l i t y o f n u d i b r a n c h s t o s u r v i v e s i n c e t h e i r e s c a p e i s u s u a l l y s l o w i n c o m p a r i s o n t o t h e p r e d a t o r ' s s p e e d . S p i c u l e s o f a c a l c a r e o u s n a t u r e a r e p r e s e n t i n t h e m a n t l e o f some d o r i d s p e c i e s . P a i n e ^ p o s t u l a t e d t h a t t h e s e g i v e t h e n u d i b r a n c h s a r a t h e r r i g i d s h a p e a n d make t h e m d i f f i c u l t f o r o t h e r o p i s t h o b r a n c h s t o s w a l l o w . N e m a t o c y s t s a r e c e l l s c o n t a i n i n g s t i n g i n g s t r u c t u r e s o r i g i n a t i n g f r o m i n g e s t e d c o e l e n t e r a t e s . S t o r e d by some n u d i b r a n c h s , t h e y c a n be r e l e a s e d when t h e a n i m a l i s d i s t u r b e d ^ . D i f f e r e n t t y p e s o f n e m a t o c y s t e x i s t a n d some n u d i b r a n c h s a p p e a r t o s e l e c t t h e t y p e t h e y s t o r e . I t i s b e l i e v e d t h a t some t y p e s o f n e m a t o c y s t a r e m o r e e f f e c t i v e a g a i n s t c e r t a i n p r e d a t o r s . Of t h e - 5 -f o u r n u d i b r a n c h s u b o r d e r s , o n l y t h r e e a r e known t o f e e d o n c o e l e n t e r a t e s ; t h e E o l i d a c e a , D e n d r o n o t a c e a a n d A r m i n a c e a . D o r i d n u d i b r a n c h s f e e d 5 p r e d o m i n a n t l y on s p o n g e s , b r y o z o a n s a n d c o l o n i a l t u n i c a t e s a n d do n o t u t i l i z e n e m a t o c y s t s f o r d e f e n s e . C o l o r a t i o n may be i n t e r p r e t e d a s a c a m o u f l a g e i n some c a s e s ( w h i t e n u d i b r a n c h s on w h i t e c o r a l ) , o r a s a w a r n i n g i n t h e c a s e o f b r i g h t l y c o l o r e d n u d i b r a n c h s . O f t e n , t h e p i g m e n t a t i o n o f t h e n u d i b r a n c h v a r i e s w i t h i t s g d i e t . The a b i l i t y o f f i s h t o p e r c e i v e c o l o r i s s t i l l u n c e r t a i n a n d i n f o r m a t i o n on o t h e r p r e d a t o r s i s l a c k i n g . H e n c e , a s p e c t s o f t h i s d e f e n s i v e m e c h a n i s m r e m a i n t o be i n v e s t i g a t e d . T h e f i n a l a n d m o s t i n t e r e s t i n g means o f p r o t e c t i o n f r o m a c h e m i s t ' s p o i n t o f v i e w a r e t h e s e c r e t i o n s e m a n a t i n g f r o m e p i d e r m a l g l a n d s . T h e s e s e c r e t i o n s a r e d e s i g n a t e d a s d e f e n s i v e b e c a u s e t h e y a r e u s u a l l y e m i t t e d when t h e a n i m a l i s d i s t u r b e d . I t was r e p o r t e d i n t h e e a r l y l i t e r a t u r e t h a t t h e s e c r e t i o n s f r o m e o l i d n u d i b r a n c h s m i g h t be s t r o n g a c i d s s u c h a s HC1 a n d ^ 2 ^ 4 ^ ' Re c e n tl y > i t h a s b e e n shown t h a t o r g a n i c m o l e c u l e s w i t h i n t e r e s t i n g 8 11 s t r u c t u r e s a r e s e c r e t e d b y some s p e c i e s ' . I n some c a s e s t h e d e f e n s i v e Q m o l e c u l e s a r e r e l a t e d t o a d i e t a r y s o u r c e . A c r i t i c a l s t u d y o f t h e r e l a t i v e i m p o r t a n c e o f t h e d i f f e r e n t d e f e n s i v e m e c h a n i s m s i n n u d i b r a n c h s i s d i f f i c u l t d ue t o t h e l i m i t e d a m o u n t o f i n f o r m a t i o n a v a i l a b l e c o n c e r n i n g p r e d a t o r - p r e y i n t e r a c t i o n s . H o w e v e r , i t seems v e r y l i k e l y t h a t c h e m i c a l s e c r e t i o n s may p l a y an i m p o r t a n t d e f e n s i v e r o l e . I t m u s t be s t a t e d t h a t s u c h d e f e n s i v e s u b s t a n c e s h a v e n o t b e e n u n e q u i v o c a l l y p r o v e n t o e x i s t i n n u d i b r a n c h s . H o w e v e r , on t h e b a s i s o f 12 s t u d i e s i n v o l v i n g o t h e r o r g a n i s m s s u c h a s a r t h r o p o d s , i t w o u l d be l o g i c a l t o h y p o t h e s i z e t h a t d e f e n s i v e s e c r e t i o n s a r e a l s o o p e r a t i v e i n n u d i b r a n c h s . - 6 -R e s e a r c h i n m a r i n e n a t u r a l p r o d u c t s c h e m i s t r y h a s made s i g n i f i c a n t a d v a n c e s i n t h e l a s t t e n y e a r s . The f i r s t b o o k t o a p p e a r i n t h i s f i e l d was 13 . • e d i t e d b y P . J . S c h e u e r i n 1 9 7 3 , w h i l e o n e o f t h e f i r s t r e v i e w p a p e r s was 14 w r i t t e n i n 1974 by D . J . F a u l k n e r a n d R . J . A n d e r s e n . S i n c e t h e n , many o t h e r r e v i e w p a p e r s , s y m p o s i a p r o c e e d i n g s a n d s t r u c t u r a l p a p e r s h a v e b e e n p u b l i s h e d . Among t h e s e , t wo r e v i e w s d e a l w i t h t h e c h e m i s t r y o f t h e m o l l u s c s i n g e n e r a l ^5' ^6, a n d w i t h t h e o p i s t h o b r a n c h m o l l u s c s i n p a r t i c u l a r ^7. The f o l l o w i n g e x a m p l e s i l l u s t r a t e t h e v a r i e t y o f n o v e l s t r u c t u r e s a n d b i o l o g i c a l p r o p e r t i e s t h a t h a v e b e e n a s s i g n e d t o compounds i s o l a t e d f r o m o p i s t h o b r a n c h m o l l u s c s . The r e a r r a n g e d t e r p e n o i d 9 - i s o c y a n o p u p u k e a n a n e ( 2 J was i s o l a t e d f r o m b o t h t h e n u d i b r a n c h P h y l l i d i a v a r i c o s a a n d i t s p r e y , a s p o n g e f r o m t h e o H y m e n i a c i d o n s p . . The n u d i b r a n c h was known t o p r o d u c e a s m e l l y s u b s t a n c e l e t h a l t o s m a l l f i s h a n d c r u s t a c e a n s . A l l o m o n e 2_ was shown t o h a v e a 1 g c e r t a i n s p e c i f i c i t y i n k i l l i n g s m a l l c r u s t a c e a n s A n o v e l s t e r o i d a l k e t o n e 3_ i s o l a t e d f r o m A l d i s a s a n g u i n a c o o p e r i 19 s h o w s a n t i f e e d a n t a c t i v i t y i n a s t a n d a r d g o l d f i s h b i o a s s a y . I t i s b e l i e v e d t h a t t h e d o r i d n u d i b r a n c h o b t a i n s a n i n a c t i v e m e t a b o l i t e f r o m i t s prey, the sponge Anthoarcurata qracea, and modifies i t to produce the two steroidal ketones 3 and 4. Doridosine (5_), the first purine base isolated from a nudibranch, produces hypotension, bradycardia, coronary dilation and relaxation of smooth muscle in mammals for many hours. (Other analogs act for only a few minutes.) This new hypotensive N-methyl purine riboside 5_ has been isolated from the aqueous extract of the digestive glands of Anisodoris nobilis. R H H O O H 5 Navanax inermis of the order Cephalospidea is known to be a voracious 21 predator on other opisthobranch molluscs . It locates its prey by contact chemoreception. N. inermis recognizes the mucus trail of an acceptable prey - 8 -and f o l l o w s i t t o i t s s o u r c e . N. i n e r m i s a l s o p r o d u c e s a " t r a i l - b r e a k i n g p h e r o m o n e " . When s e c r e t e d b y a n i n d i v i d u a l , t h i s p h e r o m o n e c a u s e s a n i n d i v i d u a l o f t h e same s p e c i e s t o t u r n away f r o m t h e mucus t r a i l i t i s f o l l o w i n g a t a n a n g l e g r e a t e r t h a n 9 0 ° . N a v e n o n e s A ( 6 J , B ( 7 J a n d C ( 8 ) h a v e b e e n e x t r a c t e d f r o m t h e c o l o r e d s e c r e t i o n e m i t t e d when t h e a n i m a l s a r e i r r i t a t e d . When p r e s e n t i n a 4:2:1 m i x t u r e ( r a t i o f o u n d i n t h e e x t r a c t ) t h e y e l i c i t t h e t r a i 1 - b r e a k i n g r e s p o n s e . Many o t h e r s t r u c t u r a l l y i n t e r e s t i n g m o l e c u l e s h a v e b e e n i s o l a t e d f r o m t h e s k i n e x t r a c t s o r t h e d i g e s t i v e g l a n d e x t r a c t s o f t h e o p i s t h o b r a n c h m o l l u s c s . - 9 -1.2. R e s u l t s A s p a r t o f a p r o g r a m a i m e d a t s t u d y i n g t h e c h e m i s t r y o f B r i t i s h C o l u m b i a n u d i b r a n c h s , we h a v e e x a m i n e d O n c h i d o r i s b i l a m e l l a t a . I n t e r e s t i n t h i s o r g a n i s m a r o s e when we n o t i c e d t h a t t h e m e t h a n o l i c e x t r a c t o f t h i s s p e c i e s p o s s e s s e s a n t i b a c t e r i a l a c t i v i t y t o w a r d s t h e m i c r o o r g a n i s m s B a c i l l u s s u b t i l i s a n d S t a p h y l o c o c c u s a u r e u s . T h e r e a r e o n l y t w o s t u d i e s d i r e c t l y r e l a t e d t o 0 . b i l a m e l l a t a i n t h e 22 b i o l o g i c a l o r c h e m i c a l l i t e r a t u r e . T h e f i r s t i s c o n c e r n e d w i t h t h e p o p u l a t i o n e c o l o g y o f 0 . b i l a m e l l a t a i n R o b i n H o o d ' s B a y , E n g l a n d . The 23 s e c o n d s t u d y i s r e l a t e d t o t h e " e f f e c t s o f a r o m a t i c p e t r o l e u m h y d r o c a r b o n s on t h e c h e m o s e n s o r y b e h a v i o r o f 0 . b i l a m e l l a t a " , a n d i t was d o n e a t t h e U n i v e r s i t y o f W a s h i n g t o n , S e a t t l e . 4 " O n c h i d o r i s b i l a m e l l a t a i s c l a s s i f i e d a s f o l l o w s : P h y l l u m : M o l l u s c a C l a s s : G a s t r o p o d a S u b c l a s s : O p i s t h o b r a n c h i a O r d e r : N u d i b r a n c h i a S u b o r d e r : D o r i d a c e a S p e c i m e n s o f 0 . b i l a m e l l a t a w e r e c o l l e c t e d by h a n d , f r o m t h e s o u t h s h o r e o f E n g l i s h B a y , V a n c o u v e r , a t l o w t i d e d u r i n g t h e p e r i o d s November 1979 t o May 1980 a n d F e b r u a r y 1981 t o May 1 9 8 1 . T h e s e a b u n d a n t i n t e r t i d a l o r g a n i s m s w e r e u s u a l l y f o u n d on t h e u n d e r s i d e s o f r o c k s , e s p e c i a l l y w h e r e t h e b a r n a c l e s u p o n w h i c h t h e y f e e d a r e p r e s e n t . The n u d i b r a n c h s , w h i c h v a r y i n c o l o u r f r o m b e i g e - t a n t o b r o w n ( p r e s e n t i n b a n d s ) , h a v e a n a v e r a g e s i z e o f 1 cm a n d an a v e r a g e d r y w e i g h t o f 75 mg. F o l l o w i n g c o l l e c t i o n , t h e n u d i b r a n c h s w e r e s t o r e d i n m e t h a n o l a t -35°C f o r s e v e r a l w e e k s . A f t e r t h a w i n g , t h e s u p e r n a t a n t was f i l t e r e d , e v a p o r a t e d - 10 -t o o n e h a l f o f t h e o r i g i n a l v o l u m e a n d p a r t i t i o n e d b e t w e e n b r i n e a n d e t h y l a c e t a t e . A f t e r d r y i n g t h e o r g a n i c e x t r a c t a n d e v a p o r a t i o n o f t h e s o l v e n t , t h e o i l y r e s i d u e was p u r i f i e d by s i l i c a c o l u m n c h r o m a t o g r a p h y . E l u t i o n o f t h e a c t i v e f r a c t i o n f r o m t h e c o l u m n was f a c i l i t a t e d by a g r a d i e n t o f i n c r e a s i n g s o l v e n t p o l a r i t y . The f r a c t i o n s o b t a i n e d w e r e s c r e e n e d f o r a n t i b a c t e r i a l a c t i v i t y . The f r a c t i o n s w h i c h g a v e a p o s i t i v e r e s u l t w e r e f u r t h e r p u r i f i e d b y p r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y ( P T L C ) . C e r a m i d e 1_, w i t h a f r e e p r i m a r y a l c o h o l h a s b e e n i s o l a t e d f r o m 0 . b i l a m e l l a t a a n d i s r e s p o n s i b l e f o r t h e a n t i b a c t e r i a l a c t i v i t y . By means o f s p e c t r a l a n a l y s i s a n d c h e m i c a l c o r r e l a t i o n s , t h e l o n g c h a i n b a s e h a s b e e n c h a r a c t e r i z e d a s ( E ) - l , 3 - d i h y d r o x y - 2 - a m i n o - 1 6 - m e t h y l - 4 - o c t a d e c e n e ( 1 3 ) a n d t h e f a t t y a c i d m o i e t y a s p a l m i t i c a c i d ( 1 2 ) . 12 Ri 1 H 9 C O C H 13 H C H 3 ( C H , ) C O O H C 0 ( C H , ) u C H 3 C0 ( C H 2 ) C H , H A p p r o m i x a t e l y 20 mg o f 1_ was o b t a i n e d f r o m 1 200 t o 1 5 0 0 n u d i b r a n c h s ( y i e l d = 0 . 0 2 % o f d r y w e i g h t o f a n i m a l s ) . - n -The MS ( F i g u r e 4 ) o f 1_ g i v e s a p a r e n t i o n o f weak i n t e n s i t y a t m/z = 5 3 3 . 5 1 7 3 ( E x a c t M a s s c a l c u l a t e d 5 3 3 . 5 1 5 5 ) c o r r e s p o n d i n g t o t h e m o l e c u l a r f o r m u l a C ^ H g ^ O , , . A f r a g m e n t r e s u l t i n g f r o m t h e l o s s o f r^O a t m/z 515 i s o b s e r v e d . The MS o f t h e d i a c e t y l a t e d d e r i v a t i v e 9 ( F i g u r e 7) d i s p l a y s a m o l e c u l a r i o n a t m/z = 635.5481 ( E x a c t Mass c a l c u l a t e d 6 3 5 . 5 4 7 0 ) c o r r e s p o n d i n g t o ^ 3 9 ^ 7 3 ^ 5 a n c' fr a9m e nts r e s u l t i n g f r o m t h e l o s s o f two r e s i d u e s o f a c e t i c a c i d a t m/z = 575 a n d 5 1 5 . The l a t t e r r e s u l t i n d i c a t e d t h a t t h e m o l e c u l a r f o r m u l a o f t h e p a r e n t c o m p o u n d 1_ was t h e r e f o r e CggHggNO^ a n d t h a t t h e m o l e c u l a r i o n was n o t a c t u a l l y o b s e r v e d i n t h e MS. H e n c e , t h e i s o l a t e d m o l e c u l e h a s two s i t e s o f u n s a t u r a t i o n a n d t w o a l c o h o l f u n c t i o n a l i t i e s . A m a j o r i o n o b s e r v e d i n t h e MS o f b o t h . ] _ a n d 9_ ( F i g u r e s 4 a n d 7) a t m/z = 2 8 0 ( Cl gH3 4N 0 ) r e s u l t s f r o m an a l l y l i c c l e a v a g e b e t w e e n C ( 2 ) - C ( 3 ) f o l l o w e d b y e l i m i n a t i o n o f HgO, t o g i v e 1CJ. A f r a g m e n t a t m/z 2 9 8 r e s u l t i n g f r o m t h i s a l l y l i c c l e a v a g e b e f o r e t h e l o s s o f H~0 i s a l s o p r e s e n t . 0 10 The IR s p e c t r a o f c e r a m i d e 1 a n d i t s d i a c e t y l a t e d d e r i v a t i v e 9_ ( F i g u r e s 3 a n d 6) show a b s o r p t i o n s a t 3 4 0 0 a n d 1660 c m "1, c o r r e s p o n d i n g t o an a m i d e f u n c t i o n a l i t y , w h i c h a c c o u n t s f o r o n e d e g r e e o f u n s a t u r a t i o n . The u p f i e l d r e g i o n o f t h e 'H NMR s p e c t r u m o f 1_ ( F i g u r e 2 , T a b l e 1) i n d i c a t e d t h e p r e s e n c e o f : two p r i m a r y m e t h y l g r o u p s ( a t 6 = 0 . 8 6 , 0.89 ppm, t w o t r i p l e t s , J = 7 H z ) ; a s e c o n d a r y m e t h y l g r o u p ( a t 6 = 0.85 ppm, d o u b l e t , J = 7 Hz) a n d a s t r a i g h t c h a i n h y d r o c a r b o n . P r o t o n - p r o t o n s p i n d e c o u p l i n g e x p e r i m e n t s ( T a b l e 2 ) p e r f o r m e d by i r r a d i a t i n g t h e s i g n a l s r e s o n a t i n g b e t w e e n 6 = 3.5 a n d 6.0 ppm a n d i n t e g r a t i n g f o r s e v e n p r o t o n s , s u g g e s t e d t h e p r e s e n c e o f p a r t i a l s t r u c t u r e 1_1_ i n t h e m o l e c u l e . T h e r e f o r e p a r t i a l s t r u c t u r e ]_]_ a c c o u n t s f o r t h e s e c o n d d e g r e e o f u n s a t u r a t i o n ( a t r a n s d o u b l e b o n d ) a n d f o r t h e r e l a t i v e p o s i t i o n o f t h e two a l c o h o l f u n c t i o n a l i t i e s . A SF0RD C NMR s p e c t r u m ( T a b l e 3) o f 1_ c o n f i r m e d t h e p r e s e n c e o f a n a m i d e , a 1 , 2 - d i s u b s t i t u t e d d o u b l e b o n d a n d o f two c a r b o n s a t t a c h e d t o o x y g e n a t o m s . C o m p a r i s o n o f t h e c h e m i c a l s h i f t v a l u e s o f t h e t h r e e m e t h y l c a r b o n s ( 1 3 . 7 ppm f o r C - 1 6 , 1 0 . 8 ppm f o r C - 1 8 , 1 8 . 8 ppm f o r C-19) w i t h t h o s e 24 i n t h e l i t e r a t u r e f o r n_-decane ( 1 3 . 9 ppm) a n d 3 - m e t h y l h e p t a n e ( 1 1 . 3 ppm f o r C - l , 1 9 . 3 ppm f o r C-8) s h o w e d t h a t o n e e n d o f t h e m o l e c u l e c o n s i s t e d o f an u n b r a n c h e d c h a i n , w h i l e t h e o t h e r h a d a m e t h y l a t t h e a n t e i s o p o s i t i o n ( - C H ( C H3) C H2C H3) . - 13 -H on C# 2H-1 1H-2 1H-3 1H-4 1H-5 2H-6 ( C H2)p 2 ' 16* 18* 19 NH NHC0CH3* OCOCH3* T a b l e 1 4 0 0 MHz 'H NMR S p e c t r a l D a t a C e r a m i d e 1_ d i a c e t y l a t e d d e r i v a t i v e 9 3.93 (m) 3.71 (m) 4 . 3 3 (m) 5.53 ( d d , 1 5 , 7 ) 5.79 ( d t , 1 5 , 7 ) 2.06 ( q , 7 ) 1.26 ( s ) 2.23 ( t , 8 ) 0.86 ( t , 7 ) 0 . 8 9 ( t , 7 ) 0 . 8 5 ( d , 7 ) 6.24 ( b d , 9 ) 4.05 ( d d , 4 . 5 , 1 2 ) 4.32 ( d d , 6 , 1 2 ) 4.49 (m) 5.30 ( t , 7 ) 5.40 ( d d , 1 5 , 7 ) 5.82 ( d t , 1 5 , 7 ) 2.06 ( q , 7 ) 1.26 ( s ) 2.12 ( t , 8 ) 0.86 ( t , 7 ) 0 . 8 8 ( t , 7 ) 0.85 ( d , 7 ) 5.63 ( b d , 9 ) t r i a c e t y l a t e d d e r i v a t i v e ]3_ 4.05 ( d d , 4 . 5 , 1 2 ) 4.31 ( d d , 6 , 1 2 ) 4 . 4 4 (m) 5.28 ( t , 7 ) 5.39 ( d d , 1 5 , 7 ) 5.80 ( d t , 1 5 , 7 ) 1.26 ( s ) 0 . 8 8 ( t , 7 ) 0 . 8 5 ( d , 7 ) 5.66 ( b d , 9 ) 2.00 ( s ) 2.06 ( s ) 2.07 ( s ) * i n t e r c h a n g e a b l e Numbers r e p r e s e n t t h e c h e m i c a l s h i f t s 6 ( p p m ) . M u l t i p l i c i t i e s a n d c o u p l c o n s t a n t s ( H z ) a r e i n p a r a n t h e s e s . - 14 -T a b l e 2 P r o t o n - P r o t o n S p i n D e c o u p l i n g E x p e r i m e n t P e r f o r m e d on D i a c e t y l a t e d D e r i v a t i v e 9_ 6 a 5.82 5.63 Jb ( d t , 1 5 , 7 ) ( b d , 9 ) Ic " Dd D E E X D I D dm C P 0 E U R ( t , 7 ) D I D P L 'I 1 M D I D N E G T ( s ) ( d , 7 ) I D ( d , 1 2 ) S D I D ( b d d , D I 8,6) a . c h e m i c a l s h i f t o f o r i g i n a l s p e c t r u m ( i n ppm) b . o r i g i n a l m u l t i p l i c i t y o b s e r v e d , c o u p l i n g c o n s t a n t s i n H e r t z c . i r r a d i a t e d s i g n a l d . i n d i c a t e s d i s t o r t e d s i g n a l due t o p r o x i m i t y t o t h e i r r a d i a t e d s i g n a l o n t h e c h e m i c a l s h i f t s c a l e o r due t o a r e a l c o u p l i n g 5.40 5.30 4.49 4.32 4.05 2.06 ( d d , 1 5 , 7 ) ( t , 7 ) (m) ( d d , 6 , 1 2 ) ( d d , 4 . 5 , 1 2 ) ( q , 7 ) ( d.7) D - 15 -Table 3 100.1 MHz 1 3 C NMR Spectral Data for Ceramide 1 C # 6 (multiplicity) 1 61.9 (t) 2 53.8 (d) 3 74.0 (d) 4* 133.5 (d) 5* 128.8 (d) 6+ 31.6 (t) r 172.3 (s) 2 , t 36.3 (t) 16' 13.7 (q) 16 33.8 (d) 18 10.8 (q) 19 18.8 (q) interchangeable - 16 -I n o r d e r t o d e t e r m i n e t h e number o f c a r b o n a t o m s on e a c h s i d e o f t h e a m i d e f u n c t i o n a n d t h e l o c a t i o n o f t h e s e c o n d a r y m e t h y l , a h y d r o l y s i s r e a c t i o n a n d o z o n o l y s i s r e a c t i o n w e r e p e r f o r m e d . The h y d r o l y s i s c a r r i e d o u t u n d e r b a s i c c o n d i t i o n s c l e a v e d t h e m o l e c u l e i n t o a C-16 s t r a i g h t c h a i n f a t t y a c i d , 1_2 a n d a C-19 l o n g c h a i n u n i t p o s s e s s i n g t h e a n t e i s o m e t h y l , 1_3. The l o n g c h a i n b a s e was a c e t y l a t e d a n d t h e t r i a c e t y l d e r i v a t i v e ]_4_ c h a r a c t e r i z e d ( M S , I R , 'H NMR). The p r o d u c t s o f t h e r e d u c t i v e o z o n o l y s i s r e a c t i o n w e r e i s o l a t e d a s t h e i r 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e d e r i v a t i v e s , w i t h m o l e c u l a r f o r m u l a s o f ^ 2 1 ^ 3 4 ^ 4 ^ 4 ^o r — a n c' ^ 2 6 ^ 4 3 ^ 5 ^ 7 f o r 1_6. T h i s e x p e r i m e n t c o n f i r m e d t h e p o s i t i o n o f t h e d o u b l e b o n d , by s h o w i n g t h e p r e s e n c e o f a C-15 u n i t on o n e s i d e a n d a C-20 u n i t a n d r e m a i n i n g h e t e r o - a t o m s on t h e o t h e r s i d e . Scheme 2 R e a c t i o n s P e r f o r m e d on C e r a m i d e 1 NO 1 R, = H , R2=C0(CH2)CH3 U K 1 | NaOH /MeOH ^ 13 R1,R2 = H 12 CrL(CH 14 R,,R2 = C0CH3 - 17 -To a s c e r t a i n w h e t h e r t h e p r i m a r y a l c o h o l o f c e r a m i d e 1_ was an a r t i f a c t o f t h e i s o l a t i o n p r o c e d u r e , t h e e x t r a c t i o n o f o n e h u n d r e d a n d f i f t y n u d i b r a n c h s was p e r f o r m e d w i t h i n t e n m i n u t e s o f t h e i r c o l l e c t i o n ( s e e E x p e r i m e n t a l ) . A f t e r a c e t y l a t i o n a n d p u r i f i c a t i o n o f t h e c r u d e e x t r a c t , 2 mg o f a d i a c e t y l a t e d compound i d e n t i c a l t o 9_ ( C o - T L C a n d 'H NMR) was i s o l a t e d . T h i s y i e l d ( 0 . 0 1 5 % o f d r y w e i g h t ) i s v e r y s i m i l a r t o t h e one o b t a i n e d when t h e n u d i b r a n c h s w e r e s t o r e d i n m e t h a n o l a t -35°C f o r s e v e r a l w e e k s b e f o r e e x t r a c t i o n ( 0 . 0 2 % o f d r y w e i g h t ) . 25 29 I t i s known f r o m t h e l i t e r a t u r e ' t h a t 12 h i s n e e d e d t o h y d r o l y z e c e r e b r o s i d e s a n d g l y c o l i p i d s u n d e r a c i d i c c o n d i t i o n s : 1M H C l / M e 0 H / 1 0 0° C ; a n d 2 h t o h y d r o l y z e s p h i n g o m y e l i n s u n d e r a c i d i c c o n d i t i o n s : 2M H C 1 / 1 0 0° C , o r 20 m i n u n d e r b a s i c c o n d i t i o n s : 1M N a 0 H / M e 0 H / 3 7° C . I t seems s a f e t o a s s u m e t h a t c e r a m i d e 1_ o b t a i n e d f r o m t h e s k i n e x t r a c t s o f 0 . b i l a m e ! l a t a , e x i s t s w i t h a f r e e p r i m a r y a l c o h o l . I n o r d e r t o l e a r n m o r e a b o u t t h e b i o l i g i c a l r o l e o f c e r a m i d e 1_, we 38 p e r f o r m e d an a n t i f e e d a n t a c t i v i t y t e s t . The r e s p o n s e o f t h e f i s h t o f o o d p e l l e t s c o v e r e d w i t h X d o e s n o t e n c o u r a g e us t o b e l i e v e t h a t s p h i n g o l i p i d 1_ i s u s e d f o r c h e m i c a l d e f e n s e p u r p o s e s t o w a r d s f i s h . H o w e v e r , t h i s r e s u l t i s maybe n o t s o s u r p r i s i n g s i n c e 0 . b i l a m e l l a t a i s an i n t e r t i d a l o r g a n i s m , l i v i n g u n d e r t h e s u r f a c e o f r o c k s , w h e r e m a i n l y c r u s t a c e a n s a r e p r e s e n t . U n f o r t u n a t e l y , n o t e n o u g h s a m p l e o f 1_ was a v a i l a b l e t o p e r f o r m t e s t s on s m a l l c r a b s a n d c r u s t a c e a n s f o u n d i n t h e n a t u r a l e n v i r o n m e n t o f O n c h i d o r i s b i l a m e l l a t a . - 18 -1.3. D i s c u s s i o n The m o l e c u l e r e s p o n s i b l e f o r t h e a n t i b a c t e r i a l a c t i v i t y o f t h e o r g a n i c s k i n e x t r a c t o f t h e n u d i b r a n c h O n c h i d o r i s b i l a m e l l a t a b e l o n g s t o a c l a s s o f m o l e c u l e s c a l l e d s p h i n g o l i p i d s . T e r r e s t r i a l a n i m a l s a n d p l a n t s h a v e b e e n t h e s o u r c e o f a w i d e v a r i e t y pc pc o f s p h i n g o l i p i d s ' . I n a n i m a l s , t h e s e l i p i d s d e r i v e m a i n l y f r o m s p h i n g o s i n e ( 1 7 _ ) , w h i l e i n p l a n t s , d e r i v a t i v e s o f p h y t o s p h i n g o s i n e ( 1 8 ) p r e d o m i n a t e . The i s o l a t e d c e r a m i d e s a r e N - a c y l d e r i v a t i v e s o f 1_7 a n d 1_8 o r r e l a t e d m o l e c u l e s . O f t e n , a m o n o s a c c h a r i d e ( c e r e b r o s i d e ) , a c o m p l e x g l y c o s i d e ( g a n g l i o s i d e ) o r a p h o s p h a t e e s t e r ( s p h i n g o m y e l i n ) i s a t t a c h e d t o t h e p r i m a r y a l c o h o l . T h e r e h a v e b e e n f e w i n v e s t i g a t i o n s o f s p h i n g o l i p i d s f r o m m a r i n e o r g a n i s m s . N e v e r t h e l e s s , a v a r i e t y o f s t r u c t u r e s h a v e b e e n f o u n d as i l l u s t r a t e d b y t h e f o l l o w i n g e x a m p l e s . The c e r a m i d e a m i n o e t h y l p h o s p h o n a t e s 19 a n d 20 h a v e b e e n i s o l a t e d f r o m t h e s e a anemones A n t h o p l e u r a 27 28 e l e g a n t i s s i m a a n d M e t r i d i u m s e n i l e r e s p e c t i v e l y . V a r i o u s c e r e b r o s i d e s w i t h t w e n t y two c a r b o n b a s e s w e r e o b t a i n e d f r o m t h e s e a s t a r A s t e r i a 29 r u b e n s . - 19 -C H^ C H2), CH3(CH2)7 O-P-CHfC H2-MH3 n = 13 to 18 0 u 0-P-CH2C H2NH3 nH2n+2 n= 13-15 Caulerpicin (21_) is a toxic constituent of the marine algae 30 Caulerpa sp. and aplidiasphingosine (22_) is an antimicrobial and anti-tumor terpenoid derivative of sphingosine isolated from a marine tunicate 31 of the Aplidium sp. . CH3(CH C_Q H = 2U-26 r 22 - 20 -The l o n g c h a i n b a s e 1_3 o f t h e s p h i n g o l i p i d i s o l a t e d f r o m O n c h i d o r i s b i l a m e l l a t a h a s b e e n p r e v i o u s l y i d e n t i f i e d a s b e i n g o n e o f 31 l o n g c h a i n 32 b a s e s o b t a i n e d f r o m b o v i n e m i l k . I n t h a t e x p e r i m e n t s p h i n g o m y e l i n s , p h o s p h o r o u s a n d c h o l i n e c o n t a i n i n g s p h i n g o l i p i d s o f t h e g e n e r a l f o r m u l a 2 3 , w e r e e x t r a c t e d f r o m b u t t e r m i l k p o w d e r . T h e s e w e r e h y d r o l y z e d t o t h e c o r r e s p o n d i n g c e r a m i d e s , w h i c h w e r e i n t u r n h y d r o g e n a t e d a n d t h e l a t t e r p r o d u c t r e h y d r o l y z e d i n t o f a t t y a c i d s a n d b a s e s . T h e s e b a s e s u n d e r w e n t a s o d i u m p e r i o d a t e o x i d a t i o n a n d t h e r e s u l t i n g a l d e h y d e s w e r e a n a l y z e d by G L C . T h e s e a l d e h y d e s w e r e r e d u c e d a n d t h e a l c o h o l s a l s o a n a l y z e d by G L C . - 21 -T h e b i o s y n t h e s i s o f t h e l o n g c h a i n f a t t y b a s e , s p h i n g o s i n e (1_7) > i s b e l i e v e d t o o c c u r a s shown i n Scheme 3 t h r o u g h t h e c o n d e n s a t i o n o f 33 p a l m i t a l d e h y d e w i t h t h e a m i n o a c i d s e r i n e . The s t e r e o c h e m i s t r y o f s p h i n g o s i n e h a s a l s o b e e n e s t a b l i s h e d . C a r b o n 2 ha s t h e D c o n f i g u r a t i o n , c a r b o n 3 h a s an e r y t h r o r e l a t i o n s h i p t o c a r b o n 2 , w h i l e t h e d o u b l e b o n d i s t h e E i s o m e r . Scheme 3 B i o s y n t h e s i s o f S p h i n g o l i p i d s P a l m i t i c a c i d C H3( C H2)1 4C 0 0 H f P a l m i t o y l CoA P a l m i t i c a l d e h y d e + s e r i n e D i h y d r o s p h i n g o s i n e C H3( C H2)1 4C H ( 0 H ) C H ( N H2) C H20 H t C H3( C H2)1 2C H : C H C H ( O H ) C H ( N H2) C H2O H S p h i n g o s i n e + f a t t y a c i d + R COS CoA C e r a m i d e s C H3( C H2)1 2C H : C H C H ( 0 H ) C H ( N H C 0 R ) C H20 H - 22 -S p h i n g o l i p i d s a r e known t o be l o c a t e d m a i n l y i n t h e u p p e r h a l f o f t h e 34 l i p i d b i l a y e r o f t h e s u r f a c e membranes o f c e l l s . I t h a s b e e n s u g g e s t e d t h a t t h e p r e s e n c e o f s p h i n g o l i p i d s i n t h e membrane makes i t more d e n s e , m o r e .. p e r m e a b l e t o b o t h p o l a r a n d n o n - p o l a r s u b s t a n c e s . S e v e r a l b i o l o g i c a l p r o p e r t i e s h a v e b e e n r e p o r t e d i n t h e l i t e r a t u r e . F o r e x a m p l e , s p h i n g o l i p i d s w i t h p o l a r h e a d g r o u p s c o m p o s e d o f c a r b o h y d r a t e s + 34 h a v e b e e n a s s o c i a t e d w i t h Na t r a n s p o r t i n c e l l s . S p h i n g o s i n e was f o u n d 35 t o i n h i b i t b l o o d c l o t t i n g , , w h i l e N - a c e t y l s p h i n g o s i n e a n d s p h i n g o m y e l i n s 3fi h a v e e f f e c t s s i m i l a r t o c o r t i s o n e i n g u i n e a p i g s , a n d g l y c o s p h i n g o l i p i d s 37 h a v e i m m u n o l o g i c a l a c t i v i t y . 29 I t h a s a l s o b e e n p o s t u l a t e d t h a t t h e d i f f e r e n c e i n t h e c o m p l e x i t y o f s p h i n g o l i p i d s e x t r a c t e d f r o m d i f f e r e n t s o u r c e s m i g h t i n d i c a t e t h e i r o r i g i n . O b t a i n i n g a c o m p l e x m i x t u r e , a s i n t h e c a s e o f s e a s t a r c e r e b r o s i d e s f o r e x a m p l e , w o u l d i n d i c a t e t h e i r o r i g i n f r o m a f u n c t i o n a l l y d i s p a r a t e o r g a n o r o r g a n i s m . A s i m p l e r m i x t u r e , h o w e v e r , a s i n t h e p r e s e n t s t u d y , w o u l d i n d i c a t e t h e i r o r i g i n f r o m a s i m p l e r s t r u c t u r e . F i g u r e 2 4 0 0 MHz 'H NMR S p e c t r u m o f C e r a m i d e 1 (CDCI3) F i g u r e 4 4 0 0 MHz 'H NMR S p e c t r u m o f D i a c e t y l a t e d D e r i v a t i v e 9 (CDCI3) - 26 -- 27 -C h a p t e r 2 N a n a i m o a l I I . 1 . I n t r o d u c t i o n The s y n t h e t i c s t u d i e s o u t l i n e d i n t h i s s e c t i o n a r o s e a s a l o g i c a l s e q u e l t o my M.Sc. t h e s i s1 r e s e a r c h . T h i s p a r t l y c o n c e r n e d t h e i d e n t i f i c -a t i o n o f t h e m a r i n e n a t u r a l p r o d u c t n a n a i m o a l ( 2 4 _ ) , (25_) o r ( 2 6 ) , i s o l a t e d f r o m a B r i t i s h C o l u m b i a n u d i b r a n c h . A s t r a i g h t f o r w a r d s y n t h e t i c a p p r o a c h t o o n e o f t h e h y p o t h e t i c a l s t r u c t u r e s 24_ o f n a n a i m o a l i s p r o p o s e d . T h i s i s f o l l o w e d b y t h e r e s u l t s o b t a i n e d f r o m p u r s u i n g t h a t s y n t h e t i c r o u t e a n d a d i s c u s s i o n o f t h e c h e m i s t r y o f medium r i n g m o l e c u l e s . T h e w o r k t h a t e n a b l e d 39 t h e s t r u c t u r a l e l u c i d a t i o n o f n a n a i m o a l (26_) by c o l l e a g u e s a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a i s t h e n b r i e f l y r e p o r t e d . A s p a r t o f a p r o g r a m a i m e d a t s t u d y i n g t h e c h e m i s t r y o f B r i t i s h C o l u m b i a n u d i b r a n c h s , we e x a m i n e d t h e s k i n e x t r a c t o f A c a n t h a d o r i s  n a n a i m o e n s i s . I n t e r e s t i n t h a t o r g a n i s m a r o s e when we n o t i c e d i t s s w e e t f r a g r a n c e w h i l e s o r t i n g s p e c i m e n s a f t e r a d i v i n g e x p e d i t i o n . The 'H NMR o f t h e m a j o r c o n s t i t u e n t ( s ) o f t h e e x t r a c t o f A. n a n a i m o e n s i s i n d i c a t e d t h e p r e s e n c e o f two c l o s e l y r e l a t e d s e s q u i t e r p e n o i d a l d e h y d e s , p r e s e n t i n a 4:1 r a t i o . The MS o f t h i s m i x t u r e o f c o m p o u n d s , i t s r e d u c t i o n p r o d u c t a n d DNPH d e r i v a t i v e p o i n t e d t o a m o l e c u l a r f o r m u l a f o r n a n a i m o a l o f c- j 5H2 0 ° ' ^r o m t h e sPe c t r a l d a t a a v a i l a b l e ( I R , MS, 'H, a n d 13 C NMR) s e v e r a l f e a t u r e s o f t h i s m o l e c u l e c o u l d be d i s c e r n e d : 2 4 25 26 - 29 -1. f o u r s i t e s o f u n s a t u r a t i o n : a c a r b o n y l ( a l d e h y d e ) , a t e t r a s u b s t i t u t e d d o u b l e b o n d , a n d two r i n g s . 2 . a s e s q u i t e r p e n o i d f r a m e w o r k 3 . f r a g m e n t -C-CH2-CH0 4 . t h r e e m e t h y l g r o u p s a t t a c h e d t o q u a t e r n a r y c a r b o n s . B i o s y n t h e t i c r e a s o n i n g ( S cheme 4 ) s u g g e s t e d t h r e e h y p o t h e t i c a l s t r u c t u r e s 2 4 , 25_ a n d 26_. As a t t e m p t s t o p r e p a r e a s u i t a b l e d e r i v a t i v e f o r X - r a y d i f f r a c t i o n a n a l y s i s w e r e u n s u c c e s s f u l a n d o t h e r s p e c t r a l m e a s u r e m e n t s d i d n o t p e r m i t an u n a m b i g u o u s s t r u c t u r a l a s s i g n m e n t , a s y n t h e s i s o f one o f t h e p r o p o s e d s t r u c t u r e s 24 was u n d e r t a k e n . Two c o n v e n t i o n a l a p p r o a c h e s h a v e b e e n u s e d t o p r e p a r e b i c y c l o [ 4 . 4 . 0 ] d e c a n e s ( d e c a l i n s ) ; e i t h e r R o b i n s o n a n n u l a t i o n s o r D i e l s - A l d e r r e a c t i o n s . As i l l u s t r a t e d i n Scheme 5 ( f o r s t r u c t u r e 2 4 ) t h e s e t w o a p p r o a c h e s c o u l d s t a r t w i t h a n a p p r o p r i a t e s i x membered r i n g , s u c h a s 2_7 o r 2 8 , a n d s u b s e q u e n t l y a t t a c h t h e r e q u i r e d s e c o n d s i x membered r i n g . - 30 -Scheme 5 P o s s i b l e R o b i n s o n A n n u l a t i o n a n d D i e l s - A l d e r A p p r o a c h t o 2 4 27 / / / •CHO 24 28 ^•CH 2CH(OEt) 2 - 31 -The p h o t o c h e m i c a l b e h a v i o u r o f c y c l o d e c a n o n e (29_) was s t u d i e d i n 1959 b y B a r n a r d a n d Y a n g4 0. ' T h e y f o u n d t h a t i r r a d i a t i o n o f 29_ i n c y c l o h e x a n e f o r 132 h o u r s a f f o r d e d t h e a l c o h o l 30 ( S c h e m e 6) i n 5 2 % y i e l d ( 4 2 % c i s _ , 1 0 % t r a n s ) . No s u b s e q u e n t s t u d y o f s u b s t i t u t e d c y c l o d e c a n o n e s h a s a p p e a r e d . Our s y n t h e t i c r o u t e ( S cheme 6 ) was b a s e d on t h e e x p e c t a t i o n t h a t s e q u e n t i a l c y c l o d e c a n o n e a l k y l a t i o n s w o u l d i n t r o d u c e a t w o c a r b o n c h a i n ( s u c h a s - C h ^ C h K O E t ^ ) , f o l l o w e d by t h e r e q u i s i t e m e t h y l s u b s t i t u e n t s , t o g i v e 3 2 . P r o v i d e d t h e p h o t o l y s i s p a r a l l e l e d t h a t o f c y c l o d e c a n o n e ( 2 9 ) , d e h y d r a t i o n o f t h e a l c o h o l p r o d u c t 33 a n d d e p r o t e c t i o n o f t h e a l d e h y d e w o u l d g i v e t h e t a r g e t m o l e c u l e 2 4 . - 32 -Scheme 6 P r o p o s e d P h o t o c h e m i c a l A p p r o a c h t o N a n a i m o a l ( 2 4 ) CHfcCH (OEt)j — 29 0% 34 q p H 3 3 24 b a s e d o n CO Op 0 H 29 30 - 33 -I I .2. R e s u l t s The p r e p a r a t i o n o f 2 , 2 , 1 0 , 1 0 - t e t r a m e t h y l c y c l o d e c a n o n e was u n d e r t a k e n i n o r d e r t o a s c e r t a i n i t s p h o t o c h e m i c a l b e h a v i o u r . T r e a t m e n t o f c y c l o d e c a n o n e ( 2 9 ) w i t h s o d i u m h y d r i d e i n THF i n t h e p r e s e n c e o f e x c e s s m e t h y l i o d i d e a f f o r d e d , a f t e r r e f l u x i n g f o r 5 h , a s i n g l e new p r o d u c t . T h i s r e a c t i o n was e a s i l y m o n i t o r e d b y GLC. A l t h o u g h t h e t e t r a m e t h y l d e r i v a t i v e o f c y c l o d e c a n o n e was e x p e c t e d , t h e MS ( F i g u r e 10) i n d i c a t e d a p a r e n t i o n a t m/z = 1 9 8 c o r r e s p o n d i n g t o a m o l e c u l a r f o r m u l a o f C - j - ^ g O , w h i c h r e p r e s e n t s t h e t r i s u b s t i t u t e d d e r i v a t i v e 3 5 . L a n t h a n i d e s h i f t ( E u ( f o d )3) 'H NMR e x p e r i m e n t s c o n f i r m e d t h e 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e (35_) s t r u c t u r e A d d i t i o n a l e v i d e n c e was p r o v i d e d by a c e t a t e 43_ ( o b t a i n e d by l i t h i u m a l u m i n u m h y d r i d e r e d u c t i o n a n d a c e t y l a t i o n o f 3 5 , Scheme 7 ) , w h i c h d i s p l a y e d i n t h e 'H NMR s p e c t r u m , a d o u b l e t J = 1.5 Hz a t 6 = 4.60 ppm f o r t h e m a j o r i s o m e r a n d J = 2.5 Hz a t 6 = 5.10 ppm f o r t h e m i n o r i s o m e r4 1 ( 6 : 1 ) . T h e s e s i g n a l s w o u l d n o t h a v e a p p e a r e d a s d o u b l e t s f r o m t h e t e t r a s u b s t i t u t e d k e t o n e 32_, a n d t h e r e w o u l d h a v e b e e n o n l y o n e i s o m e r . The 'H NMR s p e c t r u m ( F i g u r e 12) o f 35_, a l s o d i s p l a y e d a s i g n a l a t 3.31 ppm ( m ) . Upon i r r a d i a t i o n o f t h i s m u l t i p l e t , t h e m e t h y l d o u b l e t a t 1.04 ppm c o l l a p s e d 13 t o a s i n g l e t . The SFORD C NMR s p e c t r u m o f 35 s h o w e d e l e v e n s i g n a l s b e t w e e n 6 = 22 a n d 40 ppm, t h e s i g n a l due t o t h e CO g r o u p a t 2 2 0 . 8 5 ppm b e i n g d e t e c t e d o n l y i n a c o n c e n t r a t e d s o l u t i o n . The b a n d a s c r i b e d t o a CO g r o u p a p p e a r e d a t 292 nm ( l o g e = 1.77) i n t h e uv s p e c t r u m . - 34 -Scheme 7 R e a c t i o n s P e r f o r m e d on 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( 3 5 ) a:hv; b:03, MeOH or KMnO^ , benzene; c: BH^, H202; d:Jones oxidation; e:LiAlH4, ether; f:Ac~0, pyridine, DMAP - 35 -The p h o t o c h e m i c a l b e h a v i o u r o f 35 was i n v e s t i g a t e d i n t h e a b s e n c e o f 3 2 . P h o t o l y s i s o f 3_5 i n c y c l o h e x a n e f o r 5 h r e s u l t e d i n t h e c o m p l e t e d i s -a p p e a r a n c e o f t h e s t a r t i n g k e t o n e . A l t h o u g h " h o mogeneous" by GLC ( o n e p e a k ) a n d TLC ( o n e s p o t ) a n a l y s i s , t h e m a j o r p h o t o l y s i s p r o d u c t was n o t a s i n g l e o l e f i n a s i m p l i e d by t h e 'H NMR s p e c t r u m . O l e f i n i c s i g n a l s a p p e a r e d i n t h e 'H NMR b e t w e e n 6 = 4.6 a n d 6.0 ppm. A b r o a d s i n g l e t a t 4.64 ppm r e p r e s e n t e d a b o u t 7 0 % o f t h e c o m b i n e d i n t e g r a t e d i n t e n s i t y o f t h e s e s i g n a l s . The p r e s e n c e o f a v i n y l m e t h y l a t 1.70 ppm ( s ) a n d o f a m e t h y l e n e ( 2 . 0 ppm, t r i p l e t , J = 7 H z ) a l p h a t o t h e d o u b l e b o n d was a l s o i n d i c a t e d . T h e s e t h r e e s i g n a l s w e r e i d e n t i c a l t o t h o s e d i s p l a y e d by 5 - b r o m o - 2 - m e t h y l - h e x e n e ( 4 4 ) a n d t o g e t h e r w i t h t h e MS ( E x a c t Mass c a l c u l a t e d f o r C] 2H2 4: 1 6 8 . 1 8 7 2 , o b s e r v e d : 1 6 8 . 1 8 6 0 ) p e r m i t t e d 42 t h e i d e n t i f i c a t i o n o f t h i s m a j o r o l e f i n a s 2 - m e t h y l - 1 - u n d e c e n e ( 3 6 _ ) . The p r e s e n c e o f a 1 , 1 - d i s u b s t i t u t e d d o u b l e b o n d was a l s o r e v e a l e d i n t h e IR a t 8 8 0 c m- 1. 4 4 The s t r u c t u r e o f t h i s m a j o r o l e f i n 36 was p r o v e d by p e r f o r m i n g t h e f o l l o w i n g s e r i e s o f r e a c t i o n s ( S cheme 7 ) . O x i d a t i o n o f t h e o l e f i n i c f r a c t i o n w i t h p o t a s s i u m p e r m a n g a n a t e i n b e n z e n e i n t h e p r e s e n c e o f c r o w n 42 e t h e r , g a v e a s i n g l e k e t o n e 39_. T h i s same m e t h y l k e t o n e p r o d u c t was o b t a i n e d i n b e t t e r y i e l d when o z o n o l y s i s was p e r f o r m e d , f o l l o w e d by a d i m e t h y l s u l f i d e r e d u c t i v e w o r k - u p . The 'H NMR i n d i c a t e d t h e p r e s e n c e o f a m e t h y l k e t o n e ( 2 . 0 7 ppm, s i n g l e t ) t h e IR c o n f i r m e d t h e p r e s e n c e o f a c a r b o n y l g r o u p ( 1 7 1 5 cm"1) a n d t h e MS ( E x a c t Mass c a l c u l a t e d f o r CnH? ?0 : 1 7 0 . 1 6 6 5 , - 36 -o b s e r v e d : 1 7 0 . 1 6 2 2 ) a n d b . p . ( 2 2 8 - 2 3 0 ° o b s e r v e d , l i t e r a t u r e 2 3 1 - 2 3 2H J) p r o v e d t h a t 2 - u n d e c a n o n e ( 3 9 ) was t h e p r o d u c t . 44 H y d r o b o r a t i o n o f t h e o l e f i n i c f r a c t i o n f o l l o w e d by t r e a t m e n t w i t h b a s i c h y d r o g e n p e r o x i d e a f f o r d e d a p r i m a r y a l c o h o l 4 0 . The 'H NMR s p e c t r u m o f a l c o h o l 4Jj d i s p l a y e d a d o u b l e t ( J = 6 Hz) a t 3.31 ppm, a n d t h e IR s p e c t r u m h a d a b a n d a t 3 3 0 0 - 3 4 0 0 c m "1. The MS o f 2 - m e t h y l - l - u n d e c a n o l ( 4 0 ) was a l m o s t i d e n t i c a l t o t h a t o f 2 - m e t h y l - l - u n d e c e n e (36_) i n d i c a t i n g t h a t H^O i s r e a d i l y l o s t f r o m t h e e x p e c t e d p a r e n t i o n . The p r i m a r y n a t u r e o f t h e 44 a l c o h o l was f u r t h e r p r o v e d b y J o n e s o x i d a t i o n t o t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d 41_. A n o n - p o l a r f r a c t i o n h a v i n g t h e same R^ a s t h e s t a r t i n g m a t e r i a l was i s o l a t e d i n a b o u t 2 0 % y i e l d f r o m t h e h y d r o b o r a t i o n a n d o z o n o l y s i s r e a c t i o n s . The 'H NMR s p e c t r u m o f t h i s f r a c t i o n s h o w e d no d e s h i e l d e d s i g n a l s , t h e IR s h o w e d no b a n d s c o r r e s p o n d i n g t o a c a r b o n y l o r a h y d r o x y l g r o u p , a n d t h e MS ' s t i l l d i s p l a y e d a m o l e c u l a r i o n a t m/z = 164 ( C - ^ H ^ ) . S t r u c t u r e 3_7 i s t e n t a t i v e l y a s s i g n e d t o t h i s m i n o r p r o d u c t o f t h e p h o t o l y s i s r e a c t i o n . On o n e o c c a s i o n when b u b b l i n g o f n i t r o g e n was o m i t t e d b e f o r e t h e p h o t o -c h e m i c a l r e a c t i o n , a more p o l a r p r o d u c t h a v i n g t h e r i g h t s p e c t r a l p r o p e r t i e s ( I R , 'H NMR, MS) f o r 2 , 1 0 - d i m e t h y l - 1 0 - u n d e c e n e - l - a l ( 3 8 ) was i s o l a t e d . W h i l e t h e p h o t o c h e m i c a l r e a c t i o n was u n d e r s t u d y , we a t t e m p t e d t o s y n t h e s i z e a t e t r a s u b s t i t u t e d c y c l o d e c a n o n e . The t e t r a h y d r o p y r a n y l ( T H P ) d e r i v a t i v e o f 2 - c h l o r o - l - e t h a n o l was p r e p a r e d u n d e r c a t a l y t i c a c i d i c c o n d i t i o n s4 4. S i n c e t h e a l k y l a t i o n o f c y c l o d e c a n o n e d i d n o t t a k e p l a c e w i t h t h e c h l o r i n e a s t h e l e a v i n g g r o u p , t h e i o d i n e c o n t e r p a r t was p r e p a r e d . I n b o t h c a s e s ( C l , I ) , i t seems t h a t e l i m i n a t i o n o f HC1 o r HI t a k e s p l a c e a t a h i g h e r r a t e t h a n a l k y l a t i o n . T h i s i s d e d u c e d f r o m t h e p r e s e n c e o f t h r e e - 37 -new o l e f i n i c s i g n a l s i n t h e 'H NMR s p e c t r u m ( t y p i c a l v i n y l g r o u p , ABX p a t t e r n ) o f t h e 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 a n d t h e r e c o v e r y o f c y c l o d e c a n o n e . V a r i o u s c y c l o d e c a n o n e a l k y l a t i o n s w i t h e l e c t r o p h i l e s s u c h " a s a l k y l i o d i d e , c i n n a m y l i o d i d e a n d b e n z y l b r o m i d e , f o l l o w e d by m e t h y l i o d i d e , u s i n g b a s e s s u c h a s N a H , K H , LDA, K C H2S 0 C H3, K N H2, KOR, a n d a v a r i e t y o f s o l v e n t s s u c h a s T H F , DMSO, HMPA, DME, DMF, NH^, ROH, w e r e i n v e s t i g a t e d u n d e r v a r i o u s t e m p e r a t u r e c o n d i t i o n s , i n c l u d i n g s e a l e d t u b e s . U n f o r t u n a t e l y n o n e o f t h e s e e x p e r i m e n t s g a v e a t e t r a s u b s t i t u t e d p r o d u c t . S u b s e q u e n t a t t e m p t s t o p r e p a r e e n o l e t h e r s a n d a c e t a t e s o f 2 , 2 , 1 0 - t r i m e t h y l -c y c l o d e c a n o n e a l s o m e t w i t h no s u c c e s s , w h i l e a D20 q u e n c h i n g e x p e r i m e n t was i n c o n c l u s i v e . T h u s t h i s p h o t o c h e m i c a l a p p r o a c h t o n a n a i m o a l ( 2 4 J was a b a n d o n e d . - 38 -I I . 3 . D i s c u s s i o n 45 46 47 I n s p i t e o f i m p o r t a n t c o n t r i b u t i o n s ' ' t o t h e c o n f o r m a t i o n a n d r e a c t i v i t y o f m e d i u m - r i n g Cg t o C ^ c y c l o a l k a n e s , c y c l o a l k a n o n e s a n d r e l a t e d m o l e c u l e s made i n t h e l a s t t w e n t y y e a r s d e t a i l e d u n d e r s t a n d i n g i s s t i l l l a c k i n g . C l e a r l y , t wo s i g n i f i c a n t a s p e c t s o f t h i s s t u d y a r e t h e f a i l u r e o f t h e p h o t o c h e m i c a l r e a c t i o n t o f o l l o w t h e a n t i c i p a t e d p a t h , a n d t h e d i f f i c u l t y i n p r e p a r i n g a t e t r a s u b s t i t u t e d c y c l o d e c a n o n e . The c o u r s e o f t h e s e r e a c t i o n s i s l a r g e l y a c o n s e q u e n c e o f t h e c o n f o r m a t i o n a l p r e f e r e n c e s o f t h e m o l e c u l e . The p r e f e r r e d c o n f o r m a t i o n o f 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( 3 5 ) c a n be t e n t a t i v e l y d e d u c e d b a s e d on t h e p r e s e n t w o r k a n d e a r l i e r s t u d i e s o f t e n membered r i n g m o l e c u l e s . A l t h o u g h t h e c y c l o d e c a n e m o l e c u l e i s c a p a b l e o f e x i s t i n g i n a number 4 8 o f c o n f o r m a t i o n s ( F i g u r e 6 ) , t h e BCB c o n f o r m a t i o n h a v i n g a l l s t a g g e r e d 47 l i n k a g e s i s p r e f e r r e d . I n t h e c a s e o f c y c l o d e c a n o n e , t h e r e a r e t h r e e 49 p o s s i b l e BCB ( " d i a m o n d - l a t t i c e " ) c o n f o r m a t i o n s ( F i g u r e 7 ) . O n l y B C B - 3 , w i t h t h e c a r b o n y l i n an e n d o c y c l i c p o s i t i o n , h a s no s t e r i c h i n d r a n c e w i t h t h e h y d r o g e n a t o m s on t h e o p p o s i t e s i d e o f t h e r i n g . I t i s s i g n i f i c a n t l y 50 m o r e s t a b l e a c c o r d i n g t o s t r a i n e n e r g y c a l c u l a t i o n s a n d 1H NMR 51 m e a s u r e m e n t s . T h i s c o n f o r m a t i o n r e l i e v e s a p a r t i c u l a r l y s e r i o u s " t r a n s a n n u l a r n o n - b o n d e d r e p u l s i o n " . T h i s i s a l s o c o n s i s t e n t w i t h t h e 40 p h o t o c h e m i c a l r e s u l t s o f B a r n a r d a n d Yang . The c a r b o n y l g r o u p i s p a r t i a l l y l o c a t e d i n s i d e t h e r i n g a n d p a r t i c i p a t e s r e a d i l y i n t h e o b s e r v e d t r a n s a n n u l a r r e a c t i o n . The BCB-1 c o n f o r m a t i o n h as b e e n p r o p o s e d a s b e i n g 52 m o r e i n a c c o r d a n c e w i t h C-13 m e a s u r e m e n t s , w h i l e d i p o l e moment 45 c a l c u l a t i o n s f a v o r a n e n d o c y c l i c c a r b o n y l a s i n BBC-1 O t h e r m o r e s t a b l e c o n f o r m a t i o n s h a v e b e e n f o u n d o r p r o p o s e d f o r s u b s t i t u t e d c y c l o d e c a n e s , a n d some e x a m p l e s f o l l o w . The TBC c o n f o r m a t i o n - 39 -F i g u r e 6 Some C o n f o r m a t i o n s o f C y c l o d e c a n e B: b o a t C : c h a i r L: l o n g T ; t w i s t e d BCC C C C TBCC - 40 -F i g u r e 7 Some C o n f o r m a t i o n s o f C y c l o d e c a n o n e - : R e F e r s to n u m b e r i n g u s e d For c y c l o d e c a n e , F i g u r e 6 - 41 -h a s b e e n s u g g e s t e d a s m o r e s t a b l e i n t h e c a s e o f 4 , 4 , 8 , 8 - t e t r a m e t h y l c y c l o -54 55 d e c a n o n e . T h r o u g h X - r a y a n a l y s i s ' o f 4 , 4 , 7 , 7 - t e t r a m e t h y l c y c l o d e c a n e -1 - c a r b o x y l i c a c i d , t h e two c o n f o r m a t i o n s TBC a n d TBCC w e r e a s s i g n e d t o t h i s m o l e c u l e i n t h e s o l i d s t a t e . C y c l o d e c a n e - 1 , 6 - d i o n e h a s b e e n t h e s u b j e c t o f 47 56 s e v e r a l s t u d i e s ' w h i c h i n d i c a t e a d i f f e r e n c e b e t w e e n t h e c o n f o r m a t i o n o f t h e m o l e c u l e i n t h e l i q u i d s t a t e ( I R , UV, 'H a n d 1 3C NMR) a n d t h e same m o l e c u l e i n t h e s o l i d s t a t e ( I R , X - r a y ) . The m a j o r c o n f o r m e r i n s o l u t i o n seems t o b e a d i s t o r t e d " d e c a l i n - 1 i k e " o r TCCC m o l e c u l e . T h i s l a t t e r s t u d y i n d i c a t e d t h a t t r y i n g t o o b t a i n a s o l i d d e r i v a t i v e ( s u c h a s 2 , 4 - d i n i t r o -p h e n y l h y d r a z o n e ) o f 3_5 p r o b a b l y w o u l d n o t be w a r r a n t e d . 46 57 The r e a c t i v i t y o f m o l e c u l e s a l s o d e p e n d s on t h e i r r i n g s i z e ' . F o r e x a m p l e , r e a c t i o n r a t e s v a r y when o x i d a t i o n s o r r e d u c t i o n s a r e p e r f o r m e d1. The p r o d u c t s o b t a i n e d f r o m t r a n s a n n u l a r r e a c t i o n s g o i n g t h r o u g h a c a r b a n i o n o r c a r b o n i u m i o n i n t e r m e d i a t e a l s o c h a n g e w i t h t h e s i z e o f a r i n g . I n 40 59 60 a d d i t i o n , a s h a s b e e n o b s e r v e d p r e v i o u s l y ' ' a n d i n t h e p r e s e n t s t u d y , t h e p r o d u c t s o f a p h o t o l y s i s r e a c t i o n v a r y w i t h t h e s i z e a n d t h e s u b s t i t u t i o n o f t h e r i n g . T h r e e d i f f e r e n t s t u d i e s , a n d e s p e c i a l l y X - r a y d i f f r a c t i o n a n a l y s i s ^ , i n d i c a t e t h a t " t h e s t r u c t u r e s o f m e d i u m - r i n g m o l e c u l e s a r e v e r y d i f f e r e n t f r o m w h a t i s s u g g e s t e d by t h e f l o p p y n e c k l a c e s o f a t o m s p r o d u c e d by fi? fi 3 c o n v e n t i o n a l m o l e c u l a r m o d e l s " . ' I n v i e w o f t h e c o n f o r m a t i o n a l s t u d i e s o u t l i n e d a b o v e , i t a p p e a r s t h a t 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( 3 5 ) i n s o l u t i o n a d o p t s a c o n f o r m a t i o n i n w h i c h a b s t r a c t i o n o f a p r o t o n f r o m c a r b o n - 1 0 i s e x t r e m e l y d i f f i c u l t . 1 CO C o m p a r i s o n o f t h e a l k y l a t i o n o f c y c l o h e x a n o n e a n d c y c l o d e c a n o n e u s i n g b e n z y l b r o m i d e / N a H / T H F . A f t e r 5 h r e f l u x , c y c l o h e x a n o n e g a v e : 6 2 % mono-a l k y l a t e d p r o d u c t , 1 0 % d i a l k y l a t e d p r o d u c t a n d no s t a r t i n g m a t e r i a l . A f t e r 4 8 h r e f l u x , c y c l o d e c a n o n e g a v e : 7 0 % m o n o a l k y l a t e d p r o d u c t , < 1% d i a l k y l a t e d p r o d u c t , 1 5 % s t a r t i n g m a t e r i a l . - 4 2 -A r e c e n t p a p e r , p u b l i s h e d a f t e r t h i s w o r k was f i n i s h e d , d e a l s w i t h t h e e f f e c t o f a m e t h y l s u b s t i t u e n t on t h e " s t e r e o s e l e c t i v e f o r m a t i o n o f a new a s y m m e t r i c c e n t r e " . A t a b l e g i v e s t h e e n e r g y ( m o l e c u l a r m e c h a n i c s . c a l c u l a t i o n s ) n e e d e d t o i n t r o d u c e a m e t h y l i n t o t h e t h r e e n o n - e q u i v a l e n t p s e u d o a x i a l p o s i t i o n s o f c y c l o d e c a n e e x i s t i n g i n t h e BCB c o n f o r m a t i o n : 6.6 k c a l / m o l e a t C - l , 0 k c a l / m o l e a t C-2 a n d 9.2 k c a l / m o l e a t C - 3 . T h i s means t h a t f o r s i t e s 2 , 5 , 7 a n d 10 ( F i g u r e 8 ) a t t h e f o u r c o r n e r s o f t h e B C B , t h e r e i s no e n e r g e t i c p e n a l t y a s s o c i a t e d w i t h t h e i n t r o d u c t i o n o f an a x i a l m e t h y l s u b s t i t u e n t . H o w e v e r , f o r t h e r e m a i n i n g s i x p o s i t i o n s , t h e e n e r g y r e q u i r e d i s s o l a r g e t h a t t h e i n t r o d u c t i o n o f a n a x i a l s u b s t i t u e n t i s a c t u a l l y f o r b i d d e n . T h e r e f o r e i f we c o n s i d e r 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( 3 5 ) i n a TBC c o n f o r m a t i o n , " t u b s h a p e d " l i k e t h e c y c l o o c t a n e s , ( b a s e d on t h e a r g u m e n t s a b o v e ) , t h e i n t r o d u c t i o n o f t h e f o u r t h g r o u p m u s t be t a k i n g p l a c e a t a 64 p o s i t i o n e q u i v a l e n t t o C-4 a n d i s e f f e c t i v e l y e n e r g e t i c a l l y f o r b i d d e n . I n o u r o p i n i o n a t w i s t e d - b o a t - c h a i r c o n f o r m a t i o n i s b e s t s u i t e d t o t h e p h o t o c h e m i c a l a n d s p e c t r a l d a t a o b t a i n e d f o r 3 5 , w h e r e : 0 TBC 1 . The p h o t o c h e m i c a l r e a c t i o n i n d i c a t e d t h a t a b s t r a c t i o n o f a t r a n s a n n u l a r p r o t o n b y t h e CO g r o u p i s n o t p r e f e r r e d . 2 . The c h e m i c a l s h i f t o f t h e C-10 p r o t o n , 6 = 3.31 ppm ( s i m i l a r t o t h a t o f a m e t h y l e n e a t o t h e CO o f a s i x membered r i n g l a c t o n e , 6 = 3.31 p p m4 1 a) i n d i c a t e d t h a t , i n t h e a v e r a g e c o n f o r m a t i o n a d o p t e d i n s o l u t i o n by 3 5 , H-10 i s i n t h e d e s h i e l d i n g c o n e o f t h e c a r b o n y l g r o u p . T h i s r e q u i r e m e n t - 4 3 -i m p l i e s t h a t t h e s u b s t i t u t e d s i d e o f t h e m o l e c u l e i s p a r t l y f l a t . To o b t a i n a n a n g l e c l o s e t o 0 ° b e t w e e n t h e CO a t C - l a n d t h e m e t h i n e p r o t o n a t C - 1 0 , a TB c o n f o r m a t i o n i s n e c e s s a r y . 3 . T h e e l e v e n a l k y l s i g n a l s o b t a i n e d i n t h e SFORD 1 3C NMR ( C1 3H2 20 : 1 CO a n d 12 a l k y l C) i n d i c a t e an a b s e n c e o f s y m m e t r y i n t h e a v e r a g e c o n f o r m a t i o n 65 a d o p t e d by 35_ . The r e s u l t s o f t h e p h o t o l y s i s r e a c t i o n c a n be e x p l a i n e d by c o m p a r i s o n t o t h e b e h a v i o u r o f s m a l l r i n g k e t o n e s s u c h a s c y c l o h e x a n o n e ^7 , r a t h e r t h a n r e l a t e d medium r i n g k e t o n e s ^ ' ^ ' ^ . F o r e x a m p l e , when 69 2 , 2 , 6 , 6 - t e t r a m e t h y l c y c l o h e x a n o n e (45_) was p h o t o l y s e d , f o u r p r o d u c t s , 46 t o 49_, w e r e i d e n t i f i e d ( S c heme 8 ) . The s t a b i l i t y o f t h e a c y l a l k y l d i r a d i c a l i n t e r m e d i a t e i s i n c r e a s e d by t h e s u b s t i t u e n t s i n t h e a a n d a' p o s i t i o n s . T h e r e f o r e , t h e l o s s o f c a r b o n m o n o x i d e w i t h s u b s e q u e n t i n t r a -m o l e c u l a r r e a c t i o n s ( d i s p r o p o r t i o n a t e a n d c o m b i n a t i o n ) was p r o m o t e d i n 45_. Scheme 8 P h o t o c h e m i c a l B e h a v i o u r o f 2 , 2 , 6 , 6 - t e t r a c y c l o h e x a n o n e ( 4 5 ) 69 0 + 4 5 46 4 7 + CHO 48 4 9 - 44 -I n t h e c a s e o f 35_, m i n o r p r o d u c t 3_7 r e s u l t e d f r o m a N o r r i s h t y p e . I c l e a v a g e ( o n t h e more s u b s t i t u t e d s i d e o f t h e CO g r o u p ) f o l l o w e d by a d e c a r b o n y l a t i o n a n d c y c l i z a t i o n ( S c heme 9 ) . P r o d u c t 38_ r e s u l t e d f r o m a • N o r r i s h t y p e I c l e a v a g e f o l l o w e d by a p r o t o n a b s t r a c t i o n f r o m o n e o f t h e gem d i m e t h y l s . The m a j o r p r o d u c t 36 i s o b t a i n e d f r o m a N o r r i s h t y p e I c l e a v a g e , a d e c a r b o n y l a t i o n a n d a p r o t o n a b s t r a c t i o n . The N o r r i s h t y p e I I c l e a v a g e a n t i c i p a t e d i s n o t f a v o r e d due t o t h e g e o m e t r i c a l r e q u i r e m e n t s o f !35_. T h e r e f o r e , no d e c a l i n p r o d u c t was o b t a i n e d . Scheme 9 P h o t o c h e m i c a l b e h a v i o u r o f 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e 35 - 45 -A s m e n t i o n e d i n t h e i n t r o d u c t i o n , t h e p r e s e n t s t u d y was d i r e c t e d a t t h e s y n t h e s i s o f 24_, o n e o f t h e t h r e e (24_, 25_ o r 26_) h y p o t h e t i c a l s t r u c t u r e s p r o p o s e d f o r n a n a i m o a l . S u b s e q u e n t t o t h i s s t u d y , t h e e l u c i d a t i o n o f t h e . s t r u c t u r e o f n a n a i m o a l (26_) was s u c c e s s f u l l y a c c o m p l i s h e d by A n d e r s e n 39 a n d c o l l a b o r a t o r s , a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a . The D i e l s - A l d e r s y n t h e s i s o f 50_, t h e p - b r o m o p h e n y l i s o c y a n a t e d e r i v a t i v e o f n a n a i m o a l i s o u t l i n e d i n Scheme 1 0 . 3.0 35 ,- 4 0 MOONS j 5 0 L i 1 ', I 1 I 1 ,' ' 1 !.' 1 •' 1 I _ .1 H MICRONS ,o.o I K WOO 1200 1000 MtOutNCV C". 'I I I F i g u r e 8 IR s p e c t r u m o f 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( ^ n e a r ) -48-1 i I i I 1 1 1 1 1 1 100 MOO W O 1200 600 t Hi MO 1200 « K ) 800 300 0 ' 5 0 600 460 300 ISO 0 Figure 9 80 MHz 'H NMR Spectrum of 2,2,10-trimethyl cycl odecanone (35_ CDCL) - 49 -C h a p t e r 3  C a p n e l l e n e I I I . l . I n t r o d u c t i o n 9 12 A C a p n e l l e n e (51_) i s a member o f a f a m i l y o f s e v e n s e s q u i t e r p e n o i d s i s o l a t e d f r o m t h e s o f t c o r a l C a p n e l ! a i m b r i c a t a , c o l l e c t e d i n I n d o n e s i a a n d New G u i n e a . The m o s t a b u n d a n t a l c o h o l 52 was f i r s t i s o l a t e d i n 1 9 7 47 0, f o l l o w e d by t h e s t r u c t u r e d e t e r m i n a t i o n o f o u r o t h e r a l c o h o l r e p r e s e n t a t i v e s 7 1 - 7 3 The t r i c y c l i c h y d r o c a r b o n c a p n e l l e n e (5J_) 53 t o 5 6 , i n 1 9 7 6 a n d 1977 74 was i d e n t i f i e d i n 1 9 7 8 a n d t h e u n s t a b l e a n d v o l a t i l e b i c y c l i c h y d r o c a r b o n 75 p r e c a p n e l l a d i e n e (57_) i n 1 9 7 9 . Scheme 11 B i o g e n e t i c R e l a t i o n s h i p o f t h e C a p n e l l a n e s H H 58 h u m u I • n • 57 H c a p n « M « n • 51 P r OH 52 53 54 55 56 l At 1,2 I A3 1,2,5 1,2,4,6 H "t,4.8 " 3,4,5,6 R 4,5,6 R 3,4,6 R3,5 c a p n i l l o l i - 50 -I t h a s b e e n s u g g e s t e d7* * t h a t c o m p o unds 51_ t o 5_7 c o u l d s e r v e i n a c h e m i c a l d e f e n s e m e c h a n i s m , " t o w a r d o f f a l g a l a n d m i c r o b i a l g r o w t h a n d p r e v e n t t h e 71 s e t t l e m e n t o f l a r v a e " on t h e s o f t c o r a l . The b i o g e n e t i c r e l a t i o n s h i p o u t l i n e d i n Scheme 11 h a s b e e n p r o p o s e d f o r t h e c a p n e l l a n e f a m i l y7 1'7 4'7 5'7 7. T h e c a p n e l l a n e s a n d h i r s u t a n e s ( w h i c h c o m p r i s e f o r e x a m p l e h i r s u t e n e (59) a n d c o r i o l i n (60_)) a r e t w o t r i c y c l o p e n t a n o i d f a m i l i e s f u s e d i n a c i s - t r a n s - c i s a r r a n g e m e n t . T h e s e t r i q u i n a n e s h a v e r e c e i v e d c o n s i d e r a b l e a t t e n t i o n f r o m s y n t h e t i c c h e m i s t s i n t h e l a s t f e w y e a r s . H 4?? 59 78 When we d e c i d e d t o s y n t h e t i z e c a p n e l l e n e (5j_) o n l y o n e c o m m u n i c a t i o n d e a l i n g w i t h t h e s y n t h e s i s o f e p i - p r e c a p n e l l a d i e n e h a d a p p e a r e d i n t h e l i t e r a t u r e . S i n c e t h e n , 51_ h a s b e e n t h e s u b j e c t o f s e v e r a l t o t a l 79 8fi 87 s y n t h e s e s , t h e c a r b o n s k e l e t o n h a s b e e n p r e p a r e d a n d d i o l 53_ op h a s a l s o b e e n s y n t h e s i z e d . I n t h e n e x t f e w p a g e s , t h e s e s y n t h e s e s a r e o u t l i n e d b r i e f l y . T h e k e y s t e p s i n t h e s e s y n t h e s e s a r e shown i n S chemes 12 t o 21. The 79 f i r s t t o t a l s y n t h e s i s o f 51_ by L i t t l e ' s g r o u p i n v o l v e d a D i e l s - A l d e r r e a c t i o n ( 0°, 3 h ; >91% y i e l d o f 62J b e t w e e n t h e f u l v e n e 6j_ a n d d i m e t h y l -a z o d i c a r b o x y l a t e . T h i s was f o l l o w e d by a n o v e l 1,3-diyl t r a p p i n g r e a c t i o n - 51 -( d r o p w i s e a d d i t i o n o f 6_3, 66 h , r e f l u x i n g T H F , >56% y i e l d o f 6 4 ) o f t h e r e l a t e d a z o compound 63_, w i t h e l i m i n a t i o n o f n i t r o g e n , t o p r o d u c e 64_ ( a n d . 2 i s o m e r s ) a t r i c y c l i c p r e c u r s o r o f 5J_. Scheme 12 S y n t h e s i s o f 51_, by R.D. L i t t l e a n d G.L. C a r r o l l 61 62 63 64 P a q u e t t e ' s s y n t h e s i s i s shown i n Scheme 1 3 . I n i t i a l l y t h e s e n s i t i v e d i e n o n e 6 5 u n d e r w e n t a N a z a r o v c y c l i z a t i o n ( 8 % P2°5» C H3S 03H , 2 0 ° , 2 m i n , 6 8 % y i e l d ) t o b i c y c l i c k e t o n e 66_. F u r t h e r 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 t h e r e s u l t i n g y - k e t o - a l d e h y d e 6_7 u n d e r b a s i c c o n d i t i o n s ( 5 % KOH, e t h e r , T H F , 7 9 % y i e l d ) l e d t o 68^, a d i f f e r e n t p r e c u r s o r o f 5J_. Scheme 13 80 S y n t h e s i s o f 5J_, b y L . A . P a q u e t t e a n d K.E. S t e v e n s I n D r i e d i n g ' s s y n t h e s i s , t h e a - a l k y n o n e 69_ was p r e p a r e d f r o m m e t h y l 2 - o x o c y c l o p e n t a n e c a r b o x y l a t e . T h e r m o l y s i s ( 6 2 0 ° , 7 8 % y i e l d ) o f 69_ a f f o r d e d t h e u n s a t u r a t e d k e t o n e 7 0 , w h i c h was c o n v e r t e d t o a s e c o n d a - a l k y n o n e 7 l _ . - 52 -Thermolysis (620°, 33% yield) of 7]_ gave 68_ (and one isomer). Scheme 14 Synthesis of 51_, by L. Huguet, M. Karpf and A.S. Drieding Fujita et al's synthesis started with the preparation of a humulene derivative 72^  which after several transformations led to tricyclic epoxide 73. The key steps in this synthesis involved an initial rearrangement (TMSOTf, toluene, RT; IN HCl; 54% yield of 73) with migration of a methyl, followed by solvolytic rearrangement (MsCl, CH2C12, DMAP, 0° to RT, 20 min; NaOAc, AcOH, 7 0° , 6 h; 93% yield of 74, plus 1 isomer). Another series of steps afforded capnellene (and an isomer). Scheme 15 Synthesis of 51_, by 82 T. Fujita, T. Ohtsuka, H. Shirahama and T. Matsumoto 72 73 74 83 In Oppolzer's synthesis rings A and B were formed through two "magnesium-ene" reactions. The linear allylic chloride 75, and the monocyclic - 53 -a l l y l i c c h l o r i d e 77_ w e r e c y c l i z e d u n d e r m i l d c o n d i t i o n s (Mg p o w d e r , e t h e r ; 6 0 ° , 23 h ; a c r o l e i n ; 5 7 % y i e l d ) t o 76 a n d (Mg p o w d e r , e t h e r ; R T , 2 h; 02; 7 0 % y i e l d ) t o 7 8 . S u b s e q u e n t t r a n s f o r m a t i o n o f 78 a f f o r d e d y - k e t o - a l d e h y d e 67 w h i c h u n d e r w e n t a n a l d o l c o n d e n s a t i o n t o g i v e 51_. Scheme 16 83 S y n t h e s i s o f 51_, by W. O p p o l z e r a n d K. B a t t i g 75 76 7 7 78 84 The f i r s t b i o g e n e t i c t y p e s y n t h e s i s was u n d e r t a k e n by P a t t e n d e n ( S c h e m e 1 7 ) . I n t h i s c a s e , t h e s t a r t i n g m a t e r i a l was 1 , 3 - d i m e t h o x y b e n z e n e . T h i s a r o m a t i c m o l e c u l e was c o n v e r t e d t o 79_. P h o t o c h e m i c a l c y c l i z a t i o n ( 6 h , 4 5 0 w, h e x a n e , >90% y i e l d ) o f 79 t o 80_, f o l l o w e d b y f r a g m e n t a t i o n i n b a s e (K O H , E t O H , 4 8 h , 2 5 ° , 3 6 % y i e l d ) g a v e d i k e t o n e 8J_. F u r t h e r r e a c t i o n o f 81_ l e d t o e p i p r e c a p n e l l a d i e n e (82_ a n d o n e i s o m e r ) , t h e b i o s y n t h e t i c p r e c u r s o r o f 51_. The t r a n s a n n u l a r c y c l i z a t i o n was a c c o m p l i s h e d u s i n g b o r o n t r i f l u o r i d e e t h e r a t e ( b e n z e n e , r e f l u x , 1 h , 5 0 % y i e l d , p l u s t w o i s o m e r s ) . Scheme 17 S y n t h e s i s o f 5 j _ , b y A.M. B i r c h a n d G. P a t t e n d e n - 54 -M e h t a ' s s y n t h e s i s s t a r t e d w i t h a D i e l s - A l d e r r e a c t i o n ( T H F , RT) b e t w e e n m e t h y l c y c l o p e n t a d i e n e a n d p - b e n z o q u i n o n e . An i n t r a m o l e c u l a r p h o t o -c h e m i c a l c y c l o a d d i t i o n ( E t O A c , 4 5 0 w, 7 5 % y i e l d ) o f 85^ a f f o r d e d t h e p e n t a -c y c l i c d i o n e 8 6 . F l a s h c o l u m n p y r o l y s i s ( 5 3 0 ° , 0.1 mm H g , 6 0 % y i e l d ) o f 86 l e d t o t h e t r i c y c l o p e n t a n o i d 87_ w i t h c i s - c i s o i d - c i s f u s e d r i n g s . I s o m e r i z a t i o n o f t h e d o u b l e b o n d i n r i n g C o f 87 a n d r e d u c t i o n o f t h e d o u b l e b o n d i n r i n g A g a v e 6 8 , a known p r e c u r s o r o f 51_. Scheme 18 S y n t h e s i s o f 51_, by G. M e h t a , D.R. R e d d y a n d A . N . M u r t y8 5 A v e r y r e c e n t s y n t h e s i s by P i e r s i s o u t l i n e d i n Scheme 1 9 . C o n j u g a t e a d d i t i o n o f a v i n y l i c G r i g n a r d r e a g e n t a f f o r d e d c h l o r o k e t o n e 8 8 . I n t r a -m o l e c u l a r a l k y l a t i o n ( K H , T H F , R T , 7 5 % y i e l d ) o f 8 8 g a v e 8 9 . A f t e r - 55 -f u r t h e r p r e p a r a t i o n o f c h l o r o k e t o n e 9 0 , t h e s e c o n d k e y s t e p was a c h i e v e d b y p e r f o r m i n g a s e c o n d m e t h y l e n e c y c l o p e n t a n e a n n u l a t i o n ( K H , T H F , R T , 6 9 % y i e l d ) , a n d d e o x y g e n a t i o n t o a f f o r d 9J_. Scheme 19 Rfi S y n t h e s i s o f 51_, b y E. P i e r s a n d V. K a r u m a r a t n e Two o t h e r s y n t h e s e s r e l a t e d t o 51_ s h o u l d be m e n t i o n e d . The f i r s t s hown i n Scheme 2 0 c o n s i s t s o f t h e s y n t h e s i s o f a t r i c y c l o u n d e c a n e s k e l e t o n 96 t h a t c o u l d b e a d a p t e d t o a s y n t h e s i s o f t h e c a p n e l l a n e s o r h i r s u t a n e s . A p h o t o c h e m i c a l a d d i t i o n (MeOH, uv l i g h t o f 254 nm, 9 0 % y i e l d ) i n v o l v i n g c y c l o h e x a n e - 1 , 3 - d i o n e 92^ a n d c y c l o p e n t e n e ( 9 3 ) a f f o r d e d b i c y c l i c d i k e t o n e 9 4 . C o u p l i n g o f 94 u s i n g a l o w v a l e n c e t i t a n i u m s p e c i e s ( T i C l ^ , K, T H F , 5 m i n , o n l y p r o d u c t ) g a v e o l e f i n 96_. - 56 -Scheme 20 S y n t h e s i s o f a C s k e l e t o n r e l a t e d t o 5 1 , 87 b y J . E . Paw a n d A . C . Weedon A- + ° o 9 2 93 i 94 OH 96 95 88 F i n a l l y , a n o t h e r s y n t h e s i s by P a t t e n d e n h a s d i o l 53 f o r i t s t a r g e t ( S c heme 2 1 ) . A s t a n n i c c h l o r i d e ( m o i s t C F ^ C ^ , 6 3 % y i e l d ) i n d u c e d c y c l i z a t i o n o f e n o l a c e t a t e 97 p r o d u c e d b i c y c l o o c t a n o n e 9 8 . F u r t h e r r e a c t i o n s l e d t o t h e k e t o a c e t y l e n e 99_. The l a s t c y c l i z a t i o n was a c c o m p l i s h e d w i t h s o d i u m n a p h t h a l e n e r a d i c a l a n i o n ( T H F , 2 5 ° , 2 6 % y i e l d ) a n d a f f o r d e d a f t e r a n o x i d a t i o n s t e p , d i o l 53_. - 57 -Scheme 21 S y n t h e s i s o f 5_3, by G. P a t t e n d e n a n d S . J . T e a q u e ' I n summary, the ten syntheses presented in Schemes 12 to 21 can be divided into 3 categories. I n the first, the rings were assembled one at a time. F o r example, in Schemes 1 3 , 14 and 1 6 , ring B was attached to ring A; then ring C added; in Schemes 1 2 , 19 and 2 1 , rings A and C were joined to ring B. The second group consists of the biogenetic type syntheses. I n one case, Scheme 1 5 , the "starting material" was a medium ring molecule ( h u m u l e n e ) possessing the 15 carbons necessary for 51_. A f t e r several transformations via tricycloLe.3.0 1' 8.0 2' 4] and tricyclor.6.3.01 ^ . O 7 ' 1 1 ] -undecanes, the triquinane system was obtained. I n Schemes 17 and 2 0 , the key intermediate was a bicyclo[6.3.0]undecane molecule (related to precapnelladiene). The required tricyclopentanoid was then obtained through an intramolecular cyclization. - 58 -Scheme 18 represents another special approach. Starting with a 5 and a 6 membered ring, a t r i c y c l i c intermediate was formed, followed by a pentacyclic ring system and f i n a l l y the t r i c y c l i c target. - 59 -I I I . 2 . R e s u l t s a n d D i s c u s s i o n T h i s s e c t i o n d e s c r i b e s s t u d i e s a i m e d a t t h e t o t a l s y n t h e s i s o f t h e t r i c y c l o p e n t a n o i d m a r i n e n a t u r a l p r o d u c t , c a p n e l l e n e ( 5 J _ ) . The r e s u l t s a r e d i s c u s s e d c h r o n o l o g i c a l l y i n o r d e r t o show t h e l o g i c a l d e v e l o p m e n t o f t h e p r e s e n t w o r k . Ou r f i r s t r e t r o s y n t h e t i c a n a l y s i s ( S cheme 2 2 ) o f 51_ e n v i s a g e d t h e d i s c o n n e c t i o n o f t h e C - 5 , C-6 b o n d o f r i n g B , p r e c e d e d by t h e d i s c o n n e c t i o n o f t h e C - 1 0 , C - l l b o n d . T h e r e f o r e , t h e s y n t h e s i s b e g i n s w i t h t h e p r e p a r a t i o n 89 o f t h e a p p r o p r i a t e r i n g A , w h i c h w o u l d l a t e r be j o i n e d t o r i n g C . Scheme 22 E n o l e t h e r a p p r o a c h t o 51 numbered 1 0 0 according to capnellene Eto 103 102 As i l l u s t r a t e d i n Scheme 2 3 , o u r f i r s t a p p r o a c h t o r i n g A s t a r t e d w i t h c y c l o p e n t a n o n e ( 1 0 4 ) . A f t e r f o r m a t i o n o f m e t h y l 2 - o x o c y c l o p e n t a n e c a r b o x y l a t e 90 ( 1 0 5 ) , t r i m e t h y l a t i o n o f t h e B - k e t o - e s t e r a n d r e d u c t i o n o f k e t o n e 107_ , a l c o h o l 1 0 8 was o b t a i n e d w i t h a v e r y g o o d o v e r a l l y i e l d ( 3 0 % f r o m 1 0 4 , o r 5 6 % f r o m 1 0 5 ) . T h e 1H NMR o f a l c o h o l 1 0 8 d i s p l a y s a s i n g l e t a t 4.05 ppm, w h i c h i s a s s i g n e d t o t h e m e t h i n e p r o t o n . T h e p r e s e n c e o f o n l y o n e new s i n g l e t , - 60 -i n d i c a t e s t h a t p r o b a b l y o n l y o n e a l c o h o l i s o m e r i s f o r m e d . The o r i e n t a t i o n 91 i s u n c e r t a i n b u t i f t h e r e a g e n t c o o r d i n a t e s w i t h t h e e s t e r , t h e n i s o m e r 1 0 8 b w o u l d b e o b t a i n e d . A l l a t t e m p t s t o d i s p l a c e t h e a l c o h o l b y a b r o m i n e o r c h l o r i n e s e e m e d t o be u n s u c c e s s f u l1. A s p a c e - f i l l i n g m o d e l o f 108 s h o w e d t h a t t h e d i f f i c u l t y e n c o u n t e r e d i n d i s p l a c i n g t h e a l c o h o l i s due t o s t e r i c h i n d r a n c e , r e g a r d l e s s o f t h e a l c o h o l i s o m e r c o n s i d e r e d . I t was a p p r e c i a t e d t h a t t h e r e s u l t i n g G r i g n a r d ( o r l i t h i u m ) r e a g e n t w o u l d be q u i t e h i n d e r e d , h o w e v e r t - b u t y l g r o u p s w e r e s u c c e s s f u l l y a d d e d t o 103 i n r e l a t e d e x p e r i m e n t s1 1. Scheme 23 S y n t h e s i s o f 1 0 8 O O Q O Q 104 105 1 0 6 108 107 o : « O H b:—OH c: Br I H y d r o x y l g r o u p d i s p l a c e m e n t s t r i e d : • t r i p h e n y l p h o s p h i n e , b r o m i n e , DMF; p h o s p h o r u s t r i b r o m i d e , e t h e r ; p - t o l u e n e s u l f o n y l c h l o r i d e , p y r i d i n e ; h y d r o b r o m i c a c i d ( g ) , THF; p h o s p h o r u s d i b r o m i d e , p y r i d i n e , s o d i u m b r o m i d e ; t h i o n y l c h l o r i d e , p y r i d i n e , r e f l u x , o r s o d i u m c h l o r i d e i n b e n z e n e ; a l u m i n u m t r i c h l o r i d e , e t h e r ; m e t h a n e s u l f o n y l c h l o r i d e , p y r i d i n e ; p h o s p h o r u s p e n t a c h l o r i d e , c a l c i u m c a r b o n a t e , c h l o r o f o r m . No MS was a v a i l a b l e a t t h e t i m e . I I S . J . A l w a r d , u n p u b l i s h e d r e s u l t s , r e a c t i o n b e t w e e n t - b u t y l l i t h i u m a n d 3 - e t h o x y - 2 - m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 0 3 ) . - 61 -W h i l e t h e s e e x p e r i m e n t s w e r e i n p r o g r e s s c y c l o p e n t e n o n e a n n u l a t i o n 93 r e s u l t s b ecame a v a i l a b l e . The w o r k u n d e r t a k e n by c o l l e a g u e s i n o u r l a b o r a t o r y i n d i c a t e d t h a t s t e p " f " ( S cheme 2 2 ) w o u l d n o t be s t r a i g h t -f o r w a r d . T h u s , i t was d e c i d e d t h a t a n o t h e r r o u t e t o w a r d s t h e s y n t h e s i s o f 5J_ m i g h t p r o v e m o r e r e w a r d i n g . Th e s e c o n d a p p r o a c h s e l e c t e d ( S cheme 2 4 ) was b a s e d o n a n i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n o f 1 0 9 . I t was a n t i c i p a t e d t h a t B a e y e r - V i l l i g e r o x i d a t i o n o f t e t r a c y c l i c k e t o n e 110 w o u l d be d i r e c t e d by t h e p r e s e n c e o f t h e a l l y l i c d o u b l e b o n d . R i n g o p e n i n g o f l a c t o n e T_T_1_ f o l l o w e d by h y d r o -g e n a t i o n w o u l d l e a d t o c a p n e l l e n e 51_. The i n t r o d u c t i o n o f a k e t o n e ( l a t e r a d o u b l e b o n d ) t o r i n g C c o u l d be a c c o m p l i s h e d by a l l y l i c o x i d a t i o n a t s e v e r a l p o t e n t i a l p o i n t s . The p r o p o s e d r o u t e w o u l d p r o v i d e a c c e s s t o o x y g e n a t e d c a p n e l l a n e s . I t was h o p e d t h a t i n t e r m e d i a t e 112 c o u l d e v e n t u a l l y be u s e d t o p r e p a r e r e l a t e d t r i q u i n a n e s v i a o z o n o l y s i s a n d b a s e c a t a l y z e d r i n g c l o s u r e . T h i s a p p r o a c h ( S c h e m e 2 4 ) was s e l e c t e d s i n c e i t a l l o w s g o o d s t e r e o c o n t r o l a n d v e r s a t i l i t y . A s w i l l be o u t l i n e d b e l o w , t h e p r e p a r a t i o n o f a c y c l o p e n t a d i e n e d e r i v a t i v e r e l a t e d t o 109 h a s p r o v e d p a r t i c u l a r l y c h a l l e n g i n g . I n s p i t e o f s e v e r a l p o s s i b l e s t a r t i n g m a t e r i a l s a n d r o u t e s t o 1 0 9 , e s t a b l i s h i n g t h e d o u b l e b o n d s i n t h e r e q u i r e d p o s i t i o n r e p r e s e n t e d a m a j o r t a s k . - 62 -Scheme 24 C y c l o p e n t a d i e n e A p p r o a c h t o C a p n e l l e n e 115 114 - 63 -Our f i r s t a p p r o a c h t o 109 a p p e a r e d t o be d i r e c t , a n d o f f e r e d t h e o p p o r t u n i t y t o i n c r e a s e o u r u n d e r s t a n d i n g o f t h e b e h a v i o u r a n d r e a c t i v i t y o f f u s e d b i c y c l o p e n t a d i e n e s y s t e m s . A l k y l a t i o n o f c y c l o p e n t a d i e n e ( 1 1 6 , Scheme 2 5 ) w i t h a s u i t a b l e t h r e e c a r b o n c h a i n , f o l l o w e d b y a n i n t r a m o l e c u l a r a l k y l a t i o n , was e x p e c t e d t o g i v e b i c y c l o [ 3 . 3 . 0 ] o c t a d i e n e 1 2 0 . T h i s s e c o n d s t e p c o u l d p r o d u c e e i t h e r s t r u c t u r a l i s o m e r 119 o r 1 2 0 . ( O n l y o n e p o s i t i o n a l i s o m e r o f 120 i s i l l u s t r a t e d i n Scheme 2 5 ) . The s p i r o s y s t e m 1_1_9 i s known t o be u n s t a b l e1, a n d t h u s 120^ s h o u l d be p r e f e r r e d . A l s o , i f Y i n s t r u c t u r e 118 ( S c h e m e 2 5 ) r e p r e s e n t s a s p e c i e s p o s s e s s i n g a c a r b o n y l g r o u p , a p r o d u c t s u c h a s 120 s h o u l d be e v e n m o r e f a v o u r e d .1 1 Scheme 25 A l k y l a t i o n o f c y c l o p e n t a d i e n e 116 116 117 118 y ^ J ^ 1 2 0 S p i r o m o l e c u l e 1_1_9_ was r e p o r t e d o v e r t h i r t y y e a r s a g o , a n d some 9 5 _ 9 7 c o n t r o v e r s y s u r r o u n d s i t s f i r s t s y n t h e s i s 1 1 A c c o r d i n g t o B a l d w i n ' s r u l e s , 5 - e x o - t e t a n d 4 - e x o - t e t p r o c e s s e s a r e f a v o u r e d , h o w e v e r " f i v e a n d s i x membered r i n g c ompounds a r e f o r m e d m o r e 98 e a s i l y t h a n t h e i r a n a l o g u e s w i t h s m a l l e r o r l a r g e r r i n g s " . - 6 4 -T a b l e 4 C o n d i t i o n s f o r t h e a l k y l a t i o n o f 1_1_6 117 T e m p e r a t u r e T i m e Y i e l d (%) X • Y (°C) ( h ) o f 1 1 8 C l C 0 0 C H3 0 4 75 C0C1 C l -78 1 i 0 1 i i CHO C l 20 2 i i i C l C H ( 0 C H2)2 0 16 82 C l C H ( 0 C H3)2 20 4 89 B r C H20 C 0 C H3 0 4 90 B r CH2C1 -78 6 65 B r C H2B r -45 1 8 8 I CH,I 0 .5 91 - 4 0 % , y i e l d o f p o s s i b l y 1,3:1,1 d i a c e t y l a t e d c y c l o p e n t a d i e n e ( 1 : 4 ) - 4 0 % , y i e l d o f p o s s i b l y 1,3:1,1 d i a c e t y l a t e d c y c l o p e n t a d i e n e ( 1 : 1 ) - 5 % , p o s s i b l y p r o d u c t w i t h a l c o h o l a t o t h e c y c l o p e n t a d i e n e - 65 -A s e x p e c t e d , t h e f i r s t a l k y l a t i o n o f c y c l o p e n t a d i e n e ( 1 1 6 ) p r o v e d s t r a i g h t f o r w a r d i n a number o f c a s e s ( S c h e m e 25 a n d T a b l e 4 ) . H o w e v e r , when 3 - c h l o r o p r o p i o n y l c h l o r i d e ( 1 1 7 b ) was u s e d , two d i a c y l a t e d p r o d u c t s w e r e o b t a i n e d . A l s o , r e a c t i o n o f c y c l o p e n t a d i e n e w i t h 3 - c h l o r o p r o p a n a l p r o c e e d e d i n p o o r y i e l d ( u n s t a b l e p r o d u c t i f n o t k e p t i n s o l u t i o n ) . P r o d u c t s 1 1 8 w e r e b e s t p u r i f i e d b y c o l u m n c h r o m a t o g r a p h y on n e u t r a l a l u m i n a . When s t a n d a r d f l a s h c h r o m a t o g r a p h y was u s e d , m o r e d e c o m p o s i t i o n o c c u r r e d . I t was a l s o p o s s i b l e t o d i s t i l l some o f t h e s e p r o d u c t s ( i n v a c u o ) , b u t t h e y i e l d s w e r e r e d u c e d t o 2 0 % f r o m 65 t o 9 0 % . M o s t p r o d u c t s c o u l d be r e a d i l y i d e n t i f i e d . O n l y t h e p r o d u c t s o f t h e r e a c t i o n o f c y c l o -p e n t a d i e n e w i t h 3 - c h l o r o p r o p i o n y l c h l o r i d e a n d 3 - c h l o r o p r o p a n a l a r e t e n t a t i v e , a s i n d i c a t e d i n T a b l e 4 . I n o r d e r t o c y c l i z e p r o d u c t s 1 1 8 d a n d 118e ( a c e t a l s ) i t was n e c e s s a r y t o d e p r o t e c t t h e a l d e h y d e . T h i s s t e p c o u l d n o t be a c h i e v e d c l e a n l y u n d e r a v a r i e t y o f c o n d i t i o n s1. C y c l o p e n t a n e a n n u l a t i o n s o f 118a (Y = C 0 0 C H3) , 1 1 8 f (Y c o n v e r t e d t o C H20 T s , C H O ) , 118g (Y = C H2C 1 ) , 118h (Y = C H2B r ) , 1 1 8 i (Y = C H2I ) w e r e a t t e m p t e d u s i n g NaH o r KH (1 o r 2 e q u i v a l e n t s ) , i n d i f f e r e n t s o l v e n t s , ( e t h e r , T H F , DME, DMF, DMSO) a n d a t d i f f e r e n t t e m p e r a t u r e s ( f r o m -78°C t o 1 0 0° C ) . No p r o d u c t was d e t e c t e d f r o m a n y o f t h e s e r e a c t i o n s . U s u a l l y t h e s t a r t i n g m a t e r i a l ( m i l d c o n d i t i o n s ) o r some i n s o l u b l e p r o d u c t 99 was r e c o v e r e d . T h e r e i s a p r e c e d e n t f o r a l k y l a t i n g c y c l o p e n t a d i e n e w i t h e t h y l a c e t a t e a n d a c a t a l y t i c a m o u nt o f b a s e ( N a O E t ) . T h i s m i l d p r o c e d u r e was t r i e d on 1 1 8 a a n d o t h e r m o d i f i c a t i o n s . A l l t h e s e r e a c t i o n s w e r e u n s u c c e s s f u l , w h i c h i s p r o b a b l y p a r t l y d u e t o t h e h i g h s e n s i t i v i t y o f 1 2 0 , t o h e a t a n d b a s e . 1 D e p r o t e c t i o n s t r i e d : 1% h y d r o c h l o r i c a c i d ; o x a l i c a c i d a n d a c e t o n e ; a l u m i n u m t r i c h l o r i d e , d i c h l o r o m e t h a n e ; b o r o n t r i f l u o r i d e e t h e r a t e , e t h e r ; t r i m e t h y l s i l y l c h l o r i d e , s o d i u m i o d i d e , a c e t o n i t r i l e ; t r i m e t h y l s i l y l c h l o r i d e , s o d i u m i o d i d e , a c e t o n i t r i l e a n d b u t a d i e n e . - 6b -Scheme 26 Synthesis of 120, by M.S. Baird and C.B. Reese 120 Q Compound 120 has been previously synthesized as shown in Schemes 26 and 27. However these procedures are not of preparative value. Scheme 27 97 Synthesis of 120, by A. De Meijere and L. Meyer 9 0—OO —CO+120° 0 119 120b Since molecule 1_20 was elusive, a modified approach to 1_26 (Scheme 28), which bears a methyl substituent was examined. The enol ether 103 formed from 2-methyl-1,3-cyclopentanedione (121) has been converted by Koreeda, Liang and Akagi1^ into bicyclic enol ether 122. This sequence was repeated, followed by hydrolysis and reduction of 122. Several dehydrations1 of allylic alcohol 124 were attempted, but no dehydrated product of type 126 1 Dehydrations tried: hydrogen chloride (g), chloroform; phosphorus oxychloride; thionyl chloride; N-phenylselenophthalimide, n-tributyl-phosphine; phosphorus pentachloride, chloroform; trifluoroacetic anhydride, dimethylaminopyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene; p-toluenesulfonyl chloride, pyridine, dichloromethane. In retrospect, the Burgess reagent or methanesulfonyl chloride and the sulfur dioxide dehydrations (see experimental) might have given a better result. - 67 -could be isolated. Thus, alternative step "e" (Scheme 28) which would introduce a second substituent in ring B before dehydration was explored. It is known101 that 3-diketones such as 121_ can be alkylated using methyl vinyl ketone. The product of this Michael addition depends on the reaction conditions (Scheme 29). Under neutral conditions (reaction in water), 121 afforded 128. Under catalytic basic conditions (chromatography of 128_ on alumina, or standing of 128 at 20°C for a few days), ketol 130 was produced. In contrast, when 128 was submitted to acidic conditions, 129 was obtained. Scheme 28 Reactions of 8-diketone 121 121 103 1 2 2 0 • JOH e 0 0 - 6 8 -Scheme 29 Known a l k y l a t i o n o f 121 121 0 127 \ 0 128 1 29 A M i c h a e l a d d i t i o n b e t w e e n 123 a n d m e t h y l v i n y l k e t o n e p r o c e e d e d s a t i s f a c t o r i l y t o g i v e 1 2 5 , a s i n d i c a t e d by t h e IR s p e c t r u m ( n o OH) a n d 'H NMR s p e c t r u m ( C H3 > s , 0.94 a n d 2.02 p p m ) , c h a r a c t e r i s t i c o f a n o n - c y c l i z e d p r o d u c t . S e l e c t i v e f u n c t i o n a l i z a t i o n1 o f t h e m e t h y l k e t o n e i n 125 d i d n o t p r o c e e d a s e x p e c t e d . T h e r e f o r e a 1 , 6 - a d d i t i o n b e t w e e n 2 - m e t h y l - 1 , 3 - c y c l o p e n t a n e -d i o n e 121 o r b i c y c l i c k e t o n e 123 a n d 144b was a t t e m p t e d . T he l a t t e r r e a c t i o n 102 d i d n o t a f f o r d t h e r e q u i r e d p r o d u c t e v e n t h o u g h l i t e r a t u r e p r e c e d e n t e x i s t s . S i n c e t h e s e a t t e m p t s w e r e u n s u c c e s s f u l a d i f f e r e n t a p p r o a c h t o t h e b i c y c l i c s k e l e t o n was a d o p t e d . Q R2lR3=H,COOEf b R2=R3=COOMe 1 U R e a c t i o n s a t t e m p t e d : W i t t i g , H o r n e r - E m m o n d s a n d K n o e v e n a g a l c o n d e n s a t i o n s , a s w e l l a s G r i g n a r d a d d i t i o n s . One o f t h e r e s u l t s o b t a i n e d w h i l e i n v e s t i g a t i n g t h e a l k y l a t i o n o f 3 - d i k e t o n e 121 i s p r e s e n t e d i n Scheme 3 0 . I n k e e p i n g w i t h l i t e r a t u r e 103 p r e c e d e n t , 0 r a t h e r t h a n C - a l k y l a t i o n o c c u r r e d when 121 was t r e a t e d w i t h an a l k y l i o d i d e i n a n a p r o t i c p o l a r s o l v e n t (DMF o r HMPA) a n d a m i l d b a s e ( K2C 03) , 121 Scheme 30 O - a l k y l a t i o n o f 121 it 0 0 132 » K> The IR a n d 'H NMR s p e c t r a o f t h e O - a l k y l a t e d p r o d u c t e n a b l e d i t s i d e n t i f i c a t i o n . Two b a n d s a p p e a r e d i n t h e IR s p e c t r u m a t 1700 a n d 1640 cm~\ a n d t h e s e w e r e a s s i g n e d t o a c a r b o n y l a n d a c o n j u g a t e d d o u b l e b o n d . The 'H NMR s p e c t r u m d i s p l a y e d t h e f o l l o w i n g s i g n a l s a t : 6 =. 5.00 ppm ( I H , t , J = 7 H z ) ; 4 . 3 0 ppm ( 2 H , t , J = 7 H z ) ; 3.92 ppm ( 4 H , b s ) a n d 1.58 ppm ( 3 H , b s ) . The r e m a i n i n g s i x p r o t o n s a p p e a r e d a s a m u l t i p l e t b e t w e e n 2.1 a n d 2.8 ppm. The MS o f 132 d i s p l a y e d a v e r y weak ( 3 % ) p a r e n t i o n a t m/z = 2 1 2 . 104 A p a p e r b y C o a t e s a n d Hobbs w h i c h a p p e a r e d i n e a r l y 1 9 8 4 , o f f e r s a v a r i a n t t o t h e M i c h a e l r e a c t i o n . I t i n v o l v e s t h e r e a c t i o n o f r e a d i l y e n o l i z a b l e c a r b o n y l c o m p o unds w i t h a , 3 - e n o l s o r e t h o x y a l l e n e s . I t was o b s e r v e d t h a t t h e r e a c t i o n b e t w e e n 2 - m e t h y l - 1 , 3 - c y c l o p e n t a n e d i o n e ( 1 2 1 ) a n d a c r o l e i n a c e t a l ( C H9C H C H ( O E t )9) t a k e s p l a c e n e a t i n a s e a l e d t u b e , a t 200°C - 70 -i n 33 h ( 8 2 % ) o r i n r e f l u x i n g 1 , 2 - d i c h l o r o e t h a n e , 8 5 ° , i n 0.25 h ( 6 7 % ) . T h i s r e a c t i o n may p r e s e n t a n o t h e r p o s s i b l e a p p r o a c h . A p p r o a c h t o 1 3 8 The r e s u l t s d e s c r i b e d a b o v e i n f l u e n c e d t h e n e x t r o u t e e x a m i n e d w h i c h 1 5 s t a r t s w i t h A ' b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 3 8 ) , a k e t o n e p r e v i o u s l y p r e p a r e d b y s e v e r a l g r o u p s1 0^ '1 0^ . A n o t h e r a p p r o a c h t o t h i s k e t o n e w h i c h h a s a p r e c e d e n t ( f o r a n d a g a i n s t i t ! ! ) i n t h e l i t e r a t u r e1 0 7 , 1 0 8 i s o u t l i n e d i n Scheme 3 1 . D i o l 133 was p r e p a r e d f r o m G r i g n a r d a d d i t i o n o f p r o p a r g y l a l c o h o l ( C l M g C C C H2O M g C l ) t o c y c l o p e n t a n o n e ( 1 0 0 ) . A l t h o u g h t h e ( M e y e r r e a r r a n g e m e n t ) a c i d - c a t a l y z e d r e a r r a n g e m e n t o f t h e t e r t i a r y a - a c e t y l e n i c a l c o h o l 133 t o o k p l a c e ( s i n c e 1 3 4 , 135 a n d t r a c e s o f 136 w e r e p a r t i a l l y i d e n t i f i e d t h r o u g h 'H NMR a n d IR s p e c t r a , s e e E x p e r i m e n t a l ) , t h e s e n s i t i v e d i e n o n e 136 d i d n o t u n d e r g o t h e N a z a r o v c y c l i z a t i o n . I n s t e a d , k e t o n e 137 ( s e l f - c o n d e n s a t i o n o f 1 0 4 ) , f o r m e d b y d e c o m p o s i t i o n o f t h e G r i g n a r d p r o d u c t was i s o l a t e d . A l t h o u g h t h e IR a n d 'H NMR s p e c t r a o f b i c y c l o p e n t y l i d e n - 2 - o n e 1 5 ( 1 3 7 ) w e r e s i m i l a r t o t h o s e o f A ' - b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e 1_38, t h e MS o f t h e DNPH d e r i v a t i v e o f 1_37 ( M+ = 3 3 0 C1 6H1 8N40c, t h e r e f o r e t h e m o l e c u l a r 13 f o r m u l a o f t h e k e t o n e i s C ^ H ^ O ) a n d t h e C NMR s p e c t r u m ( 1 0 s i g n a l s o b s e r v e d a t : 2 0 . 0 9 , 2 5 . 2 3 , 2 6 . 9 4 , 2 9 . 5 2 , 3 2 , 5 5 , 3 4 . 3 0 , 3 9 . 7 9 , 1 2 8 . 6 9 , 1 5 8 . 6 6 a n d 2 0 7 . 3 9 ppm) l e f t no d o u b t a s t o t h e d i m e r i c n a t u r e o f t h i s p r o d u c t . T h e r e f o r e , 138 was s y n t h e s i z e d a c c o r d i n g t o t h e known r o u t e shown i n Scheme 3 11 0 5. The a p p r o a c h i l l u s t r a t e d i n Scheme 3 1 , c o n s i s t s o f a l k y l a t i n g B - k e t o -e s t e r 105 w i t h m e t h y l a c r y l a t e ; d e c a r b o x y l a t i n g t h e B - k e t o - e s t e r a n d h y d r o l y z i n g t h e p r i m a r y e s t e r o f 139_ i n o n e s t e p . . R e d u c i n g t h e k e t o n e o f 1_40 a n d f i n a l l y p e r f o r m i n g a M e y e r r e a r r a n g e m e n t . The f o u r s t e p s o f t h i s s y n t h e s i s w e r e r e p o r t e d t o g i v e 9 2 , 9 0 , 97 a n d 7 7 % y i e l d , r e s p e c t i v e l y . The f i r s t t h r e e s t e p s - 71 -c o u l d be r e p r o d u c e d i n t h e same q u a n t i t a t i v e way ( 7 3 % o v e r a l l y i e l d ) , h o w e v e r t h e c y c l i z a t i o n s t e p p r o c e e d e d i n 3 0 - 4 0 % y i e l d .1 T h e r e f o r e , i n s t e a d o f u s i n g p o l y p h o s p h o r i c a c i d ( f ^ O g , "3^4) a s i n K i i l k a r n i a n d D e v ' s s y n t h e s i s 1 0 5 ; E a s t o n , C a r l s o n a n d L e e ' s i m p r o v e d a l t e r n a t i v e1 1 0 ( ^ 2 ^ 5 ' C^SO^rl) was f o l l o w e d . T h i s m i x t u r e was e a s i e r t o h a n d l e a n d d i d n o t r e q u i r e a c o n t i n u o u s e x t r a c t i o n i n t h e w o r k - u p p r o c e d u r e . When t h i s m o d i f i e d c y c l i z a t i o n p r o c e d u r e was u s e d , t h e y i e l d s i n c r e a s e d t o 6 0 % . A c c o r d i n g t o t h e IUPAC N o m e n c l a t u r e o f O r g a n i c C h e m i s t r y A1 , 5b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 3 8 ) c a n a l s o be named b i c y c l o [ 3 . 3 . 0 ] -o c t - 1 ( 5 ) - e n - 2 - o n e o r 1 ( 5 ) - b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e . T h e s e two v a r i a t i o n s a p p l y t o t h e m o l e c u l e s w h e r e t h e d e l t a n o m e n c l a t u r e h a s b e e n u s e d . - 72 -Scheme 31 S y n t h e s i s o f 1 , 5- b i c y c 1 o 3 . 3 . 0 o c t e n o n e ( 1 3 8 ) 140 141 - 73 -The n e x t s t e p s i n t h e s y n t h e s i s r e q u i r e s e q u e n t i a l a 1 a l k y l a t i o n s o f 1 3 8 . H o w e v e r , due t o i t s r e a d y a v a i l a b i l i t y , 3 - m e t h y l - 2 - c y c l o p e n t e n o n e 142 was c h o s e n a s a m o d el f o r m o s t o f t h e n e x t r e a c t i o n s . The s e l e c t i v e f o r m a t i o n a n d r e a c t i o n o f a n a n i o n f r o m t h e s e c y c l o p e n t e n o n e s was e x p e r i m e n t a l l y t r o u b l e s o m e . M o d e l compound 142 was e v e n m o r e s e n s i t i v e t h a n 1 3 8 . I n o r d e r t o m i n i m i z e t h e s e l f - c o n d e n s a t i o n o f t h e s e k e t o n e s , i t was n e c e s s a r y t o p e r f o r m t h e r e a c t i o n s ( i n v o l v i n g a c a r b a n i o n ) a t l o w t e m p e r a t u r e s (< 2 0 ° C ) , u s i n g r e l a t i v e l y r e a c t i v e e l e c t r o p h i l e s ( r e a c t i n g i n a f e w m i n u t e s ) . T h e r e f o r e , an a c t i v a t i n g g r o u p was n e e d e d a s t h e f i r s t a' s u b s t i t u e n t t o f a c i l i t a t e t h e i n t r o d u c t i o n o f t h e s i d e c h a i n . T h i s a c t i v a t i n g g r o u p c o u l d l a t e r b e c o n v e r t e d i n t o a m e t h y l g r o u p . A number o f r e a g e n t s w e r e e x a m i n e d : d i m e t h y l c a r b o n a t e ( C 0 ( 0 M e )2) was n o t s u f f i c i e n t l y r e a c t i v e , m e t h y l c h l o r o -f o r m a t e (CICOOMe) was t o o r e a c t i v e , b u t d i e t h y l p y r o c a r b o n a t e ( D E P C , 0 ( C 0 0 E t )2) d i e t h y l o x a l a t e ( ( C 0 0 E t )2) a n d e t h y l f o r m a t e (HCOOEt) c o u l d be u s e d a s d e s c r i b e d i n t h e n e x t p a g e s . 0 0 1 4 2 138 - 74 -A p p r o a c h U s i n g 138 a n d D i e t h y l O x a l a t e I t h a s b e e n r e p o r t e d i n t h e l i t e r a t u r e1 1 1, t h a t u p o n r e a c t i o n o f c y c l o -h e x a n o n e w i t h d i e t h y l o x a l a t e , 143_ i s o b t a i n e d i n 65% y i e l d (Scheme 32). D e c a r b o n y l a t i o n o f 143, u s i n g p o w d e r e d g l a s s a n d i r o n p o w d e r , a t 165-175°C p r o d u c e s t h e r e l a t e d B - k e t o - e s t e r (65%). The same r e a c t i o n s w e r e e x p e c t e d w i t h 138 a n d 142, a n d t h u s t h e a c y l a t i o n was c o n d u c t e d a c c o r d i n g t o t h e l i t e r a t u r e (95% a n d 65% y i e l d ) . D e c a r b o n y l a t i o n o f t h e c y c l o p e n t e n o n e d e r i v a t i v e s , u n d e r t h e r e p o r t e d c o n d i t i o n s a n d h i g h e r t e m p e r a t u r e s ( i n c l u d i n g s e a l e d t u b e s ) p r o v e d i m p o s s i b l e . T h e r e f o r e , t h e r e d u c t i o n a n d a l k y l a t i o n o f 145 was s t u d i e d (Scheme 33). Scheme 32 A known r e a c t i o n o f c y c l o h e x a n o n e 143 R e d u c t i o n o f 145 ( w i t h NaBH^ i n MeOH), c l e a n l y r e d u c e d t h e u n s a t u r a t e d c a r b o n y l (76%). The t r i f l u o r o e s t e r o f t h i s a l c o h o l 146 was f o r m e d q u a n t i t a t i v e l y (98%, upon a d d i t i o n o f T F A A , DMAP i n CH2C12 a t 20°C). The p r o p o s e d s t r u c t u r e f o r 146 was s u p p o r t e d by i t s 'H NMR a n d IR s p e c t r a . A d e s h i e l d e d s i g n a l a p p e a r e d i n t h e 'H NMR s p e c t r u m a t 5.40 ppm ( d , J = 3 H z ) . The c h e m i c a l s h i f t o f t h i s m e t h i n e c o r r e s p o n d e d t o t h e r e d u c t i o n o f t h e u n s a t u r a t e d c a r b o n y l4 1 (6 e x p e c t e d : -v5.6 p p m ) , r a t h e r t h a n t o t h e s i d e c h a i n c a r b o n y l4 1 (6 e x p e c t e d : -6.1 p p m ) . The s m a l l c o u p l i n g o b s e r v e d r e p r e s e n t e d a v i c i n a l c o u p l i n g b e t w e e n H-l a n d H-8 (0ft_Q e x p e c t e d t o be - 75 -7 H z ) . The IR s p e c t r u m o f t h i s e s t e r d i s p l a y e d b a n d s a t 1 8 0 0 , 1 7 5 0 , 1700 an d 1 6 3 0 c m "1. T h e f i r s t b a n d was a s s i g n e d t o t h e t r i f l u o r o e s t e r , t h e s e c o n d t o t h e e t h y l e s t e r , t h e t h i r d t o t h e k e t o n e a n d t h e l a s t p o s s i b l y t o a d o u b l e b o n d . A n o t h e r o b s e r v a t i o n t h a t s u p p o r t e d t h i s i n t e r p r e t a t i o n , t h a t t h e r e d u c t i o n t o o k p l a c e a t t h e u n s a t u r a t e d c a r b o n y l , comes f r o m TLC a n a l y s i s . A DNPH s p r a y was u s e d t o v i s u a l i z e t h e s p o t s on T L C . I n t h e c a s e o f compound 1 4 5 , a r e d c o l o u r was o b s e r v e d w h i l e f o r 1 4 6 , a n o r a n g e c o l o u r was p r o d u c e d . 112 S i n c e DNPH d e r i v a t i v e s o f u n s a t u r a t e d c a r b o n y l s a r e known t o be c o l o u r e d r e d r a t h e r t h a n o r a n g e ( q u a l i t a t i v e t e s t , n o t q u a n t i t a t i v e ) , t h i s r e s u l t w o u l d t e n d t o s u p p o r t t h e s p e c t r a l d a t a . Scheme 33 R e a c t i o n s p e r f o r m e d on 145 COOMe The t r i f l u o r o e s t e r o f 146 c o u l d r i o t be r e a d i l y e l i m i n a t e d ( u s i n g DBU) t o g i v e t h e d i e n e . S i n c e a l c o h o l 146 d o e s n o t r e p r e s e n t a v e r y g o o d model f o r a l c o h o l 1 4 8 ( w h i c h h a s a t e t r a s u b s t i t u t e d a c a r b o n , Scheme 3 3 ) , t h e d e h y d r a t i o n o f 146 was n o t e x t e n s i v e l y s t u d i e d . - 76 -I n v i e w o f t h e e n c o u r a g i n g r e s u l t s o f t h e r e d u c t i o n s t u d y , o u r a t t e n t i o n was t u r n e d t o t h e a l k y l a t i o n o f 145_. A m e t h o d was d e v e l o p e d f o r t h e a l k y l a t i o n o f 5 - c a r b o x y - 2 - c y c l o p e n t e n o n e s w i t h a c h l o r o e s t e r s u c h as-131 ( a o r b ) . T h i s a l k y l a t i n g r e a g e n t c a n r e a c t i n two c o m p e t i n g m a n n e r s . I n t h e p r e s e n t c a s e , d i s p l a c e m e n t o f t h e c h l o r i n e was a n t i c i p a t e d , h o w e v e r a b s t r a c t i o n o f t h e y p r o t o n (y t o t h e e s t e r ) f o l l o w e d by e l i m i n a t i o n may c o m p e t e . C o n d i t i o n s w e r e f o u n d w h i c h f a v o r e d t h e a l k y l a t i o n a n d r e d u c e d t h e s i d e r e a c t i o n . T h e s e c o n s i s t e d o f u s i n g s o d i u m e t h o x i d e t o g e n e r a t e an i n s o l u b l e a n i o n o f t h e 5 - c a r b o x y - 2 - c y c l o p e n t e n o n e i n e t h e r a t 2 0°C, a d d i n g DMSO a n d t h e a l k y l h a l i d e , a n d s t i r r i n g t h e r e a c t i o n m i x t u r e i n a p r e - w a r m e d ( 7 5 - 8 0°C ) b a t h , f o r t w o h o u r s ( s e e E x p e r i m e n t a l , T a b l e 7 , f o r s e v e r a l e x a m p l e s ) . When r e a g e n t 1 3 1 a ( 1 : 1 , E;Z) was u s e d , t h e E i s o m e r ( t r a n s ) r e a c t e d a t a h i g h e r r a t e t h a n t h e Z i s o m e r . T h e r e f o r e , t w o e q u i v a l e n t s o f t h e a l k y l c h l o r i d e 1 3 1 a w e r e u s e d a n d t h e Z i s o m e r ( c i s ) r e c o v e r e d a f t e r w o r k - u p . When r e a g e n t 1 31b was u s e d , t h e d e h y d r o h a l o g e n a t e d d i e s t e r was r e c o v e r e d . I n t h i s c a s e , 1.1 e q u i v a l e n t s o f 131b w e r e u s e d . The b i c y c l i c m o l e c u l e 1_45_ was a l k y l a t e d w i t h d i e s t e r 131b ( 9 0 % y i e l d ) . D u r i n g t h i s a l k y l a t i o n , t h e d o u b l e b o n d i n t h e s i d e c h a i n i s o m e r i z e d o u t o f c o n j u g a t i o n ( a s i n 1 4 7 , Scheme 3 3 ) . The i s o m e r i z a t i o n was e a s i l y i d e n t i f i e d f r o m t h e 'H NMR s p e c t r u m . The c h e m i c a l s h i f t o f t h e s i g n a l a s s i g n e d t o t h e Cl 131 - 77 -v i n y l m e t h y l c h a n g e d f r o m 2.01 ppm ( s ) i n 131b t o 1.68 ppm ( b s ) i n 1 4 7 , w h i l e a new o l e f i n i c s i g n a l a p p e a r e d a t 5.04 ppm ( t , J = 7 H z )1. The p r e s e n c e o f b a s e i n t h e s o l u t i o n a p p e a r e d t o p r o m o t e t h e f o r m a t i o n o f t h e m o r e s t a b l e d o u b l e b o n d i s o m e r ( n o n - c o n j u g a t e d ! ) . T h i s b e h a v i o u r has a l s o 113 b e e n o b s e r v e d by D a n i s h e f s k y , K o p p e l a n d L e v i n e A f t e r a l k y l a t i o n o f 145 a n d r e d u c t i o n o f 1 4 7 , a p r o d u c t w i t h no e t h o x y g r o u p was i s o l a t e d t o g e t h e r w i t h t h e e x p e c t e d a l c o h o l (Scheme 3 3 ) . The r e d u c t i o n was p e r f o r m e d w i t h s o d i u m b o r o h y d r i d e o r s o d i u m c y a n o b o r o h y d r i d e i n m e t h a n o l o r w a t e r i n t h e p r e s e n c e o f ammonium c h l o r i d e o r a t pH 4 . H o w e v e r t h e f o r m a t i o n o f t h e s i d e p r o d u c t 149 c o u l d n o t be e l i m i n a t e d . S t r u c t u r e 149_ ( S c h e m e 3 3 ) h a s b e e n t e n t i t a t i v e l y a s s i g n e d t o t h i s m a j o r r e d u c t i o n p r o d u c t ( a l c o h o l : l a c t o n e , 1 : 4 ) , b a s e d on t h e l a c k o f O E t g r o u p i n t h e 'H NMR s p e c t r u m a n d t h e IR s p e c t r u m w h i c h s h o w e d no b a n d c o r r e s p o n d i n g t o a n OH. T r e a t m e n t o f a l c o h o l 148 w i t h t r i f l u o r o a c e t i c a n h y d r i d e , d i m e t h y l a m i n o -p y r i d i n e , a n d t h e n 1 , 5 - d i a z a b i c y c l o [ 5 . 4 . 0 ] u n d e c - 5 - e n e , a c h i e v e d p a r t i a l i s o m e r i z a t i o n o f t h e s i d e c h a i n d o u b l e b o n d ( b a c k i n t o c o n j u g a t i o n a s i n s t r u c t u r e 13,1b), a n d t h e i s o l a t i o n o f t h e t r i f l u o r o e s t e r o f 1 4 8 . The p r e s e n c e , o f t h e t r i f l u o r o e s t e r was m a i n l y d e d u c e d f r o m i t s IR s p e c t r u m . The 3 3 0 0 - 3 5 0 0 c m- 1 b a n d a s s i g n e d t o a n OH g r o u p h a d d i s a p p e a r e d a n d a new b a n d c h a r a c t e r i s t i c o f 0 C 0 C F3 a p p e a r e d a t 1800 c m "1. A s i g n a l due t o H C ( 0 C 0 C F3) was o b s e r v e d i n t h e i s o m e r i z e d d e r i v a t i v e a t 5.06 ppm ( s ) . When a s t r o n g e r b a s e was u s e d t o e l i m i n a t e H 0 C 0 C F3, o n l y h y d r o l y s i s o f t h e e s t e r was o b s e r v e d upon w o r k - u p ( n o e l i m i n a t i o n ) . O t h e r d e h y d r a t i o n p r o c e d u r e s p e r f o r m e d on a l c o h o l 148 d i d n o t l e a d t o a c y c l o p e n t a d i e n e d e r i v a t i v e . 1 E t h y l 3 - m e t h y l - 2 , 4 - p e n t a d i e n o a t e 1 4 4 a h a s a l s o b e e n u s e d i n l a t e r a l k y l a t i o n e x p e r i m e n t s ( M i c h a e l a d d i t i o n , s e e T a b l e 7 i n e x p e r i m e n t a l f o r m o d e l r e a c t i o n s w h i c h w i l l n o t be d i s c u s s e d ) . An i s o m e r i z a t i o n o f t h e s i d e c h a i n d o u b l e b o n d was a l s o o b s e r v e d . The c h e m i c a l s h i f t o f t h e v i n y l m e t h y l a n d o l e f i n i c p r o t o n a r e d i f f e r e n t f o r 1 4 4 a ( 2 . 1 8 ppm, C H3, s f o r E i s o m e r ; 5.71 ppm, I H , b s ) a n d f o r t h e p r o d u c t (1.71 ppm, C HV b s ; 5.06 ppm, I H , t , J = 7 H z ) . - 78 -A p p r o a c h U s i n g 1 3 8 a n d E t h y l C h l o r o f o r m a t e Due t o t h e c o m p l i c a t i o n s e n c o u n t e r e d w i t h t h e f i r s t a c t i v a t i n g g r o u p ( C O C O O E t ) , a n o t h e r known a c t i v a t i n g g r o u p (CHO) was c h o s e n . R e a c t i o n o f . 114 e t h y l c h l o r o f o r m a t e w i t h k e t o n e s p r o d u c e s B - k e t o - a l d e h y d e s . I t was a n t i c i p a t e d t h a t o x i d a t i o n o f t h e u n s a t u r a t e d g - k e t o - a l d e h y d e 150 (Scheme 3 4 ) a n d e s t e r i f i c a t i o n o f t h e r e s u l t i n g c a r b o x y l i c a c i d w o u l d g i v e a s t a b l e B - k e t o - e s t e r . I n p r a c t i c e , t h e a c y l a t i o n o f t h e c y c l o p e n t e n o n e s t o o k p l a c e ( 4 5 a n d 6 0 % y i e l d , r e a c t i o n o f 142 a n d 1 3 8 ) , b u t t h e a l d e h y d e c o u l d n o t be c o n v e r t e d i n t o a B - k e t o - e s t e r1. T h e r e f o r e , t h e a l k y l a t i o n o f 1_50 w i t h 131b was p e r f o r m e d a s d e s c r i b e d i n t h e p r e v i o u s s e c t i o n ( 5 8 % ) a n d t h e t o s y l h y d r a z o n e d e r i v a t i v e 152 o f t h e a l d e h y d e was p r e p a r e d . S i m u l t a n e o u s r e d u c t i o n o f t h e c a r b o n y l a n d h y d r a z o n e l e a d i n g t o an u n s a t u r a t e d a l c o h o l a n d m e t h y l g r o u p 115 was e x p e c t e d . S o d i u m b o r o h y d r i d e a n d c a t e c h o l b o r a n e r e d u c t i o n s w e r e t r i e d a t s e v e r a l t e m p e r a t u r e s . The a l c o h o l was o b t a i n e d , b u t t h e t o s y l -h y d r a z o n e d i d n o t a f f o r d a m e t h y l g r o u p . T h e s e o b s e r v a t i o n s a r e b a s e d on t h e 'H NMR a n d IR s p e c t r a l d a t a . No m e t h y l d e r i v a t i v e was i s o l a t e d . R e d u c t i o n o f t h e B - k e t o - a l d e h y d e t o a d i o l , t o s y l a t i o n o f t h e p r i m a r y a l c o h o l a n d s u b s e q u e n t r e d u c t i o n t o a m e t h y l g r o u p a l s o d i d n o t g i v e e n c o u r a g i n g r e s u l t s . O x i d a t i o n s t r i e d : J o n e s r e a g e n t ; m a n g a n e s e d i o x i d e , s o d i u m c y a n i d e , a c e t i c a c i d ; s i l v e r o x i d e , T H F , w a t e r . - 79 -Scheme 34 R e a c t i o n s p e r f o r m e d on T_50 COOMe 152 - 8 0 -The U s e o f D i e t h y l P y r o c a r b o n a t e ( D E P C ) " ° : A t t h i s p o i n t o f o u r i n v e s t i g a t i o n s , i t seemed d e s i r a b l e t o c o n s t r u c t u n s a t u r a t e d 3 - k e t o - e s t e r s 1_59 a n d l_6fJ_ ( T a b l e 6 ) d i r e c t l y f r o m t h e r e q u i s i t e u n s a t u r a t e d k e t o n e . As i n d i c a t e d i n T a b l e 5 s e v e r a l r e a g e n t s h a v e b e e n e m p l o y e d i n t h e l i t e r a t u r e t o e n c o u r a g e C a c y l a t i o n o f v a r i o u s c y c l i c k e t o n e s b u t many o f t h e s e r e q u i r e a d d i t i o n a l s t e p s a f t e r t h e b a s e c a t a l y z e d c o n d e n s a t i o n . A c i d c h l o r i d e s d i s p l a y a t e n d e n c y t o y i e l d e n o l d e r i v a t i v e s a l t h o u g h t h i s may be s u p p r e s s e d by e m p l o y i n g a 2-3 f o l d e x c e s s o f k e t o n e1 1 7, a n i m p r a c t i c a l s o l u t i o n i n t h e m i d d l e o f a t o t a l s y n t h e s i s . T a b l e 5 A c y l a t i o n R e a g e n t s RCOOET R e a c t i o n c o n d i t i o n s B a s e Y i e l d R e f e r e n c e 1 R=H E t h e r , 0-22°C NaOEt 7 0 - 8 0 % 114 2 R=C1 DME, 23°C P h3K 2 9 % ( e n o l ) 118 3 R=0Et B e n z e n e , 80°C NaH 9 2 % 1 1 9 - 1 2 2 4 R =C00Et E t O H , 10°C NaOEt 6 5 % 123 5 R = P 0 ( 0 E t )2 n - B u20 , 3 0 - 6 0°C NaH 8 0 % 124 6 M g ( 0 C 0 0 M e )2 M e2N C H 0 , 130°C Mg 4 5 % 125 I n u n s y m m e t r i c a l k e t o n e s an a d d i t i o n a l c o m p l i c a t i o n o f t e n a r i s e s d ue t o t h e g e n e r a t i o n o f b o t h k i n e t i c a n d t h e r m o d y n a m i c e n o l a t e a n i o n s w h i c h may r e a c t a t d i f f e r e n t r a t e s a n d a f f o r d c o m p l e x p r o d u c t m i x t u r e s , a ; g - U n s a t u r -a t e d k e t o n e s a r e p a r t i c u l a r l y c h a l l e n g i n g s i n c e d o u b l e b o n d m i g r a t i o n may 1 pc a l s o o c c u r . S e l e c t i v e i n t r o d u c t i o n o f a c a r b o e t h o x y g r o u p a t t h e a' p o s i t i o n u s u a l l y r e q u i r e s a s t r o n g n o n n u c l e o p h i 1 i c b a s e , a n a p r o t i c s o l v e n t , - 81 -a n d a r e a c t i v e a c y l a t i o n r e a g e n t i n o r d e r t h a t t h e r e a c t i o n may be c o n d u c t e d a t l o w t e m p e r a t u r e . Our i n v e s t i g a t i o n s r e v e a l e d t h a t d i e t h y l p y r o c a r b o n a t e (DEPC) f u l f i l l s t h e s e r e q u i r e m e n t s p r o v i d i n g a c o n v e n i e n t r o u t e t o b o t h s a t u r a t e d a n d u n s a t u r a t e d 3 - k e t o - e s t e r s a s i l l u s t r a t e d i n t h e g e n e r a l s c h e m e b e l o w . Scheme 35 The U s e o f DEPC The r e s u l t s o f t h i s s t u d y a r e s u m m a r i z e d i n T a b l e 6 . F o r t h e s a t u r a t e d c y c l i c k e t o n e s 153 a n d 104 t h e r e a c t i o n was c o n t r o l l e d b y v a r y i n g t h e c o n d i t i o n s t o g i v e e i t h e r t h e 0 a c y l a t i o n (-78°C, d i e t h y l e t h e r ) o r C a c y l a t i o n ( 8 0°C, b e n z e n e ) p r o d u c t s 154 a n d 156 o r 155 a n d 105 a s d e s i r e d ( e n t r i e s a - h ) . Of t h e b a s e s e x a m i n e d l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y ^ ) w i t h d i e t h y l e t h e r a s t h e s o l v e n t was p r e f e r r e d , p a r t i c u l a r l y f o r t h e u n s a t u r a t e d k e t o n e s i n w h i c h s e l f c o n d e n s a t i o n c o u l d be a p r o b l e m . The n u c l e o p h i l i c a t t a c k o f t h e b a s e on DEPC was m i n i m i z e d by a d d i n g a m i x t u r e o f DEPC a n d t h e k e t o n e t o t h e b a s e a n d c o n d u c t i n g t h e a c y l a t i o n a t - 7 8°C. T h e c o n d i t i o n s T a b l e 6 P r e p a r a t i o n o f C y c l i c 3 - K e t o P r o d u c t E n t r y 1 04 I I 1 05 138 160 R = Et 161 R-Me E s t e r s B a s e P r o c e d u r e Y i e l d ( s e e e x p e r i m e n t a l ) KH A 9 8 % KOtBu A 5 0 % L i N C y2 A 4 7 % KH B 7 2 % KOtBu A 5 2 % KOtBu B 6 2 % L i N C y2 B 6 0 % KH B 6 1 % KOtBu A 0 % ( 5 0 % ) L i N C y2 A 5 8 % ( 2 5 % ) L i N C y2 B . 6 4 % ( 1 4 % ) LDA 6 0 % L i N C y2 A 6 4 % ( 1 5 % ) L i N C y2 B 7 1 % ( 8 % ) LDA 3 5 % L i N C y2 A 3 7 % L i N C y2 B 7 8 % ( 1 5 % ) L i N C y2 B 4 6 % ( 2 2 % ) - 33 -e m p l o y e d w e r e m i l d a n d w e r e e s p e c i a l l y u s e f u l w i t h s e n s i t i v e c o m p o u n d s . I s o l a t e d y i e l d s a r e i n d i c a t e d f o l l o w e d by t h e a m o unt o f r e c o v e r e d s t a r t i n g m a t e r i a l i n p a r e n t h e s e s . The p r o c e d u r e s (A o r B) u s e d a r e d e s c r i b e d i n d e t a i l i n t h e e x p e r i m e n t a l s e c t i o n . D i e t h y l p y r o c a r b o n a t e h a s b e e n u s e d p r e v i o u s l y f o r N a c y l a t i o n i n 127 1 2 8 e n zyme s t u d i e s ' a n d i t s r e a c t i v i t y w i t h n i t r o g e n , o x y g e n , a n d s u l p h u r 129 n u c l e o p h i l e s c o m p a r e d b u t i t s u s e f o r c a r b o n a c y l a t i o n s a p p e a r s n o t t o h a v e b e e n e x a m i n e d . R e c e n t l y d i m e t h y l p y r o c a r b o n a t e became c o m m e r c i a l l y a v a i l -130 a b l e a n d a s a n t i c i p a t e d , ( e n t r y r ) i t b e h a v e d i n a n a l o g o u s f a s h i o n a l t h o u g h t h e y i e l d s w e r e l o w e r . T h e s e r e a g e n t s a r e u s e f u l a d d i t i o n s t o t h e a r s e n a l o f t h e s y n t h e t i c o r g a n i c c h e m i s t f o r t h e p r e p a r a t i o n o f B - k e t o - e s t e r s u n d e r m i l d r e a c t i o n c o n d i t i o n s . 131 A p a p e r d e a l i n g w i t h an a l t e r n a t i v e p r o c e d u r e f o r t h e i n t r o d u c t i o n o f an a c t i v a t i n g g r o u p ( u s i n g m e t h y l c y a n o f o r m a t e ) a t t h e a' p o s i t i o n o f an u n s a t u r a t e d k e t o n e a p p e a r e d a f t e r t h e w o r k d e s c r i b e d a b o v e was c o m p l e t e d . A p p r o a c h u s i n g DEPC: Our n e x t a p p r o a c h s t a r t e d w i t h u n s a t u r a t e d k e t o - e s t e r 160 ( S c h e m e 36) p r e p a r e d b y t h e m e t h o d d e s c r i b e d i n t h e p r e v i o u s s e c t i o n . T h e n , an a l k y l a t i o n was p e r f o r m e d b e t w e e n b i c y c l i c m o l e c u l e 160 a n d c h l o r o e s t e r 131b ( 7 6 % , Scheme 3 6 , a s d e s c r i b e d f o r t h e a l k y l a t i o n o f 150)'. N e x t , r e d u c t i o n o f t h e k e t o n e i n 162 was c o n s i d e r e d . The r e d u c t i o n was 132 a c c o m p l i s h e d m o s t e f f e c t i v e l y u s i n g s o d i u m b o r o h y d r i d e a n d c e r o u s c h l o r i d e The a d d i t i o n o f c e r o u s c h l o r i d e m i n i m i z e s 1 , 4 - p r o t o n a d d i t i o n w h i c h i s o f t e n o b s e r v e d w i t h c y c l o p e n t e n o n e s , i n c l u d i n g t h i s c a s e . Gemal a n d L u c h e h a v e shown t h a t t h e p r e s e n c e o f l a n t h a n o i d c h l o r i d e s w i t h t h e s o d i u m b o r o h y d r i d e i n +3 m e t h a n o l , f a c i l i t a t e s a c o m p l e x a t i o n o f t h e s o l v e n t by Ln . T h i s c o m b i n a t i o n i n c r e a s e s t h e a c i d i t y o f t h e m e d i u m . The r e d u c i n g s p e c i e s i n t h i s c a s e i s n o t - 84 -B H4~ b u t t h e d e r i v e d a l k o x y b o r o h y d r i d e s N a B H4_n( 0 R )n. T h e s e s p e c i e s a r e m o r e r e a c t i v e t h a n B H ^ ", c o n s i s t e n t w i t h t h e e n h a n c e m e n t o f t h e r e a c t i o n r a t e . A l s o , t h e s u b s t i t u t i o n o f h y d r i d e s i n BH^" by a l k o x y g r o u p s i n c r e a s e s t h e -132 h a r d n e s s o f t h e r e a g e n t ( h a r d a n d s o f t a c i d - b a s e t h e o r y ) , t h i s e x p l a i n s t h e h i g h e r s e l e c t i v i t y ( 1 , 2 - r e d u c t i o n ) o b s e r v e d w i t h t h i s s y s t e m . The a t t a c k o f t h e c y c l o p e n t e n o n e s ( a n d c o n j u g a t e e n o n e s i n g e n e r a l ) i s e n h a n c e d a t t h e h a r d s i t e , w h i c h i s t h e c a r b o n y l . Scheme 36 Some r e a c t i o n s p e r f o r m e d on 160 164 163 - 8 5 -The d e h y d r a t i o n s t e p was p e r f o r m e d u s i n g s e v e r a l p r o c e d u r e s ( M s C l . S C ^ , DMAP, p y r i d i n e i n C H2C 12, 1 h , 2 0 ° C1 3 3, 7 0 % ; o r C H C 13, HC1 ( g ) , 2 h , 2 0 ° C1 3 4, 6 0 % ) . T h e s e d i f f e r e n t p r o c e d u r e s g a v e d i f f e r e n t d e h y d r a t i o n p r o d u c t s ( s h o w n b e l o w ) , a s d e d u c e d f r o m 'H NMR s p e c t r a l a n a l y s i s o f 1 6 4 . The p r o d u c t o b t a i n e d f r o m t h e s e c o n d d e h y d r a t i o n ( HC1) d i s p l a y e d t h r e e s i g n a l s i n t h e o l e f i n i c r e g i o n a t 6 = 5.21 ( m ) , 5.77 ( b s ) , 6.22 ppm ( b s ) , p r e s e n t i n a 1 1 : 4 : 2 r a t i o , i n t e g r a t i n g f o r t h r e e p r o t o n s . The p r o d u c t o f t h e m e t h a n e s u l f o n y l c h l o r i d e d e h y d r a t i o n d i s p l a y e d o l e f i n i c s i g n a l s a t 6 = 5.36 (bm) a n d 5.77 ppm ( b s ) , 4 : 1 , i n t e g r a t i n g f o r t h r e e p r o t o n s . The B u r g e s s 1 oc r e a g e n t c o u l d a l s o be u s e d ( 3 0 % ) . A l l t h e s e 'H NMR s p e c t r a a l s o d i s p l a y e d a o n e p r o t o n s i n g l e t a t ~ 4 . 0 0 ppm, c h a r a c t e r i s t i c o f ( MeOOC^CFU w h i c h i n d i c a t e s t h a t t h e d o u b l e b o n d o f t h e s i d e c h a i n i s n' J ' c o n j u g a t i o n . or o r d e r t o e x a m i n e t h e D i e l s - A l d e r r e a c t i o n , a c o n j u g a t e d d o u b l e b o n d i s r e q u i r e d i n t h e s i d e c h a i n , a s w e l l a s a d i e n e i n r i n g B o f 164 (Scheme 3 6 ) . A l t h o u g h i t h a d p r e v i o u s l y b e e n p o s s i b l e t o i s o m e r i z e t h e s i d e c h a i n d o u b l e b o n d ( o f t h e t r i f l u o r o e s t e r o f 1 4 8 ) w i t h b a s e , r e a c t i o n o f 162_, 163_ o r 164 w i t h p y r i d i n e o r o t h e r b a s e s , h i g h e r t e m p e r a t u r e s , l o n g e r r e a c t i o n t i m e s d i d n o t g i v e t h e r e q u i r e d p r o d u c t . F o r e x a m p l e , on o n e o c c a s i o n , ( D B U , THF r e f l u x , 18 h , 8 0 % ) t h r e e d o u b l e b o n d i s o m e r s o f 162 w e r e o b t a i n e d i n a 3:2:5 r a t i o . The p r e s e n c e o f t h r e e o l e f i n i c s i g n a l s (m) was o b s e r v e d i n t h e 'H NMR s p e c t r u m a t 4 . 5 2 , 5.00 a n d 5.52 ppm. A l s o , t h r e e p o s s i b l e m e t h y l s i g n a l s ( b s ) a p p e a r e d a t 1 . 6 5 , 1.87 a n d 2.06 ppm. E a r l i e r i n o u r s y n t h e t i c s t u d i e s , t h e i s o m e r i z a t i o n o f 165 d i d n o t t a k e p l a c e u n d e r a c i d i c c o n d i t i o n s - 86 -( u s i n g ( C O O H )2, pTsOH o r CH3COOH i n r e f l u x i n g e t h a n o l ) . T h e r e f o r e , t h e D i e l s - A l d e r r e a c t i o n ( o n a m i x t u r e o f 1_64 i s o m e r s ) was t r i e d , w h i l e h o p i n g 136 f o r a f a v o r a b l e t h e r m a l i s o m e r i z a t i o n t o t a k e p l a c e . The D i e l s - A l d e r was a l s o t r i e d u s i n g a L e w i s a c i d ( B F ^ . E t ^ O ) o r a c a t a l y t i c a m o u nt o f b a s e a t v a r i o u s t e m p e r a t u r e s , b u t m a i n l y d e c o m p o s i t i o n was o b s e r v e d . I n one c a s e , w h e r e N , N , N ' , N ' - t e t r a m e t h y l e t h y l e n e d i a m i n e was u s e d a s a c a t a l y s t , a d e c a r b o x y l a t i o n (-COOMe f r o m 164,Scheme 36 s e a l e d t u b e r e a c t i o n , i n t o l u e n e 1 1 0° t o 1 9 0 ° , 4 d a y s , 2 5 % ) was o b s e r v e d , a c c o r d i n g t o MS a n d 'H NMR s p e c t r a l a n a l y s i s . 0 0 ^OEr 165 6^ MeOOC COOMe 137 A r e c e n t p a p e r w h i c h a p p e a r e d a f t e r t h e s e a t t e m p t s w e r e u n d e r t a k e n , u s e s p o l y p h o s p h o r i c a c i d (1 e q ) i n r e f l u x i n g d i c h l o r o m e t h a n e , c o n t a i n i n g s i l i c a g e l , f o r 24 h t o c o n v e r t 166 t o 167 (Scheme 3 7 ) . T h e s e u n u s u a l c o n d i t i o n s r e v e a l t h e d i f f i c u l t y i n a c c o m p l i s h i n g s u c h a t r a n s f o r m a t i o n ( i s o m e r i z a t i o n i n t o c o n j u g a t i o n ) , e v e n i n a " s i m p l e " s y s t e m s u c h a s 1 6 6 . Scheme 37 I s o m e r i z a t i o n o f 166 ^ • ^ C C O E t Q ^ C O O E t 166 167 - 87 -S u c c e s s f u l D i e l s - A l d e r a p p r o a c h I n t h e n e x t f e w p a g e s , t h e m o d el s t u d y p e r f o r m e d on compound 142 w i l l be d i s c u s s e d f i r s t , t h e n t h e w o r k p e r f o r m e d on b i c y c l o o c t e n o n e 1_38. The new r o u t e (Scheme 3 8 ) s t a r t s w i t h t h e a l k y l a t i o n o f B - k e t o - e s t e r 159 w i t h m e t h y l v i n y l k e t o n e . T h i s M i c h a e l a d d i t i o n h a d t o be p e r f o r m e d u n d e r " v e r y c o n t r o l l e d " c a t a l y t i c c o n d i t i o n s . I f t h e a m o u n t o f b a s e was n o t k e p t t o a m i n i m u m , a n d / o r t h e r e a c t i o n t i m e was t o o l o n g , s i d e p r o d u c t V7J_ was o b t a i n e d i n v a r y i n g a m o u n t s . B i c y c l o [ 2 . 2 . 1 ] h e p t a n - 2 - o n e ( 1 7 1 ) r e s u l t s f r o m a b a s e c a t a l y z e d 1 , 4 - i n t r a m o l e c u l a r - a d d i t i o n b e t w e e n t h e e n o l i z e d m e t h y l k e t o n e a n d t h e u n s a t u r a t e d k e t o n e o f 170 ( Scheme 3 9 ) . S t r u c t u r e 1 7 1 was d e d u c e d f r o m 4 0 0 MHz 'H NMR, IR a n d MS s p e c t r a . A l t h o u g h some i m p u r i t y o r d e c o m p o s i t i o n was p r e s e n t ( F i g u r e 3 4 , s i g n a l s a t 6 = 5.92 ( b s ) a n d 6.12 ( b s ) p p m ) , t h e two s i n g l e t s a p p e a r i n g a t 1.45 (-C-CH3) a n d 2.22 ( C 0 C H3) ppm i n t h e 'H NMR s p e c t r u m , c o u l d d e f i n i t e l y be a s s i g n e d t o m e t h y l g r o u p s . The s i g n a l s a t 4.22 ppm ( q , J = 7 H z , 0 C H2) a n d 1.30 ppm ( t , J = 7 H z , C H3) a r e e a s i l y a s s i g n e d t o t h e e t h y l e s t e r . A n o t h e r s e t o f s i g n a l s i n t e g r a t i n g f o r o n e p r o t o n a p p e a r e d a t 3.02 ppm ( d d d , J = 2 , 6 , 12 H z ) . B e c a u s e t h e c o u p l i n g c o n s t a n t s ( v i c i n a l a n d l o n g - r a n g e ) i n n o r b o r n a n e 41 s y s t e m s h a v e b e e n w e l l s t u d i e d , i n t e r p r e t a t i o n o f t h i s c o u p l i n g was p o s s i b l e . - 88 -Scheme 38 D i e l s - A l d e r A p p r o a c h t o 1 7 6 , 177 176 177 - 8 9 -Scheme 39 F o r m a t i o n o f S i d e P r o d u c t 171 COOEt I t i s known t h a t i n m o l e c u l e s s u c h a s 1 6 9 , t h e c o u p l i n g c o n s t a n t s a r e a s f o l l o w s : J2D-3D = 6 - 7 H z ; J2 X - 3 X = 9 - 1 0 H z ; J2X-*-»-3D = 2 , 5 H z ; J1 - 2 X = 3"4 H Z' J1 - 2 D = ° "2 H z' J3 X - 5 X = ]"2 H z ; J5 D - 7 B = K 5"5 H z" T h e r e f o r e , t h e 2 Hz c o u p l i n g i n 171 was d u e t o a W l o n g - r a n g e c o u p l i n g ( H - 5 , H - 7 ) , t h e 6 Hz c o u p l i n g t o an e n d o - e x o c o u p l i n g ( H - 5 , H - 6 ) , a n d t h e 12 Hz c o u p l i n g t o a n e x o - e x o c o u p l i n g ( H - 5 , H - 6 ) . I n t e r p r e t a t i o n o f t h i s c o u p l i n g a l l o w s us t o p l a c e p r o t o n 5 i n t h e e x o p o s i t i o n a s shown f o r 171 i n Scheme 3 9 ; a n d t h e m e t h y l k e t o n e s u b s t i t u e n t i n t h e e n d o p o s i t i o n . The IR o f 171 i n d i c a t e d t h a t a s t r a i n e d k e t o n e (CO b a n d a t 1765 c m- 1) was p r e s e n t i n a d d i t i o n t o o t h e r c a r b o n y l s ( b r o a d CO b a n d a t 1 7 1 5 c m "1, C 0 C H3 a n d C O O E t ) . The MS d i s p l a y e d a m o l e c u l a r i o n a t m/z = 2 3 8 ( C ^ H - i g O ^ ) . B v7/A D«Endo X«Exo 169 - 90 -The d e s i r e d p r o d u c t 170 o f t h e M i c h a e l a d d i t i o n was e a s i l y i d e n t i f i e d f r o m t h e 'H NMR, IR a n d MS. I n t h e n e x t s t e p o f t h e s y n t h e s i s , t h e m e t h y l k e t o n e i n 1 7 0 was r e a c t e d s e l e c t i v e l y . A l t h o u g h t h e d i t h i o k e t a l o f t h e m e t h y l k e t o n e was s e l e c t i v e l y f o r m e d (BF-j.Etp^O, 2 0 ° , 1 h , 7 0 % ) when t h e r e a c t i o n was 1 OR •; p e r f o r m e d i n a c e t i c a c i d , t h e d e p r o t e c t i o n c o u l d n o t be a c c o m p l i s h e d on 139 t h i s d e r i v a t i v e , t h e c o r r e s p o n d i n g a l c o h o l , o r d i o l . A Horner-Emmonds r e a c t i o n o f 170 p r o c e e d e d s e l e c t i v e l y i n v e r y l o w y i e l d ( 1 0 % ) . The 'H NMR s p e c t r u m o f t h e m a j o r p r o d u c t i n d i c a t e d t h e p r e s e n c e o f t h r e e e t h o x y g r o u p s a n d a m e t h i n e p r o t o n ( 2 . 8 2 ppm, d , J = 20 Hz) c o u p l e d t o p h o s p h o r u s . P r o b a b l y a n i n t e r n a l r e a c t i o n , g i v i n g a 6 - m e m b e r e d - r i n g l a c t o n e p r e d o m i n a t e d o v e r t h e u s u a l r e a r r a n g e m e n t o f t h e p h o s p h o n a t e . A l s o , a W i t t i g r e a c t i o n o f 170 was n o t s e l e c t i v e ( 3 0 % o f t h e d i r e a c t e d p r o d u c t , a c c o r d i n g t o MS a n d 'H NMR a n a l y s i s ) . Scheme 40 P o s s i b l e R e a r r a n g e m e n t R e a c t i o n A K n o e v e n a g e l r e a c t i o n u s i n g t i t a n i u m t e t r a c h l o r i d e a n d d i m e t h y l m a l o n a t e ( C H , ( C O O M e ) , a t 2 0 ° , 12 h ) , g a v e 1 7 2 . S i d e p r o d u c t 1_73 was f o r m e d when t h e r e a c t i o n t i m e e x c e e d e d 12 h . (Scheme 4 1 ) . 1 D e p r o t e c t i o n s t r i e d : m e r c u r y ( I I ) c h l o r i d e , p o t a s s i u m c a r b o n a t e , 8 0 % a c e t o n i t r i l e , w a t e r , r e f l u x ; s i l v e r n i t r a t e , a c e t o n i t r i l e , w a t e r ; t h a i l i e t r i f l u o r o a c e t a t e , t e t r a h y d r o f u r a n . - 91 -H, a: R 2 5 R 3 = H,COOEr b : R 2 3 R 3 = COOMe T r i u n s a t u r a t e d t r i e s t e r 1_73 ( S c h e m e 4 1 ) c o u l d r e s u l t f r o m an a c i d c a t a l y z e d i n t r a m o l e c u l a r a d d i t i o n ( t a k i n g p l a c e b e t w e e n t h e e n o l i z e d m e t h y l k e t o n e a n d t h e u n s a t u r a t e d c a r b o n y l o f 1 7 0 ) , f o l l o w e d by a K n o e v e n a g e l c o n d e n s a t i o n . Compound 173 was s e n s i t i v e t o s i l i c a c h r o m a t o g r a p h y , e s p e c i a l l y P T L C , a n d d e c o m p o s e d r a p i d l y . The u n s a t u r a t e d k e t o n e p r e c u r s o r w o u l d a l s o be e x p e c t e d t o be u n s t a b l e . P r o d u c t 173 d i s p l a y e d i n i t s 'H NMR s p e c t r u m , two o l e f i n i c p r o t o n s a t 6.58 ( s ) a n d 6.02 ( b s ) ppm. T h e s e w e r e t e n t a t i v e l y a s s i g n e d t o H-2 a n d H-4, b y c o m p a r i s o n o f t h e c h e m i c a l s h i f t v a l u e s t o 144b ( H - 4 , 7.00 ppm; H£- 5 , 5.43 ppm; Hz~ 5 , 5.68 ppm); 144a ( R2 = COOEt; R~ = H a t 5.79 ppm; H-4, 6.70 ppm; ^ - 5 , 5.28 ppm) a n d t h e l i t e r a t u r e4 1. A l s o , t h e s i g n a l a t 6.02 ppm a p p e a r e d a s a b r o a d s i n g l e t , w h i c h i s c h a r a c t e r i s t i c o f l o n g - r a n g e c o u p l i n g b e t w e e n t h i s p r o t o n a n d t h e v i n y l i c m e t h y l . The v i n y l i c m e t h y l s i g n a l a p p e a r e d a t 1.91 ( b s ) ppm; two s i n g l e t s a t 3.70 a n d 3.73 ppm w e r e due t o t h e m e t h y l e s t e r s ; w h i l e s i g n a l s a s s i g n e d t o t h e e t h o x y g r o u p a p p e a r e d a t 4 . 1 0 ( C H2, q , J = 7 Hz) a n d 1.21 ( C H3, t , J = 7 H z ) ppm. The p a r e n t i o n o b s e r v e d i n t h e MS a t m/z = 3 3 4 , c o n f i r m e d t h a t t h e m o l e c u l a r f o r m u l a o f 173 was C1 8H2 20g, a n d d i f f e r e d f r o m 172 by t h e l o s s o f H20 . Scheme 41 F o r m a t i o n o f S i d e P r o d u c t 173 0 MeOOC COOMe COOEt - 92 -Scheme 42 rDi e l s - A l d e r R e a c t i o n o f 175 R - 93 -The p r o d u c t 172 f r o m t h e K n o e v e n a g e l c o n d e n s a t i o n was c h a r a c t e r i z e d t h r o u g h i t s 'H NMR, MS a n d IR s p e c t r a l d a t a . Compound 172 was t h e n r e d u c e d 140 u s i n g z i n c b o r o h y d r i d e . T h i s r e d u c t i o n p r o c e d u r e r e s u l t e d i n b e t t e r y i e l d s when t h e r e a c t i o n was p e r f o r m e d on a l a r g e s c a l e . A f t e r d e h y d r a t i o n o f 174 ( M s C l . S 02 o r M s C l , no S 02) t h e D i e l s - A l d e r was a t t e m p t e d . A r e l a t e d i n t e r m o l e c u l a r e x a m p l e t o o u r i n t r a m o l e c u l a r D i e l s - A l d e r ( d i a c t i v a t e d d i e n e , c y c l o p e n t a d i e n e - a s d i e n o p h i l e ) h a s b e e n d e s c r i b e d by L e v i n a a n d G o d o v i k o v , 141 i n 1 9 5 5 . I t t a k e s p l a c e b e t w e e n c y c l o p e n t a d i e n e a n d d i e t h y l m e t h y l e n e m a l o n a t e ( C H2= H C ( C 0 0 E t )2) i n r e f l u x i n g b e n z e n e f o r 6 h ( 6 0 % ) . The D i e l s - A l d e r r e a c t i o n o f 175 t o o k p l a c e i n t o l u e n e , a t 1 4 0 ° ( s e a l e d t u b e ) d u r i n g 10 h ( 4 0 % ) . As i n d i c a t e d i n Scheme 4 2 , two r e g i o i s o m e r s c a n be f o r m e d d u r i n g t h e D i e l s - A l d e r s t e p . The 'H NMR s p e c t r u m o b t a i n e d on t h e p u r i f i e d r e a c t i o n p r o d u c t w o u l d t e n d t o i n d i c a t e t h e p r e s e n c e o f two a d d u c t s . The s i g n a l s a s s i g n e d t o t h e v i n y l m e t h y l ( 2 . 0 2 a n d 2.04 ppm) a n d o l e f i n i c p r o t o n a r e d o u b l e d ( 6 . 2 0 a n d 7.10 ppm) a n d p r e s e n t i n a 5:4 r a t i o . The s e r i e s o f r e a c t i o n s d e s c r i b e d a b o v e was n e x t p e r f o r m e d on b i c y c l i c 3 - k e t o - e s t e r 160 (Scheme 4 3 ) . The M i c h a e l a d d i t i o n p e r f o r m e d b e t w e e n 160 a n d m e t h y l v i n y l k e t o n e p r o d u c e d 1 7 8 , a n d no s i d e p r o d u c t was d e t e c t e d . K n o e v e n a g e l c o n d e n s a t i o n o f U 8 w i t h d i m e t h y l m a l o n a t e ( 2 0°C, 20 t o 24 h) a f f o r d e d t r i e s t e r 1 7 9 . I n t h i s c a s e , o n l y t r a c e s (< 1%) o f a s i d e p r o d u c t s i m i l a r t o 173 w e r e o b t a i n e d on o n e o c c a s i o n . R e d u c t i o n o f t h e k e t o n e i n 179 ( Z n ( B H4)2) a n d d e h y d r a t i o n o f a l c o h o l 180 ( M s C l . S O g o r M s C l , no S 02) p r o d u c e d d i e n e 181 ( m o r e t h a n o n e d o u b l e b o n d i s o m e r , a s m e n t i o n e d e a r l i e r f o r t h e d e h y d r a t i o n o f a l c o h o l 1 6 3 , p.- 8 5 ) . The i n t r a m o l e c u l a r D i e l s -A l d e r t o o k p l a c e i n t o l u e n e , a t 140°C ( s e a l e d t u b e ) d u r i n g 10 h . - 94 -I n t h e p r e s e n t c a s e , t h e D i e l s - A l d e r c y c l i z a t i o n c a n o n l y g i v e o n e p r o d u c t ( t w o e n a n t i o m e r s , Scheme 4 4 ) . T h i s i s d u e t o t h e p r e s e n c e o f a p l a n e o f s y m m e t r y i n t h e r i n g m o i e t y o f 1 8 1 . H o w e v e r , a n i s o m e r i z a t i o n o f t h e n e w l y f o r m e d d o u b l e b o n d i n 182 i s o b s e r v e d . A 4 : 1 : 3 m i x t u r e o f t r i : t r i : t e t r a - s u b s t i t u t e d d o u b l e b o n d i s p r e s e n t , a c c o r d i n g t o t h e 'H NMR s p e c t r u m . The m a j o r o l e f i n i c s i g n a l a p p e a r s a t 5.45 ppm ( m ) , a n d t h e m i n o r o n e a t 5.76 ppm ( m ) . Two s t r u c t u r e s ( 1 8 7 a n d 1 8 8 ) c a n be d r a w n f o r t h e i s o m e r i z e d D i e l s -A l d e r a d d u c t . M o l e c u l a r m e c h a n i c s c a l c u l a t i o n s p e r f o r m e d a t t h e U n i v e r s i t y de S h e r b r o o k e i n d i c a t e t h a t s t r u c t u r e 187 w i t h t h e d o u b l e b o n d a t C-9 a n d t h e r i n g e x o i s s l i g h t l y m o r e s t a b l e (~ 1.5 k c a l ) t h a n a d d u c t 1 8 2 , a n d t h a t s t r u c t u r e 1 8 8 i s l e s s s t a b l e (~ 5.5 k c a l ) t h a n 1 8 2 .1 I n o r d e r t o e s t a b l i s h t h e a c c u r a c y o f s t r u c t u r e 1 8 7 , an X - r a y d i f f r a c t i o n a n a l y s i s i s r e q u i r e d . U n f o r t u n a t e l y n o n e o f t h e d e r i v a t i v e s p r e p a r e d t o d a t e1 1 h a v e p r o v e d s a t i s f a c t o r y f o r X - r a y a n a l y s i s . I We a r e g r a t e f u l t o C. B a y l y a n d P. D e s l o n g c h a m p s f o r t h e c a l c u l a t i o n s . The two o l e f i n i c s i g n a l s o b s e r v e d i n t h e 'H NMR s p e c t r u m c o u l d be due t o e x o 187 a n d e n d o 1 8 7 . I I D e r i v a t i v e s o f 183 p r e p a r e d : d i c a r b o x y l i c a c i d , d i o l , d i - p - b r o m o b e n z o a t e , t h e d i a n i l i d e d e r i v a t i v e . - 95 -Scheme 4 3 D i e l s - A l d e r A p p r o a c h t o 182 186 185 - 96 -Scheme 44 D i e l s - A l d e r R e a c t i o n o f 181 R - 97 -S e v e r a l r o u t e s c a n be e n v i s a g e d t o c o n v e r t t h e m a l o n i c e s t e r f u n c t i o n a l i t y i n k e y m o l e c u l e 1_82 t o t h e r e q u i r e d k e t o n e f u n c t i o n a l i t y ( a s i n 1 8 4 , Scheme 4 3 ) . 142 A c o n v e n t i o n a l m e t h o d a p p l i e d i n t h e 1 9 6 0 s t o p e r f o r m t h i s t r a n s f o r m a t i o n c o n s i s t s o f t h e f o l l o w i n g s i x s t e p p r o c e d u r e : h y d r o l y s i s o f a m a l o n i c e s t e r , d e c a r b o x y l a t i o n o f a m a l o n i c a c i d , t r e a t m e n t o f t h e c a r b o x y l i c a c i d w i t h m e t h y l l i t h i u m , c o n v e r s i o n o f t h e m e t h y l k e t o n e t o an a c e t a t e , h y d r o l y s i s o f t h e a c e t a t e a n d f i n a l l y o x i d a t i o n o f t h e a l c o h o l . A l t h o u g h t h i s s e q u e n c e o f r e a c t i o n s w o u l d c o n v e r t a m a l o n i c a c i d i n t o a k e t o n e , i n o u r c a s e t h e e t h y l e s t e r a n d d o u b l e bond w o u l d a l s o be a f f e c t e d . 143 A n o t h e r p o s s i b i l i t y w h i c h h a s b e e n a p p l i e d i n s e v e r a l c a s e s , b u t u n f o r t u n a t e l y g i v e s r i s e t o d i f f e r e n t s i d e p r o d u c t s i n t h e c a s e o f t h e 144 n o r b o r n a n e s y s t e m , i n v o l v e s t h e u s e o f l e a d t e t r a a c e t a t e . T h i s o x i d a t i v e d e c a r b o x y l a t i o n l e a d s d i r e c t l y f r o m a m a l o n i c a c i d t o a k e t o n e . A d i f f e r e n t a p p r o a c h w o u l d c o n s i s t o f t h e d e c a r b o x y l a t i o n o f t h e m a l o n i c e s t e r (NaCN i n H M P A1 4 5 o r L i C l i n H20 - D M S 01 4 6) , f o l l o w e d by h y d r o l y s i s o f t h e m e t h y l e s t e r ( A l C l ^ i n E t S H1 4 7) a n d o x i d a t i v e d e c a r b o x y l a t i o n ( s e e b e l o w ) . D e c a r b o x y l a t i o n o f t h e m a l o n i c e s t e r u s i n g s o d i u m c y a n i d e o r l i t h i u m c h l o r i d e was u n s u c c e s s f u l i n o u r c a s e . H o w e v e r t r e a t m e n t o f 182 w i t h a l u m i n u m t r i c h l o r i d e i n e t h a n e t h i o l h y d r o l y z e d t h e m e t h y l e s t e r s i n t h e p r e s e n c e o f t h e e t h y l e s t e r , i n a c c e p t a b l e y i e l d s (> 4 0 % ) . The 'H NMR o f t h i s c r u d e p r o d u c t d i s p l a y e d o n l y o n e s i n g l e t i n t h e o l e f i n i c r e g i o n a t 5.85 ppm. The p r e s e n c e o f t h e L e w i s a c i d a p p a r e n t l y i s o m e r i z e d t h e d o u b l e b o n d m i x t u r e o f t h e D i e l s - A l d e r a d d u c t s , t o t h e C-9 d o u b l e b o n d . D e c a r b o x y l a t i o n was a c c o m p l i s h e d by r e f l u x i n g t h e m a l o n i c a c i d i n t o l u e n e f o r two h o u r s . The 'H NMR s p e c t r u m o f 183 s howed an u p f i e l d s h i f t f o r t h e m e t h y l s i n g l e t , f r o m 1.23 t o 1.10 ppm. T h i s r e s u l t w o u l d t e n d t o i n d i c a t e t h a t t h e e x o c a r b o x y l i c a c i d h a s b e e n e l i m i n a t e d , t h e r e f o r e t h e e f f e c t d u e - 98 -" t o t h i s s u b s t i t u e n t h a s d i s a p p e a r e d . Endo s u b s t i t u t e d n o r b o r n a n e s h a v e b e e n 146 r e p o r t e d t o be more s t a b l e t h a n t h e e x o i s o m e r s 1 no W a s s e r m a n a n d L i p s h u t z ' s o x i d a t i v e d e c a r b o x y l a t i o n ( L D A , 0 ^ ; DMF-149 a c e t a l ) a s w e l l a s T r o s t a n d T a m a r u ' s p r o c e d u r e ( L D A , M e2S2; N a H C 03, N - C l - s u c c i n i m i d e ) w e r e a t t e m p t e d , h o w e v e r no p r o d u c t 184 c o u l d be i s o l a t e d i n e i t h e r c a s e ( r e a c t i o n i n THF a n d i n THF-HMPA). T h e r e f o r e , model r e a c t i o n s w e r e p e r f o r m e d on 4 - c a r b o x y b i c y c l o [ 2 . 2 . 1 ] h e p t e n e (Scheme 4 5 ) . T h e s e s t u d i e s i n d i c a t e d t h a t t h e c a r b o x y l i c a c i d d i a n i o n c o u l d o n l y be g e n e r a t e d a t 0 ° t o 2 0°C , a n d t h a t t h e m e t h y l d i s u l f i d e p r o c e d u r e was m o r e r e l i a b l e , s i n c e t h e i n t e r m e d i a t e s u l f e n y l a t e d a c i d c o u l d be i s o l a t e d a n d c h a r a c t e r i z e d b e f o r e t r e a t m e n t w i t h N - c h l o r o s u c c i n i m i d e . T h e s e r e s u l t s a l s o s h o w e d t h a t a t e m p e r a t u r e o f 20°C was n e e d e d f o r t h e s u l f e n y l a t i o n t o t a k e p l a c e a n d t h a t i n t h e p r e s e n c e o f a n e s t e r , t h i s r e a c t i o n d i d n o t p r o c e e d a s e x p e c t e d . S i n c e o u r e a r l i e r a t t e m p t s t o s u l f e n y l a t e 183 showed t h a t t h e e t h y l e s t e r d i d n o t s u r v i v e t h e r e a c t i o n c o n d i t i o n s , t h e e s t e r was h y d r o l y z e d . The t r i a n i o n o f t h i s d i c a r b o x y l i c a c i d was t h e n g e n e r a t e d , h o w e v e r t h e s u l f e n y l a t i o n d i d n o t p r o c e e d . Scheme 45 M o d e l S t u d i e s o f t h e O x i d a t i v e D e c a r b o x y l a t i o n C00H C00H ° R=00H,SMe - 99 -C o n c l u s i o n : T h e s e s t u d i e s r e v e a l e d t h a t a C i e l s - A l d e r a p p r o a c h t o c a p n e l l e n e ( 5 1 ) may be f e a s i b l e . T h e y h a v e r e s u l t e d i n a u s e f u l new a c y l a t i o n p r o c e d u r e f o r c y c l i c k e t o n e s a n d e n o n e s . I n a d d i t i o n , t h e t y p e s o f i n t e r m e d i a t e s a n d r e a c t i o n s w h i c h w i l l p e r m i t f u r t h e r d e v e l o p m e n t o f t h i s s t r a t e g y h a v e b e e n d e l i n e a t e d . , I t i s a n t i c i p a t e d t h a t u p o n g e n e r a t i o n o f k e t o n e 1 8 4 , t h e B a e y e r - V i l l i g e r o x i d a t i o n (mCPBA) w o u l d be d i r e c t e d by t h e d o u b l e b o n d t o a f f o r d l a c t o n e 185 p r e f e r e n t i a l l y . R e d u c t i o n ( L i A l H ^ ) o f t h i s l a c t o n e w o u l d g i v e t r i o l 186 w i t h t h e c a p n e l l a n e c a r b o n s k e l e t o n , e x c e p t f o r o n e c a r b o n . T h i s m i s s i n g c a r b o n r e p r e s e n t s t h e e x o c y c l i c d o u b l e b o n d w h i c h c o u l d be i n t r o d u c e d a t an e a r l i e r s t e p i n t h e s y n t h e s i s , p o s s i b l y by a l l y l i c o x i d a t i o n ( S e G ^ ) f o l l o w e d b y W i t t i g c o n d e n s a t i o n . O t h e r m o d i f i c a t i o n s o f t h i s r o u t e a r e a l s o p o s s i b l e . 1 F i g u r e 10 IR S p e c t r u m o f A1 ' 5 - b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e (1 38 , neat) - 101 -F i g u r e 11 6 0 MHz 'H NMR S p e c t r u m o f A1 '5- b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e (1_38, C C I J o F i g u r e 12 IR S p e c t r u m o f A 1 ' 5 3 - c a r b o e t h o x y b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e (1_60, neot) - 103 -F i g u r e ^ IR S p e c t r u m o f A 1 '5- 3 - ( b u t a n - 3 - o n e ) - 3 - c a r b o e t h o x y b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e - 105 -F i g u r e 15 8 0 MHz 'H NMR S p e c t r u m o f 1 5 A ' - 3 - ( b u t a n - 3 - o n e ) - 3 - c a r b o e t h o x y b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e (178, CDCI3) - 106 -F i g u r e 16 8 0 MHz 'H NMR S p e c t r u m o f A 1 ' 5 - 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 3 - m e t h y l - 3 - b u t e n y l - ^ - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 9 , F i g u r e 17 1 5 IR S p e c t r u m o f A ' - 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 3 - m e t h y l - 3 - b u t e n y l - c , i . - d i c a r b o x y l a t e ) b i c y c l o p . 3 . 0 ] o c t e n - 2 - o n e f17 9. neat) - 107 -F i g u r e 18 1 5 60 MHz 'H NMR S p e c t r u m o f A ' - 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 3 - m e t h y l -3 - b u t e n y l - i , c - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o l ( 1 8 0 , CO/ ) 4000 m o F i g u r e 19 IR S p e c t r u m o f A 1 ' 5 - 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 3 - - m e t h y l -3 - b u t e n y l - t , a - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o l ( 1 8 0; neat) F i g u r e 20 IR S p e c t r u m o f 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l 2 - m e t h y l - 1 - b u t e n y l - 1 , l - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t a - l , 4 - d i e n e (181, neat) F i g u r e 21 8 0 MHz 'H NMR S p e c t r u m o f 3 - c a r b o e t h o x y - 3 - ( d i m e t h y l - 2 - m e t h y l - l -b u t e n y l - 1 , l - d i c a r b o x y l a t e ) b i c y c l o [ 3 . 3 . 0 ] o c t a - l , 4 - d i e n e (181,CDC L) F i g u r e 22 Q 10 IR S p e c t r u m o f A ' - 6 - c a r b o e t h o x y - 2 - d i c a r b o m e t h o x y - 3 - m e t h y l -t e t r a c y c l o [ 6 . 4 . 01'6. 03'7. 08'1 2] - d o d e c e n e ( l _ B _ 2 , n e a t ) - I l l -i l L F i g u r e 23 4 0 0 MHz 'H NMR S p e c t r u m o f A 8 ' 1 2 - 6 - c a r b o e t h o x y - 2 - d i c a r b o m e t h o x y - 3 -m e t h y l t e t r a c y c l o t e ^ . O1 '6. 03 , 7. 08 , 1 2] - d o d e c e n e (1_B2,CDC U ) - 1 1 3 -f i 1 T f l S F i g u r e 25 4 0 0 MHz 'H NMR S p e c t r u m o f endo-1 - c a r b o e t h o x y - 4 - m e t h y l - 5 -a c e t y l b i c y c l o [ 2 . 2 . 1 ] h e p t a n - 2 - o n e ( 1 7 ] , C D C 13) F i g u r e 26 IR S p e c t r u m o f 6 - c a r b o e t h o x y - 8 - m e t h y l - 3 - d i m e t h y l m e t h y l e n e d i c a r b o x y l a t e b i c y c l o r . 4 . 3 . 01 '6] n o n a - l , 8 - d i e n e ( 1 7 3 , neat) - 115 -A hi ' i v i • J I ; F i g u r e 27 6 0 MHz 'H NMR S p e c t r u m o f 6 - c a r b o e t h o x y - 8 - m e t h y l - 3 -d i m e t h y l m e t h y l e n e d i c a r b o x y l a t e b i c y c l o [ 4 . 3 . 0 ] n o n a - l , 8 - d i e n e (1_7_3 CCf, - 116 -F i g u r e 29 11 12 IR S p e c t r u m o f A - 6 - c a r b o e t h o x y - 2 - d i c a r b o x y l i c a c i d S - m e t h y l t e t r a c y c l o l e . A . O1'6. 03'7. o8'1 2] - d o d e c e n e (neat) - 117 -F i g u r e 31 q 1 n IR S p e c t r u m o f A ' - 6 - c a r b o e t h o x y - 2 - c a r b o x y l i c a c i d 3 - m e t h y l t e t r a c y c l o [ 6 . 4 . 0 1 , 6 . 0 3 ' 7 . 0 8 , 1 2 ] d o d e c e n e (l_BJ, neat) F i g u r e 32 Q ] n IR S p e c t r u m o f A 2 , 6 - d i c a r b o x y l i c a c i d 3 - m e t h y l t e t r a c y c l o [ 6 . 4 . 01'6. 03'7. 08'1 2] d o d e c e n e (C HC13) - 1 2 0 -F i g u r e 3 3 q i n MHz 'H NMR S p e c t r u m o f A 2 , 6 - d i c a r b o x y l i c a c i d - m e t h y l t e t r a c y c l o [ 6 . 4 . 01'6. 03'7. 08'1 2] d o d e c e n e (CDC 13 ) - 121 -E x p e r i m e n t a l I n f r a r e d s p e c t r a w e r e r e c o r d e d on P e r k i n E l m e r 70B ( c o m p o u n d s 1_, 9_, 12 a n d 13J, 2 3 7 B ( c o m p o u n d s 35 t o 4 3 ) , 451 o r 1 3 2 0 ( o t h e r c o m p o u n d s ) s p e c t r o p h o t o m e t e r s . S p e c t r a w e r e c a l i b r a t e d w i t h t h e 1601 cm"1 b a n d o f p o l y s t y r e n e f i l m . B a n d s w e r e a s s i g n e d when p o s s i b l e o r t h e i n t e n s i t i e s w e r e i n d i c a t e d ( s : s t r o n g , m: m e d i u m , w: w e a k ) . U l t r a v i o l e t s p e c t r a w e r e r e c o r d e d on a P e r k i n - E l m e r 202 u v - v i s i b l e s p e c t r o p h o t o m e t e r a n d w e r e c a l i b r a t e d w i t h t h e 2 7 9 . 4 nm b a n d o f a H o l m i u m o x i d e f i l t e r . P r o t o n m a g n e t i c r e s o n a n c e s p e c t r a w e r e r e c o r d e d on N i c o l e t - O x f o r d H-270 o r B r u c k e r WH 4 0 0 ( c o m p o u n d s 1 , 9 , 12 a n d 13_ a t UBC; 171 a n d 182 a t U. o f A l b e r t a ) , o r B r u c k e r WP-80 o r V a r i a n EM-360 ( o t h e r c o m p o unds a t MUN). S i g n a l p o s i t i o n s a r e r e p o r t e d i n ppm d o w n f i e l d f r o m t e t r a m e t h y l s i l a n e ( d e l t a s c a l e ) u s e d a s a n i n t e r n a l s t a n d a r d . The number o f p r o t o n s , m u l t i p l i c i t y , c o u p l i n g c o n s t a n t s ( H z ) a n d p r o t o n a s s i g n m e n t a r e i n d i c a t e d i n p a r e n t h e s e s . Low r e s o l u t i o n mass s p e c t r a w e r e o b t a i n e d on a A . E . I . MS-902 s p e c t r o -m e t e r a n d h i g h r e s o l u t i o n mass s p e c t r a on A . E . I . MS-50 ( c o m p o u n d s 1 , 9 , 12, 1 3 , 15 a n d 16) . The i n t e n s i t i e s f o r t h e p l o t t e d mass s p e c t r a w e r e c a l c u l a t e d f r o m t h e l o w r e s o l u t i o n s p e c t r a . P l o t t i n g s t a r t s w i t h t h e p e a k a t m/z = 32 a n d p e a k s o f 3% i n t e n s i t y a n d h i g h e r a r e i n d i c a t e d . The o t h e r l o w a n d h i g h r e s o l u t i o n mass s p e c t r a w e r e d e t e r m i n e d on a V . 6 . M i c r o m a s s 7070-HS i n s t r u m e n t u s i n g an i o n i z a t i o n e n e r g y o f 70 e l e c t r o n v o l t s . ( I n some c a s e s , t h e f r a g m e n t l o s t f r o m M+ i s i n d i c a t e d . ) O p t i c a l r o t a t i o n s w e r e m e a s u r e d on a P e r k i n - E l m e r 141 p o l a r i m e t e r , u s i n g a 1 dm c e l l . M e l t i n g p o i n t s w e r e o b t a i n e d on a F i s h e r - J o h n s a p p a r a t u s a n d v a l u e s a r e u n c o r r e c t e d . Gas l i q u i d c h r o m a t o g r a p h i c a n a l y s e s w e r e c o n d u c t e d on a H e w l e t t P a c k a r d 4 0 2 B g a s c h r o m a t o g r a p h e q u i p p e d w i t h a c o l u m n (3m x 6mm i . d . ) c o n t a i n i n g 1.5% 0V-17 s u p p o r t e d on Gas Chrome Q ( n o e ) - 1 22 -u s i n g h e l i u m a s t h e c a r r i e r g a s . P h o t o c h e m i c a l e x p e r i m e n t s w e r e c o n d u c t e d i n s t o p p e r e d q u a r t z c o n t a i n e r s u s i n g a w a t e r - c o o l e d H a n o v i a n 450W medium p r e s s u r e m e r c u r y a r c l a m p . T h i n l a y e r c h r o m a t o g r a p h i c a n a l y s e s w e r e c a r r i e d o u t on p r e c o a t e d s i l i c a g e l p l a t e s w i t h f l u o r e s c e n t i n d i c a t o r ( E a s t m a n K o d a k s i l i c a g e l 1 3 1 8 1 ) . P r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y was c o n d u c t e d on 20 x 20 cm g l a s s p l a t e s c o a t e d w i t h s i l i c a g e l P F25 4 + 366 t y p e 6 0 (M e r c k) - M e r c k s i l i c a g e l 6 0 , p a r t i c l e s i z e 0 . 0 6 3 - 0 . 2 0 0 mm ( 7 0 - 2 3 0 mesh ASTM) was u s e d f o r c o l u m n s ( c o m p o u n d s 1_, 9_, 1_2 a n d 1 3 J , w h i l e f l a s h c h r o m a t o g r a p h y u s i n g BDH s i l i c a g e l 6 0 , 2 3 0 - 4 0 0 mesh was u s e d f o r a l l o t h e r c o l u m n s . S o l v e n t s u s e d w e r e HPLC g r a d e o r d i s t i l l e d r e a g e n t g r a d e s . P e t r o l e u m e t h e r r e f e r s t o a f r a c t i o n w i t h b o i l i n g r a n g e 3 0 - 6 0° C . A n h y d r o u s d i e t h y l e t h e r ( e t h e r ) , t e t r a h y d r o f u r a n , d i m e t h o x y e t h a n e a n d d i o x a n e w e r e o b t a i n e d by d i s t i l l a t i o n f r o m l i t h i u m a l u m i n u m h y d r i d e o r p o t a s s i u m / b e n z o p h e n o n e . A b s o l u t e e t h a n o l a n d m e t h a n o l w e r e d r i e d by d i s t i l l a t i o n f r o m m a g n e s i u m . D r y h e x a m e t h y l p h o s p h o r a m i d e , d i m e t h y l f o r m a m i d e , d i m e t h y l s u l f o x i d e a n d d i i s o p r o p y l a m i n e w e r e p r e p a r e d b y d i s t i l l a t i o n f r o m c a l c i u m h y d r i d e . S o l u t i o n s i n o r g a n i c s o l v e n t s w e r e d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d t h e s o l v e n t was r e m o v e d u s i n g a B l i c h i r o t a r y e v a p o r a t o r c o n n e c t e d t o a w a t e r a s p i r a t o r . S o d i u m b i c a r b o n a t e a n d ammonium c h l o r i d e r e f e r t o a q u e o u s s a t u r a t e d s o l u t i o n s , w h i l e 5 a n d 1 0 % HC1 r e f e r s t o a q u e o u s s o l u t i o n s . U n l e s s o t h e r w i s e i n d i c a t e d a l l r e a c t i o n s w e r e c o n d u c t e d u n d e r a n a t m o s p h e r e o f d r y n i t r o g e n . - 123 -E x t r a c t i o n a n d C r u d e S e p a r a t i o n ( O n c h i d o r i s b i l a m e l l a t a ) F o l l o w i n g c o l l e c t i o n , t h e n u d i b r a n c h s w e r e i m m e r s e d i n m e t h a n o l a n d s o a k e d a t -35°C f o r s e v e r a l w e e k s . The s u p e r n a t a n t was t h e n f i l t e r e d t h r o u g h Whatman #1 f i l t e r p a p e r a n d e v a p o r a t e d t o a b o u t o n e h a l f o f t h e o r i g i n a l v o l u m e . The c o n c e n t r a t e d e x t r a c t was t h e n p a r t i t i o n e d b e t w e e n b r i n e a n d e t h y l a c e t a t e . T h i s e x t r a c t i o n p r o c e d u r e was r e p e a t e d t h r e e t i m e s . T h e o r g a n i c p h a s e was d r i e d o v e r s o d i u m s u l f a t e , f i l t e r e d a n d e v a p o r a t e d t o g i v e a n o i l y r e s i d u e . T h e c r u d e e x t r a c t was p u r i f i e d b y s i l i c a c o l u m n c h r o m a t o g r a p h y . E l u t i o n o f t h e a c t i v e f r a c t i o n f r o m t h e c o l u m n was f a c i l i t a t e d by a g r a d i e n t o f i n c r e a s i n g s o l v e n t p o l a r i t y ( d i c h l o r o m e t h a n e - e t h y l a c e t a t e ) . The f r a c t i o n s o b t a i n e d w e r e s c r e e n e d f o r a n t i b a c t e r i a l a c t i v i t y . The f r a c t i o n e l u t i n g w i t h e t h y l a c e t a t e g a v e a p o s i t i v e r e s u l t a n d was f u r t h e r p u r i f i e d b y p r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y ( P T L C ) . The b a n d h a v i n g an Rf o f 0.05 i n e t h y l a c e t a t e : c h l o r o f o r m ( 1 : 1 ) c o r r e s p o n d e d t o c e r a m i d e ] _ . T h i s c o mpound was s u b s e q u e n t l y shown t o i n h i b i t t h e g r o w t h o f t h e m i c r o o r g a n i s m s B a c i l l u s s u b t i l i s a n d S t a p h y l o c o c c u s a u r e u s . C e r a m i d e 1 A p p r o x i m a t e l y 2 0 mg o f c e r a m i d e 1_ w e r e o b t a i n e d f r o m 1 2 0 0 t o 1500 n u d i b r a n c h s ( y i e l d = 0 . 0 2 % o f d r y w e i g h t ) . IR ( F i g u r e 4 ) : 3 4 2 0 ( N H ) , 1 6 6 0 (CO) cm"1 'H NMR: ( F i g u r e 2 , T a b l e 1) 1 3C NMR: ( T a b l e 2) MS ( m / z , r e l a t i v e % i n t e n s i t y , F i g u r e 4 ) : 5 3 3 ( 3 ) , 5 1 5 ( 3 ) , 2 9 8 ( 1 0 ) , 2 8 0 ( 1 2 ) E x a c t M a s s c a l c u l a t e d f o r C3 5H6 7N 02: 5 3 3 . 5 1 5 5 , o b t a i n e d : 5 3 3 . 5 1 7 3 . - 124 -MP = 7 7 - 7 8°C [ a ]D = -ll°(c 1 . 0 , C H C 13) A c e t y l a t i o n o f 1 A s a m p l e o f c e r a m i d e 1_ ( 1 0 mg, 1.8 x 10 mmole) was a d d e d t o a s o l u t i o n c o n t a i n i n g a c e t i c a n h y d r i d e ( 0 . 2 m L ) , p y r i d i n e ( 0 . 2 mL) a n d d i m e t h y l a m i n o p y r i d i n e ( 2 m g ) . The r e a c t i o n m i x t u r e was s t i r r e d f o r 18 h a t 2 0°C. R e m o v a l o f t h e s o l v e n t s i n v a c u o a n d p u r i f i c a t i o n by PTLC ( Rf = 0 . 5 8 , c h l o r o f o r m : e t h y l a c e t a t e , 1:1) g a v e d i a c e t y l a t e d d e r i v a t i v e 9 , 10 mg ( 1 . 5 x 1 0 "2 m m o l e , 8 7 % ) . IR ( F i g u r e 6 ) : 3 4 0 0 ( N H ) , 1 7 2 0 ( C O ) , 1660 (CO) c m- 1. 'H NMR: ( F i g u r e 5 , T a b l e 1) MS ( m / z , r e l a t i v e % i n t e n s i t y , F i g u r e 7 ) : 6 3 5 ( 3 ) , 5 7 5 ( 3 ) , 5 1 5 ( 5 ) , 2 8 0 ( 8 5 ) , 4 3 ( 1 0 0 ) . E x a c t M a s s c a l c u l a t e d f o r C3q H7 3N 05: 6 3 5 . 5 4 7 0 , o b t a i n e d : 6 3 5 . 5 4 8 1 . MP: 8 8 - 90°C [ a ] D = -40°(c 1 . 5 , C H C 1 3 ) H y d r o l y s i s o f 1 A s o l u t i o n o f 1_ ( 1 0 mg, 1.8 x 10 m m o l e s ) , d i o x a n e ( 0 . 2 m L ) , s o d i u m h y d r o x i d e i n m e t h a n o l (1 mL, 1 N) was r e f l u x e d f o r 48 h r s . The r e a c t i o n m i x t u r e was p a r t i t i o n e d b e t w e e n w a t e r a n d e t h e r , a n d t h e a q u e o u s l a y e r a c i d i f i e d a n d r e e x t r a c t e d w i t h e t h e r . The t w o o r g a n i c e x t r a c t s w e r e n e u t r a l i z e d a n d r e e x t r a c t e d , t h e o r g a n i c l a y e r s d r i e d o v e r s o d i u m s u l f a t e a n d t h e s o l v e n t s e v a p o r a t e d i n v a c u o t o g i v e t h e l o n g c h a i n b a s e 1_3 a n d t h e f a t t y a c i d 12_. - 125 -The f r a c t i o n c o n t a i n i n g 1_3 was a c e t y l a t e d a s d e s c r i b e d f o r 1_ a n d p u r i f i e d b y PTLC ( R ^ = 0 . 5 3 , e t h y l a c e t a t e : c h l o r o f o r m , 1:1) t o g i v e t r i a c e t y l a t e d d e r i v a t i v e 1_4, 2 mg ( 4 . 5 x 10 m m o l e , 2 5 % ) a n d s t a r t i n g _p m a t e r i a l 1_, 6 mg (1.1 x 10 m m o l e s , 6 0 % ) . I R : 3 4 0 0 ( N H ) , 1 7 2 0 ( C O ) , 1660 (CO) cm"1 'H NMR: ( T a b l e 1) MS ( m / z , r e l a t i v e •% i n t e n s i t y ) : 4 3 9 ( 3 ) , 3 9 7 ( 3 ) , 3 8 0 ( 5 ) , 2 7 8 ( 5 ) , 1 4 4 ( 8 5 ) , 4 3 ( 1 0 0 ) . E x a c t M a s s c a l c u l a t e d f o r C25H4 5N 05: 4 3 9 . 3 2 8 7 , o b s e r v e d : 4 3 9 . 3 3 0 4 O z o n o l y s i s o f 1 O z o n e was p a s s e d f o r t e n m i n u t e s t h r o u g h a s o l u t i o n c o n t a i n i n g 1_ ( 2 mg, 3.6 x 1 0 " ^ m o l e s ) a n d m e t h a n o l (1 mL) m a i n t a i n e d a t - 7 8°C . O x y g e n was t h e n b u b b l e d t h r o u g h t h e r e a c t i o n m i x t u r e t o f l u s h t h e r e m a i n i n g o z o n e a n d d i m e t h y l s u l f i d e was a d d e d i n e x c e s s . A f t e r t h e s o l v e n t - w a s e v a p o r a t e d , t h e r e s i d u e was r e a c t e d w i t h a 2 , 4 - d i n i t r o p h e n y l h y d r a z i n e s o l u t i o n ( 5 mg i n 1 mL m e t h a n o l a n d 1 d r o p o f c o n c e n t r a t e d H C 1 ) . The p r o d u c t s o f t h i s r e a c t i o n w e r e p u r i f i e d b y PTLC a n d two c o m p o u n d s 1_5 a n d 1_6 h a v i n g R^ v a l u e s o f 0.20 a n d 0.72 i n c h l o r o f o r m w e r e c o l l e c t e d . 1 5 , MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 5 3 7 ( 1 ) , 4 2 9 ( 1 ) , 3 3 5 ( 2 ) , 2 8 0 ( 3 ) , 2 5 0 ( 3 ) . D e c o m p o s e d b e f o r e a h i g h r e s o l u t i o n MS c o u l d be o b t a i n e d . 1 6 , MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 4 0 6 ( 5 ) , 3 0 8 ( 5 ) , 2 3 5 ( 6 ) , 2 0 6 ( 5 0 ) , 1 8 1 ( 1 2 ) . E x a c t M a s s c a l c u l a t e d f o r C,,,H? AH A0 A: 4 0 6 . 2 5 7 2 , o b s e r v e d : 4 0 6 . 2 5 7 1 . 2 , 2 , 1 0 - t r i m e t h y 1 c y c l o d e c a n o n e ( 3 5 ) C y c l o d e c a n o n e ( 2 . 0 g , 13 m m o l , A l d r i c h ) was a d d e d t o a m a g n e t i c a l l y s t i r r e d s u s p e n s i o n o f d r y THF ( 8 0 mL) c o n t a i n i n g s o d i u m h y d r i d e ( 3 . 6 g , - 126 -6 0 % i n o i l , 9 3 m m o l ) . A f t e r 15 m i n , m e t h y l i o d i d e ( 1 5 g , 105 mmol) was a d d e d d r o p w i s e a n d s t i r r i n g c o n t i n u e d f o r 4 h w i t h GLC m o n i t o r i n g u n t i l t h e r e a c t i o n was c o m p l e t e . T h e r e a c t i o n f l a s k was c o o l e d t o 0 ° a n d m e t h a n o l a d d e d d r o p -w i s e t o d e s t r o y e x c e s s s o d i u m h y d r i d e f o l l o w e d by w a t e r , a n d t h e a q u e o u s s o l u t i o n e x t r a c t e d w i t h e t h e r ( 5 x 30 m l ) . The c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( d i c h l o r o -m e t h a n e ) t o g i v e 3 5 , 2.56 g ( 9 9 % y i e l d ) a s a v i s c o u s o i l . UV (Xmax ( l o g E ) ) : 2 9 0 ( 1 . 3 ) IR ( n e a t , F i g u r e 2 ) : 1 7 0 0 cm"1 (CO) 'H NMR ( C D C 13, F i g u r e 3 ) : 1.03 ppm ( s , 3 H , C H3) , 1.04 ppm ( D , J = 7 H z , 3 H , C H3) , 1.17 ppm ( s , 3 H , C H3) , 3.31 ppm ( m , I H ) MS ( m / z , r e l a t i v e % i n t e n s i t y , F i g u r e 1 ) : 1 9 6 ( 3 0 ) , 1 7 8 ( 5 ) , 1 6 3 ( 3 ) , 6 9 ( 7 2 ) , 5 6 ( 1 0 0 ) E x a c t M a s s c a l c u l a t e d f o r C-^H^O: 196.1821 , o b s e r v e d : 1 9 6 . 1 8 3 5 SF0RD 1 3C NMR ( C D C l - j ) : 2 2 . 2 4 , 2 2 . 5 8 , 23.11 , 2 5 . 5 4 , 26.41 , 2 7 . 2 3 , 2 7 . 8 2 , 2 9 . 7 6 , 3 5 . 3 0 , 3 8 . 5 5 , 3 8 . 6 9 ( t , e a c h ) a n d 2 2 0 . 8 5 ( s ) ppm f o r t h e CO. P h o t o l y s i s o f 35 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e (35_) ( 0 . 9 0 g , 4.6 mmol) was d i s s o l v e d i n c y c l o h e x a n e ( 1 8 0 mL) p l a c e d i n a q u a r t z c o n t a i n e r f l u s h e d w i t h n i t r o g e n a n d s t o p p e r e d . T h i s s o l u t i o n was i r r a d i a t e d ( 4 5 0 w, medium p r e s s u r e H a n o v i a ) f o r 5 h ( f o l l o w e d b y G L C , u n t i l c y c l o d e c a n o n e (29_) was no l o n g e r p r e s e n t ) t h e s o l v e n t e v a p o r a t e d a n d t h e r e s i d u e p u r i f i e d by c h r o m a t o g r a p h y ( 1 0 0 % p e t r o l e u m e t h e r t o 1 5 % e t h y l a c e t a t e - p e t r o l e u m e t h e r ) t o g i v e an " o l e f i n i c m i x t u r e " ( 4 0 % ) . 3 6 , IR ( n e a t ) : 1 6 4 0 , 1 4 7 0 , 1 4 6 0 , 1 4 5 0 , 8 8 0 cm"1 ( a l l m i n t e n s i t y p e a k s ) 'H NMR ( C D C 13) : 4 . 64 ppm ( b s , 2 H , = C H2) , 2.0 ppm ( t , J = 7 H z , 2 H , C H2- C 0 ) , 1.70 ppm ( s , 3 H , C H3C 0 ) - 127 -MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 6 8 ( 5 ) , 7 0 ( 7 2 ) , 5 6 ( 1 0 0 ) E x a c t M a s s c a l c u l a t e d f o r C1 2H2 4: 1 6 8 . 1 8 7 2 , o b s e r v e d : 1 6 8 . 1 8 6 0 . 37_, IR ( n e a t ) : 1 4 6 0 , 1 4 5 5 , 1 4 4 5 , 1 3 7 5 , 1 2 6 0 , 1 2 4 0 cm"1 ( a l l m i n t e n s i t y • p e a k s ) 1H NMR ( C C 14) : 0 . 8 - 2 . 0 ppm (m) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 6 8 ( 1 0 ) , 1 6 6 ( 6 ) , 6 9 ( 7 5 ) , 5 7 ( 1 0 0 ) , 5 5 ( 9 6 ) , 4 3 ( 1 0 0 ) , 4 1 ( 1 0 0 ) When t h e b u b b l i n g o f N^ was o m i t t e d , t h e p r o d u c t s c o n s i s t e d o f t h e o l e f i n i c m i x t u r e ( 2 5 % ) a n d 38 ( 4 0 % ) . 3 8 , IR ( n e a t ) : 1 7 2 5 ( C 0 ) 'H NMR ( C C 14) : 9 .54 ppm ( d , J = 2 H z , I H , C H O ) , 4.54 ppm ( b s , 2 H , = C H2) , 1.96 ( t , J = 6 H z , 2H., C H2) , 1.66 ( s , 3 H , C H3) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 9 6 ( 2 0 ) , 1 7 8 ( 3 ) , 6 9 ( 6 8 ) , 5 6 ( 1 0 0 ) . 2 , 2 , 1 0 - t r i m e t h y l a c e t o x y c y c l o d e c a n e ( 4 3 ) 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o n e ( 3 5 ) ( 0 . 2 1 5 g , 1.1 mmol) was a d d e d t o a s t i r r e d e t h e r ( 5 mL) s u s p e n s i o n o f l i t h i u m a l u m i n u m h y d r i d e ( 0 . 0 4 2 g , 1.1 mmol) a t 22°C a n d s t i r r i n g c o n t i n u e d f o r 0.85 h . A f t e r d r o p w i s e a d d i t i o n o f w a t e r , t h e s o l u t i o n was e x t r a c t e d w i t h e t h e r ( 3 x 25 m l ) , t h e c o m b i n e d o r g a n i c e x t r a c t s d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o g i v e 2 , 2 , 1 0 - t r i m e t h y l c y c l o d e c a n o l ( 4 2 J , 0 . 1 9 0 g ( 8 2 % ) . 4 2 , IR ( n e a t ) : 3 3 0 0 - 3 5 0 0 cm"1 (OH) 'H NMR ( C D C 13) : 0 . 8 0 - 1 . 1 5 ppm (m, 9 H , 3 C H3) , 1 . 2 0 - 2 . 0 0 ppm (m, 1 6 H ) , 3.14 ppm ( m , I H ) . The a l c o h o l 42_ was d i s s o l v e d i n C C 14 ( 2 m L ) , a c e t i c a n h y d r i d e ( 0 . 2 m L ) , a n d p y r i d i n e ( 0.1 mL) a d d e d a n d t h e s o l u t i o n s t i r r e d a t 2 2 ° f o r 15 h . E t h e r ( 3 0 mL) was a d d e d a n d t h e s o l u t i o n w a s h e d w i t h 5% a q u e o u s H C 1 , b r i n e , t h e - 128 -o r g a n i c l a y e r d r i e d a n d c o n c e n t r a t e d t o g i v e t h e a c e t a t e 4 3 , 0 . 1 8 5 g ( 8 5 % ) . 4 3 : IR ( n e a t ) : 1725 cm"1 (CO) 'H NMR ( C D C 13) : 0 . 8 3 ppm ( s , 3 H , C H3) , 0.93 ppm ( s , 3 H , C H3) , 0.97 ppm .. ( d , J = 7 H z , 3 H , C H3) , 2.07 ppm ( s , 3 H , C H3) , 4.56 a n d 5.10 ppm ( d , J = 1.5 a n d 2.5 H z , I H , C H ( O A c ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 3 9 ( 5 5 ) , 2 2 5 ( 2 8 ) , 1 8 1 ( 7 2 ) , 4 3 ( 1 0 0 ) . P o t a s s i u m P e r m a n g a n a t e O x i d a t i o n o f O l e f i n s ( o b t a i n e d f r o m p h o t o l y s i s o f 3 5 ) 1 8 - C r o w n - 6 - e t h e r ( 3 0 mg, 0 . 0 8 mmol) a n d p o t a s s i u m p e r m a n g a n a t e ( 2 5 2 mg, 1.6 mmol) w e r e a d d e d t o a b e n z e n e s o l u t i o n ( 1 5 mL) o f t h e o l e f i n i c m i x t u r e ( 1 0 0 mg, 5.6 mmol) a n d t h e r e a c t i o n s t i r r e d f o r 120 h a t 2 3 ° . W a t e r was a d d e d , t h e r e a c t i o n m i x t u r e e x t r a c t e d w i t h e t h e r ( 3 x 25 m L ) , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e n e u t r a l m a t e r i a l p u r i f i e d b y PTLC ( 5 % e t h y l a c e t a t e : d i c h l o r o m e t h a n e ) t o g i v e k e t o n e 39_, 10 mg ( 9 % ) . IR ( n e a t ) : 1 7 1 5 cm"1 (CO) 'H NMR ( C C 14) : 2.07 ( s , 3 H , C H3 > C O ) , 2.10 ( t , J = 7 H z , 2 H , C H2C 0 ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 7 0 ( 1 1 ) , 5 8 ( 1 0 0 ) , 4 3 ( 8 3 ) E x a c t M a s s c a l c u l a t e d f o r C ^ H ^ O : 1 7 0 . 1 6 6 5 , o b s e r v e d : 1 7 0 . 1 6 8 2 . H y d r o b o r a t i o n o f O l e f i n s ( o b t a i n e d f r o m p h o t o l y s i s o f 3 5 ) The THF s o l u t i o n ( 4 m l ) c o n t a i n i n g t h e o l e f i n i c m i x t u r e ( 1 0 0 mg, 0.56 mmol) was c o o l e d t o 0 ° a n d BH3~THF ( 0 . 6 4 mL, 0.6 m m o l , A l d r i c h ) a d d e d d r o p -w i s e . A f t e r 5 m i n t h e i c e b a t h was r e m o v e d a n d t h e s o l u t i o n s t i r r e d a t 2 3 ° f o r 2 h . A 3N a q u e o u s s o l u t i o n o f s o d i u m h y d r o x i d e ( 0 . 0 8 mL) a n d 3 0 % h y d r o g e n p e r o x i d e ( 0 . 0 8 mL) w e r e a d d e d a n d s t i r r i n g c o n t i n u e d f o r an a d d i t i o n a l 2 h . W a t e r was a d d e d , t h e r e a c t i o n m i x t u r e e x t r a c t e d w i t h e t h e r ( 3 x 2 0 m l ) , t h e c o m b i n e d o r g a n i c e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d - 129 -t h e r e s u l t i n g o i l p u r i f i e d by PTLC ( d i c h l o r o m e t h a n e ) t o g i v e h y d r o c a r b o n 1_5, 20 mg ( 2 0 % ) a n d p r i m a r y a l c o h o l 4 0 , 60 mg ( 6 0 % ) 4 0 : IR ( n e a t ) : 3 6 0 0 - 3 3 0 0 cm"1 (OH) 'H NMR ( C C 14) : 3.30 ppm ( d , J = 5 H z , 2 H , C H2- 0 H ) , .8-1.4 (m, 22H) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 6 8 ( 5 % ) , 5 7 ( 1 0 0 % ) , 4 3 ( 9 5 ) E x a c t M a s s c a l c u l a t e d f o r C1 2H2 4: ( M+ - H20 ) 1 6 8 . 1 8 7 8 , o b s e r v e d : 1 6 8 . 1 8 7 5 . J o n e s O x i d a t i o n o f 4 0 To a n a c e t o n e s o l u t i o n ( 2 mL) c o n t a i n i n g a l c o h o l 4 0 ( 1 5 mg, 0 . 0 8 m m o l ) , J o n e s r e a g e n t7 was a d d e d d r o p w i s e u n t i l a g r e e n p r e c i p i t a t e was o b t a i n e d . T h i s m i x t u r e was s t i r r e d f o r a n a d d i t i o n a l 15 m i n a n d 2 - p r o p a n o l ( 2 mL) was a d d e d t o d e s t r o y a n y e x c e s s J o n e s r e a g e n t . The r e a c t i o n m i x t u r e was t h e n f i l t e r e d , d r i e d , f i l t e r e d a g a i n a n d t h e s o l v e n t c o n c e n t r a t e d t o g i v e t h e c a r b o x y l i c a c i d 41_, 15 mg ( 9 3 % ) . IR ( n e a t ) : 3 4 0 0 - 2 8 0 0 ( O H ) , 1 7 0 0 (CO) cm"1 'H NMR ( C D C 13) : 10.2 ppm ( b s , I H ) , . 8 - 2 . 0 ppm ( m , ~23H) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 0 0 ( 1 0 ) , 1 4 0 ( 1 2 ) , 7 4 ( 1 0 0 ) . O z o n o l y s i s o f O l e f i n i c M i x t u r e ( o b t a i n e d f r o m p h o t o l y s i s o f 3 5 ) O z o n e was p a s s e d d u r i n g 5 m i n t h r o u g h a s o l u t i o n c o n t a i n i n g t h e o l e f i n i c m i x t u r e ( 1 0 0 mg, 5.6 mmol) i n m e t h a n o l ( 2 m L ) , a t - 7 8°C . O x y g e n was t h e n b u b b l e d t h r o u g h t h e s o l u t i o n t o f l u s h a n y r e m a i n i n g o z o n e a n d d i m e t h y l s u l f i d e ( 0 . 5 mL) was a d d e d . A f t e r s t i r r i n g f o r 1 h a t 2 0 ° , t h e s o l u t i o n was c o n c e n t r a t e d a n d t h e r e s i d u e p u r i f i e d b y PTLC ( 5 % e t h y l a c e t a t e : d i c h l o r o -m e t h a n e ) t o a f f o r d h y d r o c a r b o n 3_7, 20 mg ( 2 0 % ) a n d k e t o n e 39_, 60 mg ( 5 4 % ) . S p e c t r a l d a t a r e p o r t e d i n p r e v i o u s e x p e r i m e n t a l s e c t i o n s . - 130 -M e t h y T - 2 - o x o c y c l o p e n t a n e c a r b o x . y l a t e ( 1 0 5 ) S o d i u m h y d r i d e ( 2 . 4 6 g , 6 0 % o i l d i s p e r s i o n , 63 m m o l , BDH) a n d d i m e t h y l -c a r b o n a t e ( 2 0 g , 2 2 0 m m o l , E a s t m a n ) w e r e a d d e d t o b e n z e n e ( 5 0 mL) a n d t h e s o l u t i o n r e f l u x e d . C y c l o p e n t a n o n e ( 2 . 4 7 g , 29 m m o l , A l d r i c h ) was a d d e d d r o p -w i s e a n d s t i r r i n g c o n t i n u e d f o r 2 h . The c o l d r e a c t i o n (0°C) was a c i d i f i e d ( 5 % H C l ) a n d e x t r a c t e d w i t h e t h e r . The c o m b i n e d e x t r a c t s w e r e w a s h e d w i t h s o d i u m b i c a r b o n a t e , b r i n e , d r i e d , f i l t e r e d a n d c o n c e n t r a t e d , t o a f f o r d 105 a f t e r d i s t i l l a t i o n , 2.1 g ( 5 5 % ) . bp 9 7 - 1 0 0° C / 1 2 T o r r IR ( C C 14) : 1 7 5 0 ( s ) , 1 6 6 0 (m) cm"1 1H NMR ( C C 14) : 6 = 7.50 ppm ( I H , s , e n o l ) , 3.78 ppm ( 3 H , s , C H30 C 0 ) , 1.5-2.5 ppm ( 6 H , m ) . M e t h y l 1 - m e t h y l - 2 - o x o c y c l o p e n t a n e c a r b o x y l a t e ( 1 0 6 ) A s o l u t i o n c o n t a i n i n g 3 - k e t o - e s t e r 105 ( 1 . 8 g , 13 mmol) a n d p o t a s s i u m c a r b o n a t e ( 7 . 3 g , 53 m m o l , BDH) i n a c e t o n e ( 2 5 mL) was h e a t e d t o 4 0°C. I o d o m e t h a n e ( 3 . 8 g , 26 m m o l , A l d r i c h ) a d d e d d r o p w i s e , a n d t h e m i x t u r e s t i r r e d f o r 1 h . The r e a c t i o n was c o o l e d , f i l t e r e d , w a t e r a d d e d a n d e x t r a c t e d w i t h e t h e r . T h e c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o g i v e 1 0 6 , 1.8 g ( 9 8 % ) . IR ( C C 14) : 1 7 2 5 ( s ) , 1 6 7 5 ( m ) , 1625 (w) cm"1 'H NMR ( C C 14) : 6 = 3.50 ppm ( 3 H , s , C H30 C 0 ) , 1.5-2.5 ppm ( 6 H , m ) , 1.18 ppm ( 3 H , s , C H3) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 4 2 ( 3 8 ) , 1 1 0 ( 5 2 ) - MeOH. M e t h y l 1 , 3 , 3 - t r i m e t h y l - 2 - o x o c y c l o p e n t a n e c a r b o x y l a t e ( 1 0 7 ) A p o t a s s i u m - t - a m y l o x i d e s o l u t i o n was p r e p a r e d by r e f l u x i n g DME ( 2 0 0 m L ) , - 131 -t - a m y l a l c o h o l ( 2 2 . 5 2 g , 0 . 2 5 6 m o l , F i s h e r ) a n d p o t a s s i u m ( 1 1 . 9 [ g , 0.306 m o l , BDH) f o r 2 d a y s . T i t r a t i o n o f a n a l i q u o t ( 2 mL) c o n t a i n i n g p h e n o l -p h t h a l e i n , w i t h H C 1 , d e t e r m i n e d t h e c o n c e n t r a t i o n o f t h e s o l u t i o n ( 1 . 2 M ) . K e t o n e 106 ( 2 1 0 mg, 1.3 mmol) was a d d e d t o DMF ( 3 mL) c o n t a i n i n g p o t a s s i u m - t -a m y l o x i d e ( 2 . 2 mL, 2.6 mmol) a n d s t i r r e d a t - 2 0°C . I o d o m e t h a n e ( 0 . 9 3 g , 6.5 m m o l , A l d r i c h ) ' w a s a d d e d t o t h e o r a n g e s o l u t i o n , a n d s t i r r i n g c o n t i n u e d f o r 10 m i n . E x c e s s ammonium c h l o r i d e was a d d e d , a n d t h e s o l u t i o n e x t r a c t e d w i t h e t h e r . The c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d b y c h r o m a t o g r a p h y ( 5 % e t h y l a c e t a t e - p e t r o l e u m e t h e r ) t o a f f o r d 1 0 7 , 155 mg ( 7 0 % ) . IR ( C C 14) : 1 7 5 0 ( w ) , 1 7 3 0 (w) cm"1 'H NMR ( C C 14) : 6 = 3.69 ppm ( 3 H , s , C H30 C 0 ) , 1.5-2.5 ppm 4 H , m ) , 1 . 2 3 , 1.10 a n d 1.02 ppm ( e a c h , 3 H , s , C H3) . M e t h y l 1 , 3 , 3 - t r i m e t h y l - 2 - h y d r o x y c y c l o p e n t a n e c a r b o x y l a t e ( 1 0 8 ) S o d i u m b o r o h y d r i d e ( 0 . 9 0 g , 24 m m o l , BDH) was a d d e d t o a m e t h a n o l ( 1 0 mL) s o l u t i o n o f k e t o n e 107 (3.1 g , 17 m m o l ) . A f t e r s t i r r i n g f o r 1 h , t h e s o l u t i o n was a c i d i f i e d ( 5 % HCL) a n d e x t r a c t e d w i t h e t h e r . The c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( 1 0 % e t h y l a c e t a t e -p e t r o l e u m e t h e r ) , t o a f f o r d 1 0 8 , 2.4 g ( 8 3 % ) . IR ( C C 14) : 3 5 0 0 ( O H ) , 1725 (CO) cm"1 'H NMR ( C C 14) : 6 = 4.05 ppm ( I H , s , C H ( 0 H ) ) , 3.83 ppm ( 3 H , s , C H30 C 0 ) , 3.20 ppm ( I H , b s , O H ) , 1 . 1 8 , 1.02 a n d 0.92 ppm ( e a c h , 3 H , s , C H3) . M e t h y l 3 - c h l o r o p r o p a n o a t e ( 1 1 7 a ) P r e p a r e d f r o m 3 - c h l o r o p r o p i o n y l c h l o r i d e , b a s e d on t h e p r o c e d u r e o f C a r p i n o e t a l1 5 0 ( 9 7 % ) . IR ( C C 14) : 1 740 (CO) cm"1 - 132 -'H NMR ( C C 14) : 6 = 2.78 ppm ( 2 H , t , J = 7 H z , C H2C O O ) , 3.69 ppm ( 3 H , s , COOMe), 3.73 ppm ( 2 H , t , J = 7 H z , C H2C 1 ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 2 3 ( 2 2 ) , 8 7 ( 8 5 ) - H C l , 6 3 ( 1 0 0 ) - C H2C H2C 1 . 3 - C h l o r o p r o p a n a l ( 1 1 7 c ) P r e p a r e d a s 1 1 7 d , n e a t , no s o l v e n t ( 8 5 % ) . The p r o d u c t was o b t a i n e d a s a t r i m e r : m o n o m e r ( 1 0 : 1 ) , a c c o r d i n g t o 'H NMR a n a l y s i s . IR ( C C 14) : 1 7 2 5 (CO) cm"1 *H NMR ( C C 14) : 6 = 8.42 a n d 5.07 ppm ( I H , b s : t , J = 4 H z , CH = CHOH), 3.56 ppm ( 2 H , t , J = 7 H z , C H2C 1 ) , 2.10 ppm ( 2 H , d t , J = 4 , 7 H z , C H2C H 0 ) . 3 - C h l o r o p r o p a n a l e t h y l e n e a c e t a l ( 1 1 7 d ) E t h y l e n e g l y c o l ( 3 0 g , 0.49 m o l , F i s h e r ) was p l a c e d i n a f l a s k e q u i p p e d w i t h a m e c h a n i c a l s t i r r e r , c o n d e n s e r a n d d r y i n g t u b e , a t 0°C. G a s e o u s h y d r o c h l o r i c a c i d ( 1 6 g , 0.42 m o l , F i s h e r ) was b u b b l e d i n t o t h e f l a s k , , f o l l o w e d b y t h e d r o p w i s e a d d i t i o n o f a c r o l e i n ( 2 3 . 8 mL, 0.4 m o l , A l d r i c h ) . The i c e b a t h was t h e n r e m o v e d a n d t h e r e a c t i o n s t i r r e d f o r 4 h a n d e x t r a c t e d w i t h p e t r o l e u m e t h e r . The c o m b i n e d e x t r a c t s w a s h e d w i t h s o d i u m b i c a r b o n a t e , w a t e r , d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d 1 1 7 d , 5 5 . 6 g ( 8 3 % ) . bp 4 0 - 4 2° C / 0 . 0 7 T o r r IR ( C C 14) : 2 9 5 0 , 2 8 5 0 (CH) cm"1 1H NMR ( C C 14) : 6 = 4 . 8 6 ppm ( I H , t , J = 4 H z , H C ( 0 C H2)2) , 3.84 ppm ( 4 H , s , C H20 ) , 3.47 ppm ( 2 H , t , J = 7 H z , C H2C 1 ) , 2.02 ppm ( 2 H , d t , J = 4 , 7 H z , C H2C H ( 0 C H2)2 MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 3 7 ( 8 ) , 7 3 ( 1 0 0 ) - H C ( 0 C H2)2 > - 133 -3 - C h l o r o - l , 1 - d i m e t h o x y p r o p a n e ( 1 1 7 e ) P r e p a r e d a s a b o v e , u s i n g m e t h a n o l ( 1 . 2 5 m o l ) i n s t e a d o f e t h y l e n e g l y c o l ( 7 5 % ) . IR ( C C 14) : 2 9 7 5 , 2 9 4 0 , 2 8 1 0 (CH) cm'1 'H NMR ( C C 14) : 6 = 4 . 7 5 ppm ( I H , t , J = 4 H z , H C ( 0 M e )2) , 3.54 ppm ( 2 H , t , J = 7 H z , C H2C 1 ) , 3.28 ppm ( 6 H , s , C H30 ) , 1.9 Lppm ( 2 H , d t , J = 4 , 7 H z , CH_2CH(0Me)2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 0 7 ( 1 0 0 ) M+-0Me, 1 0 3 ( 1 5 ) - C l E x a c t M a s s c a l c u l a t e d f o r C g H ^ O g C l : 1 3 8 . 0 4 4 4 , o b s e r v e d : 1 3 8 . 0 3 8 0 . 3 - B r o m o p r o p a n o l a c e t a t e ( 1 1 7 f ) P r e p a r e d f r o m t h e r e l a t e d a l c o h o l ( 1 4 g , 0.1 m o l ) , s t i r r e d a t 20°C w i t h a c e t i c a n h y d r i d e (11 g , 0.11 m o l , F i s h e r ) , p y r i d i n e ( 8 . 8 g , 0 . 1 2 m o l ) i n C C 14 ( 1 0 m L ) , f o r 16 h . C o l d w a t e r a n d c h l o r o f o r m w e r e t h e n a d d e d t o t h e s o l u t i o n . The c h l o r o f o r m e x t r a c t s w e r e w a s h e d w i t h 1 0 % H C 1 , d r i e d , f i l t e r e d , a n d c o n c e n t r a t e d , t o a f f o r d 1 1 7 f , 1 4 . 3 g ( 8 3 % ) . IR ( C C 14) : 1 7 4 0 (CO) cm"1 'H NMR ( C C 14) : 6 = 4.11 ppm ( 2 H , t , J = 7 H z , C H g B r ) , 3.43 ppm ( 2 H , t , J = 7 H z , C H20 ) , 2 . 28 ppm ( 2 H , q u i n t . , J = 7 H z , C H2C H _2C H2) , 2.20 ppm ( 3 H , s , C H3C 0 ) . T y p i c a l A l k y l a t i o n o f C y c l o p e n t a d i e n e u s i n g 117 F r e s h l y d i s t i l l e d c y c l o p e n t a d i e n e ( 5 m m o l , A l d r i c h , bp 3 8 - 4 0°C ) i n THF (2 mL) was a d d e d d r o p w i s e t o s o d i u m h y d r i d e ( 5 . 5 m m o l , 6 0 % o i l d i s p e r s i o n , A l d r i c h ) i n THF ( 1 5 m L ) , s t i r r i n g a t 0°C. The s o l u t i o n s t o p p e d b u b b l i n g a f t e r 5-10 m i n , a n d t h e a l k y l a t i n g r e a g e n t 1J_7 ( 5 mmol) was a d d e d . The r e a c t i o n was s t i r r e d a t t h e a p p r o p r i a t e t e m p e r a t u r e , f o r t h e r e q u i s i t e t i m e ( T a b l e 4 ) . - 134 -The s o l u t i o n was c o o l e d , a c i d i f i e d ( 5 % H C l , d r o p w i s e ) a n d e x t r a c t e d w i t h e t h e r . T h e c o m b i n e d e t h e r e x t r a c t s w a s h e d w i t h b r i n e , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( n e u t r a l a l u m i n a , -e t h e r - p e t r o l e u m e t h e r ) . The r e a c t i o n o f 117b was p e r f o r m e d u s i n g 4 e q u i v . o f c y c l o p e n t a d i e n e , w h i l e r e a c t i o n o f 1 1 7 i was d o n e i n THF:DME, 1 : 1 . T y p i c a l s p e c t r a l d a t a f o r p r o d u c t s 1 1 8 , i n t h i s c a s e , 1 1 8 e . IR ( C C 14) : . 3 0 0 - 2 8 1 0 , 1 6 1 5 , 1605 (CH) cm"1 'H NMR ( C C l ^ ) : <5 = 6 . 3 - 5 . 8 ppm (m, 3 H , o l e f i n i c c y c l o p e n t a d i e n e p r o t o n s ) , 4.27 ppm ( I H , t , J = 4 H z , C H ( 0 M e )2) , 3.23 ppm ( 6 H , s , C H30 ) , 2.85 ppm ( 2 H , b s , C H2 i n c y c l o p e n t a d i e n e ) , 2.35 a n d 1.84 ppm ( e a c h , C H2, m, CH_2CH(0Me)2 o r C H2- c y c l o p e n t a d i e n e ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 6 8 ( 1 3 ) , 1 3 6 ( 7 4 ) - MeOH, 1 0 4 ( 6 2 ) - 2 Me0H, * E x a c t M a s s c a l c u l a t e d f o r C ,0H1 602: 1 6 8 . 1 1 4 6 , o b s e r v e d : 1 6 8 . 1 1 3 5 . 1 , 1 - d i a c y l a t e d p r o d u c t " 1 1 8 b " , 'H NMR: ( C C 14) <5 = 6.3 ppm ( 4 H , b s , o l e f i n s ) , 3.68 ppm ( 4 H , m, C H g C l ) , 3.0 ppm ( 4 H , m, C H2C 0 ) 1 , 3 - d i a c y l a t e d p r o d u c t " 1 1 8 b " , 'H NMR: ( C C 14) 6 = 7.30 ppm ( 2 H , d , J = 4 H z ) , 6.32 ppm ( I H , t , J = 4' H z ) , 3.82 ppm ( 4 H , t , J = 7 H z ) , 3.30 ppm ( 4 H , t , J = 7 H z ) , 2.70 ppm ( I H , t , J = 4 H z ) . 3 - E t h o x y - 2 - m e t h y 1 - 2 - c y c l o p e n t e n o n e ( 1 0 3 ) P r e p a r e d f r o m 2 - m e t h y l c y c l o p e n t a n e - 1 , 3 - d i o n e , b a s e d on t h e p r o c e d u r e o f H o u s e e t a l9 1 ( 9 0 % ) . IR ( C C 14) : 1 6 8 0 ( C O ) , 1 6 2 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 4.23 ppm ( 2 H , q , J = 7 H z , C H _2CH3), 2 . 8 - 2 . 3 ppm ( 4 H , m, C H2C H2) , 1.56 ppm ( 3 H , b s , C H3C = C ) , 1.40 ppm ( 3 H , t , J = 7 H z , CH_3CH2). - 135 -4 - E t h o x y - 3 - m e t h y l b i c y c l o [ 3 . 3 . 0 ] o c t - 3 - e n - 2 - o n e ( 1 2 2 ) P r e p a r e d f r o m e n o l e t h e r 103 b y t h e m e t h o d o f K o r e e d a e t a l1 1 0 ( 6 8 % ) . bp 9 0 - |B°C/0.5 T o r r IR ( C C 14) : 1 7 0 0 ( C O ) , 1 6 4 5 (C=C) cm'1 'H NMR ( C C 14) : 6 = 4 . 2 8 ppm ( 2 H , q , J = 7 H z , 0 C H _2C H3) , 3.20 ppm ( I H , m, C H C = C ) , 2.73 ppm ( I H , m, C H C O ) , 1.58 ppm ( 9 H , b s ) , 1.36 ppm ( 3 H , 5 , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 8 1 ( 3 0 ) M+ + 1 , 1 8 0 ( 1 0 0 ) , 1 5 2 ( 4 8 ) - E t , 1 2 4 ( 8 3 ) - C H2C H2C 0 E x a c t Mass c a l c u l a t e d f o r C ^ H ^ O ^ 1 8 0 . 1 1 4 6 , o b s e r v e d : 1 8 0 . 1 1 5 8 . 2 - M e t h y 1 - 2 , 4 - b i c y c l o [ 3 . 3 . 0 ] o c t a d i o n e ( 1 2 3 ) E n o l e t h e r 122 ( 1 . 8 g , 10 mmol) was h y d r o l y z e d u s i n g s u l f u r i c a c i d ( c o n e . 3.5 mL, 7 0 mmol) a n d w a t e r ( 7 mL, 70 mmol) a t 1 0 0°C , f o r 18 h . The r e a c t i o n was c o o l e d t o 2 0°C , a n d e x t r a c t e d w i t h h o t e t h y l a c e t a t e a n d h o t d i c h l o r o -m e t h a n e . The c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h s o d i u m b i c a r b o n a t e , b r i n e , d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d 1 2 3 , 0 . 6 - 1 . 2 g ( 4 0 - 8 0 % ) , r e c r y s t a l l i z e d i n h o t d i c h l o r o m e t h a n e . mp 1 5 8 - 1 6 0°C IR ( C H C 13) : 1 7 0 0 ( C O ) , 1 6 4 5 (C=C) cm"1 'H NMR (CDC13-): 6 = 7.10 a n d 4 . 1 8 ppm ( I H , b s , O H ) , 2.60 ppm ( I H , s , C H - O C ) , 2.20 ppm ( I H , s , C H C O ) , 1.26 ppm ( 3 H , s , C H3) MS ( m / z , r e l a t i v e & i n t e n s i t y ) : 1 5 2 ( 5 4 ) , 1 2 4 ( 6 3 ) -CO, 2 8 ( 1 0 0 ) -CO E x a c t M a s s c a l c u l a t e d f o r CQH ,o09: 1 5 2 . 0 8 3 4 , o b s e r v e d : 1 5 2 . 0 8 3 3 . 3 - M e t h y 1 b i c y c 1 o [ 3 . 3 . 0 ] - 3 - o c t e n - 2 - o l ( 1 2 4 ) L i t h i u m a l u m i n u m h y d r i d e ( 4 2 mg, 1.1 mmol o r 4.4 e q u i v . , A l d r i c h ) was - 136 -a d d e d t o e n o l e t h e r 122 ( 1 8 0 mg, 1 mmol) d i s s o l v e d i n e t h e r ( 1 0 mL) a n d t h e r e a c t i o n s t i r r e d a t 2 0°C. A f t e r 2 h , w a t e r (0.1 mL, 5.6 mmol) was a d d e d t o t h e c o l d (0°C) r e a c t i o n . The m i x t u r e was t h e n f i l t e r e d , a n d t h e r e s i d u e w a s h e d w i t h e t h e r . The c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t s p u r i f i e d by c h r o m a t o g r a p h y ( 8 % e t h y l a c e t a t e - d i c h l o r o m e t h a n e ) . 1 2 4 a , l e a s t p o l a r p r o d u c t , 70 mg ( 4 0 % ) , IR ( C C 14) : 3 6 0 0 ( w , OH) cm"1 'H NMR ( C C 14) : 6 = 5.20 ppm ( I H , b s ) , 4.0 ppm ( I H , b s ) , 3.10 ppm ( I H , b s ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 3 8 ( 5 7 ) , 1 2 0 ( 3 8 ) -Hp_0, 1 2 3 ( 3 8 ) - C H3 > 1 0 9 ( 1 0 0 ) 1 2 4 b , more p o l a r p r o d u c t , 88 mg ( 4 9 % ) , IR ( C C 14) : 3 6 0 0 ( s , O H ) , 3 4 5 0 (m) cm"1 1H NMR ( C C 14) : 6 = 5.10 ppm ( I H , b s ) , 4.36 ppm ( I H , b d , J = 7 H z ) , 2.80 ppm ( 2 H , m) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 3 8 ( 6 0 ) , 1 2 3 ( 3 0 ) -CHy 1 2 0 ( 2 0 ) - H20 , 1 0 9 ( 1 0 0 ) . 3 - M e t h y l - 3 - ( 3 - o x o b u t y l ) - 2 , 4 - b i c y c 1 o [ 3 . 3 . 0 ] o c t a d i o n e ( 1 2 5 ) P r e p a r e d f r o m 3 - m e t h y l - 2 , 4 - b i c y c l o [ 3 . 3 . 0 ] o c t a d i o n e , b a s e d on t h e p r o c e d u r e o f H a j o s a n d P a r r i s h1 0 1 a ( 8 5 % ) . IR ( n e a t ) : 1 760 ( m ) , 1725 ( s ) cm"1 'H NMR ( C D C 13) : 6 = 3.68 ppm ( 2 H , t , J = 7 H z , C H2C H2C 0 ) , 3.30 ppm ( 2 H , m ) , 2.57 ppm ( 2 H , t , J = 7 H z , C H2C 0 ) , 2.05 ppm ( 3 H , s , C 0 C H3) , 0.96 ppm ( 3 H , s , C H3) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 2 2 ( 2 0 ) , 1 5 2 ( 7 7 ) - C ^ O , 1 2 4 ( 1 0 0 ) - C ^ O , CO E x a c t M a s s c a l c u l a t e d f o r C] 3H1 803: 2 2 . 1 2 5 1 , o b s e r v e d : 2 2 2 . 1 2 4 9 . - 137 -3 - ( P r o p y l o x y - 3 - a l e t h y l e n e a c e t a l ) - 2 - m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 3 2 ) 3 - i o d o p r o p a n a l e t h y l e n e a c e t a l ( 2 e q u i v . , A l d r i c h ) , 1 8 - c r o w n - 6 ( c a t a l y t i c , A l d r i c h ) , a n d s o d i u m c a r b o n a t e ( 2 e q u i v . , BDH) w e r e a d d e d t o d i k e t o n e 1 2 1 ' (1 e q u i v . ) , p r e s e n t i n s o l v e n t s y s t e m a , b . The r e a c t i o n m i x t u r e was r e f l u x e d f o r 18 h a n d w a t e r a d d e d t o q u e n c h t h e r e a c t i o n ( 2 0° ) , t h i s was f o l l o w e d by e x t r a c t i o n w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w e r e w a s h e d , d r i e d , f i l t e r e d a n d c o n c e n t r a t e d . P u r i f i c a t i o n by c h r o m a t o g r a p h y ( e t h e r ) a f f o r d e d 1 3 2 . S o l v e n t s u s e d , a : T H F , 0 % ; b: HMPA a t 1 5 0°C , 3 5 % . IR ( C C 14) : 1 7 0 0 ( C 0 ) , 1 6 4 0 ( C = C ) cm"1 'H NMR ( C D C 13) : 5.0 ppm ( I H , t , J = 4 H z , C H ( 0 C H2)2) , 4 . 3 0 ppm ( 2 H , t , J = 7 H z , C H _2C H2( C H20 )2) , 3.90 ppm ( 4 H , b s , C H20 ) , 1.62 ppm ( 3 H , b s , C H3) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 1 2 ( 2 ) , 1 6 8 ( 3 4 ) - C H3C 0 , 1 2 4 ( 3 6 ) . E t h y l 3 - m e t h y l - 2 , 4 - p e n t a d i e n o a t e ( 1 3 1 a ) P r e p a r e d a s f o r 1 4 4 a , e x c e p t 4 - c h l o r o b u t a n o n e was r e p l a c e d by m e t h y l v i n y l k e t o n e . The p r o d u c t o b t a i n e d a f t e r e x t r a c t i o n ( 9 0 % ) was p u r e e n o u g h f o r f u r t h e r u s e . H o w e v e r , i t c o u l d be d i s t i l l e d , bp 8 0 - 8 2° C / 1 5 T o r r ( 1 9 % ) IR ( n e a t ) : 1715 ( C O ) , 1 6 3 5 , 1 6 1 0 , 1605 ( O C ) cm"1 'H NMR ( C C 14) : 6 = 7.62 ppm a n d 6.17 ppm ( I H , d d , J = 1 2 , 18 Hz a n d HC=C a n d J = 1 0 , 18 H z , 1 : 1 , C H = C H2) , 5.49 ppm ( 2 H , b s , 1 o f CH_2=C), 5.15 ppm ( I H , m, 1 o f C H2= C ) , 3.86 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 2.00 a n d 1.72 ppm ( 3 H , s : s , 1 : 1 , C H3C = C ) , 1.00 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 4 0 ( 3 ) , 1 1 1 ( 1 8 ) - E t , 9 5 ( 6 3 ) - O E t , 4 3 ( 1 0 0 ) E x a c t M a s s c a l c u l a t e d f o r C g H1 202: 1 4 0 . 0 8 3 4 , o b s e r v e d 1 4 0 . 0 8 4 3 . - 138 -3 - M e t h y l - 4 , 4 - d i c a r b o m e t h o x y - 1 , 3 - b u t a d i e n e ( 1 3 1 b ) A l k y l c h l o r i d e 1 4 4b ( 3 g , 17 mmol) was a d d e d d r o p w i s e t o a s t i r r e d s o l u t i o n o f s o d i u m ( 0 . 4 g , 17 m m o l , BDH) i n m e t h a n o l ( 5 0 m L ) . A f t e r s t i r r i n g f o r 1 h a t 0°C, t h e s o l u t i o n was n e u t r a l i z e d ( 1 0 % H C l ) , a n d t h e a q u e o u s l a y e r e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d 1 3 1 b , 2.1 g ( 9 0 % ) p u r e e n o u g h f o r f u r t h e r u s e . IR ( n e a t ) : 1 7 10 C O ) , 1 6 1 0 , 1575 (C=C) cm"1 'H NMR ( C C 14) : 6 = 7.00 ppm ( I H , d d , J = 1 0 , 16 H z , H O C ) , 5.68 ppm ( I H , b d , J = 16 H z , CH=CH, E ) , 5.43 ppm ( I H , b d , J = 10 H z , CH=CH, Z ) , 3.70 ppm ( 6 H , s , C H3C 0 0 ) , 2.10 ppm ( 3 H , s , C H3C = C ) . l - ( p r o p - 1 - y n - 3 - o l ) - 1 - c y c l o p e n t a n o 1 ( 1 3 3 ) M e t h y l m a g n e s i u m c h l o r i d e ( 1 3 . 1 mL, 39 m m o l , 2.99 M s o l u t i o n , A l d r i c h ) was a d d e d s l o w l y t o f r e s h l y d i s t i l l e d p r o p a r g y l a l c o h o l (1 g , 18 m m o l , bp 2 8 - 3 0° C / 1 0 T o r r , A l d r i c h ) . i n THF ( 2 5 m L ) . The s o l u t i o n was s t i r r e d f o r 10 m i n a t 0°C, t h e n 3 0 m i n a t 2 0°C. C y c l o p e n t a n o n e ( 1 . 5 g , 18 m m o l , A l d r i c h ) i n THF ( 2 mL) was a d d e d t o t h e c o l d (0°C) s o l u t i o n . The m i x t u r e was f i l t e r e d t h r o u g h c e l i t e , e x t r a c t e d w i t h e t h y l a c e t a t e , d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d 1 3 3 , 2.2 g ( 8 7 % ) . IR ( n e a t ) : 3 5 0 0 - 3 4 0 0 (OH) cm"1 'H NMR ( C D C 13) : 6 = 4.27 ppm ( 2 H , s , C H20 H ) , 4 ppm ( 2 H , b s , O H ) , 1.88 ppm ( 8 H , b s ) MS ( m / z , r e l a t i v e ' % i n t e n s i t y ) : 1 4 0 ( 2 ) , 7 9 ( 1 0 0 ) E x a c t M a s s c a l c u l a t e d f o r CgH1 202: 1 4 0 . 0 8 3 4 , o b s e r v e d : 1 4 0 . 0 8 3 2 . - 139 -" I n t e r m e d i a t e s " 134 t o 136 a n d p r o d u c t 137 D i o l 133 o r a c e t y l a t e d 133 ( p r e p a r e d a s d e s c r i b e d p r e v i o u s l y f o r 1 1 7 f ) , was t r e a t e d w i t h s u l f u r i c a c i d : m e t h a n o l , 1 : 1 , a t v a r i o u s t e m p e r a t u r e s (0°.to 2 0 ° C ) , f o r d i f f e r e n t l e n g t h s o f t i m e ( 5 m i n t o 2 h ) . I n t e r m e d i a t e s 1_34 t o 137 w e r e i s o l a t e d ( f r o m 5 t o 3 0 % ) a n d p r o d u c t 137 ( - 3 0 - 4 0 % ) . 1 3 4 , IR ( n e a t ) : 3 5 0 0 ( O H ) , 1 7 3 0 (CO) cm"1 'H NMR ( C C 14) : <5 = 4 . 1 8 ppm ( 2 H , s , C H20 H ) , 3.20 ppm ( 2 H , s , O H ) , 1.8 ppm ( 8 H , m) 1 3 5 , IR ( n e a t ) : 3 5 0 0 (OH) 1700 (CO) cm'1 'H NMR ( C C 14) : 6 = 5.92 ppm (IH, s , H O C ) , 4 . 2 0 ppm ( 2 H , s , C H20 H ) , 1.5-2.5 ppm ( 8 H , m) 1 3 6 , 'H NMR ( C C 14) : 6.50 ppm ( 2 H , m ) , 6.10 ppm (IH, m ) , 5.80 (IH, d d , J = 2 , 10 Hz) 1 3 7 , IR ( n e a t ) : 1 7 0 0 ( C O ) , 1 6 3 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 1.5-2.8 ppm (m) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 5 0 ( 1 8 ) , 1 4 9 ( 1 0 0 ) , M+- l E x a c t M a s s c a l c u l a t e d f o r C1 ( )H1 40 : 150.1041 , o b s e r v e d : 1 5 0 . 1 0 4 1 . 1 3C NMR ( C D C 13) : 6 = 2 0 . 0 9 , 2 5 . 2 3 , 2 6 . 9 4 , 2 9 . 5 2 , 3 2 . 5 5 , 3 4 . 3 0 , 3 9 . 7 9 , 1 2 8 . 6 9 , 1 5 8 . 6 6 a n d 2 0 7 . 3 9 ppm. 2 , 4 - D i n i t r o p h e n y l h y d r a z o n e d e r i v a t i v e o f 137 K e t o n e 137 ( 3 0 0 mg, 2 mmol) was a d d e d t o a s o l u t i o n o f 2 , 4 - d i n i t r o p h e n y l -h y d r a z i n e ( 5 0 0 mg, 2.5 m m o l , A l d r i c h ) i n m e t h a n o l ( 5 mL) a n d HC1 ( c o n e . 2 d r o p s ) . A p r e c i p i t a t e f o r m e d i n s t a n t a n e o u s l y , i t was t h e n f i l t e r e d o f f a n d r e c r y s t a l l i z e d i n c h l o r o f o r m : m e t h a n o ! , t o a f f o r d t h e DNPH d e r i v a t i v e o f 1 3 7 , 6 5 0 mg ( 9 8 % ) . mp 2 2 6 - 2 2 8°C - 140 -IR ( C H C 13) : 1 6 5 0 , 1 6 0 0 , 1520 cm"1 'H NMR ( C D C 13) : 9.10 ppm ( I H , d , J = 2 H z ) , 8.30 ( I H , d d , J = 2 , 10 H z ) , 7.80 ppm ( H , d , J = 10 H z ) , 1.7-3.0 ppm ( 1 0 H , m) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 3 0 ( 8 ) , 1 4 9 ( 1 0 0 ) - C6H3N304 E x a c t M a s s c a l c u l a t e d f o r C - |6Hi 8N4° 5: 3 3 0 . 1 3 2 8 , o b s e r v e d : 3 3 0 . 1 3 7 2 . A 1 , 5 - b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 3 8 ) P r e p a r e d f r o m m e t h y l - 2 - o x o c y c l o p e n t a n e c a r b o x y l a t e b y t h e m e t h o d o f 115 K u l k a r n i a n d Dev ( 3 0 - 4 0 % ) . A l s o p r e p a r e d f r o m 83_, b a s e d on t h e p r o c e d u r e o f 120 E a s t o n C a r l s o n a n d L e e ( - 6 0 % ) . The l a r g e s t s c a l e on w h i c h t h i s r e a c t i o n c o u l d b e p e r f o r m e d i s 0.11 m o l e o f h y d r o x y - a c i d u s i n g f i v e e q u i v a l e n t s o f p h o s p h o r u s p e n t o x i d e a n d m e t h a n e s u l f o n i c a c i d , i n s t e a d o f t e n e q u i v a l e n t s r e c o mmended i n t h e l i t e r a t u r e ( 5 8 % ) . IR ( n e a t ) : 1 7 0 0 ( C O ) , 1 640 (C=C) cm"1 'H NMR ( C C 14) : 2.2 t o 2.8 ppm (m) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 2 2 ( 1 0 0 ) , 1 0 7 ( 5 ) , 9 3 ( 2 0 ) , 7 9 ( 9 5 ) E x a c t Mass c a l c u l a t e d f o r C g H ^ O : 1 2 2 . 0 7 2 9 , o b s e r v e d : 1 2 2 . 0 7 1 3 . UV (X max ( l o g e)): 241 ( 3 . 5 ) 5 - E t h o x a l y l - 3 - m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 8 9 ) a n d A 1 ' 5 - e t h o x a 1 y 1 b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 4 5 ) A s o d i u m e t h o x i d e s o l u t i o n ( p r e p a r e d f r o m s o d i u m , 0 . 1 1 5 g , 5 mmol BDH, a n d d r y e t h a n o l , 1.8 mL, 30 mmol) was d i s s o l v e d i n - e t h e r ( 1 0 mL) a n d c o o l e d t o 0 ° w i t h a n e x t e r n a l i c e b a t h . D i e t h y l o x a l a t e ( 0 . 7 3 g , 5 m m o l , A l d r i c h ) was a d d e d , f o l l o w e d a f t e r 5 m i n by k e t o n e 138 o r 142 ( 5 m m o l ) , r e s u l t i n g i n a n i m m e d i a t e p r e c i p i t a t e . A f t e r a f u r t h e r 10 m i n , t h e s o l u t i o n was a c i d i f i e d ( 1 0 % H C l ) , e x t r a c t e d w i t h e t h y l a c e t a t e , t h e c o m b i n e d e x t r a c t s d r i e d , - 141 -f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( 1 5 % e t h y l a c e t a t e p e t r o l e u m e t h e r ) t o a f f o r d 1 4 5 , 1 g ( 9 0 % ) , mp 6 5 - 6 7°C ; o r 1 8 9 , 6 0 0 mg ( 6 2 % ) , mp 6 0 - 6 2° C . 145 IR ( C H C 13) : 1760 ( m ) , 1725 ( s ) , 1 7 0 0 ( w ) , 1660 ( s ) , 1 6 2 5 ( w ) , 1600 (w) c m- 1 1H NMR ( C D C 13) : 6 = 1 1 . 8 0 ppm ( I H , b s , e n o l ) , 4 . 3 3 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3 . 3 8 ppm ( 2 H , b s , ( C = C )2- C H2) ; 2.48 ppm ( 6 H , m ) , 1.38 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 2 3 ( 1 2 ) M+ + 1 , 2 2 2 ( 1 3 ) , 1 9 4 ( 4 ) - E t , 1 4 9 ( 1 0 0 ) - C O O E t , 1 2 1 ( 3 1 ) - COCOOEt. 189 IR ( C H C 13) : 1 7 4 0 ( m ) , 1 7 2 0 ( s ) , 1660 ( s ) , 1 6 1 0 (w) c m- 1 'H NMR ( C D C 13) : 6 = 1 2 . 3 2 ppm ( I H , b s , e n o l ) , 6.06 ppm ( I H , b s , H C = C ) , 4 .28 ppm ( 2 H , q , J = 7 H z , C H2C H3) , 3.37 ppm ( 2 H , b s , ( O C )2- C H ) , 2.20 mmp ( 3 H , s , C H3C 0 ) , 1.37 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 9 7 ( 9 ) M+ + 1 , 1 9 6 ( 1 0 ) , 1 6 8 ( 3 ) - CO, 1 2 3 ( 1 0 0 ) - C O O E t , 9 5 ( 5 5 ) - COCOOEt. 1 5 5 - F o r m y l - 3 - m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 8 9 ) a n d A ' - 3 - f o r m y l b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 5 0 ) A s o d i u m e t h o x i d e s o l u t i o n ( p r e p a r e d f r o m s o d i u m , 0 . 3 5 g , 15 mmol BDH, a n d d r y e t h a n o l , 5.1 mL, 90 mmol) was d i s s o l v e d i n e t h e r ( 2 0 m L ) , a n d c o o l e d t o 0°C w i t h a n e x t e r n a l i c e b a t h . A m i x t u r e o f e t h y l f o r m a t e ( 1 . 3 mL, 16.5 m m o l , A l d r i c h ) a n d k e t o n e 1 3 8 o r 142 ( 1 5 mmol) i n e t h e r ( 5 mL) was a d d e d , r e s u l t i n g i n a n i m m e d i a t e p r e c i p i t a t e . A f t e r s t i r r i n g f o r 30 m i n , t h e s o l u t i o n was a c i d i f i e d ( 1 0 % H C 1 ) , e x t r a c t e d w i t h e t h y l a c e t a t e , t h e c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( 2 0 % e t h y l a c e t a t e - p e t r o l e u m e t h e r ) t o a f f o r d 1 5 0 , 1.3 g ( 5 8 % ) , mp 1 2 0°-12 2°C; - 142 -o r 1 8 9 , 8 3 0 mg ( 4 5 % ) , mp 7 0 - 8 0° C . 1 5 0 , IR ( N u j o l ) : 2 8 0 0 - 2 6 0 0 ( w , e n o l ) , 1 7 0 5 ( s ) , 1 7 0 0 (m) 1615 ( s ) , 1 5 6 0 (m) cm"1 'H NMR ( C D C 13) : 6 = 7 . 7 0 , 7 . 2 2 , 7.0 ppm ( I H , b s : s : s , e n o l ) , 2.98 ppm ( 2 H , b s , ( C = C )1- C H2) , 2.40 ppm ( 6 H , b s ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 5 1 ( 1 2 ) M+ + 1 , 1 5 0 ( 1 0 0 ) , 1 2 2 ( 5 9 ) - CO, 9 4 ( 9 0 ) , 9 3 ( 4 0 ) - C0CH0 E x a c t M a s s c a l c u l a t e d f o r CgH1 Q02: 1 5 0 . 0 6 8 0 , o b s e r v e d : 1 5 0 . 0 6 8 0 . 1 8 9 , IR ( N u j o l ) : 3 3 0 0 - 3 5 0 0 ( e n o l ) , 1 7 0 0 ( s ) , 1 6 9 5 ( s ) , 1 6 2 0 (m) cm"1 'H NMR ( C D C 13) : 5 = 9 . 7 2 , 8 . 8 0 , 7 . 1 0 , 6 . 0 2 , 5.84 ppm ( 3 H , s , b s , s , b s , b s , r e p r e s e n t i n g a l d e h y d e , e n o l , o l e f i n i c p r o t o n s , 1 : 3 : 3 : 2 : 2 ) , 3.03 ppm ( 2 H , b s , ( C = C )2C H2) , 2 . 1 2 ppm ( 3 H , b s , C H g - O C ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 2 5 ( 2 2 ) M+ + 1 , 1 2 4 ( 5 5 ) , 9 6 ( 1 0 0 ) - CO, 9 5 ( 6 8 ) - CHO, 6 7 ( 5 9 ) - C 0 C H ) . E x a c t M a s s c a l c u l a t e d f o r C-,H802: 1 2 4 . 0 5 2 2 , o b s e r v e d 1 2 4 . 0 5 2 6 . G e n e r a l A c y l a t i o n P r o c e d u r e s ( 1 ) P o t a s s i u m H y d r i d e ( K H ) , P r o c e d u r e A: C y c l o h e x a n o n e ( 1 5 3 ) ( 0 . 4 9 0 g , 5 m m o l , A l d r i c h ) i n d i e t h y l e t h e r ( 1 0 mL) was a d d e d d r o p w i s e o v e r 20 m i n t o a s t i r r e d m i x t u r e o f p o t a s s i u m h y d r i d e ( 1 . 2 5 g , 11 m m o l , 3 5 % o i l d i s p e r s i o n , A l d r i c h ) i n r e f l u x i n g e t h e r ( 1 5 mL) u n d e r n i t r o g e n . A f t e r an a d d i t i o n a l 0.5 h t h e r e a c t i o n m i x t u r e was c o o l e d t o -78°C a n d d i e t h y l p y r o c a r b o n a t e ( D E P C , 0 . 8 9 0 g , 5.5 m m o l , A l d r i c h ) i n e t h e r ( 2 mL) a d d e d i n o n e a l i q u o t . A f t e r 1 h a t -78°C a q u e o u s 1 0 % HCl ( 3 0 mL) was a d d e d , t h e r e a c t i o n was a l l o w e d t o warm t o 2 2°C , e x t r a c t e d w i t h e t h e r , t h e c o m b i n e d e t h e r e x t r a c t s w a s h e d w i t h b r i n e , d r i e d (MgSO^) a n d t h e s o l v e n t r e m o v e d u n d e r r e d u c e d p r e s s u r e . F l a s h c h r o m a t o g r a p h y on s i l i c a g e l ( 4 0 0 - 2 3 0 m e s h , 5% e t h e r - p e t r o l e u m e t h e r ) a f f o r d e d 1 - c y c l o -- 143 -h e x e n y l e t h y l c a r b o n a t e ( 1 5 4 ) 9 . 8 2 0 g ( 9 8 % ) . IR ( n e a t ) : y = 1 7 5 3 , 1695 cm"1 'H NMR ( C C 14) : 6 = 1.30 ( t , 3 H , C H2C H3, J = 7 H z ) , 1.70 (m, 4 H , C H2C H2) , 2.10 ( m , 4 H , C H2C H2) , 4 . 2 0 ( q , 2 H , - 0 C H2C H3, J = 7 H z ) , 5.38 ( b r s , I H , H O C - 0 ) . ( 2 ) P o t a s s i u m t - B u t o x i d e ( K O t B u ) , P r o c e d u r e A: C y c l o p e n t a n o n e ( 1 0 4 ) ( 0 . 4 2 0 g , 5 m m o l , A l d r i c h ) was a d d e d d r o p w i s e o v e r 20 m i n t o a s t i r r e d m i x t u r e o f p o t a s s i u m t - b u t o x i d e ( 0 . 6 1 5 g , 5.5 mmol) i n e t h e r a t -78°C u n d e r n i t r o g e n . A f t e r a n a d d i t i o n a l 0.5 h a t -78°C a q u e o u s 1 0 % HC1 ( 3 0 mL) was a d d e d a n d t h e r e a c t i o n w o r k e d up a s a b o v e t o g i v e 1 - c y c l o p e n t e n y l e t h y l c a r b o n a t e ( 1 5 6 ) 0 . 4 1 0 g ( 5 2 % ) . IR ( n e a t ) : y = 1 7 5 8 , 1 6 8 8 cm" 1 'H NMR ( C C 14) : 5 = 1.27 ( t , 3 H , C H2C H3 > J = 7 H z ) ; 1.6-2.6 ( m , 6 H , C H2C H2C H2) ; 4. 1 3 ( q , 2 H , 0 C H2C H3, J = 7 H z ) ; 5.32 ( b r s , I H , H C = C - 0 ) . ( 3 ) P o t a s s i u m t - B u t o x i d e ( K O t B u ) , P r o c e d u r e B: C y c l o p e n t a n o n e ( 1 0 4 ) ( 0 . 4 2 0 g , 5 mmol) a n d DEPC ( 1 . 2 0 g , 7.5 mmol) was d i s s o l v e d i n e t h e r ( 2 mL) a n d a d d e d d r o p w i s e o v e r 5 m i n t o a s t i r r e d m i x t u r e o f p o t a s s i u m t - b u t o x i d e ( 0 . 6 1 5 g , 5.5 mmol) i n e t h e r a t -78°C u n d e r , n i t r o g e n . A f t e r 1 h a t -78°C a q u e o u s 1 0 % HC1 ( 3 0 mL) was a d d e d a n d t h e r e a c t i o n w o r k e d up a s a b o v e t o g i v e 1 - c y c l o -p e n t e n y l e t h y l c a r b o n a t e ( 1 5 6 ) 0 . 4 8 0 g ( 6 2 % ) . ( 4 ) P o t a s s i u m H y d r i d e ( K H ) , P r o c e d u r e B: C y c l o h e x a n o n e ( 1 5 3 ) ( 0 . 4 9 0 g , 5 m m o l , A l d r i c h ) i n b e n z e n e ( 2 mL) c o n t a i n i n g DEPC ( 1 . 2 2 g , 7.5 mmol) was a d d e d r a p i d l y (1 m i n ) t o a s t i r r e d m i x t u r e o f p o t a s s i u m h y d r i d e ( 1 . 2 5 g , 11 m m o l , 3 5 % o i l d i s p e r s i o n , A l d r i c h ) i n r e f l u x i n g b e n z e n e ( 1 5 mL) u n d e r n i t r o g e n . A f t e r an a d d i t i o n a l 0.5 h t h e r e a c t i o n m i x t u r e was c o o l e d i n a n i c e b a t h , a q u e o u s 1 0 % HC1 ( 3 0 mL) a d d e d a n d t h e r e a c t i o n a l l o w e d t o warm t o 22°C t o g i v e a f t e r w o r k up a s a b o v e a n d f l a s h c h r o m a t o g r a p h y ( 5 % e t h e r -- 144 -p e t r o l e u m e t h e r ) 2 - c a r b o e t h o x y c y c l o h e x a n o n e ( 1 5 5 ) 0 . 6 0 2 g ( 7 2 % ) . IR ( n e a t ) : y = 1 7 4 0 , 1 7 2 2 , 1 6 6 0 , 1 6 2 0 cm" 1 'H NMR ( C C 14) : 6 = 1.31 ( t , 3 H , C H2C H3, J = 7 H z ) ; 1.61 (m, 4 H , C H2C H2) ; -2.10 ( m , 4 H , C H2C H2) ; 4 . 2 0 ( q , 2 H , - 0 C H2C H3, J = 7 H z ) ; 1 2 . 1 2 ( s , I H , H 0 - O C C 0 ) . . ( 5 ) P o t a s s i u m H y d r i d e ( K H ) , P r o c e d u r e B: C y c l o p e n t a n o n e ( 1 0 4 ) ( 0 . 4 2 0 g , 5 m m o l , A l d r i c h ) i n b e n z e n e ( 2 mL) c o n t a i n i n g DEPC ( 1 . 2 2 g , 7.5 mmol) was a d d e d r a p i d l y (1 m i n ) t o a s t i r r e d m i x t u r e o f p o t a s s i u m h y d r i d e ( 1 . 2 5 g , 11 m m o l , 3 5 % o i l d i s p e r s i o n , A l d r i c h ) i n r e f l u x i n g b e n z e n e ( 1 5 mL) u n d e r n i t r o g e n . A f t e r a n a d d i t i o n a l 0.5 h t h e r e a c t i o n m i x t u r e was c o o l e d i n an i c e b a t h , a q u e o u s 1 0 % HCl ( 3 0 mL) a d d e d a n d t h e r e a c t i o n a l l o w e d t o warm t o 22°C t o g i v e a f t e r w o r k up a s a b o v e a n d f l a s h c h r o m a t o g r a p h y ( 5 % e t h e r -p e t r o l e u m e t h e r ) 2 - c a r b o e t h o x y c y c l o p e n t a n o n e ( 1 0 5 ) 0 . 4 7 2 g ( 6 1 % ) IR ( n e a t ) : y = 1 7 6 5 , 1 7 3 5 , 1 6 6 0 ( w ) , 1 6 2 0 (w) cm" 1 'H NMR ( C C 14) : 6 = 1.23 ( t , 3 H , C H2C H3, J = 7 H z ) ; 2.22 ( m , 6 H , C H2) ; 3.02 ( b r t , I H , C 0 - C H - C 0 ) ; 4 . 1 4 ( q , 2 H , - 0 C H2C H3, J = 7 H z ) . ( 6 ) L i t h i u m D i c y c l o h e x y l a m i d e ( L i N C y2) , P r o c e d u r e A: 3 - M e t h y l - 2 - c y c l o -h e x e n o n e ( 1 5 7 ) ( 0 . 5 5 0 g , 5 m m o l , A l d r i c h ) i n e t h e r ( 1 0 mL) was a d d e d d r o p w i s e o v e r 2 0 m i n t o a s t i r r e d s o l u t i o n o f l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y2 > p r e p a r e d f r o m 4.2 mL o f n - b u t y l l i t h i u m ( 2 . 5 M, 10.5 m m o l , A l d r i c h ) , d i c y c l o h e x y l a m i n e ( 2 . 1 5 mL, 11 m m o l ) ) i n e t h e r ( 1 5 mL) a t -78°C u n d e r n i t r o g e n . A f t e r a n a d d i t i o n a l 0.5 h DEPC ( 0 . 8 9 0 g , 5.5 mmol) i n e t h e r ( 2 mL) was a d d e d i n o n e a l i q u o t . A f t e r 1 h a t -78°C t h e r e a c t i o n was q u e n c h e d w i t h a q u e o u s 1 0 % c i t r i c a c i d ( 1 0 mL) a l l o w e d t o warm t o 22°C t o g i v e a f t e r w o r k up a s a b o v e a n d f l a s h c h r o m a t o g r a p h y ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) 6 - c a r b o e t h o x y -3 - m e t h y l - 2 - c y c l o h e x e n o n e ( 1 5 8 ) 0 . 5 3 0 g ( 5 8 % ) . IR ( n e a t ) : y = 1 7 4 0 , 1 6 7 0 , 1 6 3 0 cm" 1 - 145 -•H NMR ( C C 14) : 6 = 1.21 ( t , 3 H , C H2C H3, J = 7 H z ) : 1.90 ( s , 3 H , = C C H3) ; 2- 2.4 ( m , 4 H ) ; 3.21 ( m , 1 H , C 0 - C H - C 0 ) ; 4 . 1 0 ( q , 2 H , O C H2C H3, J = 7 H z ) ; 5.70 ( b r s , 1 H , = C H ) . ( 7 ) L i t h i u m D i c y c l o h e x y l a m i d e ( L i N C y2) , P r o c e d u r e B: 3 - M e t h y l - 2 -c y c l o h e x e n o n e ( 1 5 7 ) ( 0 . 5 5 0 g , 5 mmol) i n e t h e r ( 1 0 mL) c o n t a i n i n g DEPC ( 1 . 2 g , 7.5 mmol) was a d d e d r a p i d l y ( 5 m i n maximum) t o a s t i r r e d s o l u t i o n o f l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y2 > p r e p a r e d f r o m 4.2 mL o f n _ - b u t y l l i t h i u m ( 2 . 5 M, 1 0 . 5 m m o l , A l d r i c h ) , d i c y l c o h e x y l a m i n e ( 2 . 1 5 mL, 11 m m o l ) ) i n e t h e r ( 1 5 mL) a t -78°C u n d e r n i t r o g e n . A f t e r 1 h a t -78°C t h e r e a c t i o n was q u e n c h e d w i t h a q u e o u s 1 0 % c i t r i c a c i d ( 1 0 mL) a l l o w e d t o warm t o 22°C t o g i v e a f t e r w o r k u p a s a b o v e a n d f l a s h c h r o m a t o g r a p h y ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) 6 - c a r b o e t h o x y - 3 - m e t h y l - 2 -c y c l o h e x e n o n e ( 1 5 8 ) 0 . 5 8 0 g ( 6 4 % ) . ( 8 ) L i t h i u m D i c y c l o h e x y l a m i d e ( L i N C y2) , P r o c e d u r e B: 3 - M e t h y l - 2 -c y c l o p e n t e n o n e ( 1 4 2 ) ( 0 . 4 8 0 g , 5 mmol) i n e t h e r ( 1 0 mL) c o n t a i n i n g DEPC ( 1 . 2 g , 7.5 mmol) was a d d e d r a p i d l y ( 5 m i n maximum) t o a s t i r r e d s o l u t i o n o f l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y2, p r e p a r e d f r o m 4.2 mL o f n _ - b u t y l l i t h i u m ( 2 . 5 M, 10.5 m m o l , A l d r i c h ) , d i c y c l o h e x y l a m i n e ( 2 . 1 5 mL, 11 m m o l ) ) i n e t h e r ( 1 5 mL) a t -78°C u n d e r n i t r o g e n . A f t e r 1 h a t -78°C t h e r e a c t i o n was q u e n c h e d w i t h a q u e o u s 1 0 % c i t r i c a c i d ( 1 0 mL) a l l o w e d t o warm t o 22°C t o g i v e a f t e r w o r k up a s a b o v e a n d f l a s h c h r o m a t o g r a p h y ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) 5 - c a r b o e t h o x y -3- m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 5 9 ) 0 . 5 9 0 g ( 7 1 % ) . IR ( n e a t ) : y = 1 7 3 0 , 1 6 9 0 , 1615 cm"1 'H NMR ( C C 14) : 6 = 1.27 ( t , 3 H , C H2C H3, J = 7 H z ) ; 2.19 ( b r s , 3 H , = C C H3) ; 2.80 ( m , 2 H , C H2~ C = ) ; 3.31 (m, I H , C 0 - C H - C 0 ) ; 4 . 1 2 ( q , 2 H , 0 C H2C H3, J = 7 H z ) ; 5.80 ( b r s , I H , = C H ) . MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 6 9 ( 2 8 ) M+ + 1 , 1 2 3 ( 6 4 ) - O E t , 9 6 ( 1 0 0 ) -HCOOEt. - 146 -E x a c t Mass c a l c u l a t e d f o r CgH1 203: 1 6 8 . 0 7 8 3 , o b s e r v e d : 1 6 8 . 0 7 8 7 . ( 9 ) L i t h i u m D i c y c l o h e x y l a m i d e ( L i N C y2) , P r o c e d u r e B: 3 - M e t h y l - 2 -c y c l o p e n t e n o n e ( 1 4 2 ) ( 9 . 6 0 g , 100 mmol) i n e t h e r ( 5 0 mL) c o n t a i n i n g DEPC ( 2 4 . 3 g , 150 mmol) was a d d e d r a p i d l y ( 5 m i n maximum) t o a m e c h a n i c a l l y s t i r r e d s o l u t i o n o f l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y2) , p r e p a r e d f r o m 21 mL o f i i - b u t y l l i t h i u m ( 2 . 5 M, 2 0 0 m m o l , A l d r i c h ) , d i c y c l o h e x y l a m i n e ( 4 1 . 8 mL, 210 mmol) i n e t h e r ( 2 0 0 mL) a t -78°C u n d e r n i t r o g e n . A f t e r 1 h a t -78°C t h e r e a c t i o n was q u e n c h e d w i t h a q u e o u s 2 0 % c i t r i c a c i d ( 1 0 0 mL) a l l o w e d t o warm t o 2 2°C , e x t r a c t e d w i t h e t h e r , t h e c o m b i n e d e t h e r e x t r a c t s w a s h e d w i t h b r i n e , d r i e d (MgSO^) a n d t h e s o l v e n t r e m o v e d u n d e r r e d u c e d p r e s s u r e . D i s t i l l a t i o n o f t h e r e s i d u a l DEPC a n d k e t o - e s t e r ( 4 0 - 6 0°C / 0 . 1 T o r r ) f o l l o w e d by f l a s h c h r o m a -t o g r a p h y ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) g a v e 5 - c a r b o e t h o x y - 3 - m e t h y l - 2 -c y c l o p e n t e n o n e ( 1 5 9 ) 7.56 g ( 4 5 % ) . ( 1 0 ) L i t h i u m D i c y c l o h e x y l a m i n e ( L i N C y2) , P r o c e d u r e B: A 1 ' ^ - B i c y c l o [ 3 . 3 . 0 ] o c t -e n - 2 - o n e ( 1 3 8 ) ( 0 . 6 1 0 g , 5 mmol) i n e t h e r ( 1 0 mL) c o n t a i n i n g DEPC ( 1 . 2 g , 7.5 mmol) was a d d e d r a p i d l y ( 5 m i n maximum) t o a s t i r r e d s o l u t i o n o f l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y2, p r e p a r e d f r o m 4.2 mL o f r v - b u t y l 1 i t h i u m ( 2 . 5 M, 10.5 m m o l , A l d r i c h ) , d i c y c l o h e x y l a m i n e ( 2 . 1 5 mL, 11 m m o l ) ) i n e t h e r ( 1 5 mL) a t -78°C u n d e r n i t r o g e n . A f t e r 1 h a t -78°C t h e r e a c t i o n was q u e n c h e d w i t h a q u e o u s 1 0 % c i t r i c a c i d ( 1 0 mL) a l l o w e d t o warm t o 22°C t o g i v e a f t e r w o r k up a s a b o v e 1 5 a n d f l a s h c h r o m a t o g r a p h y ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) A ' - 3 - c a r b o e t h o x y b i c y c l o -[ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 6 0 ) 0 . 7 6 0 g ( 7 8 % ) . IR ( n e a t ) : y = 1 7 3 5 , 1 7 0 0 , 1 6 4 0 cm" 1 'H NMR ( C C 14) : 6 = 1.28 ( t , 3 H , C H2C H3, J = 7 H z ) ; 2 . 1 - 2 . 9 (m, 8 H ) ; 3.61 ( b r t , I H , J = 5 H z , C 0 - C H - C 0 ) ; 4 . 1 8 ( q , 2 H , 0 C H2C H3, J = 7 H z ) . MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 9 5 ( 1 0 0 ) M+ + 1 , 1 9 4 ( 3 9 ) , 1 4 9 ( 7 3 ) - O E t , 1 2 0 ( 8 6 ) - HCOOEt. - 147 -E x a c t M a s s c a l c u l a t e d f o r C ^ H ^ C y 1 9 4 . 0 9 3 9 , o b s e r v e d : 1 9 4 . 0 9 3 1 . UV (A max ( l o g e ) ) : 2 4 5 ( 3 . 6 ) . The same p r o c e d u r e e m p l o y i n g d i m e t h y l p y r o c a r b o n a t e i n p l a c e o f DEPC a f f o r d e d A 1 ' 5 - 3 - c a r b o m e t h o x y b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 6 1 ) i n 4 6 % y i e l d . IR ( n e a t ) : y = 1 7 4 5 , 1 7 1 0 , 1 6 4 0 cm" 1 *H NMR ( C C 14) : 6 = 2. 1 - 2 . 9 (m, 8 H ) ; 3.59 (m, I H , C 0 - C H - C 0 ) ; 3.63 ( s , 3 H , 0 C H3) . ( 1 1 ) L i t h i u m D i c y c l o h e x y l a m i d e ( L i N C y2) , P r o c e d u r e B: A 1 ' 5 B i c y c l o [ 3 . 3 . 0 ] -o c t e n - 2 - o n e ( 1 3 8 ) ( 4 . 8 8 g , 40 mmol) i n e t h e r ( 2 0 mL) c o n t a i n i n g DEPC ( 9 . 7 g , 6 0 mmol) was a d d e d r a p i d l y (-5 m i n maximum t o a m e c h a n i c a l l y s t i r r e d s o l u t i o n o f l i t h i u m d i c y c l o h e x y l a m i d e ( L i N C y2, p r e p a r e d f r o m 8.6 mL o f i i - b u t y l l i t h i u m ( 9 . 5 M, 80 m m o l , A l d r i c h ) , d i c y c l o h e x y l a m i n e ( 1 8 mL, 88 m m o l ) ) i n e t h e r ( 7 0 mL) a t -78°C u n d e r n i t r o g e n . A f t e r 1 h a t -78°C t h e r e a c t i o n was q u e n c h e d w i t h a q u e o u s 2 0 % c i t r i c a c i d ( 1 0 0 mL) a l l o w e d t o warm t o 2 2°C , e x t r a c t e d w i t h e t h e r , t h e c o m b i n e d e t h e r e x t r a c t s w a s h e d w i t h b r i n e , d r i e d (MgSO^) a n d t h e s o l v e n t r e m o v e d u n d e r r e d u c e d p r e s s u r e . D i s t i l l a t i o n o f t h e r e s i d u a l DEPC a n d t h e k e t o - e s t e r ( 4 0 - 6 0°C / 0 . 1 T o r r ) f o l l o w e d by f l a s h 1 5 c h r o m a t o g r a p h y ( 1 5 % e t h e r - p e t r o l e u m e t h e r ) g a v e A ' - 3 - c a r b o e t h o x y b i c y c l o -[ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 6 0 ) 5.58 g ( 7 2 % ) . A l k y l a t i o n o f t h e 5 - c a r b o x y - 2 - c y c l o p e n t e n o n e d e r i v a t i v e s 189 a n d 1 9 0 , M e t h o d A 5 - C a r b o x y - 2 - c y c l o p e n t e n o n e ( 5 mmol) was a d d e d t o a s o d i u m e t h o x i d e s o l u t i o n ( p r e p a r e d f r o m s o d i u m , 5 m m o l , BDH a n d d r y e t h a n o l , 30 mmol) i n e t h e r ( 4 m L ) , a t 2 0°C , r e s u l t i n g i n a n i m m e d i a t e p r e c i p i t a t e . T he r e a c t i o n m i x t u r e was l o w e r e d i n t o an o i l b a t h ( 7 5 - 8 0 ° C ) , d i m e t h y l s u l f o x i d e ( 1 0 mL) a d d e d , f o l l o w e d b y t h e a l k y l h a l i d e ( 6 mmol o f 1 3 1 a o r 10 mmol o f 1 3 1 b ) , a n d s t i r r i n g c o n t i n u e d f o r 2 h . The s o l u t i o n was t h e n c o o l e d ( 0° ) , a c i d i f i e d - 148 -( 1 0 % HC1) a n d e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w a s h e d w i t h b r i n e , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( e t h e r - p e t r o l e u m e t h e r ) . Y i e l d s o f v a r i o u s r e a c t i o n s a r e r e p o r t e d i n T a b l e 7 , 'H NMR s p e c t r a l d a t a i n T a b l e s 8 a n d 1 1 , IR d a t a i n T a b l e s 9 a n d 1 2 , a n d MS r e s u l t s i n T a b l e s 10 a n d 1 3 . A l k y l a t i o n o f t h e 5 - c a r b o x y - 2 - c y c l o p e n t e n o n e d e r i v a t i v e s 189 a n d 1 9 0 ,  M e t h o d B 5 - C a r b o x y - 2 - c y c l o p e n t e n o n e ( 5 mmol) i n t - b u t y l a l c o h o l ( 2 mL) was a d d e d t o a p o t a s s i u m - t - b u t o x i d e s o l u t i o n ( p r e p a r e d f r o m p o t a s s i u m , 0.01 m m o l , BDH a n d t - b u t y l a l c o h o l 4 mL, i n e t h e r , 2 mL, F i s h e r ) , a t 2 0°C. T h e a c t i v a t e d d i e n e 144b ( 1 0 mmol) i n t - b u t y l a l c o h o l ( 2 mL) was a d d e d a t a r a t e t h a t k e p t t h e t e m p e r a t u r e o f t h e r e a c t i o n c o n s t a n t ( 2 0° C ) . A f t e r s t i r r i n g f o r 16 h , t h e r e a c t i o n was c o o l e d (0°) a n d a c i d i f i e d ( 1 % H C 1 ) . A f t e r e x t r a c t i o n o f t h e a q u e o u s l a y e r w i t h e t h y l a c e t a t e , t h e c o m b i n e d e x t r a c t s w e r e w a s h e d w i t h b r i n e , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d b y c h r o m a t o g r a p h y ( e t h e r - p e t r o l e u m e t h e r ) . Y i e l d s a r e r e p o r t e d i n T a b l e 7 , 'H, NMR, IR a n d MS d a t a a r e r e p o r t e d i n T a b l e s 8 t o 1 3 . A ~ * > 5 - 3 - C a r b o e t h o x y - 3 - m e t h y l b i c y c 1 o [ 3 . 3 . 0 ] o c t e n - 2 - o n e P r e p a r e d by a l k y l a t i o n o f 160 (R-j = O E t , R^ = Me) by t h e p r e v i o u s l y d e s c r i b e d M e t h o d A ( 8 2 % ) . I R : 1 7 4 0 ( C O ) , 1 7 0 5 ( C O ) , 1 6 4 0 C=C) c m- 1 'H NMR ( C C 14) : 6 = 4 . 1 3 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 2.45 ppm ( 8 H , b s ) , 1.33 ppm ( 3 H , s , C H3) , 1.23 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 0 8 ( 2 8 ) , 1 8 0 ( 5 9 ) - CO, 1 3 5 ( 9 2 ) - C O O E t , - 149 -T a b l e 7 Y i e l d s O b t a i n e d i n V a r i o u s A l k y l a t i o n s o f 189 a n d 190 S t a r t i n g m a t e r i a l Rl R4 = H M e t h o d P r o d u c t R 2 R 3 % Y i e l d 190 COOEt A 192 COOMe COOMe 90 189 COOEt A 191 COOMe COOMe 62 189 H. A 191 COOMe COOMe 58 189 H A 192 COOMe COOMe 45 189 O E t A 192 H COOEt 76 190 O E t A 192 COOMe COOMe 65 190 OMe A 192 H COOEt 45 190 OEt B 192 H COOEt 86 189 O E t B 191 H COOEt 90 190 OEt C 190 R 4 = Me 82 190 O E t D 190 R 4 = 7 5 - 9 5A 190 OEt D 190 RA = 4 0 - 9 5 3 a : S e e t e x t ( C h a p t e r 3) f o r v a r i a t i o n i n y i e l d . M e t h o d A: a l k y l a t i o n u s i n g 131 M e t h o d B: a l k y l a t i o n u s i n g j_44 M e t h o d C: a l k y l a t i o n u s i n g m e t h y l i o d i d e ( M e l ) M e t h o d D: a l k y l a t i o n u s i n g m e t h y l v i n y l k e t o n e (CH 2=CHC0CH 3) o o. - 150 -T a b l e 8 60 MHz 'H NMR S p e c t r a l D a t a R e l a t e d t o 192 Rl R2 R3 H-2' 3H - 5 ' H-41 Rl R2 R3 1) H COOMe COOMe 5.22 1.80 4 . 0 4 9.50 3.72 3.72 ( t , 7) ( s ) ( s ) ( s ) ( s ) ( s ) 2) O E t COOMe COOMe 5.18 1.78 3.93 1.27 3.70 3.70 ( t , 7) ( b s ) ( s ) ( t , 7 ) ( s ) ( s ) 4 . 1 4 ( q . 7) 3) COOEt COOMe COOMe 5.04 1.68 3.83 1.27 3.70 3.70 ( t , 7) ( b s ) ( s ) ( t , 7 ) ( s ) 4 . 1 5 ( q , 7) 4) O E t H COOEt 5.06 1.72 1.14 1.14 ( t , 7) ( b s ) ( t , 7) ( t , 7) 4 . 0 6 * 4 . 1 1 * ( q , 7) ( q , 7) 5) OMe H COOEt 5.01 1.73 3.66 1.18 ( t , 7) ( b s ) ( s ) ( t , 7) 3.68 4.04 ( s ) ( q . 7) Numbers i n T a b l e r e p r e s e n t t h e c h e m i c a l s h i f t (6 i n p p m ) . P a r e n t h e s e s i n d i c a t e t h e m u l t i p l i c i t y a n d t h e c o u p l i n g c o n s t a n t s ( i n H z ) . V a l u e s a r e i n t e r c h a n g e a b l e . - 151 -T a b l e 9 IR S p e c t r a l D a t a R e l a t e d t o 1 9 2 R1 R2 R3 b a n d s ( c m- 1) 1) H COOMe COOMe 1745 ( s ) , 1 7 0 0 ( s ) , 1630 (m) 2 ) O E t COOMe COOMe 1745 ( s ) , 1 7 0 0 ( s ) , 1640 (m) 3) COOEt COOMe COOMe 1 7 4 0 ( s ) , 1 7 0 0 ( s ) , 1 6 40 (m) 4) O E t H COOEt 1 7 4 5 ( s ) , 1 7 0 5 ( s ) , 1 6 4 5 (m) 5) OMe H COOEt 1 7 4 5 ( s ) , 1 7 00 ( s ) , 1 6 3 5 (m) - 152 -T a b l e 10 MS R e s u l t s R e l a t e d t o 192 "1 1) H 2) O E t 3) O E t 4) OMe "2 COOMe R3 COOMe m/z ( r e l a t i v e % i n t e n s i t y ) 3 3 5 ( 4 ) M+ + 1 , 3 3 4 ( 5 ) , 3 0 5 ( 1 2 ) - CHO, 1 5 0 ( 1 0 0 )a COOMe COOMe 3 7 8 ( 2 ) , 3 1 6 ( 3 ) - COOMe, 3 0 5 ( 7 ) - C O O E t , 1 9 4 ( 1 1 2 )a H COOEt 3 3 5 ( 1 1 ) M+ + 1 , 3 3 4 ( 4 ) , 2 8 8 ( 7 ) - E t O H , 2 6 1 ( 4 8 ) - C O O E t , 2 1 5 ( 5 0 ) - COOEt - E t O H , 194 ( 1 0 0 )b H COOEt 3 2 1 ( 3 ) M+ + 1 , 2 8 8 ( 6 ) - MeOH, 2 6 1 ( 2 0 ) -COOMe, 2 1 5 ( 3 3 ) - COOMe - MeOH, 1 8 0 ( 1 0 0 )b a - C g H ^ O ^ , -186 ( r e a r r a n g e m e n t w i t h l o s s o f s i d e c h a i n ) , b - C g H ^ O g j - 140 ( r e a r r a n g e m e n t w i t h l o s s o f s i d e c h a i n ) 1 5 1 , e n t r y 1 : 1 6 2 , e n t r y 2: e n t r y 3: E x a c t M a s s c a l c u l a t e d f o r C1 8H2 206: 3 3 4 . 1 4 1 0 , o b s e r v e d : 3 3 4 . 1 4 0 7 . E x a c t Mass c a l c u l a t e d f o r C ^ H ^ O ^ : 3 7 8 . 1 6 7 1 , o b s e r v e d : 3 7 8 . 1 7 2 5 . E x a c t Mass c a l c u l a t e d f o r C ^ H ^ O ^ 3 3 4 . 1 6 9 4 , o b s e r v e d : 3 3 4 . 1 7 9 2 . - 1 5 3 -T a b l e 11 60 MHz 'H NMR S p e c t r a l D a t a R e l a t e d t o 191 R] R2 R3 H-2 3 H - 61 H-2' 3 H - 5 ' H-4' R] R2 R3 1.08 ( t , 7) COOEt COOMe COOMe 5.73 2.00 5.08 1.58 3.73 4.06 3.67 3.62 ( b s ) ( b s ) ( t , 7) ( b s ) ( s ) ( q , 7) ( s ) ( s ) COOMe COOMe 5.68 2.12 5.06 1.68 3.80 9.60 3.68 3.68 ( b s ) ( b s ) ( t , 7) ( b s ) ( s ) ( s ) ( s ) ( s ) OE t H COOEt '5.72 2.12 5.00 1.70 2.86 , 1 . 2 2b 1 . 2 6b ( b s ) ( b s ) ( t , 7) ( b s ) ( b s ) ( t , 7) ( t , 7) 4.02 4.05 ( q , 7) ( q , 7) Numbers i n T a b l e r e p r e s e n t t h e c h e m i c a l s h i f t (6 i n p p m ) . P a r e n t h e s e s i n d i c a t e t h e m u l t i p l i c i t y a n d t h e c o u p l i n g c o n s t a n t s ( i n H z ) . t o s y l h y d r a z o n e d e r i v a t i v e v a l u e s a r e i n t e r c h a n g e a b l e . 154 -T a b l e 12 IR S p e c t r a l D a t a R e l a t e d t o 1 9 1 Rl 1) a COOEt 2) H R2 COOMe R3 COOME COOMe COOMe b a n d s ( c m- 1) 1740 ( s ) , 1700 ( s ) , 1625 ( m ) , 1600 (w) 1 7 4 0 ( s ) , 1705 ( s ) 1620 (m) 3) O E t COOEt 1740 ( s ) , 1 7 1 0 ( s ) , 1 6 3 0 (m) a t o s y l h y d r a z o n e d e r i v a t i v e T a b l e 13 MS R e s u l t s R e l a t e d t o 191 m/z ( r e l a t i v e % i n t e n s i t y ) l )a COOEt COOMe COOMe 5 4 9 ( 1 2 ) M + 1 , 5 3 1 ( 8 ) - C H3, 4 8 9 ( 5 ) -COOMe, 3 9 3 ( 3 0 ) - CgH6S 02 - C H3 2) O E t 3) O E t COOMe COOMe COOEt 3 5 2 ( 3 ) , 3 2 1 ( 6 ) - OMe, 2 8 8 ( 1 0 ) - 2MeOH, 1 6 8 ( 1 0 0 ) - s i d e c h a i n , CgH] 204 3 0 9 ( 3 ) M+ + 1 , 2 6 2 ( 5 ) - E t O H , 2 3 5 ( 5 0 ) - COOEt a t o s y l h y d r a z o n e d e r i v a t i v e E x a c t Mass f o r 1 8 8 , e n t r y 2: no p a r e n t i o n , b u t b a s e p e a k f o r CgH ^203, c a l c u l a t e d : 1 6 8 . 0 7 8 6 , o b s e r v e d : 1 6 8 . 0 8 1 1 . - 155 -1 3 4 ( 1 0 0 ) - HCOOEt E x a c t M a s s c a l c u l a t e d f o r C1 2Hl g03: 2 0 8 . 1 0 9 4 , o b s e r v e d : 2 0 8 . 1 0 9 1 . A1 , 5- 3 - M e t h , y l b i c y c 1 o [ 3 . 3 . 0 ] o c t e n - 2 - o n e K e t o n e 1_60 ( 3 5 0 mg, 1.68 mmol) was a d d e d t o a s o l u t i o n o f HC1 ( c o n e . 1 m L ) , w a t e r (1 mL) a n d m e t h a n o l (1 m L ) . T h i s r e a c t i o n m i x t u r e was r e f l u x e d f o r 24 h . I t was t h e n c o o l e d (0°C) a n d e x t r a c t e d w i t h e t h e r , t h e c o m b i n e d 1 5 e x t r a c t s d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d A ' - 3 - m e t h y l b i c y c l o -[ 3 . 3 . 0 ] o c t e n - 2 - o n e , 160 mg ( 7 0 % ) . IR ( h e a t ) : 1 7 0 0 ( C O ) , 1635 (C=C) cm"1 'H NMR ( C C 14) : 6 2.32 ppm ( 9 H , b s ) , 1.11 ppm ( 3 H , d , J = 7 H z , CH3CH) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 3 6 ( 8 6 ) , 1 2 1 ( 1 0 0 ) - C H3, 9 3 ( 6 9 ) - C H3 - CO. E x a c t M a s s c a l c u l a t e d f o r CgH1 20 : 1 3 6 . 0 8 8 5 , o b s e r v e d : 1 3 6 . 0 8 6 8 . T o s y l h y d r a z o n e d e r i v a t i v e o f 151 p - T o l u e n e s u l f o n y l h y d r a z i d e ( 3 6 0 mg, 2 m m o l , A l d r i c h ) d i s s o l v e d i n m e t h a n o l : w a t e r ( 5 mL, 7:3) was a d d e d t o 151 ( 6 4 0 mg, 2 mmol) a n d s t i r r e d a t 2 0 ° f o r 4 h . T h i s s o l u t i o n was t h e n e x t r a c t e d w i t h e t h e r , t h e c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , a n d c o n c e n t r a t e d t o a f f o r d t h e h y d r a z o n e d e r i v a t i v e , l ' g ( 9 6 % ) . IR ( n e a t ) : 3 2 0 0 ( N H ) , 1750 ( s ) , 1 7 0 0 ( s ) , 1 6 4 0 ( m ) , 1605 (m) cm"1 'H NMR ( C D C 13) : 6 = 9.0 ppm ( I H , b s , N H ) , 7.80 ppm ( 2 H , d , J = 8 H z , a r o m a t i c ) , 7.30 ppm ( 2 H , d , J = 8 H z , a r o m a t i c ) , 5.10 ppm ( I H , t , J = 7 H z , HC=C ) , 3.92 ppm ( I H , s , C H ( C 0 0 M e )2) , 3.75 ppm ( 6 H , s , COOMe), 1.70 ppm ( 3 H , b s , CH3C=C) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 5 0 3 ( 8 ) M+ + 1 , 4 4 3 ( 6 ) - COOMe, 3 1 8 ( 1 0 ) -s i d e c h a i n , CQH , , 0 « , 9 1 ( 1 0 0 ) . - 156 -E x a c t M a s s c a l c u l a t e d f o r C2 5H3 ( )07N2S : 5 0 2 . 1 7 6 5 , o b s e r v e d : 5 0 2 . 1 7 4 5 . A l c o h o l s 1 46: S o d i u m b o r o h y d r i d e (1 m o l e - e q , BDH) was a d d e d t o k e t o n e (1 e q ) i n m e t h a n o l , a t 2 0°C. A f t e r s t i r r i n g f o r 16 h , t h e s o l u t i o n was a c i d i f i e d ( 5 % HC1) a n d e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d a n d c o n c e n t r a t e d . I n t h e c a s e o f k e t o n e 1 4 5 , s o d i u m c y a n o b o r o h y d r i d e (1 e q , BDH) was u s e d , a n d ammonium c h l o r i d e ( 2 e q ) , i n m e t h a n o l o r i n a q u e o u s a c i d (0.1 HC1) f o r h y d r o l y s i s . On o n e o c c a s i o n t h e d i f f e r e n t a l c o h o l i s o m e r s w e r e s e p a r a t e d by c h r o m a t o g r a p h y ( e t h y l a c e t a t e -p e t r o l e u m e t h e r ) b e f o r e a t t e m p t i n g t h e d e h y d r a t i o n s . L a t e r , t h e m i x t u r e was u s e d ( y i e l d s b e t w e e n 40 a n d 7 0 % ) . A1 , 5- 3 - e t h o x a l y 1 b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o 1 ( 1 4 6 ) Same p r o c e d u r e a s f o r p r e v i o u s a l c o h o l s ( 7 0 % ) . IR ( n e a t ) : 3 5 0 0 ( O H ) , 1 7 5 0 ( C O ) , 1 7 1 0 ( C O ) , 1635 (C=C) cm"1 'H NMR ( C C 14) : 6 = 4.20 ppm ( 3 H , m, 0 C H2, C H ( 0 H ) ) , 3.30 ppm ( 2 H , m, C H2) , 1.32 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 2 5 ( 7 ) M+ + 1 , 2 2 4 ( 5 ) , 1 5 1 ( 2 5 ) - C O O E t , 1 2 3 ( 1 0 ) - COCOOEt E x a c t M a s s c a l c u l a t e d f o r C ^ i e V 2 2 4 . 1 0 4 4 , o b s e r v e d : 2 2 4 . 1 0 5 0 . T r i f 1 u o r o a c e t a t e o f 146 1 , 5 - d i a z a b i c y c l o [ 5 . 4 . 0 ] u n d e c - 5 - e n e ( 0 . 0 4 mL, 0.27 m m o l , 9 6 % , A l d r i c h ) was a d d e d t o a l c o h o l 146 ( 5 0 mg, 0 . 2 5 m m o l ) , N , N - d i m e t h y l a m i n o p y r i d i n e ( 2 A l d r i c h ) a n d t r i f l u o r o a c e t i c a n h y d r i d e ( 0 . 0 4 mL, 0.27 m m o l , A l d r i c h ) i n d i c h l o r o m e t h a n e ( 5 m L ) , s t i r r e d a t - 7 8°C . The r e a c t i o n was warmed t o 0°C, - 157 -T a b l e 14 60 MHz 'H NMR S p e c t r a l D a t a R e l a t e d t o 1 9 3a Rl R2 R3 H-2' H-l 3 H - 5 ' H-4' COOEt COOMe COOMe 4.37 4 . 9 8 1.70 3 . 8 8 ( s ) (m) ( b s ) ( s ) Hb COOMe COOMe 4 . 5 0 5.00 1.70 3.90 (m) ( t , 7) ( b s ) ( s ) O E t COOMe COOMe 4 . 7 0 5.36 1.76 3.98 (m) (m) ( b s ) ( s ) O E tC COOMe COOMe 5.35 1.75 3.92 ( t , 7) ( b s ) ( s ) OMe H COOEt 4 . 7 0 5.18 1 .68 2.87 (m) (m) ( b s ) ( b s ) COOEt 4 . 7 0 (m) 5.20 (m) 1.70 ( b s ) 2.90 ( b s ) Rl 1.30 ( t , 7) 4.2 0 (m) 1.28 ( t , 7) 4.12 (q. 7) 1.17 ( t , 7) 4.07 (q, 7) 3.62 3.64 ( s : s ) 1.27 ( t , 7) 4. 0 8 (q. 7) "2,3 3.62 ( s ) 3.77 ( s ) 3.70 ( s ) 3.70 ( s ) 1 .25 ( t , 7) 4. 0 8 (q. 7) 1.27 ( t , 7) 4.08 (q. 7) 193 ri 2 Numbers i n T a b l e r e p r e s e n t t h e c h e m i c a l s h i f t (6 i n p p m ) . P a r e n t h e s e s i n d i c a t e t h e m u l t i p l i c i t y a n d t h e c o u p l i n g c o n s t a n t s ( i n Hz) S p e c t r a l d a t a i n T a b l e s 1 4 , 1 5 , 16 f o r m a j o r i s o m e r . T o s y l h y d r a z o n e d e r i v a t i v e . T o s y l a t e d e r i v a t i v e . - 1 5 8 -T a b l e 15 IR S p e c t r a l D a t a R e l a t e d t o 193 Rl R2 R3 b a n d s (cm-1) 1) COOEt COOMe COOMe 3 5 0 0 ( w ) , 1750 ( s ) , 1 7 00 ( s ) , 1 6 40 (m) 2 ) Hb 3 5 0 0 1625 ( m ) , 1 7 5 0 ( s ) , 1 7 2 5 ( s ) , 1 6 7 0 (m), (m) 3 ) O E t COOMe COOMe 3 5 0 0 (m), 1 7 6 0 - 1 7 2 5 ( s ) , 1 6 30 (w) 4 ) 0 E tC COOMe COOMe 3 5 0 0 ( m ) , 1 7 5 0 - 1 7 2 0 ( s ) , 1 6 30 (m) 5) OMe H COOEt 3 5 0 0 (m), 1 7 5 0 - 1 7 2 5 ( s ) , 1640 (m) 6) O E t H COOEt 3 5 0 0 ( m ) , 1 7 30 ( s ) T a b l e 16 MS R e s u l t s R e l a t e d t o 193 " l *2 3 1) O E t COOMe COOMe 2) O E tc COOMe COOMe 3) OMe 4) O E t COOEt COOEt m/z ( r e l a t i v e % i n t e n s i t y ) 3 8 0 ( 2 ) , 3 6 2 ( 2 ) - H20 , 3 1 8 ( 1 0 ) - 2 0 M e , 1 7 7 ( 3 2 ) - s i d e c h a i n , CgH-j^O^ 5 3 3 ( 1 2 ) M+ + 1 , 4 7 4 ( 5 ) - HCOOMe, 3 6 2 ( 6 0 ) -HOTs, 3 1 6 ( 8 0 ) - HOTs - EtOH 3 2 2 ( 3 ) , 2 8 8 ( 8 ) - HOMe, 2 6 1 ( 1 9 ) - COOMe, 1 8 0 ( 1 0 0 ) - s i d e c h a i n , CgH-|202 2 6 4 ( 1 4 ) - C O O E t , 1 9 5 ( 3 2 ) - s i d e c h a i n , C8H1 3 ° 2 1 9 0 , e n t r y 3 : E x a c t Mass c a l c u l a t e d f o r C1RH?fiO,-: 3 2 2 . 1 6 9 5 , o b s e r v e d : 3 2 2 . 1 6 3 6 . - 159 -i n ~ 2 h , a n d ammonium c h l o r i d e was a d d e d . The a q u e o u s l a y e r was s e p a r a t e d a n d e x t r a c t e d w i t h d i c h l o r o m e t h a n e . The c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d t h e p r o d u c t , 78 mg ( 9 8 % ) . IR ( n e a t ) : 1 8 0 0 ( C D C F3) , 1 7 5 0 ( C O ) , 1 7 0 0 ( C O ) , 1 6 3 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 5.40 ppm ( I H , d , J = 3 H z , C H C 0 C F3) , 4.12 ppm ( 2 H , q , J = 7 H z , C H2C H3) , 3.30 ppm ( 2 H , b s , C H2) , 2.35 ppm ( 6 H , b s ) , 1.20 ppm ( 3 H , t , J = 7 H z , C H3C H2) . 1 5 A ' - 7 - ( 3 - m e t h y l - 4 , 4 - d i c a r b o m e t h o x y - 2 - b u t e n y l ) - 1 0 - o x a t r i c y c l o [ 6 . 3 . 01 , 5. 07 , 1 1] u n d e c e n - 8 , 9 - d i o n e ( 1 4 9 ) L a c t o n e 149 was s e p a r a t e d f r o m k e t o n e 147 a s t h e DNPH d e r i v a t i v e a f t e r a l k y l a t i o n o f 1 4 5 . The l a c t o n e : k e t o n e r a t i o was f o u n d t o be ~ 1:4. The l a c t o n e 149 a l s o s e p a r a t e d f r o m a l c o h o l 1 4 8 upon r e d u c t i o n o f k e t o n e 1 4 7 . The a l c o h o l : l a c t o n e r a t i o i n t h i s c a s e was f o u n d t o be ~ 4 : 1 . 1 4 9 , IR ( n e a t ) : 1 7 5 0 ( C O ) , 1 7 0 0 ( C O ) , 1 6 4 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 5.20 ppm ( I H , t , J = 7 H z , C H ( C 0 0 M e )2) , 3.83 ppm ( I H , s , C H O ) , 3.70 ppm ( 6 H , s , C H30 C 0 ) , 2.30 ppm ( 1 0 H , b s ) , 1.68 ppm ( 3 H , b s , CH3C=C) no MS c o u l d b e o b t a i n e d on 1 4 9 . 2 , 4 - D i n i t r o p h e n y l h y d r a z o n e d e r i v a t i v e o f 147 K e t o n e 147 ( 1 0 0 mg, 0 . 2 5 mmol) i n m e t h a n o l (1 mL) was a d d e d t o a s o l u t i o n o f 2 , 4 - d i n i t r o p h e n y l h y d r a z i n e ( 5 5 mg, 0.27 m m o l , A l d r i c h ) i n m e t h a n o l ( 2 mL) a n d HCl (1 d r o p ) . A p r e c i p i t a t e was i n s t a n t a n e o u s l y f o r m e d . I t was f i l t e r e d a n d p u r i f i e d b y c h r o m a t o g r a p h y ( 2 5 % p e t r o l e u m e t h e r - e t h e r ) t o a f f o r d t h e h y d r a z o n e d e r i v a t i v e 1 4 7 , 90 mg ( 6 4 % ) ; a n d o f 1 4 9 , 40 mg ( 3 0 % ) . mp 1 4 6 - 1 4 8°C f o r t h e DNPH d e r i v a t i v e o f 147 a n d 1 5 8 - 1 6 0°C f o r 149 - 160 -DNPH d e r i v a t i v e o f 1 4 7 , IR ( N u j o l ) : 1 7 60 ( m ) , 1740 ( s ) , 1700 ( s ) , 1645 ( m ) , 1620 ( m ) , 1595 (m) cm"1 'H NMR ( C D C 13) : 6 = 9.00 ppm ( I H , d , J = 2 H z ) , 8.40 ppm ( I H , d d , J = 2,. 10 H z ) , 8 . 0 0 ppm ( H , d , J = 10 H z ) , 5.40 ppm ( I H , t , J = 7 H z , H C = C ) , 4.27 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 4 . 0 2 ppm ( I H , s , C H ( C 0 0 M e )2) , 3 . 7 3 , 3.70 ppm ( e a c h , 3 H , s , C H3C 0 0 ) , 1.83 ppm ( 3 H , b s , C H3C = C ) , 1.27 ppm ( 3 H , t , J = 7 H z , C H3C H2) no MS c o u l d be o b t a i n e d ( F A B o r E I ) DNPH d e r i v a t i v e o f J 4 9 , IR ( N u j o l ) : 1 7 5 5 ( m ) , 1740 ( m ) , 1 6 0 0 ( s ) , 1590 (m) cm"1 'H NMR ( C D C 13) : 6 = 1 1 . 2 5 ppm ( I H , b s , N H ) , 8.95 ppm ( I H , d , J = 2 H z ) , 8.23 ppm ( I H , d d , J = 2 , 10 H z ) , 7.90 ppm ( I H , d , J = 10 H z ) , 5.48 ppm ( I H , t , J = 7 H z , H C = C ) , 4 . 0 8 ppm ( I H , s , C H ( C 0 0 M e )2) , 3.76 ppm ( 6 H , s , C H30 C 0 ) , 1.85 ppm ( 3 H , b s , CH3C=C) no MS c o u l d b e o b t a i n e d ( F A B o r E I ) . T o s y l h y d r a z o n e d e r i v a t i v e o f " m o n o c y c l i c " 147 ( 1 4 2 a s s t a r t i n g m a t e r i a l ) K e t o n e 142 ( 9 0 mg, 0 . 2 4 mmol) i n m e t h a n o l (1 mL) was a d d e d t o a s o l u t i o n o f p - t o l u e n e s u l f o n y l h y d r a z i d e ( 4 5 mg, 0.24 m m o l , A l d r i c h ) i n m e t h a n o l ( 2 mL) and s t i r r e d a t 15°C f o r 6 h . A f t e r c o n c e n t r a t i o n o f t h e s o l u t i o n , t h e p r o d u c t was p u r i f i e d by c h r o m a t o g r a p h y ( 2 0 % p e t r o l e u m e t h e r - e t h e r ) t o a f f o r d t h e " m o n o c y c l i c " h y d r a z o n e d e r i v a t i v e 1 4 7 , 100 mg ( 7 9 % ) a n d 1 4 9 , 20 mg ( 1 8 % ) . T o s y l h y d r a z o n e o f 1 4 7 , IR ( C H C 13) : 1 7 4 0 ( s ) , 1700 ( s ) , 1 6 30 ( m ) , 1 6 0 0 (w) cm'1 'H NMR ( C C 14) : 6 = 7.74 ppm ( 2 H , d , J = 8 H z ) , 7.22 ppm ( 2 H , d , J = 8 H z ) , 7.02 ppm ( I H , s ) , 5.73 ppm ( I H , b s , H C = C ) , 5.08 ppm ( I H , m, H C = C ) , 4.06 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3.73 ppm ( I H , s , C H ( C 0 0 M e )2) , 3.62 ppm ( 6 H , s , - 161 -COOMe), 2 . 0 0 , 1.58 ppm ( e a c h , 3 H , b s , C H3C = C ) , 1.08 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 5 4 9 ( 3 ) M+ + 1 , 4 4 7 ( 2 ) - COCOOEt, 9 1 ( 1 0 0 ) - . T o s y l h y d r a z o n e o f 1491R ( C H C 13) : 1 7 5 0 - 1 6 8 0 ( s ) , 1630 ( m ) , 1605 (m) cm"1 'H NMR ( C C 14) : 6 = 7.79 ppm ( 2 H , d , J = 8 H z ) , 7.24 ppm ( 2 H , d , J = 8 H z ) , 7.10 ppm ( I H , s ) , 5.82 ppm ( I H , b s , H O C ) , 5.18 ppm ( I H , m, H O C ) , 3.89 ppm ( I H , s , C H ( C 0 0 M e )2) , 3.70 ppm ( 6 H , s , COOMe) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 4 4 9 ( 1 2 ) M+ - 5 5 , 4 1 7 ( 5 ) - HOMe f r o m 4 4 9 , 3 8 9 ( 8 ) - HCOOMe f r o m 4 4 9 , 2 9 3 ( 2 8 ) - C7H g S 02 f r o m 4 4 9 , 9 1 ( 1 0 0 ) . A 1 ' ^ - 3 - H y d r o x y m e t h y l - 3 - ( 3 - m e t h y l - 4 , 4 - d i c a r b o m e t h o x y - 2 - b u t e n y l )  b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o l T h i s a l c o h o l was p r e p a r e d b y r e d u c t i o n o f 1 5 1 , u s i n g s o d i u m b o r o h y d r i d e i n m e t h a n o l a s d e s c r i b e d p r e v i o u s l y . IR ( n e a t ) : 3 5 0 0 - 3 4 0 0 ( O H ) , 1735 (CO) cm"1 'H NMR ( C D C 13) : 5.22 ppm ( 2 H , m, CH-(OH) a n d C H O C ) , 4. 9 2 ppm ( I H , s , C H ( C 0 0 M e )2) , 3. 6 8 ppm ( 6 H , s , C H30 C 0 ) , 3.35 ppm ( 2 H , b s , C H20 H ) , 1.70 ppm ( 3 H , b s , C H3O C ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 3 8 ( 5 ) , 3 0 2 ( 1 2 ) - 2 H20 , 1 8 5 ( 2 0 ) s i d e c h a i n , C9H1 304. 3 - C a r b o e t h o x y - 3 - ( 3 - m e t h y l - 4 , 4 - d i c a r b o m e t h o x y - 2 - b u t e n y 1 )  b i c y c 1 o [ 3 . 3 . 0 ] o c t a d i e n e ( 1 6 4 ) o r ( 1 9 4 ) A l c o h o l 1_63 was d e h y d r a t e d u s i n g s e v e r a l m e t h o d s , a ) T o s y l a t i o n m e t h o d A l c o h o l 163 ( 7 6 0 mg, 2 mmol) was a d d e d t o THF ( 2 mL) c o n t a i n i n g p - t o l u e n e s u l f o n y l - c h l o r i d e ( 3 8 0 mg, 2 m m o l , A l d r i c h ) , p y r i d i n e ( 0 . 4 mL, - 162 -5 mmol) a n d N , N - d i m e t h y l a m i n o p y r i d i n e ( 1 0 mg, A l d r i c h ) . The s o l u t i o n was s t i r r e d a t ~ 20°C f o r 16 h , a c i d i f i e d ( 1 0 % H C l ) a n d e x t r a c t e d w i t h e t h e r . The c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t s -p u r i f i e d b y c h r o m a t o g r a p h y ( e t h e r - p e t r o l e u m e t h e r ) , t o a f f o r d t h e t o s y l a t e d e r i v a t i v e , 6 85 mg ( 6 8 % ) a n d a d e h y d r a t e d p r o d u c t 164 ( o r d i e n e i s o m e r ) , 4 0 mg ( 5 % ) . b ) H y d r o c h l o r i c a c i d m e t h o d A l c o h o l 163 ( 1 0 0 mg, 0.26 mmol) was a d d e d t o a c h l o r o f o r m ( 5 mL) s o l u t i o n i n t o w h i c h h y d r o g e n c h l o r i d e ( F i s h e r ) h a d b e e n b u b b l e d f o r 10 m i n . T h i s m i x t u r e was s t i r r e d a t 20°C f o r 2 h . I t was t h e n p o u r e d i n t o a c o l d s o d i u m b i c a r b o n a t e s o l u t i o n , a n d ' t h e a q u e o u s l a y e r e x t r a c t e d w i t h c h l o r o f o r m . The c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( 1 0 % e t h e r - p e t r o l e u m e t h e r ) t o a f f o r d p r o d u c t 164 ( o r d i e n e i s o m e r ) , 55 mg ( 6 0 % ) . c ) B u r g e s s r e a g e n t m e t h o d A l c o h o l 1 6 3 ( 1 9 0 mg, 0.5 mmol) i n b e n z e n e (1 mL) was a d d e d t o m e t h y l ( c a r b o x y s u l f a m o y l ) t r i e t h y l a m m o n i u m h y d r o x i d e i n n e r s a l t ( E t ^ l ^ S O ^ ' N C O O M e , p r e p a r a t i o n b a s e d on t h e p r o c e d u r e o f B u r g e s s a n d P e n t o n1 4^0, 150 mg, 0.55 mmol) i n b e n z e n e (1 m L ) . The r e a c t i o n m i x t u r e was h e a t e d t o 50°C f o r 1 h . I t was t h e n c o o l e d a n d a d d e d t o w a t e r . The a q u e o u s l a y e r was e x t r a c t e d w i t h e t h e r , t h e c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d b y c h r o m a t o g r a p h y ( 1 0 % e t h e r - p e t r o l e u m e t h e r ) , t o a f f o r d p r o d u c t 164 ( o r d i e n e i s o m e r ) , 50 mg ( 3 0 % ) d) M e t h a n e s u l f o n y l c h l o r i d e m e t h o d G a s e o u s s u l f u r d i o x i d e ( F i s h e r ) was b u b b l e d i n t o a d i c h l o r o m e t h a n e (1 mL) s o l u t i o n c o n t a i n i n g m e t h a n e s u l f o n y l c h l o r i d e ( 0 . 4 8 mL, 6 m m o l , A l d r i c h ) f o r 10 m i n , a n d a d d e d t o a l c o h o l 1_63 ( 2 0 0 mg, 0.6 m m o l ) , p y r i d i n e - 163 -( 0 . 5 6 mL, 7.2 m m o l ) , N , N - d i m e t h y l a m i n o p y r i d i n e ( 2 mg, A l d r i c h ) d i s s o l v e d i n d i c h l o r o m e t h a n e ( 3 m L ) . The s o l u t i o n was s t i r r e d a t 20°C f o r 1 h , c o o l e d t o 0°C a n d w a t e r a d d e d . I t was t h e n e x t r a c t e d w i t h d i c h l o r o m e t h a n e , a n d t h e c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( 8 t o 3 0 % e t h e r - p e t r o l e u m e t h e r ) t o a f f o r d 1_64 ( o r d i e n e i s o m e r ) , 130 mg ( 7 0 % ) . T h i s p r o c e d u r e was a l s o u s e d o m i t t i n g t h e s u l f u r d i o x i d e . D e c a r b o x y l a t i o n o f 164 A s o l u t i o n o f 1 6 4 , ( 8 0 mg, 0 . 2 4 mmol) i n t o l u e n e ( 2 . 0 m L ) , was h e a t e d i n a s e a l e d t u b e w i t h t e t r a m e t h y l e t h y l e n e d i a m i n e ( 8 0 mg, 0 . 6 9 m m o l , A l d r i c h ) t o 1 8 0 - 1 9 0° C , f o r 96 h . The s o l u t i o n was t h e n c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( 1 2 % e t h e r - p e t r o l e u m e t h e r ) , t o a f f o r d 1 6 4 , 20 mg ( 2 5 % ) . IR ( n e a t ) : 1 7 3 0 - 1 7 2 5 (CO) cm"1 'H NMR ( C C 14) : 6 = 5.30 ppm ( 2 H , m, o l e f i n i c s i g n a l s ) , 4.11 ppm ( 2 H , q , 7 H z , 0 C H2C H3) , 3.62 ppm ( 3 H , s , C H30 C 0 ) , 1.68 ppm ( 3 H , b s , C H3C = C ) , 1.26 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 0 4 ( 9 ) , 2 5 8 ( 7 ) - H O E t , 2 3 1 ( 4 2 ) - C O O E t , 1 7 7 ( 1 0 0 ) - s i d e c h a i n , C8H1 3 ° 2 * E x a c t M a s s c a l c u l a t e d f o r Cl gH2 404: 3 0 4 . 1 6 6 8 , o b s e r v e d : 3 0 4 . 1 6 7 2 . UV (A max ( l o g e ) ) : 2 1 5 ( 3 . 4 ) , 2 5 0 ( 3 . 2 ) E t h y l 5 - c h 1 o r o - 3 - m e t h y l - 2 - p e n t e n o a t e ( 1 4 4 a ) a ) E t h y n y l e t h e r ( 1 8 . 5 g , 0.26 m m o l , F a r c h a n , f r e s h l y d i s t i l l e d , bp 4 9 - 5 0°C ) i n THF ( 5 0 mL) was a d d e d t o m e t h y l m a g n e s i u m c h l o r i d e ( 8 . 3 mL, 0.24 m o l , 2.99 M, A l d r i c h ) d i s s o l v e d i n THF ( 2 5 0 mL) a t 2 2°C. T h e r e s u l t i n g m i x t u r e - 164 -T a b l e 17 H' NMR S p e c t r a l D a t a R e l a t e d t o 194 ( i s o m e r s ) o r 1 6 4 D e h y d r a t i o n R] R2 R3 3 o l e f i n s 3 H - 5 ' H-4' R] R2 > R3 M e t h o d r a t i o : 6 ( a ) O E t COOMe COOMe ( b ) O E t COOMe COOMe ( b ) O E t H COOEt ( c ) O E t COOMe COOMe ( d ) O E t H COOEt 1: 5.77 2.02 4.27 1.24 3.70 ( b s ) ( s ) ( s ) ( t , 7) ( s ) 4: :5.36 1.75 4.46 On) ( b s ) (q. 7) 2: :6.22 1.68 3.85 1.22 3.66 ( b s ) ( b s ) ( s ) ( t , 7) ( s ) 4: :5.77 4.02 ( b s ) (q. 7) 11 : 5.21 (m) 1: :6.20 1.64 3.50 1 .18 1.18 ( s ) ( b s ) ( s ) ( t , 7) ( t , 7) 2: :5.72 1.69 4 . 0 3 * 3 . 9 8 * ( b s ) ( b s ) (q. 7) (q. 7) 4: :5.18 (m) 1 : :5.69 1.67 3.68 1.18 3.65 ( b s ) ( b s ) ( s ) ( t , 7) ( s ) 8 :5.18 4.06 (m) (q. 7) 1 : :5.62 1.64 - 1.20 1.20 ( b s ) ( b s ) ( t . 7) ( t , 7) 3 :5.22 4.02 4 . 0 2 (m) (q. 7) (q. 7) 194 Numbers i n T a b l e r e p r e s e n t t h e c h e m i c a l s h i f t (6 i n ppm) P a r e n t h e s e s i n d i c a t e t h e m u l t i p l i c i t y a n d t h e c o u p l i n g c o n s t a n t s ( i n H z ) v a l u e s a r e i n t e r c h a n g e a b l e - 165 -T a b l e 18 IR S p e c t r a l D a t a R e l a t e d t o 194 R1 R2 R3 b a n d s ( c m "1) O E t COOMe COOMe 1 7 5 5 - 1 7 3 0 (COO) O E t H COOEt 1 7 2 5 (COO) T a b l e 19 MS R e s u l t s R e l a t e d t o 194 R1 R2 R3 m/z ( r e l a t i v e % i n t e n s i t y ) 1) O E t COOMe COOMe 3 6 2 ( 3 ) , 2 8 9 ( 8 ) - C O O E t , 1 7 7 ( 1 0 0 ) - s i d e c h a i n , C g ^ - j O ^ 2) OEt H COOEt 3 1 8 ( 6 ) , 2 4 4 ( 1 3 ) - H C O O E t , 1 7 7 ( 1 0 0 ) -s i d e c h a i n , CgH-j - 166 -was s t i r r e d f o r 0.5 h , 4 - c h l o r o b u t a n o n e ( 1 4 g , 0.13 m o l ) i n THF ( 1 0 mL) was a d d e d o v e r 5 m i n a n d s t i r r i n g c o n t i n u e d f o r a f u r t h e r 20 h a t 22°C. The r e a c t i o n m i x t u r e was c o o l e d t o 0°C a n d w a t e r was a d d e d d r o p w i s e , u n t i l g a s e v o l u t i o n c e a s e d . T h e n , t h e m i x t u r e was f i l t e r e d t h r o u g h C e l i t e . The o r g a n i c l a y e r was s e p a r a t e d a n d t h e a q u e o u s l a y e r e x t r a c t e d w i t h e t h e r . The c o m b i n e d e x t r a c t s d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d b y c h r o m a t o g r a p h y ( 5 % e t h e r - p e t r o l e u m e t h e r ) , t o g i v e 168 a s an o r a n g e o i l , 20 g ( 8 8 % ) . IR ( n e a t ) : 3 3 - 3 5 0 0 ( O H ) , 2 2 5 0 (C=C) c m "1 , 'H NMR ( C C 14) : 6 = 4 . 0 8 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3 .60 ppm ( 2 H , m, C H2C 1 ) , 3.04 ppm ( I H , s , O H ) , 1.96 ppm ( 2 H , m, C H2C ( 0 H ) ) , 1.48 ppm ( 3 H , s , C H3C ( 0 H ) ) , 1.38 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 7 6 ( 6 ) , 1 1 3 ( 4 5 ) - O E t - H20 , 8 5 ( 1 0 0 ) E x a c t M a s s c a l c u l a t e d f o r C g H ^ O g C l : 1 7 6 . 0 6 0 0 5 , o b s e r v e d : 1 7 6 . 0 6 0 4 . b) 4 - c h l o r o - 2 - e t h y n y l e t h e r 2 - b u t a n o l ( 2 0 g , 0.11 m o l ) i n e t h a n o l ( 2 0 mL) was a d d e d d r o p w i s e t o 5 % s u l f u r i c a c i d - e t h a n o l ( 2 0 m L ) , k e p t a t 0°C. A f t e r a d d i t i o n was c o m p l e t e , t h e r e a c t i o n m i x t u r e was s t i r r e d f o r 20 h a t 0 t o 10°C. W a t e r was t h e n a d d e d t o t h e s o l u t i o n , a n d t h e p r o d u c t e x t r a c t e d w i t h e t h e r . The c o m b i n e d e t h e r e x t r a c t s w e r e w a s h e d w i t h s o d i u m b i c a r b o n a t e , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( a s a b o v e ) t o a f f o r d 1 4 4 a , 15 g ( 7 5 % ) w h i c h c o u l d be f u r t h e r p u r i f i e d by d i s t i l l a t i o n . bp 6 5 - 6 8° C / 0 . 5 T o r r IR ( n e a t ) : 1 7 1 0 ( C O ) , 1 6 5 5 ( O C ) c m- 1 'H NMR ( C C 14) : 6 = 5.70 ppm ( I H , b s , H O C ) , 4.10 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3.63 ppm ( 2 H , t , J = 7 H z , C H g C l ) , 3.02 a n d 2.67 ppm ( 2 H , t : t , 1 : 1 , J = 7 H z , 2 : E , C H g - O ) , 2 . 18 a n d 1.99 ppm ( 3 H , s : s , 1 : 1 , C H3O C ) , 1.27 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 1 7 7 ( 1 7 ) M+ + 1 , 1 7 6 ( 1 7 ) , 1 4 1 ( 8 3 ) - C l , 1 3 1 ( 1 0 0 ) - O E t , 1 1 3 ( 9 1 ) - O E t - H Q . - 167 -4- C h l o r o - 2 - m e t h y l - l , 1 - d i c a r b o m e t h o x y - l - b u t e n e 1 3 1b T i t a n i u m t e t r a c h l o r i d e (11 mL, 0 . 1 0 m o l , BDH) a n d C C 14 ( 2 5 mL) w e r e s l o w l y a d d e d ( 4 5 m i n ) t o a 1 L t h r e e n e c k f l a s k e q u i p p e d w i t h a m e c h a n i c a l s t i r r e r , c o n d e n s e r a n d d r o p p i n g f u n n e l . A f t e r a d d i t i o n was c o m p l e t e , a y e l l o w p r e c i p i t a t e was p r e s e n t . T h e n , 4 - c h l o r o b u t a n o n e ( 5 . 3 g , 0 . 0 5 m o l ) a n d d i m e t h y l m a l o n a t e ( 6 . 6 g , 0 . 0 5 m o l , E a s t m a n ) w e r e a d d e d d r o p w i s e o v e r 15 m i n , f o l l o w e d by p y r i d i n e ( 1 6 g , E a s t m a n , 0.2 m o l ) i n THF ( 4 0 mL) o v e r 30 m i n . The r e s u l t i n g d a r k o r a n g e s o l u t i o n was s t i r r e d a t 20°C f o r 24 h . The r e a c t i o n m i x t u r e was a d d e d t o c o l d w a t e r , t h e o r g a n i c l a y e r s e p a r a t e d a n d t h e a q u e o u s l a y e r e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d , a n d c o n c e n t r a t e d t o a f f o r d 1 4 4 b , 6.6 g ( 6 0 % ) . T h i s p r o d u c t was p u r e e n o u g h f o r f u r t h e r u s e . I t c o u l d a l s o be d i s t i l l e d , bp 9 6 - 9 8° C / 0 . 3 T o r r , 5.5 g ( 5 0 % ) . IR ( n e a t ) : 1 7 2 5 ( C O ) , 1 6 4 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 3.63 ppm ( 6 H , s , COOMe), 3.58 ppm ( 2 H , t , J = 7 H z , C H2C 1 ) , 2.76 ppm ( 2 H , t , J = 7 H z , C H2C = ) , 1.98 ppm ( 3 H , s , CH3C=) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 221 ( 2 ) , 1 8 8 ( 5 ) - MeOH, 1 5 3 ( 2 8 ) - MeOH - H C 1 , 1 2 1 ( 1 2 ) - 2MeOH - H C 1 . E x a c t M a s s c a l c u l a t e d f o r C g H - ^ C l (M+-MeOH): 1 8 8 . 0 2 3 7 , o b s e r v e d : 1 8 8 . 0 2 2 3 . 5- C a r b o e t h o x y - 5 ( 3 - o x o b u t y l e t h y l e n e t h i o k e t a l ) - 3 - m e t h y l - 2 - c y c l o p e n t e n o n e E t h a n e d i t h i o l ( 5 0 mg, 0.55 m m o l , A l d r i c h ) a n 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 ( 2 d r o p s , A l d r i c h ) w e r e a d d e d t o V70 ( 1 0 0 mg, A l d r i c h , 0 .42 mmol) d i s s o l v e d i n a c e t i c a c i d ( 2 mL) a t 2 0°C. The s o l u t i o n was s t i r r e d f o r 1 h , p o u r e d i n t o c o l d w a t e r a n d t h e a q u e o u s l a y e r e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w e r e w a s h e d w i t h s o d i u m b i c a r b o n a t e , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( 1 2 % e t h y l a c e t a t e - h e x a n e ) t o a f f o r d t h e t h i o k e t a l , 120 mg ( 7 0 % ) . - 168 -IR ( n e a t ) : 1 7 5 0 ( s ) , 1 7 0 5 ( s ) , 1 6 3 0 (C=C) cm'1 'H NMR ( C C 14) : 6 = 5.75 ppm ( I H , b s , C H = C ) , 4 . 1 2 ppm ( 2 H , q , J = 7 H z , 0 C H _2C H3) , 3.22 ppm ( 4 H , s , C H2S ) , 2.18 ppm ( 3 H , b s , C H3C = C ) , 1.70 ppm ( 3 H , s , C H3- C ( 5 C H2)2) , 1.22 ppm ( 3 H , t , J = 7 H z , CH_3CH2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 1 4 ( 2 ) , 1 6 8 ( 2 8 ) - C g H1 0S2, s i d e c h a i n , 1 1 9 ( 1 0 0 ) - C6H1 0S2, s i d e c h a i n , - CO. 5 - C a r b o e t h o x y - 5 ( 3 - o x o b u t y l e t h y l e n e t h i o k e t a l ) - 3 - m e t h y l - 2 - c y c l o p e n t e n o l S o d i u m b o r o h y d r i d e ( 1 8 0 mg, 4.77 m m o l , BDH) was a d d e d t o t h e a b o v e p r o d u c t ( 1 . 5 g , 4.77 mmol) a n d c e r o u s c h l o r i d e ( C e C l3. 7 H20 , 1.3 g , 4.77 m m o l , BDH) d i s s o l v e d i n m e t h a n o l ( 2 5 m L ) . The s o l u t i o n was s t i r r e d a t 20°C f o r 30 m i n . I t was t h e n a c i d i f i e d ( 5 % HC1) a n d e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w a s h e d , d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d p u r i f i e d by c h r o m a t o g r a p h y ( 2 5 % e t h y l a c e t a t e - h e x a n e ) t o a f f o r d t h e c o r r e s p o n d i n g a l c o h o l , 110 mg ( 7 6 % ) . IR ( n e a t ) : 3 5 0 0 - 3 4 0 0 ( O H ) , 1730 ( C O ) , 1625 (C=C) cm"1 'H NMR ( C C 14) : 6 = 5.82 ppm ( I H , b s , H C = C ) , 5 . 3 8 , 4 . 7 8 ppm ( I H , b s : b s , 1 : 1 , C H ( O H ) ) , 4 . 1 3 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3.27 ppm ( 4 H , s , C H2S ) , 2.20 ppm ( 3 H , b s , C H3C = C ) , 1.73 ( 3 H , s , C H3C 0 ) , 1.27 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 1 6 ( 3 ) , 2 9 8 ( 8 ) , 1 6 8 ( 2 5 ) , 1 1 9 ( 1 0 0 ) . 5 - H y d r o x y m e t h y l - 5 ( 3 - o x o b u t y l e t h y l e n e t h i o k e t a l ) - 3 - m e t h y l - 2 - c y c l o p e n t e n o l P r e p a r e d b y l i t h i u m a l u m i n u m h y d r i d e r e d u c t i o n o f t h e c o r r e s p o n d i n g 8 - k e t o - e s t e r , a s d e s c r i b e d a b o v e ( 5 0 % ) . IR ( n e a t ) : 3 3 0 0 - 3 5 0 0 (OH) cm"1 'H NMR ( C D C 13) : 6 = 6.20 ppm ( I H , m, H C = C ) , 4.8 ppm ( I H , m, C H ( 0 H ) ) , 3.42 ppm ( 2 H , b s , C H20 H ) , 3.30 ppm ( 4 H , s , C H2S ) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 5 6 ( 1 3 ) M+ - H20 , 119 ( 1 0 0 ) . - 169 -1 - ( 3 - 0 x o b u t y l e t h y l e n e t h i o k e t a l ) - l - c a r b o e t h o x y - 4 - i n e t h y 1 c y c l o p e n t a d i e n e P r e p a r e d b y t h e m e t h a n e s u l f o n y l c h l o r i d e d e h y d r a t i o n m e t h o d , o f t h e c o r r e s p o n d i n g a l c o h o l ( 6 8 % ) a s d e s c r i b e d a b o v e . IR ( n e a t ) : 1 7 2 5 ( C O ) , 1 6 2 5 (C=C) cm'1 'H NMR ( C C 14) : 6 = 6.10 ppm ( 2 H , m, o l e f i n s ) , 4 . 8 0 ppm ( I H , m, o l e f i n ) , 4 . 1 0 , 4 . 0 6 ppm ( 2 H , q : q , 1 : 1 , J = 7 H z , 0 C H2C H3) , 3.75 ppm ( 4 H , s , C H2S ) , 3.27 ppm ( 3 H , b s , C H3C = C ) , 1.73 ppm ( 3 H , s , C H3C ( S C H2)2) , 1 . 2 5 , 1.23 ppm ( 3 H , t : t , 1 : 1 , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 9 8 ( 1 8 ) , 2 2 5 ( 6 ) - C O O E t , 1 1 9 ( 1 0 0 ) . E x a c t M a s s c a l c u l a t e d f o r C1 5H2 2S202: 2 9 8 . 1 0 6 0 , o b s e r v e d : 2 9 8 . 1 0 3 8 . 5 - ( 3 - 0 x o b u t y 1 ) - 5 - c a r b o e t h o x y - 3 - m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 7 0 ) P r e p a r e d b y a l k y l a t i o n o f 142 a s d e s c r i b e d p r e v i o u s l y , M e t h o d B. T h e amount o f p o t a s s i u m - t - b u t o x i d e u s e d was k e p t t o a minimum c a t a l y t i c a m o u nt ( f o r e x a m p l e , f o r 20 mmol o f k e t o n e , 0.2 mmol o f p o t a s s i u m ) . The y i e l d o f 170 d e p e n d e d on t h e c a t a l y t i c a m o u nt o f b a s e ( 4 0 t o 9 5 % ) . IR ( n e a t ) : 1 7 3 0 ( s ) , 1 7 0 0 ( s ) , 1 6 2 5 (C=C) cm"1 'H NMR ( C C 14) : 6 = 5.87 ppm ( I H , b s , H C = C ) , 4.11 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 2.19 ppm ( 3 H , b s , C H3C = C ) , 2.10 ppm ( 3 H , s , C H3C 0 ) , 1.22 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 3 9 ( 2 ) M+ + 1 , 2 3 8 ( 1 ) , 1 9 2 ( 4 ) - H O E t , 1 6 8 ( 4 6 ) - C4H60 , s i d e c h a i n , 4 3 ( 1 0 0 ) - C H3C 0 . P r o d u c t 1 71 e n d o - l - c a r b o e t h o x y - 4 - m e t h y l - 5 - a c e t y l b i c y c l o [ 2 . 2 . l ] h e p t a n - 2 -o n e was a l s o o b t a i n e d i n v a r y i n g a m o u n t s ( 0 t o 5 0 % ) . IR ( n e a t ) : 1 7 7 5 (CO s t r a i n e d ) , 1 7 2 5 ( C O ) , 1 6 2 5 (C=C) cm"1 "H NMR ( C D C 13) : 6 = 4.21 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3.03 ppm ( I H , d d d , J = 2 , 6 , 12 H z , H-5 e x o ) , 2.21 ppm ( 3 H , s , C H3C 0 ) , 1.45 ppm ( 3 H , s , C H3- C - ) , 1.30 ppm ( 3 H , t , J = 7 H z , C H3C H2) - 170 -MS (m/z! r e l a t i v e % i n t e n s i t y ) : 2 3 9 ( 3 ) M + + 1 , 2 3 8 ( 3 ) , 1 9 3 ( 9 ) - O E t , 1 2 5 ( 1 0 0 ) C7H1 00 . E x a c t M a s s c a l c u l a t e d f o r C1 3H] 804: 2 3 8 . 1 2 0 0 , o b s e r v e d : 2 3 8 . 1 2 1 1 . UV (X max ( l o g e ) ) : 224 ( 3 . 3 ) 5 - C a r b o e t h o x y - 5 - ( d i m e t h y 1 3 - m e t h y l - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e )  3 - m e t h y l - 2 - c y c l o p e n t e n o n e ( 1 7 2 ) P r e p a r e d b y K n o e v e n a g a l c o n d e n s a t i o n ( u s i n g 1 7 0 ) a s d e s c r i b e d f o r 1 4 4 b , e x c e p t t h e r e a c t i o n t i m e was r e d u c e d t o 12 h . P u r i f i c a t i o n o f t h e p r o d u c t s by c h r o m a t o g r a p h y ( 2 0 % t o 5 0 % e t h y l a c e t a t e - p e t r o l e u m e t h e r ) a f f o r d e d 173 ( 7 % ) , 172_ ( 5 3 % ) , 170 ( 1 2 % ) . 1 7 2 , IR ( n e a t ) : 1 7 5 0 - 1 7 0 0 ( C O ) , 1 6 3 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 5.78 ppm ( I H , b s , H C = C ) , 4.11 ppm ( 2 H , q , 7 H z , 0 C H2C H3) , 3.72 ppm ( 6 H , s , C H30 C 0 ) , 2.22 ppm ( 3 H , b s , C H3C = C H ) , 2.03 ppm ( 3 H , s , C H3C = C ) , 1.23 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 5 2 ( 2 ) , 3 2 1 ( 6 ) - OMe, 2 8 8 ( 1 2 ) - HCOOMe, 1 6 8 ( 1 0 0 ) C g H1 203. 1 7 3 , 6 - c a r b o e t h o x y - 8 - m e t h y l - 3 - ( d i m e t h y l m e t h y l e n e d i c a r b o x y l a t e ) b i c y c l o [ 4 . 3 . 0 ] n o n a - 1 , 8 - d i e n e IR ( n e a t ) : 1 7 4 0 - 1 7 1 0 ( C O ) , 1 6 1 0 , 1 5 7 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 6.57 ppm ( I H , s , H C = C ) , 6.03 ppm ( I H , b s , H C = C ) , 4.07 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3. 6 8 ppm ( 6 H , s , C H30 C 0 ) , 1.91 ppm ( 3 H , b s , C H3C = C ) , 1.23 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 3 4 ( 8 ) , 3 0 2 ( 1 8 ) - HOMe, 1 1 9 ( 1 0 0 ) , 1 1 7 ( 1 0 0 ) . E x a c t M a s s c a l c u l a t e d f o r C1 8H2 20 g : 3 3 4 . 1 4 1 4 , o b s e r v e d : 3 3 4 . 1 1 9 6 . UV (X max ( l o g e ) ) : 226 ( 4 . 2 ) - 171 -5 - C a r b o e t h o x y - 5 ( d i m e t h y l 3 - m e t h y l - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e ) 3- m e t h y l - 2 - c y c l o p e n t e n o l ( 1 7 4 ) S o d i u m b o r o h y d r i d e ( 1 2 mg, 0.31 m m o l , BDH) was a d d e d t o a m e t h a n o l ( 1 0 mL) s o l u t i o n c o n t a i n i n g k e t o n e 172 ( 1 0 0 mg, 0 . 2 8 mmol) a n d c e r o u s c h l o r i d e ( C e C l3. 7 H20 , 115 mg, 0.31 m m o l , B D H ) , a n d s t i r r e d a t 2 0 ° f o r 1 h . The r e a c t i o n m i x t u r e was t h e n a c i d i f i e d ( 5 % H C l ) , a n d e x t r a c t e d w i t h e t h y l -a c e t a t e . The c o m b i n e d e x t r a c t s w e r e w a s h e d , d r i e d , f i l t e r e d , c o n c e n t r a t e d , a n d t h e p r o d u c t p u r i f i e d b y c h r o m a t o g r a p h y ( 2 5 % e t h y l a c e t a t e - h e x a n e ) t o a f f o r d 1_74 65 mg ( 6 2 % b e s t y i e l d ) . IR ( n e a t ) : 3 3 0 0 - 3 5 0 0 ( O H ) , 1725 ( C O ) , 1625 (C=C) cm"1 'H NMR ( C C 14) : 6 = 5.87 ppm ( I H , b s , H C = C ) , 5 . 3 5 , 4.90 ppm ( I H , m, 1 : 1 , C H ( 0 H ) ) , 4 . 2 0 ppm ( 2 H , q , J = 7 H z , 0 C H .2C H3) , 3.78 ppm ( 6 H , s , C H30 C 0 ) , 2.27 ppm ( 3 H , b s , C H3C = C H ) , 2.08 ppm ( 3 H , s , C H3C = C ) , 1.29 ppm ( 3 H , t , J = 7 H z , C H3C H2) . l - C a r b o e t h o x y - 1 ( d i m e t h y l 3 - m e t h y l - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e ) 4- m e t h y l c y c l o p e n t a d i e n e ( 1 7 5 ) , P r e p a r e d b y d e h y d r a t i o n o f 174 u s i n g t h e m e t h a n e s u l f o n y l c h l o r i d e m e t h o d d e s c r i b e d a b o v e . The r e a c t i o n was p u r i f i e d by c h r o m a t o g r a p h y ( t h e m e s y l a t e d e r i v a t i v e d e h y d r a t e d on t h e c o l u m n , 3 0 % e t h e r - p e t r o l e u m e t h e r ) t o a f f o r d 1_75 ( 5 3 % ) . IR ( n e a t ) : 1 7 2 5 ( C O ) , 1635 (C=C) cm"1 'H NMR ( C D C 13) : 6 = 6.10 ppm ( 2 H , m, o l e f i n s ) , 4 . 8 0 ppm ( I H , m, o l e f i n ) , 4 . 0 7 , 4 . 1 2 ppm ( 2 H , q : q , 1 : 1 , J = 7 H z , 0 C H _2C H3) , 3.65 ppm ( 6 H , s , C H30 C 0 ) , 2.01 ppm ( 3 H , s , C H3C = C ) , 1.82 ppm ( 3 H , b s , C H3C = C H ) , 1 . 2 3 , 1.26 ppm ( 3 H , t : t , 1 : 1 , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 3 6 ( 3 ) , 3 0 4 ( 5 ) - HOMe, 19 1(60), 9 1 ( 1 0 0 ) . - 172 -A2 > 3- 5 - C a r b o e t h o x y - 9 - d i c a r b o m e t h o x y - 2>8 - d i m e t h y l - t r i c y c l o [ 4 . 3 . 01 , 5. Q4 , 8]  n o n e n e ( 1 7 6 ) A s o l u t i o n o f 175 ( 3 0 mg, 0 . 0 8 9 mmol) i n t o l u e n e (1 mL) was p l a c e d i n a s e a l e d t u b e a n d h e a t e d ( o i l b a t h ) t o 140°C f o r 10 h . The s o l u t i o n was t h e n c o n c e n t r a t e d a n d p u r i f i e d b y c h r o m a t o g r a p h y ( 6 % e t h e r - p e t r o l e u m e t h e r ) t o a f f o r d 176 a n d 1 7 7 , 14 mg ( 4 0 % ) . IR ( n e a t ) : 1 7 3 0 (CO) cm"1 'H NMR ( C D C 13) : <5 = 7.10 a n d 6.20 ppm ( I H , b s , HC=C, 5 : 4 ) , 4.11 ppm ( 2 H , q , J = 7 H z , 0 C H2C H3) , 3 . 7 0 ppm ( 6 H , s , C H30 C 0 ) , 2.02 a n d 2.04 ppm ( 3 H , b s , CH3C=C, 5:4) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 3 6 ( 7 ) , 2 0 9 ( 2 3 ) - H O E t , 2 5 8 ( 4 3 ) - H O E t , HOMe, 2 2 6 ( 7 5 ) - E t O H , 2H0Me, 2 9 ( 1 0 0 ) . E x a c t M a s s c a l c u l a t e d f o r C-jgH^Og,: 3 3 6 . 1 5 7 2 , o b s e r v e d : 3 3 6 . 1 5 6 1 . A ' - 3 - ( 3 - o x o b u t y l ) - 3 - c a r b o e t h o x y b i c y c 1 o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 8 ) P r e p a r e d b y a l k y l a t i o n o f 1 6 0 , a s d e s c r i b e d p r e v i o u s l y , M e t h o d B ( 9 5 % ) . IR ( n e a t ) : 1 7 5 0 - 1 7 0 0 ( C O ) , 1645 (C=C) cm"1 •H NMR ( C D C 13) : 6 = 4.11 ppm ( C H2, q , J = 7 H z , 0 C H2C H3) , 2.11 ppm ( 3 H , s , C H3C 0 ) , 1.23 ppm ( 3 H , t , J = 7 H z , CH_3CH2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 6 4 ( 3 ) , 1 9 4 ( 9 ) - C4Hg0 , 4 3 ( 1 0 0 ) C H3C 0 . E x a c t M a s s c a l c u l a t e d f o r C1 6H2 20c: 2 6 4 . 1 3 6 0 , o b s e r v e d : 2 6 4 . 1 3 3 1 . 1 5 A ' - 3 - C a r b o e t h o x y - 3 - ( d i m e t h y l 3 - m e t h y 1 - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e )  b i c y c l o [ 3 . 3 . 0 ] o c t e n - 2 - o n e ( 1 7 9 ) P r e p a r e d b y K n o e v e n a g a l c o n d e n s a t i o n ( u s i n g 1 7 8 ) , a s d e s c r i b e d a b o v e f o r 1 5 1 b , e x c e p t t h a t t h e r e a c t i o n t i m e was 20 t o 24 h . P u r i f i c a t i o n o f t h e r e a c t i o n by c h r o m a t o g r a p h y ( 2 0 % t o 3 0 % e t h e r - p e t r o l e u m e t h e r ) a f f o r d e d 1_79 ( 6 0 % ) a n d 1 7 8 ( 3 0 % ) . IR ( n e a t ) : 1 7 5 5 - 1 7 2 5 ( C O ) , 1 6 5 0 (C=C) cm"1 - 173 -'H NMR ( C C 14) : 6 = 4.12 ppm ( 2 H , q , J = 7 H z , OCH_2CH3), 3 . 7 3 , 3.70 ppm ( 6 H , s : s , 1 : 1 , C H30 C 0 ) , 2.02 ppm ( 3 H , s , C H3C = C ) , 1.24 ppm ( 3 H , t , J = 7 H z , C H3C H2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 4 0 ( 3 ) M+ - 1 3 8 , 1 9 4 ( 1 6 ) M+ - s i d e c h a i n " , CgH1 204. On on e o c c a s i o n a c y c l i z e d p r o d u c t o f t y p e 173 was i s o l a t e d (< 1 % ) . IR ( n e a t ) : 1 7 3 0 ( C O ) , 1 6 2 0 , 1575 (C=C) cm"1 'H NMR ( C D C 13) : 6 = 6.52 ppm ( I H , s , H C = C ) , 4.11 ppm ( 2 H , q , J = 7 H z , 0 C H _2C H3) , 3.74 a n d 3.77 ppm (3H e a c h , s , C H3C 0 0 ) , 1.22 ppm ( 3 H , t , J = 7 H z , C H3C H20 ) . MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 6 0 ( 6 ) , 3 2 8 ( 1 3 ) -MeOH, 2 5 5 ( 2 8 ) -MeOH, C O O E t . 1 5 A ' - 3 - C a r b o e t h o x y - 3 - ( d i m e t h y l - 3 - m e t h y l - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e )  b i c y c 1 o [ 3 . 3 . 0 ] o c t e n - 2 - o l ( 1 8 0 ) P r e p a r e d b y r e d u c t i o n o f 179 a s d e s c r i b e d p r e v i o u s l y f o r 172 ( 6 7 % : b e s t y i e l d ) . IR ( n e a t ) : 3 5 0 0 ( O H ) , 1 7 5 0 - 1 7 0 5 ( C O ) , 1 6 5 0 (C=C) cm"1 'H NMR ( C C 14) : 6 = 4 . 6 0 ppm ( I H , b s , C H ( O H ) ) , 4.05 ppm ( 2 H , q , J = 7 H z , 0 C H _2C H3) , 3.64 ppm ( 6 H , s , C H30 C 0 ) , 1.27 ppm ( 3 H , t , J = 7 H z , CH_3CH2). 151 T h i s r e d u c t i o n was a c c o m p l i s h e d a l s o u s i n g z i n c b o r o h y d r i d e . A z i n c b o r o h y d r i d e s o l u t i o n ( 6 0 mL, - 0 . 1 6 M i n e t h e r , 8.8 mmol) was a d d e d t o an e t h e r ( 4 0 mL) s o l u t i o n c o n t a i n i n g k e t o n e 1_79_ ( 3 g , 7.9 mmol) a t 0°C. A f t e r s t i r r i n g f o r 30 m i n a t 0°C, a n d 30 m i n a t 2 0°C , a s a t u r a t e d s o l u t i o n o f s o d i u m t a r t r a t e was a d d e d d r o p w i s e (-1.5 mL) u n t i l b u b b l i n g c e a s e d . T h i s s o l u t i o n was t h e n d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( 3 0 % e t h e r - p e t r o l e u m e t h e r ) t o a f f o r d 1 8 0 , 1.6 g ( 5 8 % ) . - 174 -3 - C a r b o e t h o x y - 3 - ( d i m e t h y l - 3 - m e t h y l - 3 - b u t e n y l - 4 , 4 - d i c a r b o x y l a t e )  b i c y c l o [ 3 . 3 . 0 ] o c t a - l , 4 - d i e n e ( 1 8 1 ) P r e p a r e d b y d e h y d r a t i o n o f 180 u s i n g t h e m e t h a n e s u l f o n y l c h l o r i d e m e t h o d d e s c r i b e d a b o v e ( 6 0 % ) . IR ( n e a t ) : 1 7 30 ( C O ) , 1635 (C=C) cm"1 'H NMR ( C D C 13) : 6 = 5 . 7 3 , 5 . 3 5 , 5.20 ppm ( 2 H , b s : b s : b s , o l e f i n s ) , 4 . 1 0 , 4.06 ppm ( 2 H , q : q , - 2 : 1 , 0 C H _2C H3) , 3 . 7 2 , 3.64 ppm ( 6 H , s : s , - 2 : 1 , C H30 C 0 ) , 2.01 ppm ( 3 H , s , C H3C = C ) , 1 . 5 1 , 1.48 ppm ( 3 H , t : t , - 2 : 1 , CH_3CH2) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 6 2 ( 4 ) , 2 5 7 ( 5 ) - HOMe, COOEt o r H C O O E t , OMe, 1 1 7 ( 3 8 ) . A8'9- 6 - C a r b o e t h o x y - 2 - d i c a r b o m e t h o x y - 3 - m e t h y l t e t r a c y c l o [ 6 . 4 . 01 , 6. 03 , 7. 08'1 2] - d o d e c e n e ( 1 8 1 ) ( a l s o A8 , 1 2 a n d A9 , 1 0) P r e p a r e d u s i n g 181 ( 3 0 mg, 0.081 mmol) i n t o l u e n e (1 mL) a s d e s c r i b e d a b o v e f o r t h e D i e l s - A l d e r r e a c t i o n o f 175 ( 5 0 % ) . IR ( n e a t ) : 1 7 3 5 (CO) cm"1 'H NMR ( C D C 13) : 5 . 4 5 , 5.26 ppm ( 4 : 1 , 5/8 o f t h e i n t e g r a t i o n o f I H ; b s : b s , o l e f i n ) , 4 . 1 4 a n d 4 . 1 5 ppm ( 2 H , 4 : 1 , q : q , J = 7 H z , 0 C H2C H3) , 3 . 7 1 , 3.65 a n d 3 . 6 9 , 3.66 ppm ( 6 H , s : s : s : s , 4 : 4 : 1 : 1 , C H30 C 0 ) , 1.25 ppm ( 3 H , t , J = 7 H z , C H3C H2) , 1.17 ppm ( 3 H , s , CH3~C-) MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 3 6 3 ( 1 5 ) M+ + 1 , 3 6 2 ( 1 5 ) , 3 0 2 ( 1 9 ) - HCOOMe, 2 8 8 ( 1 7 ) - HCOOEt, 2 2 8 ( 1 9 ) - HCOOEt, HCOOMe, 1 5 3 ( 5 9 ) , 1 1 7 ( 1 0 0 ) . E x a c t M a s s c a l c u l a t e d f o r C2 QH2 606: 3 6 2 . 1 7 2 7 , o b s e r v e d : 3 6 2 . 1 7 2 0 . A1 1'1 2- 6 - C a r b o e t h o x y - 3 - m e t h y 1 t e t r a c y c l o [ 6 . 4 . 01 > 6. 03'7.  d o d e c e n e - 2 - d i c a r b o x y l i c a c i d T r i e s t e r 182 ( 2 0 0 mg, 0 . 5 5 mmol) was a d d e d t o a s o l u t i o n c o n t a i n i n g a l u m i n u m t r i c h l o r i d e - ( 1 4 0 mg, 1.1 m m o l , F i s h e r ) i n e t h a n e t h i o l ( 2 mL, - 175 -E a s t m a n ) . I m m e d i a t e l y a v e r y v i s c o u s p r e c i p i t a t e was f o r m e d a n d s t i r r i n g c o n t i n u e d a t 20°C f o r 20 h . The r e a c t i o n m i x t u r e was t h e n p o u r e d i n t o c o l d a c i d ( 1 % HC1) a n d e x t r a c t e d w i t h e t h e r a n d c h l o r o f o r m . T h e c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d , c o n c e n t r a t e d a n d t h e c r u d e p r o d u c t , 170 mg ( 9 4 % ) u s e d i n t h e n e x t r e a c t i o n . IR ( n e a t ) : 3 7 0 0 - 2 8 0 0 ( O H ) , 1725 (CO) cm"1 'H NMR ( C D C 13) : 6 = 8.80 ppm ( 2 H , b s , C 0 0 H ) , 5.85 ppm (IH, s , H C = C ) , 4 . 0 8 ppm ( 2 H , q , J = 7 H z , CH.2CH3), 1.25 ppm ( 3 H , t , J = 7 H z , C H g C H g ) , 1.23 ppm ( 3 H , s , C H3) . A9»1 ° - 6 - C a r b o e t h o x y - 3 - m e t h y 1 t e t r a c y c l o [ 6 . 4 . 01 , 6. 03'7.  d o d e c e n e - 2 - c a r b o x y l i c a c i d ( 1 8 3 ) T h e a b o v e d i c a r b o x y l i c a c i d ( 1 7 0 mg, 0 . 5 0 mmol) was d i s s o l v e d i n t o l u e n e ( 2 mL) a n d t h e s o l u t i o n r e f l u x e d f o r 2 h . The s o l v e n t was e v a p o r a t e d a n d t h e p r o d u c t p u r i f i e d by c h r o m a t o g r a p h y ( 2 0 % e t h e r - p e t r o l e u m e t h e r ) t o o b t a i n t h e m o n o c a r b o x y l i c a c i d p r o d u c t 1 8 3 , 6 5 mg ( 3 8 % f o r two s t e p s ) . IR ( n e a t ) : 3 7 0 0 - 2 8 0 0 ( O H ) , 1 7 2 0 (CO) cm"1 'H NMR ( C D C 13) : 6 = 5.85 ppm (IH, b s , C 0 0 H ) , 5.82 ppm (IH, s , H C = C ) , 4.09 ppm ( 2 H , q , J = 7 H z , CH_2CH3), 1.25 ppm ( 3 H , t , J = 7 H z , CH_3CH2), 1.10 ppm ( 3 H , s , C H3) . MS ( m / z , r e l a t i v e % i n t e n s i t y ) : 2 9 1 ( 1 3 ) M+ + 1 , 2 9 0 ( 6 ) , 2 4 6 ( 4 5 ) - 0 E t , 2 1 7 ( 4 5 ) - C 0 0 E t , 1 7 2 ( 9 8 ) - C 0 0 E t , C00H a n d d i c a r b o x y l i c a c i d 1 8 3 , 60 mg ( 3 5 % f o r two s t e p s ) . S p e c t r a l d a t a i n n e x t p a r a g r a p h . - 176 -A9 , 1 Q- 3 - M e t h . y 1 t e t r a c y c 1 o r 6 . 4 . O1 , 6. 03 , 7. 08'1 2] d o d e c e n e - 2 , 6 - d i c a r b o x y l i c a c i d E s t e r 183 ( 1 1 0 mg, 0.38 mmol) was a d d e d t o a s o d i u m h y d r o x i d e s o l u t i o n ( 1 0 % a q u e o u s NaOH, 1 mL, - 2 . 5 mmol) a n d t h i s m i x t u r e r e f l u x e d f o r 2 h . A f t e r c o o l i n g t h e s o l u t i o n , i t was a c i d i f i e d ( 1 0 % H C l ) a n d e x t r a c t e d w i t h e t h y l a c e t a t e . The c o m b i n e d e x t r a c t s w e r e d r i e d , f i l t e r e d a n d c o n c e n t r a t e d t o a f f o r d - 1 0 0 mg ( 9 9 % ) . IR ( C H C 13) : 3 5 0 0 - 3 0 0 ( C 0 0 H ) , 1 7 2 0 (CO) cm'1 'H NMR ( C D C 13) : 6 = 1 0 . 8 0 ppm ( I H , b s , C 0 0 H ) , 5.85 ppm ( I H , s , H O C ) , 1.10 ppm ( 3 H , s , C H3) . MS (m/z, r e l a t i v e % i n t e n s i t y ) : 2 6 2 ( 5 ) , 2 1 7 ( 1 8 ) - C 0 0 H , 1 7 2 ( 2 8 ) - 2 C 0 0 H . MP: 2 0 6 - 2 0 8° C . - 177 -B i b l i o g r a p h y 1. (Some p a r a g r a p h s i n s e c t i o n 1.1 a r e t a k e n f r o m ) J . H e l l o u . M.Sc. T h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 8 0 . 2 . R.D. B a r n e s . I n v e r t e b r a t e Z o o l o g y , W.B. S a u n d e r s C o m p a n y . P h i l a d e l p h i a , L o n d o n a n d T o r o n t o , 1 9 6 8 . 3 . A . J . K h o n . A m e r . Z o o l . , 7 , 291 ( 1 9 6 1 ) . 4 . E.N. K o z l o f f . K e y s t o t h e M a r i n e I n v e r t e b r a t e s o f P u g e t S o u n d , San  J u a n A r c h i p e l a g o a n d A d j a c e n t R e g i o n s , U o f W a s h i n g t o n P r e s s , S e a t t l e a n d L o n d o n , 1 9 7 4 . 5 . L . G . H a r r i s . C u r r e n t T o p i c s ' i n C o m p a r a t i v e P a t h o b i o l o g y , 2_, 2 1 3 - 3 1 5 ( 1 9 7 3 ) . 6 . D.R. W o b b e r . V e l i g e r , 1_2, 383 ( 1 9 7 0 ) . 7. R . J . P a i n e . V e l i g e r , 6 , 1 ( 1 9 6 3 ) . 8 . R.E. J o h a n n e s . V e l i g e r , 5_, 104 ( 1 9 6 3 ) . 9 . J . £ . B a r d a s h . T h e C h e m i c a l S e n s e s o f F i s h , i n G r a n t , M a c k i e , C h e m o r e c e p t i o n i n M a r i n e O r g a n i s m s , A c a d e m i c P r e s s , N.Y., 1 9 7 4 , p p . 1 0 4 - 1 4 1 . 1 0 . M . J . E d m u n d s . J . L i m . S o c . L o n d o n , 4 6 , 46 ( 1 9 6 6 ) . 1 1 . L . B . A r e y a n d W.J. C o z i e r . J . E x p . Z o o . , 3 2 , 4 4 3 ( 1 9 2 1 ) . 1 2 . R.H. W h i t t a k e r a n d P . P . F e e n y . S c i e n c e , 171 , 3 9 7 3 , 757 (197 1 ) . 1 3 . P . J . S c h e u e r . C h e m i s t r y o f M a r i n e N a t u r a l P r o d u c t s , A c a d e m i c P r e s s , N.Y., 1 9 7 3 . 1 4 . D . J . F a u l k n e r a n d R . J . A n d e r s e n . The S e a , V o l . 5 , W i l e y - I n t e r s c i e n c e , N.Y., 1 9 7 7 . 1 5 . P . J . S c h e u e r . I s r a e l J . Chem., ]6_, 52 ( 1 9 7 7 ) . 1 6 . G.R. S c h u l t e a n d P . J . S c h e u e r . T e t r a h e d r o n , 3 8 , 1 8 5 7 ( 1 9 8 2 ) . 1 7 . D . J . F a u l k n e r a n d W. F e n i c a l , E d s . M a r i n e N a t u r a l P r o d u c t s C h e m i s t r y , P l e n u m P r e s s , N.Y., 1 9 7 7 . 1 8 . B . J . B u r r e s o n , P . J . S c h e u e r , J . F i n e r a n d J . C l a r d y . J . Am. Chem. S o c . , 9 7 , 4 7 6 3 ( 1 9 7 5 ) . 1 9 . S.W. A y e r a n d R . J . A n d e r s e n . T e t r a h e d r o n L e t t . , 2 3 , 1 0 3 9 ( 1 9 8 2 ) . 2 0 . F.A. F u h r m a n , G . J . F u h r m a n , Y.H. Kim a n d L . A . P a v e l k a . S c i e n c e , 2 0 7 , 1 9 3 ( 1 9 8 0 ) . - 178 -2 1 . G.M. B l a i r a n d R.R. S c a p y . V e l i g e r , 1_5, 119 ( 1 9 7 2 ) . 2 2 . C D . T o d d . J . E x p . M a r . B i o l . E c o l . , 4J_, 213 ( 1 9 7 9 ) . 2 3 . J . F . G a r d n e r . D i s s . A b s t . I n t . B , 4 0 , 2 4 8 9 ( 1 9 7 9 ) . 2 4 . G.L. L e v y a n d G.L. N e l s o n . C a r b o n - 1 3 N u c l e a r M a g n e t i c R e s o n a n c e f o r  O r g a n i c C h e m i s t s , J o h n - W i l e y a n d S o n s , N.Y., 1 9 7 2 . 2 5 . F o r e x a m p l e , s e e D . J . H a n a c h a n . L i p i d C h e m i s t r y , J o h n W i l e y a n d S o n s , N.Y., C h a p . 5 , 1 9 6 0 . 2 6 . R.M. B u r t o n a n d F.C. G u e r r a , E d s . F u n d a m e n t a l s o f L i p i d C h e m i s t r y , BI S c i e n c e P u b l i c a t i o n s D i v i s i o n , M i s s o u r i , C h a p . 1 3 , 1 9 7 4 . 2 7 . G. S i m o n a n d G. R o u s e . L i p i d s , 2_, 55 ( 1 9 6 7 ) . 2 8 . K.A. K a r l s s o n a n d B . E . S a m u e l s o n . B i o c h i m . B i o p h y s . A c t a , 3 3 7 , 204 ( 1 9 7 4 ) . 2 9 . K.A. K a r l s s o n . Chem. P h y s . L i p i d s , 5 , 6 ( 1 9 7 0 ) . 3 0 . G. A n g u i l a r - S a n t o s a n d M.S. D o t y i n T r a n s a c t i o n s , D r u g s f r o m t h e S e a , Rho d e I s l . 1 9 6 7 , p . 1 7 3 . 3 1 . G.T. C a r t e r a n d K . L . R i c h a r d , J r . J . Am. Chem. S o c , 1 0 0 , 7441 ( 1 9 7 8 ) . 3 2 . W.R. M o r r i s o n . B i o c h i m . B i o p h y s . A c t a , 1 7 6 , 537 ( 1 9 6 9 ) . 3 3 . E . J . M a s o r o . P h y s i o l o g i c a l C h e m i s t r y o f L i p i d s i n Mammals. W.B. S a u n d e r s C o , N.Y., 1 9 6 8 . 3 4 . S . A b r a h a m s s o n a n d I . P a s c h e r , E d s . S t r u c t u r e o f B i o l o g i c a l M e m b r a n e s , P l e n u m P r e s s , L o n d o n , N.Y. 1 9 7 6 . 3 5 . E . H e c h t a n d D. S h a p i r o . S c i e n c e , 1 2 5 , 1041 ( 1 9 5 7 ) . 3 6 . N. F i s h e r , C. H a r i n g t o r i a n d D.A. L o n g . L a n c e t , 2, 5 2 2 ( 1 9 5 1 ) . 3 7 . R . 0 . B r a d y . Chem. P h y s . L i p i d s , 5 , 261 ( 1 9 7 0 ) . 3 8 . H.H. Sun a n d W. F e n i c a l . T e t r a h e d r o n L e t t . , 6 8 5 ( 1 9 7 9 ) . 3 9 . S.W. A y e r , J . H e l l o u , M. T i s h l e r a n d R . J . A n d e r s e n . T e t r a h e d r o n L e t t . , 2 5 , 141 ( 1 9 8 4 ) . 4 0 . M. B a r n a r d a n d N.C. Y a n g . P r o c . Chem. S o c , 3 0 2 ( 1 9 5 8 ) . 4 1 . a L.M. J a c k m a n a n d S . S t e r n h e l l . I n t e r n a t i o n a l S e r i e s i n O r g a n i c C h e m i s t r y , V o l . 10 A p p l i c a t i o n s o f NMR S p e c t r o s c o p y i n O r g a n i c C h e m i s t r y , 2 n d E d . , P e r g a m o n P r e s s , N.Y., 1 9 7 8 . - 179 -4 1 . b R.M. S i l v e r s t e i n , G.C. B a s s l e r a n d T.C. M o r r i l l . S p e c t r o s c o p i c I d e n t i f i c a t i o n o f O r g a n i c C o m p o u n d s , 3 r d E d . , J o h n W i l e y a n d S o n s , N.Y., 1 9 7 4 . 4 2 . D . J . Sam a n d H.E. S i m m o n s . J . Am. Chem. S o c , 9 4 , 4 0 2 4 ( 1 9 7 2 ) . 4 3 . A l d r i c h C a t a l o g H a n dbook o f F i n e C h e m i c a l s , 1 9 8 3 - 8 4 . 4 4 . L . F . F i e s e r a n d M. F i e s e r . R e a g e n t s i n O r g a n i c S y n t h e s i s , V o l . 1 , J o h n - W i l e y a n d S o n s , I n c . , N.Y., 1967 a n d r e f e r e n c e s t h e r e i n . 4 5 . P. M a u r e t , J . P . F a y e t , D. M e r m i l l o d - B l a r d e t , P. M a z e r o l l e s a n d A . F a u c h e r . J . C h i m . P h y s . , P h y s . - C h i m . B i o l . , 7 7 , 3 2 5 ( 1 9 8 0 ) a n d r e f e r e n c e s t h e r e i n . 4 6 . J . C a s a n o v a a n d B. W e g e l l . B u l l . S o c . C h i m . F r . , 911 ( 1 9 7 4 ) a n d r e f e r e n c e s t h e r e i n . 4 7 . F . A . L . A n e t , M. S t - J a c q u e s , P.M. H e m i c h s , A.K. C h e n g , J . K r a n e a n d L . Wang. T e t r a h e d r o n , 3 0 , 1629 ( 1 9 7 4 ) a n d r e f e r e n c e s t h e r e i n . 4 8 . J . S i c h e r . P r o g r e s s i n S t e r e o c h e m i s t r y , 3 , 2 0 2 ( 1 9 6 2 ) . 4 9 . N.L. A l l i n g e r , M.T. T r i b b l e a n d M.A. M i l l e r . T e t r a h e d r o n , 2 8 , 1 1 7 3 ( 1 9 7 2 ) . 5 0 . G. Samuel a n d R. W e i s s . T e t r a h e d r o n , 2 6 , 3 0 0 5 ( 1 9 7 0 ) . 5 1 . F . A . L . A n e t , A.K. C h e n g a n d J . K r a n e . J . Am. Chem. S o c . , 9 5 , 78 7 7 ( 1 9 7 3 ) . 5 2 . F . J . W e i g e r t a n d J . D . R o b e r t s . J . Am. Chem. S o c . , 9 2 , 1 3 4 7 ( 1 9 7 0 ) . 5 3 . J . D a l e . P u r e a n d A p p l . Chem., 2 5 , 4 6 9 (1971 ) . 5 4 . J . D . D u n i t z a n d H. E s e r . H e l v . C h i m . A c t a , 5 0 , 1 5 6 5 ( 1 9 6 7 ) . 5 5 . J . D . D u n i t z , H. E s e r , M. B i x o n a n d S . L i f s o n . H e l v . C h i m . A c t a , 5 0 , 1572 ( 1 9 6 7 ) . 5 6 . T. A l i r k , G. B o r g e n a n d J . D a l e . A c t a Chem. S c a n d . , 26_, 1805 ( 1 9 7 2 ) . 5 7 . R.A. R a p h a e l . P r o c . Chem. S o c , 97 ( 1 9 6 2 ) . 5 8 . P e r s o n n a l r e s u l t s . 5 9 . W.H. U r r y , D . J . T r e c k e r a n d D.A. W i n e y . T e t r a h e d r o n L e t t . , 6 0 9 ( 1 9 6 2 ) . 6 0 . T . M o r i , K. M a t s u i a n d H. N a z a k i T e t r a h e d r o n L e t t . , 1 1 7 5 ( 1 9 7 0 ) . - 180 -6 1 . F o r e x a m p l e s e e r e f . 54 a n d 5 5 . 6 2 . W.C. S t i l l a n d I. G a l y n k e r . T e t r a h e d r o n , 3 7 , 3981 ( 1 9 8 1 ) . 6 3 . A m o d i f i e d m o l e c u l a r m o d el h a s b e e n p r o p o s e d b y J . D a l e . J . Chem. S o c , 93 ( 1 9 6 3 ) . W i t h t h a t m o d e l , t h e b o n d s o f two a d j a c e n t c a r b o n s c a n o n l y t a k e a l i m i t e d number o f v a l u e s , w h i c h a r e m u l t i p l e s o f IT/3... 6 4 . H.O. H o u s e , M. G a l l a n d H.D. O h n s t e a d . J . O r g . Chem., 3 6 , 2361 ( 1 9 7 1 ) . 6 5 . S e e r e f . 24 a n d 5 2 . 6 6 . O.L. C h a p m a n , D.S. W e i s s i n O r g a n i c P h o t o c h e m i s t r y , O.L. C h a p m a n , E d . ; V o l . 3 , C h a p . 3 , 1 9 7 3 . 6 7 . N.L. A l l i n g e r , M.P. C a v a , D.C. D e J o n g h , C R . J o h n s o n , N.A. L e b e l a n d L . C . S t e v e n s . C h i m i e O r g a n i q u e , E d i s c i e n c e , M c G r a w - H i l l , 1 9 7 5 . 6 8 . D.S. W e i s s i n O r g a n i c P h o t o c h e m i s t r y , A . P a d w a , E d . ; V o l . 5 , C h a p . 4 , 1981 a n d r e f e r e n c e s t h e r e i n . 6 9 . R.H. E a s t m a n a n d J . B e a r d . T e t r a h e d r o n L e t t . , 3 0 2 9 ( 1 9 7 0 ) . 7 0 . M. K a i s i n , Y.M. S h e i k h , L . J . D u r h a m , C. D j e r a s s i , B. T u r s c h , B. D a l o z e , J . C . B r a e k m a n , D. L o s m a n , a n d R. K a r l s s o n . T e t r a h e d r o n L e t t . , 2 2 3 9 ( 1 9 7 4 ) . 7 1 . Y.M. S h e i k h , G. S i n g y , M. K a i s i n , H. E g g e r t , C.' D j e r a s s i , B. T u r s c h , D. D a l o z e , a n d J . C . B r a e k m a n . T e t r a h e d r o n , 3 2 , 1171 ( 1 9 7 6 ) a n d r e f e r e n c e s t h e r e i n . 7 2 . Y.M. S h e i k h , C . D j e r a s s i , J . C B r a e k m a n , D. D a l o z e , M. K a i s i n , B. T u r s c h , a n d R. K a r l s s o n . T e t r a h e d r o n , 3 3 , 2 1 1 5 ( 1 9 7 7 ) . 7 3 . R. K a r l s s o n . A c t a C r y s t a l l o g r . , B 3 3 , 1 1 4 3 ( 1 9 7 7 ) . 7 4 . E. A y a n o g l u , T. G e b r e y e s u s , C M . B e e c h a n , C. D j e r a s s i , a n d M. K a i s i n . T e t r a h e d r o n L e t t . , 1671 ( 1 9 7 8 ) . 7 5 . E . A y a n o g l u , T. G e b r e y e s u s , C M . B e e c h a n , a n d C. D j e r a s s i . T e t r a h e d r o n , 35_, 1035 ( 1 9 7 9 ) . 7 6 a . L . S . C i e r s z k o . T r a n s . N.Y. A c a d . S c i . , 2 4 , 502 ( 1 9 6 2 ) . b . P.R. B u r k h o l d e r , a n d L.M. B u r k h o l d e r . S c i e n c e , 1 2 7 , 1 1 7 4 ( 1 9 5 8 ) . 7 7 . F o r r e c e n t d i s c u s s i o n s r e l a t e d t o s i m i l a r b i o s y n t h e s e s , r e f e r t o a ) K. H a y a n o , Y. O h f u n e , H. S h i r a h a m a , a n d T. M a t s u m o t o . H e l v . C h i m .  A c t a , 6 4 , 1347 ( 1 9 8 1 ) . b ) Y . M u r a t a , T. O h t s u k a , H. S h i r a h a m a , a n d T. M a t s u m o t o . T e t r a h e d r o n L e t t . , 2 2 , 4 3 1 3 ( 1 9 8 1 ) . - 181 -7 8 . A.M. B i r c h , a n d G. P a t t e n d e n . J . Chem. S o c . , Chem. Comm., 1195 ( 1 9 8 0 ) . 7 9 a . R.D. L i t t l e , a n d G.L. C a r r o l l . T e t r a h e d r o n L e t t . , 22_, 4389 ( 1 9 8 1 ) . b . R.D. L i t t l e , G.L. C a r r o l l , a n d J . L . P e t e r s e n . J . Am. Chem. S o c . , 1 0 5 , 9 2 8 ( 1 9 8 3 ) . 8 0 . A . P a q u e t t e , a n d K.E. S t e v e n s . T e t r a h e d r o n L e t t . , 2 2 , 4 3 9 3 ( 1 9 8 1 ) . 8 1 . J . H u g u e t , M. K a r p f , a n d A . S . D r i e d i n g . H e l v . C h i m . A c t a , 6 5 , 2 4 1 3 ( 1 9 8 2 ) . 8 2 . T. F u j i t a , T. O h t s u k a , H. S h i r a h a m a , a n d T. M a t s u m o t o . T e t r a h e d r o n  L e t t . , 2 3 , 4091 ( 1 9 8 2 ) . 8 3 . W. O p p o l z e r , a n d K. B a t t i g . T e t r a h e d r o n L e t t . , 2 3 , 46 6 9 ( 1 9 8 2 ) . 8 4 a . A.M. B i r c h , a n d G. P a t t e n d e n . T e t r a h e d r o n L e t t . , 2 3 , 991 ( 1 9 8 2 ) . b . A.M. B i r c h , a n d G. P a t t e n d e n . J . Chem. S o c , P e r k i n T r a n s . 1 , 1913 ( 1 9 8 3 ) . 8 5 . G. M e h t a , D.S. R e d d y , a n d A . N . M u r t y . J . Chem. S o c , Chem. Comm. 8 2 4 ( 1 9 8 3 ) . 8 6 . E. P i e r s , a n d V. K a r u m a r a t n e . C a n . J . Chem., 6 2 , 6 2 9 ( 1 9 8 4 ) . 8 7 . J . E . P aw, a n d A . C . Weedon. T e t r a h e d r o n L e t t . , 2 3 , 5 4 8 5 ( 1 9 8 2 ) . 8 8 . G. P a t t e n d e n , a n d S . J . T e a g u e . T e t r a h e d r o n L e t t . , 2 3 , 5471 ( 1 9 8 2 ) . 8 9 . P r e p a r e d a c c o r d i n g t o a p r o c e d u r e i n W.F. G a n n o n , a n d H.O. H o u s e , O r g . S y n . , 4 0 , 41 ( 1 9 6 0 ) . 9 0 a . P r e p a r e d a c c o r d i n g t o a p r o c e d u r e i n R.B. K e l l y , S . J . A l w a r d , a n d K.S. M u r t y . C a n . J . Chem., 5 6 , 2 5 0 8 ( 1 9 7 8 ) . b . A . B a r c o , S . B e n e t t i , a n d G.P. P o l l i n i . S y n t h e s i s , 316 ( 1 9 7 3 ) . c . H.N. E d w a r d s , A . F . W y c p a l e k , N.C. C o r b i n , a n d J . O . M c C h e s n e y . S y n t h .  Commun., 8 , 563 ( 1 9 7 8 ) . 9 1 . H.O. H o u s e , H. B a b a d , R.B. T o o t h i l l , a n d A.W. N o l t e s . J . O r g . Chem., 2 7 , 4141 ( 1 9 6 2 ) . 9 2 . W. L e n h e r t . T e t r a h e d r o n 2 9 , 6 3 5 ( 1 9 7 3 ) . 9 3 . K. A n t c z a k , J . F . K i n g s t o n , S . J . A l w a r d , a n d A.G. F a l l i s . C a n . J . Chem., 6 2 , 829 ( 1 9 8 4 ) . 9 4 . R.Y. L e v i n a , a n d T . I . T a n t s y r e v a . D o k l . A k a d . N a u k . S.S.S.R., 8 9 , 697 ( 1 9 5 3 ) . - 182 -9 5 a . R.D. M i l l e r , M. S n e i d e r , a n d D.L. D o l c e . J . Am. Chem. S o c . , 9 5 , 8 4 6 8 ( 1 9 7 3 ) . b . C F . W i l c o x J r . , a n d G . C W h i t n e y . J . O r g . Chem., 3 2 , 2 9 3 3 ( 1 9 6 7 ) . 9 6 . M.S. B a i r d , a n d C B . R e e s e . T e t r a h e d r o n L e t t . , 2 8 9 5 ( 1 9 7 6 ) . 9 7 a . A . De M e i j e r e , a n d L . M e y e r . A n g e w . Chem. I n t e r n a t . E d . , 1_2, 8 5 8 ( 1 9 7 3 ) . b . i b i d . Chem. B e r . , 1 1 0 , 2561 ( 1 9 7 7 ) . 9 8 . S e e f o r e x a m p l e , R.K. M a c k i e a n d D.M. S m i t h . G u i d e b o o k t o O r g a n i c  S y n t h e s i s , The P i t m a n P r e s s L t d . , B r i t a i n , 1982 pp 129-131 a n d J . E . B a l d w i n . J . Chem. S o c . , Chem. Comm., 7 3 4 , ( 1 9 7 6 ) . 9 9 . T. F u j i s a u a , a n d K. S a k a i . T e t r a h e d r o n L e t t . , 3331 ( 1 9 7 6 ) . 1 0 0 . M. K o r e e d a , Y. L i a n g , a n d H. A k a g i . J . Chem. S o c , Chem. Comm., 4 4 9 ( 1 9 7 9 ) . 1 0 1 a . Z.G. H a j o s , a n d D.R. P a r r i s h . J . O r g . Chem., 3 9 , 1 6 1 2 ( 1 9 7 4 ) . b . J . C r i p s i n , A . E . V a n s t o n e , a n d J . S . W h i t e h u r s t . J . Chem. S o c . , C 10 ( 1 9 7 0 ) a n d r e f e r e n c e s t h e r e i n . c . V. E d e r , G. S a v e r , a n d R. W i e c h e r t . A n g e w . Chem. I n t . E d . , I C 496 ( 1 9 7 1 ) . d . G. B a u d u i n , H. C h r i s t o l , a n d Y. P i e t r a s a n t a . B u l l . S o c . C h . F r . , 359 ( 1 9 7 3 ) . e . C.B.C. B o y c e , a n d J . S . W h i t e h u r s t . J . Chem. S o c , 2 0 2 2 ( 1 9 5 9 ) . 1 0 2 a . J.W. R a l l s . Chem. R e v . , 5 9 , 329 ( 1 9 5 9 ) . b . S . D a n i s h e f s k y , W.E. H a t c h , M. S a x , E. A b o l a , a n d J . P l e t c h e r . J . Am.  Chem. S o c , 9 5 , 2 4 1 0 ( 1 9 7 3 ) . 1 0 3 . H.O. H o u s e . M o d e r n S y n t h e t i c R e a c t i o n s , W.A. B e n j a m i n , I n c . , N.Y., 1972 p. 4 9 6 , 4 9 7 , 5 2 0 , 5 2 1 . 1 0 4 . R.M. C o a t e s , a n d S . J . H o b b s . J . O r g . Chem., 49_, 140 ( 1 9 8 4 ) . 1 0 5 a . S . B . K u l k a r n i , a n d S . D e v . T e t r a h e d r o n , 2 4 , 553 ( 1 9 6 8 ) . b . S . D e v , a n d R. C h a r a n j i t . J . I n d . Chem. S o c , 3 4 , 266 ( 1 9 5 7 ) . 1 0 6 a . A . L o r e n z i - R i a t s c h , Y. N a k a s h i t a , a n d H. H e s s e . H e l v . C h i m . A c t a , 6 7 , 249 ( 1 9 8 4 ) . b . E. P i e r s , J . B a n i l l e , C.K. L a u , a n d I . N a g a k u r a . C a n . J . Chem., 6 0 , 2 9 6 5 ( 1 9 8 2 ) . - 1 8 3 -c . K. S a s a k i , T. K u s h i d a , M. I y a d a , a n d M. O d a . T e t r a h e d r o n L e t t . , 2 1 1 7 ( 1 9 8 2 ) . d . C . R e e s e , a n d H.P. S a n d e r s . S y n t h e s i s , 2 7 6 ( 1 9 8 1 ) . e . F . C o o k e , R. M o e r c k , J . S c h w i d e r m a n , a n d P . M a g n u s . J . O r g . Chem., 4 5 , 1046 ( 1 9 8 0 ) a n d s e v e r a l o t h e r g r o u p s . 1 0 7 . E x a m p l e s o f N a z a r o v c y c l i z a t i o n s : a . M. K a r p f , a n d A . S . D r i e d i n g . H e l v . C h i m . A c t a , 5 9 , 1226 ( 1 9 7 6 ) . b . T . H i y a m a , M. S h i n o d a , a n d H. N o z a k i . J . Am. Chem. S o c . , 1 0 1 , 1599 ( 1 9 7 9 ) . c . C . S a n t e l l i - R o u v i e r , a n d M. S a n t e l l i . S y n t h e s i s , 4 2 9 ( 1 9 8 3 ) . 1 0 8 . E x a m p l e s o f d i f f i c u l t c y c l i z a t i o n s : a . B.B. S n i d e r , a n d P.C. C a r t a y a - M a r i n . J . O r g . Chem., 4 9 , 153 ( 1 9 8 4 ) . b . r e f . 9 0 c . r e f 4 7 b 1 0 9 . H. J u n g e . S p e c t r o c h i m . A c t a , 2 4 A , 1 9 6 5 ( 1 9 6 8 ) a n d r e f e r e n c e s t h e r e i n . 1 1 0 . P . E . E a t o n , G.R. C a r l s o n , a n d J . T . L e e . J . O r g . Chem., 3 8 , 4071 ( 1 9 7 3 ) . 1 1 1 . E.M. B o t t o r f f , a n d L . L . M o o r e . O r g . S y n t h . , C o l l . V o l . 5 , p . 687 ( 1 9 7 3 ) . 1 1 2 . D . J . P a s t o a n d C R . J o h n s o n . O r g a n i c S t r u c t u r e D e t e r m i n a t i o n , E n g l e w o o d C l i f f s , N . J . P r e n t i c e - H a l l , 1 9 6 9 . 1 1 3 . S . D a n i s h e f s k y , G. K o p p e l , a n d R. L e v i n e . T e t r a h e d r o n L e t t . , 2 2 5 7 ( 1 9 6 8 ) . 1 1 4 . S. B o a t m a n , T.M. H a r r i s , a n d C R . H a u s e r . J . Am. Chem. S o c . , 8 7 , 82 ( 1 9 6 5 ) . 1 1 5 . G.W. K a b a l k a , J . D . B a k e r , a n d G.W. N e a l . J . O r g . Chem., 4 2 , 512 ( 1 9 7 7 ) . 1 1 6 . J . H e l l o u , J . F . K i n g s t o n , a n d A.G. F a l l i s . S y n t h e s i s , ( 1 9 8 4 ) i n p r e s s . 1 1 7 . C R . H a u s e r , a n d B . P . L i n n . J . Am. Chem. S o c . , 79_, 731 ( 1 9 5 7 ) . 1 1 8 . H.O. H o u s e , R.A. A u e r b a c h , M. G a l l , a n d N.P. P e e t . J . O r g . Chem., 3 8 , 514 ( 1 9 7 3 ) . 1 1 9 . A . P . K r a p c h o , J . D i a m a n t i , C . C a y e n , a n d R. B i n g h a m . O r g . S y n t h . C o l l . , V o l . 5 , 1 9 8 ( 1 9 7 3 ) . 1 2 0 . F.W. S w a m e r , a n d C R . H a u s e r . J . Am. Chem. S o c , 7 2 , 1352 ( 1 9 5 0 ) . - 184 -1 2 1 . G. Z v i l i c h o v s k y , a n d U. F o t a d a r . O r g . P r e p . P r o c . I n t . , 6 , 5 ( 1 9 7 4 ) . 1 2 2 . P . D e s l o n g c h a m p s , a n d L . R u e s t . O r g . S y n t h . , 5 4 , 151 ( 1 9 7 4 ) . P r e p a r a t i o n o f m e t h y l e s t e r s w i t h d i m e t h y l c a r b o n a t e ( N a H / K H / T H F ) . 1 2 3 . H.R. S y n d e r , L . A . B r o o k s , a n d S.H. S h a p i r o . O r g . S y n t h . C o l l . V o l . , 2 , 531 ( 1 9 4 3 ) . 1 2 4 . I . S h a h a k . T e t r a h e d r o n L e t t . , 1 9 6 6 , 2 2 0 1 . 1 2 5 . S.W. P e l l e t i e r , R . L . C h a p p e l l , P.C. P a r t h a s a r a t h y , a n d N. L e w i n . J . O r g . Chem., 31, 1747 ( 1 9 6 6 ) . 1 2 6 . K. W i e d h a u p , A . J . N o l l e t , J . G . K o r s l o o t , a n d H.O. H u l s m a n . T e t r a h e d r o n , 2 4 , 771 ( 1 9 6 8 ) . 1 2 7 . H.H. D a r o n , a n d J . L . A u l l . B i o c h e m . , 21_, 737 ( 1 9 8 2 ) . 1 2 8 . H. S h o u n , a n d T. B e p p u . J . B i o l . Chem., 2 5 7 , 3 4 2 2 ( 1 9 8 2 ) . 1 2 9 . S . O s t e r m a n - G o l k a r , L . E h r e n b e r g , a n d F . S o l y m o s y . A c t a Chem. S c a n d . [ B ] 2 8 , 2 1 5 ( 1 9 7 4 ) . 1 3 0 . S i g m a C h e m i c a l C o . , S t . L o u i s , MO, USA: n o t e t h a t DMPC i s l e s s s t a b l e a n d m o r e h a z a r d o u s t h a n DEPC. 1 3 1 . L . N . M a n d e r a n d S . P . S e t h i . T e t r a h e d r o n L e t t . , 2 4 , 5 4 2 5 ( 1 9 8 3 ) . 1 3 2 . A . L . G e m a l , a n d J . C . L u c h e . J . Am. Chem. S o c . , 1 0 3 , 3 4 3 4 (19 8 1 ) . 1 3 3 . G.G. H a z e n , a n d D.W. R o s e n b u r g . J . O r g . Chem., 2 9 , 1930 ( 1 9 6 4 ) . 1 3 4 . J . F . K i n g s t o n , Ph.D. T h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 7 4 . 1 3 5 . E.M. B u r g e s s , H.R. P e n t o n , J r . , E.A. T a y l o r , a n d W.M. W i l l i a m s . O r g .  S y n t h . , 5 6 , 4 0 ( 1 9 7 7 ) . 1 3 6 . A . J . H u b e r t , a n d H. R e i m l i n g e r . S y n t h e s i s , 4 0 5 ( 1 9 7 0 ) a n d r e f e r e n c e s t h e r e i n . 1 3 7 . T. S u g a h a r a , Y. K o m a t s u , a n d S . T a k a n o . J . Chem. S o c . , Chem. Comm. 214 ( 1 9 8 4 ) . 1 3 8 . J . R . W i l l i a m s , a n d G.M. S a r k i s i a n . S y n t h e s i s , 32 ( 1 9 7 4 ) . 1 3 9 . W.S. W a d s w o r t h , a n d W.D. Emmunds. O r g . S y n t h . C o l l . V o l . , 5 , p . 547 ( 1 9 7 3 ) . 1 4 0 . B e t t e r y i e l d s w e r e o b t a i n e d u s i n g t h i s p r o c e d u r e : ( a ) W.G. G e n s l e r , F . J o h n s o n , a n d D.B. S l o a n . J . Am. Chem. S o c . , 8 2 , 6 0 7 5 ( 1 9 6 0 ) . ( b ) P. G r a b b e , G.A. G a r c i a , a n d C. R i u s . J . Chem. S o c . , P e r k i n I , 8 1 0 ( 1 9 7 3 ) . - 185 -1 4 1 . N.Y. L e v i n a , a n d N.N. G o d o v i k o v . Z h . O b s h c h . K h i m . , 2 5 , 986 ( 1 9 5 5 ) . Chem. A b s . , 5 0 , 3 4 5 8 c ( 1 9 5 6 ) . 1 4 2 . F o r e x a m p l e s e e a ) N.L. A l l i n g e r , M. N a k a z a k i a n d V . Z a l k o w . J . Am.  Chem. S o c , 81_, 4 0 7 4 ( 1 9 5 9 ) . - ( b ) J . M e i n w a l d , J . J . T u f a r i e l l o , a n d J . J . H u r s t . J . O r g . Chem., 2 9 , 2 9 1 4 ( 1 9 6 4 ) . ' 1 4 3 . R.A. S h e l d o n a n d J . K . K o c h i . O r g . R e a c t i o n s , 1 9 , 279 ( 1 9 7 2 ) . 1 4 4 a . W.J. K i s s e l . P h.D. T h e s i s , S t a t e U n i v e r s i t y o f New Y o r k i n B u f f a l o , 1 9 6 8 . b . R.M. M o r i a r t y , H.G. W a l s h a n d H. G o p a l . T e t r a h e d r o n L e t t . , 4 3 6 3 ( 1 9 6 6 ) . c . J . M e i n w a l d , J . J . T u f a r i e l l o a n d J . J . H u r s t . J . O r g . Chem., 2 9 , 2 9 1 4 ( 1 9 6 4 ) . 1 4 5 a . P . M u l l e r a n d B. S i e g f r i e d . T e t r a h e d r o n L e t t . , 3 5 6 5 ( 1 9 7 3 ) . b . P . M u l l e r a n d B. S i e g f r i e d . H e l v . C h i m . A c t a , 5 7 , 9 8 7 ( 1 9 7 4 ) . 1 4 6 . P. K r a p c h o . S y n t h e s i s , 8 0 5 a n d 8 9 3 ( 1 9 8 2 ) a n d r e f e r e n c e s t h e r e i n . 1 4 7 . M. N o d i , K. N i s h i d e , M. S a i , K. F u j i a n d E. F u j i t a . J . O r g . Chem., 4 6 , 1991 ( 1 9 8 1 ) . 1 4 8 . H.H. W a s s e r m a n a n d B.H. L i p s h u t z . T e t r a h e d r o n L e t t . , 4611 ( 1 9 7 5 ) . 1 4 9 a . B.M. T r o s t a n d Y. T a m a r u . J . Am. Chem. S o c , 92, 3 5 2 8 ( 1 9 7 5 ) . b . B.M. T r o s t a n d Y. T a m a r u . J . Am. Chem. S o c . , 9 9 , 3101 ( 1 9 7 7 ) . 1 5 0 . L . A . C a r p i n o , B.A. C a r p i n o , C A . G i z a , R.W. M u r r a y , A . A . S a n t e l l i a n d P.H'. T e r r y . O r g . S y n t h . C o l l . V o l . , 5 , p. 1 6 8 ( 1 9 7 3 ) . 

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