UBC Theses and Dissertations

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UBC Theses and Dissertations

The synthesis of an ionomycin fragment Nicoll-Griffith, Deborah Anne 1986

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THE SYNTHESIS OF AN IONOMYCIN FRAGMENT by DEBORAH ANNE NICOLL-GRIFFITH B.Sc. ( H o n s . ) , B i s h o p ' s U n i v e r s i t y , 1981 THESIS SUBMITTED IN PARTIAL FULFILLMENT THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES (Department of 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 as c o n f o r m i n g t o the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA May 1986 ® Deborah Anne N i c o l l - G r i f f i t h , 1986 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 requirements for an advanced degree at the University 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 UhljrNaAyS^lj  The University of B r i t i s h Columbia 1 9 5 6 Main Mall Vancouver, Canada V 6 T 1 Y 3 DE-6 n/R'-n i i ABSTRACT T h i s t h e s i s c o n c e r n s s t u d i e s d i r e c t e d towards the s y n t h e s i s of the p o l y e t h e r a n t i b i o t i c i o n o m y c i n (1_). S p e c i f i c a l l y , the aims were to p r e p a r e o p t i c a l l y a c t i v e fragments A and B, c o r r e s p o n d i n g to C - l to C-9 and to C-10 to C-15 o f i o n o m y c i n , and to c o u p l e these i n t e r m e d i a t e s . A model s t u d y was c o n d u c t e d to develop c h e m i s t r y c e n t r a l to the s y n t h e s i s of fragment A from m e t h y l a - D - g l u c o p y r a n o s i d e ( 7 3 ) . A Wadsworth-Emmons c y c l i z a t i o n of the phosphonate aldehyde 69_ f u r n i s h e d a , 8 - u n s a t u r a t e d l a c t o n e 70, the second r e p o r t e d u r o n o - 8 , 4 - l a c t o n e . A s t e r e o s e l e c t i v e c o n j u g a t e a d d i t i o n w i t h the h i g h e r o r d e r mixed organo-c u p r a t e , M e 2 C u ( C N ) L i 2 , y i e l d e d as the major p r o d u c t , l a c t o n e 82_ w i t h an a x i a l methyl group a t C-6. The minor p r o d u c t of the c u p r a t e r e a c t i o n , l a c t o n e 83^with an e q u a t o r i a l methyl group at C-6, was a l s o p r e p a r e d v i a a s e p a r a t e r o u t e . The s y n t h e s i s of the fragment A p r e c u r s o r f o r ionomycin i n v o l v e d the i n t r o d u c t i o n of t h r e e pendent methyl groups a t p o s i t i o n s C-2, C-4, and C-6 on the D - g l u c o s e frame work. N o t a b l y , the C-6 m e t h y l group was i n t r o -duced by a h i g h l y s t e r e o s e l e c t i v e c o n j u g a t e a d d i t i o n analogous to the model s t u d y . Thus, the c u p r a t e , M e 2 C u ( C N ) L i 2 , added to a , ^ - u n s a t u r a t e d l a c t o n e 110 to y i e l d l a c t o n e 112 as the s o l e r e a c t i o n p r o d u c t . The l a c t o n e r i n g was then opened to a l l o w the s t e r e o s e l e c t i v e i n t r o d u c t i o n of the methyl group at C-4 a f t e r which the p y r a n o s i d e r i n g was opened. Subsequent s y n t h e t i c m a n i p u l a t i o n s y i e l d e d the o p t i c a l l y a c t i v e fragment A p r e c u r s o r 138. i i i Fragment B was prepared from meso-2,4-dimethylglutaric anhydride (_5). An intermediate, acid ester 6, was resolved and was then modified to y i e l d the o p t i c a l l y a c t i v e mixture of epimeric epoxides 15. The fragment A precursor 138 and the fragment B mixture 15 were coupled to y i e l d the epimeric mixture of 8-hydroxy ketones 140 which contains C-2 to C-15 of ionomycin. 140 V TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF TABLES v i i i L IST OF FIGURES i x LIST OF SCHEMES * LIST OF ABBREVIATIONS AND ACRONYMS x i i i ACKNOWLEDGEMENTS x v i INTRODUCTION . . . 1 I . S y n t h e t i c P l a n s f o r Ionomycin 5 I I . Model S t u d i e s f o r Fragments A and B 7 I I I . S y n t h e t i c Approaches to M o l e c u l e s S i m i l a r to Fragment A of Ionomycin 14 IV. C a r b o h y d r a t e s as S t a r t i n g M a t e r i a l s i n the S y n t h e s i s of N a t u r a l P r o d u c t s 20 V. P l a n s f o r the S y n t h e s i s of Fragment A of Ionomycin from D-Glucose 25 VI . S t e r e o c o n t r o l a t C-6 i n H i g h e r - C a r b o n D-Glucose D e r i v a t i v e s — 27 RESULTS AND DISCUSSION 33 I . Model S t u d i e s f o r Fragment A of Ionomycin 33 A. P r e p a r a t i o n of a , B - U n s a t u r a t e d L a c t o n e 70_ 36 B. C o n j u g a t e A d d i t i o n t o a,B-Unsaturated L a c t o n e 70_ . . 41 C. S t e r e o c h e m i c a l P r o o f and C o n f o r m a t i o n a l Arguments f o r the F o r m a t i o n of the A x i a l M e t h y l L a c t o n e j?2_ 42 D. P r e p a r a t i o n of the E q u a t o r i a l M e t h y l L a c t o n e 83_ . . 49 E. P r e p a r a t i o n and I d e n t i f i c a t i o n of I s o m e r i c B y - P r o d u c t s 53 v i Page II. Synthesis of the Fragment A Precursor for Ionomycin . . 5 8 A. Introduction of the Axial Methyl Group at C - 2 . . . 5 8 B. Deoxygenation at C - 3 6 1 C. Preparation of a,8-Unsaturated Lactone 1 1 0 6 5 D. Introduction of the Axial Methyl Group at C - 6 . . . 6 9 E. Introduction of the Axial Methyl Group at C - 4 . . . 7 1 F. Opening the Pyranoside Ring 7 8 G. Deoxygenation at C - 5 7 8 H. Strategy for Homologation of the Fragment A Precursor 8 3 I. Protection of the C - 5 and C - 8 Hydroxyl Groups of the Fragment A Precursor 8 5 I I I . Synthesis of Fragment B for Ionomycin . . . . 8 8 IV. Coupling of the Fragment A Precursor and Fragment B . . 9 1 A. Attempted Coupling of Dithiane 1 3 3 with Epoxide L 5 _ 9 1 B. Preparation of the Second Fragment A Precursor . . . 9 3 C. Successful Coupling of Dithiane 1 3 8 and Epoxide 15_ 9 5 D. Conclusion 9 8 EXPERIMENTAL 9 9 I. General 9 9 I I . Model Studies 1 0 4 III. Preparation of the Fragment A Precursor 1 2 . 9 IV. Preparation of Fragment B 1 6 8 V. Coupling of the Fragment A Precursor with Fragment B . . 1 7 5 v i i Page REFERENCES 180 SPECTRAL APPENDIX 187 v i i i LIST OF TABLES T a b l e T i t l e Page I D i f f e r e n c e n.O.e. experi m e n t s on methyl l a c t o n e 82 . 44 I I D r y i n g and p u r i f i c a t i o n of s o l v e n t s and r e a g e n t s 100 i x LIST OF FIGURES Figure T i t l e Page 1 Ionomycin (JO, monensin (2_), l a s a l o c i d A (3) and a n t i b i o t i c A23187 (4_), some t y p i c a l polyether a n t i b i o t i c s 2 2 The X-ray structure of the calcium s a l t of ionomycin 3 3 Difference n.O.e. experiments on methyl lactone 82 43 4 The coupling constants which allowed the stereochemical assignment of C-6 i n methyl lactone 112 70 5 Catalyst approach to the two faces of o l e f i n 117 74 X LIST OF SCHEMES Scheme T i t l e Page 1 R e t r o s y n t h e t i c a n a l y s i s of Evans' r o u t e to i o n o m y c i n 6 2 R e t r o s y n t h e t i c a n a l y s i s o f Wuts 1 r o u t e to i o n o m y c i n 6 3 Our bond d i s c o n n e c t i o n s f o r i o n o m y c i n 7 4 P l a n f o r . c o u p l i n g f ragments A and B of i o n o m y c i n . . 8 5 P r e p a r a t i o n o f a c i d c h l o r i d e 7, a common i n t e r m e d i a t e f o r the r a c e m i c model fragments A and B 9 6 S h e l l y ' s s y n t h e s i s of the r a c e m i c fragment A model 1 1 7 S h e l l y ' s s y n t h e s i s of r a c e m i c fragment B 1 2 8 S h e l l y ' s c o u p l i n g o f model fragments A and B . 1 3 9 The method of Evans e t a l . f o r the p r e p a r a t i o n of a fragment A type m o l e c u l e 1 6 1 0 The method of S c h r e i b e r and Wang f o r the p r e p a r a t i o n of a fragment A p r e c u r s o r 1 7 1 1 The method of Evans and S h i h f o r the i n t r o d u c t i o n o f two m e t h y l groups f o r a fragment A type m o l e c u l e 1 9 1 2 I n t r o d u c t i o n o f the r e m a i n i n g m e t h y l group i n the. s y n t h e s i s of a fragment A t y p e m o l e c u l e by Evans and S h i h 2 0 1 3 The s y n t h e s i s of ( - ) - s e r r i c o r n i n by M o r i et_ a\_ 2 2 1 4 The s y n t h e s i s of ( - ) - a - m u l t i s t r i a t i n by Sum and W e i l e r . . . . 2 3 1 5 Our s y n t h e t i c p l a n f o r a fragment A p r e c u r s o r . . . . . . . . 2 6 1 6 The s y n t h e s i s of P r e l o g - D j e r a s s i l a c t o n e ( 5 4 ) by Isobe et_ a l _ . 2 8 1 7 The s t e r e o s e l e c t i v e i n t r o d u c t i o n of a m e t h y l group at C - 6 by Nakahara et al_ 3 0 1 8 The s t e r e o s e l e c t i v e i n t r o d u c t i o n of a m e t h y l group at C - 6 by F r a s e r - R e i d et a l . 3 1 x i Scheme T i t l e Page 19 The s y n t h e s i s of an a , 8 - u n s a t u r a t e d 5 - l a c t o n e by Weihe and M c M o r r i s 34 20 The proposed p r e p a r a t i o n of a , B - u n s a t u r a t e d l a c t o n e s 70_ and 72 v i a Wadsworth-Emmons c y c l i z a t i o n s 35 21 S y n t h e s i s of d i o l J6_ from m e t h y l a - D - g l u c o p y r a n o s i d e (73) . . 36 22 S y n t h e s i s of a l c o h o l s 80_ and 81_ from d i o l 76_ 38 23 P r e p a r a t i o n o f a , 8 - u n s a t u r a t e d l a c t o n e 70_ from a l c o h o l 81 . . 40 24 H i g h e r o r d e r mixed o r g a n o c u p r a t e r e a c t i o n w i t h a , ^ - u n s a t u r a t e d l a c t o n e 70 y i e l d i n g m e t h y l l a c t o n e s _82_ and _83_ 42 25 C o n f o r m a t i o n a l a n a l y s i s of m e t h y l group a d d i t i o n to a,8-u n s a t u r a t e d l a c t o n e 70 46 26 S y n t h e s i s of e q u a t o r i a l m e t h y l l a c t o n e _83_ from ald e h y d e _6_9_ . . 50 27 H y d r i d e a d d i t i o n to the 1 , 2 - d i p l a n a r c o n f o r m a t i o n o f a,8-u n s a t u r a t e d l a c t o n e 72_ to y i e l d _83_ a f t e r p r o t o n a t i o n 52 28 T r a n s - a c y l a t i o n d u r i n g the M o f f a t t o x i d a t i o n of a l c o h o l 81 y i e l d i n g k e t o n e 87 . . . 54 29 P r e p a r a t i o n of l a c t o n e s 88, 89, and 90_ w h i c h were seen as c o n t a m i n a n t s d u r i n g the model s t u d y 55 30 P r e f e r r e d s t e r e o c h e m i s t r y o f n u c l e o p h i l i c a t t a c k on a,8-u n s a t u r a t e d l a c t o n e _88^  57 31 S y n t h e s i s of compound 95 f o l l o w i n g the r o u t e of Sum and W e i l e r 59 32 H i g h e r o r d e r mixed o r g a n o c u p r a t e r e a c t o n w i t h e p o x i d e 43_ . . . 60 33 A p o s s i b l e mechanism f o r the f o r m a t i o n of k e t o n e s 97 from e p o x i d e 44 d u r i n g a c u p r a t e r e a c t i o n 62 34 D e o x y g e n a t i o n of e n o l e t h e r 96 to y i e l d compound 102 63 35 D e o x y g e n a t i o n of a l c o h o l 44 f o l l o w i n g the p r o c e d u r e of Robins e t a l 64 36 S y n t h e s i s of phosphonate 106 from a l c o h o l _9_5 66 37 S y n t h e s i s o f a , 8 - u n s a t u r a t e d l a c t o n e 110 from phosphonate 106 67 x i i Scheme T i t l e Page 3 8 H i g h e r o r d e r mixed o r g a n o c u p r a t e r e a c t i o n on a, 8 -u n s a t u r a t e d l a c t o n e 1 1 0 to y i e l d m ethyl l a c t o n e 1 1 2 6 9 3 9 P r e p a r a t i o n of p i v a l o a t e e s t e r s 114 and 115 from m e t h y l l a c t o n e r i 2 7 2 4 0 P r e p a r a t i o n of o l e f i n 117 from a l c o h o l 1 1 4 7 3 4 1 P r e p a r a t i o n of a l c o h o l 1 1 8 by h y d r o b o r a t i o n of o l e f i n 1 1 7 . . 7 5 4 2 V a r i o u s s p e c i e s a r i s i n g from W i l k i n s o n ' s c a t a l y s t i n benzene under hydrogen 7 6 4 3 H y d r o g e n a t i o n of o l e f i n 1 1 7 u s i n g W i l k i n s o n ' s c a t a l y s t . . . . 7 7 4 4 Opening the p y r a n o s i d e r i n g to y i e l d hydroxy d i t h i a n e 1 2 0 . . 7 8 4 5 Deoxygenation a t C - 5 of hydroxy d i t h i a n e 1 2 0 7 9 4 6 A p o s s i b l e mechanism f o r the f o r m a t i o n of d i t h i o a c e t a l 1 2 4 from m e s y l a t e 121 8 1 4 7 P r o t e c t i o n of the C-5 and C - 8 h y d r o x y l groups to y i e l d the fragment A p r e c u r s o r 1 3 3 8 6 4 8 P r e p a r a t i o n of the r a c e m i c a c i d e s t e r 6_ 8 8 4 9 P r e p a r a t i o n of fragment B from the r e s o l v e d a c i d e s t e r 6_ . . . 90 50 Attempted c o u p l i n g of the fragment A p r e c u r s o r 1 3 3 w i t h the epoxide m i x t u r e 1_5 9 2 5 1 Mechanism f o r the f o r m a t i o n of s i l y l e t h e r 1 3 7 from s i l y l a c e t a l 1 3 3 9 4 5 2 P r e p a r a t i o n of the second fragment A p r e c u r s o r 1 3 8 9 5 5 3 D e u t e r a t i o n of d i t h i a n e 1 3 8 and the subsequent c o u p l i n g w i t h fragment B to y i e l d the hydroxy d i t h i a n e m i x t u r e 1 4 0 9 7 x i i i L IST OF ABBREVIATIONS AND ACRONYMS Ac a c e t y l AIBN 2 , 2 ' - a z o b i s i s o b u t y r o n i t r i l e b broad Bn b e n z y l bp b o i l i n g p o i n t Bu b u t y l c_ c o n c e n t r a t i o n i n grams of s o l u t e per 100 mL of s o l u t i o n d d o u b l e t DCC 1 , 3 - d i c y c l o h e x y l c a r b o d i i m i d e DIBAL d i i s o b u t y l a l u t n i n u m h y d r i d e Diphos-4 1 , 4 - b i s ( d i p h e n y l p h o s p h i n o ) b u t a n e DMAP 4 - d i m e t h y l a m i n o p y r i d i n e DME dimethoxyethane DMF N,N_-dimethylf ormamide DMSO d i m e t h y l s u l f o x i d e 2,4-DNP-hydrazine 2 , 4 - d i n i t r o p h e n y l h y d r a z i n e EDTA e t h y l e n e d i a m i n e t e t r a a c e t i c a c i d EE 1 - e t h o x y e t h y l E t e t h y l e t h e r d i e t h y l e t h e r eV e l e c t r o n v o l t s g l c gas l i q u i d chromatography x i v h h o u r ( s ) HMPA hex a m e t h y l p h o s p h o r a m i d e Hz h e r t z 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 d e m medium ( f o r q u o t i n g i r d a t a ) or m u l t i p l e t ( f o r q u o t i n g *H nmr d a t a ) in- meta MCPBA m - c h l o r o p e r b e n z o i c a c i d Me m e t h y l MEM 2 - m e t h o x y e t h o x y m e t h y l m e s y l a t e m e t h a n e s u l f o n a t e min m i n u t e ( s ) mp m e l t i n g p o i n t ms mass s p e c t r o m e t r y Ms m e t h a n e s u l f o n y l NBS N - b r o m o s u c c i n i m i d e NBTBPS n - b u t y 1 - t e r t - b u t y l p h e n y l s i l y 1 ri-Bu n-buty 1 nmr n u c l e a r magnetic r e s o n a n c e n.O.e. n u c l e a r Overhauser enhancement p_- p a r a PCC p y r i d i n i u m c h l o r o c h r o m a t e Ph p h e n y l XV py pyridine q quartet r t room temperature s strong (for quoting i r data) or s i n g l e t (for quoting *H nmr data) sh shoulder t t r i p l e t TBDMS t e r t - b u t y l d i m e t h y l s i l y l TBMPS tert-butylmethoxyphenylsilyl Tf trifluoromethanesulfonyl THF tetrahydrofuran t i c t h i n layer chromatography TMEDA N,N,N',N'-tetramethylethylenediamine TMS t r i m e t h y l s i l y l or tetramethylsilane (for nmr standard) tosylate p-toluenesulfonate t r i f l a t e trifluoromethanesulfonate Tr triphenylmethyl t r i t y l triphenylmethyl Ts toluenesulfonyl UV u l t r a v i o l e t w weak x v i ACKNOWLEDGEMENTS I am i n d e b t e d to P r o f e s s o r L a r r y W e i l e r f o r h i s g u i d a n c e , u n d e r s t a n d i n g , and e n t h u s i a s t i c encouragement d u r i n g the c o u r s e of t h i s work. I would a l s o l i k e to acknowledge f i n a n c i a l s u p p ort from N.S.E.R.C. and the Department of C h e m i s t r y . The e f f i c i e n t c o o p e r a t i o n of the t e c h n i c a l s t a f f of the nmr, mass s p e c t r o m e t r y and m i c r o a n a l y t i c a l s e r v i c e s i s g r e a t l y a p p r e c i a t e d , as i s the c a r e f u l bench work of A n n e t t e S c h w e r d t f e g e r d u r i n g the p r e p a r a t i o n of fragment B. I would l i k e to thank P r o f e s s o r s G.S. B a t e s , G.G.S. Du t t o n , and J . T r o t t e r f o r t h e i r g u i d ance and f o r p r o v i d i n g v a l u a b l e i n p u t d u r i n g the p r e p a r a t i o n of t h i s m a n u s c r i p t . F i n a l l y , I wish to thank J i m Ounsworth whose s u p p o r t i v e f r i e n d s h i p and h e l p f u l s u g g e s t i o n s made t h i s t h e s i s p o s s i b l e . x v i i This thesis i s dedicated to my parents. 1 INTRODUCTION Ionomycin (1), our ultimate synthetic target, i s a polyether a n t i b i o t i c (1). Some other representative examples from this large class of natural products are monensin (2_), l a s a l o c i d A (3) and a n t i b i o t i c A23187 (4) which are shown along with ionomycin (1), i n Figure 1. The name polyether i s derived from the fact that these a n t i b i o t i c s usually contain c y c l i c ethers, including tetrahydrofurans and tetrahydropyrans. O r i g i n a l l y , these compounds were named acid ionophores (2) because they are carboxylic acids which possess the a b i l i t y to chelate inorganic cations (iono) and transport them across hydrophobic b a r r i e r s as l i p i d soluble complexes (from Greek phore bearer). Ionomycin was Isolated In pure form by extraction from fermenta-t i o n broths of the fungus Streptomyces conglobatus (3). T o e p l i t z , Cohen, Funke, Parker, and Gougoutas determined the structure by X-ray c r y s t a l l o -graphy, *H and * 3C nmr spectroscopy, and high resolution mass spectrometry (4). Their X-ray structure of the c r y s t a l l i n e calcium s a l t of ionomycin, shown in Figure 2, i l l u s t r a t e s how ionomycin complexes with divalent cations In a neutral 1:1 complex. Ionomycin octahedrally co-ordinates to the cation v i a the carboxylate, the 8-keto enolate, the hydroxyl groups 0-6 and 0-9, and the c y c l i c ether 0-7. The polar oxygen f u n c t i o n a l i t i e s are a l l directed towards the i n t e r i o r and the non-polar hydrocarbon portions are directed to the ext e r i o r forming a three dimensional structure i n which the cation i s protected i n a l i p o p h i l i c s h i e l d . 2 Figure 1. Ionomycin (1_), monensin (2), l a s a l o c i d A (3), and a n t i b i o t i c A23187 (4_), some t y p i c a l polyether a n t i b i o t i c s . 3 Figure 2. The X-ray structure of the calcium s a l t of ionomycin (4). 4 Ionomycin i s an important t o o l i n biochemistry, c e l l biology and related d i s c i p l i n e s because i t has an a f f i n i t y for binding p r e f e r e n t i a l l y with calcium ( C a 2 + > Mg 2 + » S r 2 + « B a 2 + ) (5). Calcium i s an important i n t r a c e l l u l a r messenger and therefore ionomycin has been used In b i o l o g i -c a l investigations for studying cation transport across b i o l o g i c a l membranes, for perturbing calcium gradients across c e l l s , for e f f e c t i n g r e d i s t r i b u t i o n of sequestered calcium, and for measuring cytoplasmic free calcium ( l a ) . Ionomycin i s active against Gram p o s i t i v e bacteria but i t i s a very toxic a n t i b i o t i c and therefore i t i s not used i n human therapy. For the organic chemist, t h i s natural product presents a formidable synthetic challenge. The molecule comprises a 32 carbon l i n e a r backbone containing a trans double bond and two tetrahydrofuran r i n g s . Projecting from the skeleton are numerous pendent methyl groups and an array of oxygen f u n c t i o n a l i t i e s . There are 14 asymmetric centres meaning that, i n p r i n c i p l e , a synthesis with no stereochemical control would re s u l t i n a mixture of 16,384 stereoisomers! In general, the polyether a n t i b i o t i c s have enticed natural product chemists to test t h e i r synthetic s k i l l . These molecules are excellent targets to test p r i n c i p l e s and reactions for c o n t r o l l i n g stereo-, regio-, and chemoselectivity because of t h e i r m u l t i p l i c i t y of asymmetric centres and functional groups (6). 5 An a d d i t i o n a l synthetic challenge i s to control the absolute configuration. O p t i c a l l y active polyether a n t i b i o t i c s have been prepared by chemical and biochemical resolutions of racemic mixtures and by asym-metric syntheses using the natural pool of amino acids, carbohydrates, hydroxy acids and terpenes for c h i r a l s t a r t i n g materials or for c h i r a l a u x i l i a r i e s ( l a ) . Monensin, l a s a l o c i d A, and a n t i b i o t i c A23187 have a l l been synthesized using such techniques (7). Although a number of research groups are known to be working on the synthesis of ionomycin, to our knowledge, a f u l l synthesis of Ionomycin has not been published. I. Synthetic Plans f o r Ionomycin For a molecule with the complexity of ionomycin, a convergent synthesis i s more e f f i c i e n t than a l i n e a r one (8). Three other research groups are working on the synthesis of ionomycin and they are a l l using a convergent approach. Schreiber and Wang (9) have published a synthesis for one section of ionomycin, C - l to C-9 (vide i n f r a ) . Evans (10) and Wuts (11) have each published synthetic plans for ionomycin and both routes involve four major sections as shown i n Schemes 1 and 2, re s p e c t i v e l y . We also envisaged a four part convergent synthesis. The four synthetic precursors a r i s i n g from the bond disconnections shown i n Scheme 3 w i l l be referred to as fragments A (C - l to C-9), B (C-10 to C-15), C (C-16 to C-22) and D (C-23 to C-32). 6 Scheme 1. Retrosynthetic analysis of Evans' route to Ionomycin (10). Scheme 2. Retrosynthetic analysis of Wuts' route to ionomycin (11). A B C D (C-1 to C-9) (C-10 to C-15) (C-16 to C-22) (C-23 to C-32) Scheme 3. Our bond disconnections for ionomycin. This thesis describes the syntheses of a fragment A precursor and fragment B (both o p t i c a l l y a c t ive) and the successful coupling of these two fragments. This work i s based, i n part, on model studies which were conducted i n our laboratory by Shelly (12) . These studies concerned the syntheses of racemic models for fragments A and B and the coupling of these two model fragments. II. Model Studies for Fragments A and B In our retrosynthetic analysis of ionomycin, the bond from C-9 to C-10 was disconnected. The plan involved a l k y l a t i o n of a metallated dithiane with an epoxide to generate this bond as shown i n Scheme 4. n S S + 0 H model fragment A model fragment B n s s OH dithioketal hydrolysis 0 OH 9U 1 oxidation 0 0 Scheme 4 . P l a n f o r c o u p l i n g fragments A and B of i o n o m y c i n . 9 Deprotection of the masked ketone at C-9 and oxidation of the alcohol at C - l l would afford the p-diketone moiety found i n Ionomycin. For t h i s model study, fragments A and B were obtained from a common intermediate which was prepared i n two steps from meso-1,3-dimethylglutaric anhydride (5) as shown i n Scheme 5 (12). Methanolysis of anhydride 5_ yielded the racemic half acid ester 6_, which was then treated with o x a l y l chloride to give acid chloride 7. C V C y M e O H , 0 0 •kA 9 1 X H O ^ Y l OMe 6 (COCI)2 92% 0 0 CI"\^Y^0Me 7 Scheme 5. Preparation of acid chloride 7_t a common intermediate for the racemic model fragments A and B (12). 1 0 Further synthetic elaboration of this Intermediate yielded the racemic fragment A model by the route outlined i n Scheme 6 . A Rosenmund reduction of acid c h l o r i d e _ 7 , followed immediately by protection of the unstable aldehyde 8, afforded dithiane 9. The ester group was reduced with l i t h i u m aluminum hydride and the r e s u l t i n g alcohol 1 0 was protected as the the t e r t - b u t y l d i m e t h y l s i l y l (TBDMS) ether to y i e l d racemic dithiane 1 1 , the fragment A model. The synthesis of the fragment B model followed the route shown i n Scheme 7 . Reduction of acid chloride 7_ as before gave 8 which was immediately treated with an act i v e methylene complex, C H 2 B r 2 - Z n - T i C l ^ , to y i e l d o l e f i n 1 2 . Lithium aluminum hydride reduction of the ester afforded alcohol 1 3 , which was subsequently protected as the ter t - b u t y l d i m e t h y l -s i l y l ether. Alkene 1 4 was converted into the desired epimeric epoxide mixture 1 J 5 by treatment with m-chloroperbenzoic a c i d . The key a l k y l a t i o n step required extensive i n v e s t i g a t i o n because i t proved to be much more d i f f i c u l t than o r i g i n a l l y a n t i c i p a t e d . The best conditions for coupling dithiane 1 1 _ with the epoxide mixture 1 5 were found by t e s t i n g a v a r i e t y of bases, solvent systems and reaction times. Complete deprotonation of dithiane 1 1 was effected using n - b u t y l l i t h i u m i n a solvent system of tetrahydrofuran (THF), _N,N_,N' ,N^'-tetramethylethylene-diaraine (TMEDA) and hexamethylphosphoramide (HMPA). The dithiane anion was treated with epoxide 1 _ 5 for 4 6 h to y i e l d the desired mixture of 8-hydroxy dithianes 1 6 as shown i n Scheme 8 . Shelly was also successful i n 11 0 0 7 H 2 , P d - C 0 n s s 10 TBDMSOTf 97% 1 n s s V<Y^VT/^0TBDMS LiAIH, 87% OMe 8 n HS SH 60% for two steps n o OMe 11 Scheme 6. Shelly's synthesis of the racemic fragment A model (12). 12 0 0 7 H 2 , P d - C OMe 0 0 OMe 13 UAIH4 56% TBDMSOTf 90% ^ Y Y ^ O T B D M S 14 MCPBA 8 C H 2 B r 2 - Z n - T i C I 4 40% for two steps 12 H 86% 15 OTBDMS Scheme 7. Shelly's synthesis of racemic fragment B (12). 13 TBDMSO 11 a) n-BuLi, TMEDA, THF b) HMPA C) S ^ Y ^ O T B D M S 1 5 3 9 % TBDMSO OTBDMS TBDMSO OTBDMS 16 Scheme 8. Shelly's coupling of model fragments A and B (12). 14 the subsequent d e p r o t e c t i o n of the d i t h i o k e t a l and o x i d a t i o n of the r e s u l t i n g 8-hydroxy ketone as shown i n Scheme 4. S h e l l y ' s work c o n t r i b u t e d to our s y n t h e t i c s t r a t e g y i n two a r e a s . We planned to r e p e a t h i s s y n t h e s i s of fragment B u s i n g the r e s o l v e d a c i d 6_, i n o r d e r to o b t a i n the o p t i c a l l y a c t i v e fragment B needed f o r ionomycin. We a l s o i n t e n d e d to use the c r i t i c a l e x p e r i m e n t a l c o n d i t i o n s t h a t he found f o r c o u p l i n g model fragments A and B. I I I . S y n t h e t i c App roaches t o M o l e c u l e s S i m i l a r t o F ragment A o f I o n o m y c i n B e f o r e i n t r o d u c i n g our p l a n f o r a p r e c u r s o r of fragment A, the approaches of o t h e r r e s e a r c h groups w i l l be d e s c r i b e d . The s y n t h e t i c c h a l l e n g e of fragment A i n v o l v e s e s t a b l i s h i n g the c o r r e c t r e l a t i v e s t e r e o -c h e m i s t r y f o r the t h r e e methyl groups which are i n a 1 , 3 , 5 - r e l a t i o n s h i p . These methyl groups are numbered 39, 40 and 41 a c c o r d i n g to ionomycin numbering ( 4 ) . G e n e r a l l y , t h e r e are two ways to a c h i e v e s t e r e o c o n t r o l i n an a c y c l i c system such as fragment A. F i r s t , one can use asymmetric i n d u c t i o n to c o n t r o l 1 , 3 - s t e r e o c h e m i s t r y i n the a c y c l i c system. Second, one can t e m p o r a r i l y form r i n g s , I n t r o d u c e the asymmetry by t a k i n g advantage of the known c o n f o r m a t i o n s of these r i n g s , and then open the r i n g s to y i e l d the c o r r e s p o n d i n g a c y c l i c c h a i n s . Three s y n t h e s e s of m o l e c u l e s s i m i l a r to fragment A have been r e p o r t e d - one uses the former approach, one the l a t t e r , and one uses a c o m b i n a t i o n of these methods. Evans, M o r r i s s e y and Dow have p r e p a r e d a C-1 t o C-10 fragment of 15 ionomycin shown i n Scheme 9 (13). The f i n a l step of t h e i r synthesis involved a hydroxyl group directed hydrogenation of homoallylic alcohol 1_7 using a homogeneous c a t a l y s t . The authors r a t i o n a l i z e the 1,3-asymmetric induction by suggesting the intermediates 1_8 and 19. The 1 , 3 - a l l y l i c i n t e r a c t i o n between methyl groups 39 and 40 i s minimized when methyl-39 adopts a pseudoequatorial p o s i t i o n and raethyl-41 adopts a pseudoaxial p o s i t i o n . The homoallylic alcohol 17_ was hydrogenated using Rh(Diphos-4) + as a cat a l y s t to aff o r d , i n excellent y i e l d , the saturated hydroxy ester 20 i n a 94:6 r a t i o of diastereomers. Schreiber and Wang have used the known conformation of s i x membered rings and the anomeric e f f e c t i n the s p i r o k e t a l i z a t i o n reaction to produce an o p t i c a l l y active precursor for a C - l to C-9 fragment of ionomycin as shown i n Scheme 10 (9). Dimethylhydrazone 21^  was al k y l a t e d with two iodides, the f i r s t of which was o p t i c a l l y a c t i v e , to give the a c y c l i c s p i r o k e t a l precursor 22_ which existed as a complex mixture of diastereomers. S p i r o k e t a l i z a t i o n of this material under e q u i l i b r a t i n g conditions produced an 8:1:0.1 mixture of diastereomers which could be separated by chromatography. The major product, s p i r o k e t a l 23, has the (benzyloxy)methyl, the hydroxymethyl, and the two methyl substituents i n equatorial p o s i t i o n s . Each keta l oxygen Is a x i a l on the other tetrahydropyran r i n g as a r e s u l t of the anomeric e f f e c t (14). Since the methyl groups can epimerize, the stereochemistry of 2_3 i s con t r o l l e d by that of the c h i r a l centre bearing the benzyl ether. The free hydroxymethyl group was then converted into a methyl substituent to y i e l d Scheme 9. The method of Evans et_ al_. for the preparation of a fragment A type molecule (13). Scheme 10. The method of Schreiber and Wang for the preparation of a fragment A precursor (9). 18 s p i r o k e t a l 2k_ i n which the three methyl groups 39, 40 and 41 a l l have the correct r e l a t i v e stereochemistry. Spiroketal 7A_ was converted into d i t h i o k e t a l Z5 and further manipulations resulted i n carboxylic acid 26, the fragment A precursor. Evans and Shih have prepared an o p t i c a l l y active C-l to C-10 fragment of ionomycin as shown i n Schemes 11 and 12 (10). Methylation of the c h i r a l enolate derived from imide 2_7 yielded a 92:8 mixture of diastereomers favoring the desired isomer 28. Reductive cleavage of the c h i r a l a u x i l i a r y and oxidation of the r e s u l t i n g alcohol, provided the o p t i c a l l y active aldehyde 29. A diastereoselective a l d o l condensation between aldehyde 2_9 and a boron enolate afforded 30, with a d i a s t e r e o s e l e c t i v i t y of 97:3. Hydrogenolysls of the benzyl ether, separation of the unwanted diastereomers, and oxidation yielded lactone 31 which contained two of the required methyl groups. Introduction of the l a s t methyl group by a l k y l a t i o n of 31^  i s i l l u s t r a t e d i n Scheme 12. As shown i n 32, a 1,3-diaxial i n t e r a c t i o n of methyl-40 with iodomethane, i n h i b i t e d a l k y l a t i o n from occurring c i s to methyl-40. Methylation therefore occurred trans to methyl-40 y i e l d i n g the desired lactone 33, with a d i a s t e r e o s e l e c t i v i t y of 50:1. This intermediate was subsequently converted into the desired ionomycin fragment 34. The approach that we used for the preparation of a fragment A precursor for ionomycin d i f f e r s from the three syntheses described above. We chose to modify D-glucose, a c h i r a l s t a r t i n g material, as outlined i n the following sections. 19 BnO base, Mel 79% 2 7 BnO 4 0 ' 0 N ^ O 2 8 D (Q-BU)2BO 0 ^ 0 2) H 2 0 2 72% BnO 1) LiAIH 4 2) oxidation 88% 0 H 4 0 ' 2 9 BnO HO o N 40" 39' 1) H 2 , Pd-C 2) oxidation 47% 0 0 0 0 N 40" 39 0 y o 30 31 Scheme 11. The method of Evans and Shih for the introduction of two methyl groups for a fragment A type molecule (10b). 20 Scheme 12. Introduction of the remaining methyl group In the synthesis of a fragment A type molecule by Evans and Shih (10b). IV. Carbohydrates as S t a r t i n g Materials l n the Synthesis of Natural  Products In recent years, organic chemists have taken advantage of carbo-hydrates as s t a r t i n g materials for the syntheses of many natural products. Some of the reasons for using carbohydrates include th e i r enantiomeric pur i t y , t h e i r ready a v a i l a b i l i t y , and t h e i r r e l a t i v e l y low cost. There i s 21 also a r i c h background knowledge about stereo-, regio-, and chemocontrol for protecting group manipulation and functional group interconversion i n carbohydrates. Numerous reviews have been published covering these topics (15). Attention i s also drawn to a book by Hanessian which describes how to use carbohydrates as c h i r a l precursors, or "chirons", i n natural products syntheses (16). Carbohydrate derivatives either exist n a t u r a l l y as, or can be trapped as, f i v e - or six-membered rings or b i c y c l i c systems which display high conformational r i g i d i t y . As a r e s u l t of t h i s r i g i d i t y , highly stereoselective reactions can be c a r r i e d out on these systems. Two natural product syntheses which i l l u s t r a t e these p r i n c i p l e s are the syntheses of (- ) - s e r r i c o r n i n by Mori, Chuman, Kato and Mori (17) shown i n Scheme 13, and ( - ) - a - m u l t i s t r i a t i n by Sum and Weiler (18) shown i n Scheme 14. Both syntheses s t a r t from a carbohydrate derived intermediate and through a series of steps 1,3-dimethyl groups are Introduced. In the synthesis of ( - ) - s e r r i c o r n i n , the b i c y c l i c enone 3_5 was prepared from c e l l u l o s e . The C-4 methyl group was introduced stereo-s e l e c t i v e l y by conjugate addition of lithium dimethylcuprate to this enone from the open, convex face of the molecule y i e l d i n g 36. Although i n t r o -duction of the second methyl by hydrogenation of o l e f i n 3_7 proceeded with poor s e l e c t i v i t y , the correct isomer was obtained by acid catalyzed epimerization of the methyl group at C-2 in 3_8_ to y i e l d compound 39. Opening of the b i c y c l i c system with 1,3-propanedithiol furnished dithiane 2 2 S c h e m e 1 3 . T h e s y n t h e s i s o f ( - ) - s e r r i c o r n i n b y M o r i e t a l . ( 1 7 ) . 23 Scheme 14. The synthesis of ( - ) - a - m u l t i s t r i a t i n by Sum and Weiler (18). 24 40 which has anti-1,3-dimethyl groups. This intermediate was elaborated i n t o ( - ) - s e r r i c o r n i n (41). In the synthesis of ( - ) - a - m u l t i s t r i a t l n (18), the methyl group at C-2 was introduced f i r s t by l i t h i u m dimethylcuprate attack on the D-glucose (42) derived epoxide 43. The stereoelectronic requirement for t r a n s - d i a x i a l opening of the epoxide r i n g ensured a x i a l o r i e n t a t i o n of the methyl group. A number of synthetic steps yielded f i r s t the ketone 45_ and subsequently the o l e f i n 46. Hydrogenation from the less hindered, bottom face gave the a x i a l methyl group at C-4. Opening of the pyranoside r i n g and s o l v o l y s i s of the t r i t y l ether of compound 47_ with 1,3-propanedithiol furnished dithiane 48_ which has syn-1,3-dimethyl groups. This i n t e r -mediate was elaborated into ( - ) - a - m u l t i s t r i a t i n (49). The usefulness of carbohydrates as s t a r t i n g materials i s i l l u s t r a t e d i n the above syntheses. The stereoselective Introduction of syn- or anti-1,3-dimethyl groups was f a c i l e because of the r i g i d nature of the c y c l i c carbohydrate d e r i v a t i v e s . Once the desired stereochemistry had been established, the rings were e a s i l y opened to allow for conversion into the corresponding natural products. According to the proposal of Masamune (19), a c y c l i c chains are drawn i n the zigzag conformation, defining a plane. Methyl groups on opposite sides of this plane have an a n t i r e l a t i o n s h i p , whereas, methyl groups on the same side have a syn r e l a t i o n s h i p . 25 V. Plans f o r the Synthesis of Fragment A of Ionomycin from D-Glucose The syntheses outlined i n the previous section were chosen not only for the stereocontrol that they demonstrate, but also because the intermediate compounds 40_ and _48 resemble our desired fragment A precursor. Dithiane 48 has syn-1,3-dimethyl groups with the correct absolute stereochemistry i n addition to the dithiane moiety which could used i n the coupling to fragment B. 4 0 4 8 n s s R = protected carboxylic acid moiety fragment A precursor Thus, we envisaged building on the synthesis of (-)-a-multi-s t r i a t i n for our synthesis of fragment A of ionomycin. Scheme 15 shows how D-glucose (42) could be manipulated into a fragment A precursor. Carbon by carbon the necessary transformations are as follows: C - l - conversion into the dithiane moiety; C-2 - introduction of the a x i a l methyl group and deoxygenation; C-3 - deoxygenation; 26 C-4 - introduction of the a x i a l methyl group and deoxygenation; C-5 - deoxygenation af t e r opening the pyranoside r i n g ; and C-6 - elongation of the carbon backbone, introduction of a methyl group with the correct stereochemistry and deoxygenation. Scheme 15. Our synthetic plan for a fragment A precursor. 27 The methodology needed to generate C-1 to C-4 with the correct substituents and functional groups can follow d i r e c t l y from the (-)-a-m u l t i s t r i a t i n synthesis. Chemistry for the manipulations of C-5 and C-6 had to be developed. Our attention was e s p e c i a l l y drawn to the need to c o n t r o l the stereochemistry at C-6 because at the time of our planning, c h i r a l induction i n a side chain exocyclic to the pyranose r i n g was normally unpredictable (20,21). VI. Stereocontrol at C -6 l n Higher-Carbon D-Glucose Derivatives Only four successful strategies for the highly stereoselective introduction of a methyl group at C-6 in D-glucose derivatives have been published. In the e a r l i e s t work, reported i n 1981, Isobe and his co-workers took advantage of the c h i r a l centres at C-5 and C-1 to e f f e c t stereoselective addition of methyllithium to an unsaturated higher-carbon sugar derivative (22). They have recently used this method in a number of natural product syntheses (23). A synthesis of Prelog-Djerassi lactone (54) from D-glucose (42) serves to i l l u s t r a t e the chemistry (24). The key steps of the Prelog-Djerassi lactone synthesis are shown In Scheme 16. Aldehyde _50_ was condensed with b i s ( t r i m e t h y l s i l y l ) -thiophenylmethyllithium and the r e s u l t i n g thioenol ether was oxidized with m-chloroperbenzoic acid to afford o l e f i n 51. Conjugate addition of methyllithium to o l e f i n _51_ proceeded with complete s t e r e o s e l e c t i v i t y to y i e l d compound 53, q u a n t i t a t i v e l y . The reason for t h i s s t e r e o s e l e c t i v i t y was explained as a chelation of the l i t h i u m cation of methyllithium by the 2 8 1) (TMS) 2PhSCLi 2) MCPBA > 60% Scheme 16. The s y n t h e s i s of P r e l o g - D j e r a s s i l a c t o n e (54) by Isobe et a l . ( 2 4 ) . 29 ace ta l oxygens, which led to de l ivery of the methyl anion exc lu s ive ly to one face of the o l e f i n in the conformation shown in 52. The r e s u l t i n g carbanion was trapped with phenylse lenyl chlor ide to y i e l d compound 53, which was then modified to give Pre log-Djerass i lactone (54). In 1981, Nakahara, Beppu and Ogawa published the i r route to a fragment of the polyether a n t i b i o t i c A23187 (25), the key steps of which are shown in Scheme 17. The higher-carbon D-glucose der iva t ive 55 was c y c l i z e d to lactam 56 and O-a lky la t ion of the lactam afforded the key b i c y c l i c iminoether 57. Deprotonation at the act ive methylene s i t e followed by a l k y l a t i o n with iodomethane from the less hindered, convex face, y ie lded compound _58 in quant i ta t ive y i e l d . Subsequent steps ca r r i ed out on this intermediate furnished dithiane 59, which was used in the synthesis of a n t i b i o t i c A23187 (7e). In 1984, Fraser-Reid , Magdzinski , and Molino described a pyranoside homologation s trategy, shown in Scheme 18 (26). A W i t t i g reac t ion on aldehyde 60, y ie lded a mixture of the c i s - and trans-a ,B-unsaturated acetals 61. Treatment of this mixture with ac id i c methanol effected methanolysis of the a c e t a l , i somerizat ion of the double bond (15a) and intramolecular aceta l formation to give the homologated pyranoside 62 as the sole react ion product. The o l e f i n _62_ reacted with aqueous N-bromosuccinimide to y i e l d a mixture of bromohydrins. However, treatment of the mixture with base afforded a s ingle epoxide 63. Trans-d i a x i a l opening of the epoxide with dimethylmagnesium, followed by pro tec t ion of the r e s u l t i n g a lcohol as a methyl ether, y ie lded compound 3 0 5 8 5 9 Scheme 17. The s t e r e o s e l e c t i v e i n t r o d u c t i o n of a methyl group by Nakahara _et_ £!_• ( 2 5 ) . 31 6 3 6 4 Scheme 18. The stereoselective introduction of a methyl group at C-6 by Fraser-Reid et (26). 32 64. F r a s e r - R e i d suggested that t h i s i n t e r m e d i a t e c o u l d be used f o r the s y n t h e s i s of p o l y m e t h y l a t e d , p o l y h y d r o x y l a t e d a n t i b i o t i c s ( 2 6 ) . The f o u r t h example of C-6 s t e r e o c o n t r o l i n a D-glucose d e r i v a t i v e i s our model study work d i r e c t e d towards the s y n t h e s i s of fragment A of ionomycin ( 2 7 ) . T h i s i n t r o d u c t o r y survey has touched b r i e f l y on a number of d i v e r s e t o p i c s which are r e l e v a n t to our proposed s y n t h e s i s of ionomycin. The f u l l d e t a i l s of our s t u d i e s d i r e c t e d towards t h i s s y n t h e s i s are c h r o n i c l e d i n the f o l l o w i n g pages. 33 RESULTS AND DISCUSSION The Results and Discussion section i s divided into four parts. In the f i r s t part the method we developed for the s t e r e o s p e c i f i c introduction of a methyl group at C-6 i n a higher-carbon D-glucose derivative i s discussed. In the second part, the synthesis of a fragment A precursor of ionomycin which involves stereoselective methyl group introduction at three centres on the carbohydrate framework i s described. In the t h i r d section, the synthesis of an o p t i c a l l y active fragment B i s outlined, and f i n a l l y , i n the fourth section, d e t a i l s of the successful coupling of a fragment A precursor and fragment B are given. I . Model Studies f o r Fragment A of Ionomycin When the plans for our synthesis of fragment A of ionomycin were germinating, no methods for the stereoselective introduction of a l k y l groups at C-6 in a higher-carbon D-glucose derivative had been published. The aim of the model study was to develop a method for the s t e r e o s p e c i f i c Introduction of a methyl group at C-6 i n a predictable and r a t i o n a l way. Our tenet was that a r i g i d , b i c y c l i c intermediate embodying the D-glucose skeleton would allow us to achieve this goal. We chose to bridge C-6 and the hydroxyl group at C-4 with an a,8-unsaturated lactone to form a r i g i d trans-fused b i c y c l i c system. We anticipated that a conjugate addition to t h i s b i c y c l i c lactone would exhibit a high degree of s t e r e o s e l e c t i v i t y (27). 34 In 1978, Weihe and McMorris published a method for the preparation of an a,8-unsaturated 6-lactone en_ route to a synthesis of 23-deoxy-a n t h e r i d i o l as shown i n Scheme 19 (28). The hydroxy ketone 65 was acylated with bromoacetyl bromide and the r e s u l t i n g bromoacetate (>6_ was heated with t r i e t h y l phosphite to give phosphonate 67. When sodium hydride was added to a solu t i o n of phosphonate 67_ i n THF and the r e s u l t i n g mixture heated, an intramolecular Wadsworth-Emmons reaction (29) occurred to afford the desired a,B-unsaturated lactone 68. Scheme 19. The synthesis of an a,8-unsaturated 6-lactone by Weihe and McMorris (28). 35 Modifications to this synthesis would allow us to prepare the a ,B-unsaturated lactones 70 and 72_ v i a the corresponding aldehyde 69 and methyl ketone 71, as shown i n Scheme 20. 0 t Scheme 20. The proposed preparation of a,8-unsaturated lactones 7_0_ and 72 via Wadsworth-Emmons c y c l i z a t i o n s . 36 I.A. Preparation of a,B-Unsaturated Lactone 70 For our model study, the C-2 and C-3 hydroxyl groups of methyl a-p_-glucopyranoside (73) were protected using standard carbohydrate chemistry as shown i n Scheme 21. 0 a) C H 3 S C H 2 0 N a DMSO b) M e l 97% Scheme 21. Synthesis of d i o l 76 from methyl a-D-glucopyranoside (73). 37 The primary hydroxyl group of d i o l 76_ was protected using t r i p h e n y l -methyl chloride and pyridine to y i e l d t r i t y l ether 77 as shown i n Scheme 22. The free hydroxyl group at C-4 was then acylated with bromoacetyl bromide to y i e l d bromoacetate 78. I n i t i a l l y , on small scale, ether was used as the solvent for this a c y l a t i o n (28). However, the s o l u b i l i t y of alcohol 77 i s only 1 g per 200 mL of ether and as a r e s u l t , the reaction was slow and Impractical on large scale. The s t a r t i n g material i s r e a d i l y soluble i n THF and reaction conditions using this solvent and an excess of bromo-ac e t y l bromide, pyridine and 4-dimethylaminopyridine (DMAP) afforded bromoacetate 7JB i n excellent y i e l d . The bromoacetate was then treated with t r i e t h y l phosphite at 150°C (28) to y i e l d phosphonoacetate 79. The f i r s t attempts to deprotect the hydroxyl group at C-6 were performed using acid catalyzed methanolysis (30). Treatment of t r i t y l ether 79_ with Amberlite IR-120 In methanol for 44 h, followed by chromato-graphy on s i l i c a gel and solvent evaporation, with heating, yielded alcohol 80_ instead of the desired alcohol 81. Acid catalyzed acyl group migration from 0-4 to 0-6 Is well documented i n the carbohydrate l i t e r a t u r e (31). The desired alcohol was obtained by hydrogenolysis i n methanol (30) using a trace of hydrochloric acid (32). These mild conditions did not cause any trans-acylation, however, attempts to p u r i f y the product on s i l i c a g e l , F l o r i s i l or C e l i t e did cause varying amounts of t r a n s - a c y l a t i o n . Separation of the triphenylmethane from alcohol _81_ was achieved by continuously extracting an a c e t o n i t r i l e solution of the crude reaction 38 .OH H O ^ V ^ " ° \ M e O - V - ^ ~ | MeO OMe 7 6 OTr TrCI, py 92% HO MeO 7 9 7 7 B r Br ( py, DMAP, THF 99% Br, OTr M e 0 OMe Amberlite IR-120, MeOH, (heat) 91% P(0Et ) 3 . o 150°C N 0 quantitative M e 0 7 8 H 2 , Pd-C, trace of HCI, (no heat) 72% ? Q ( E t O ) 2 P ^ A . H O - ^ s ~ ^ ^ ° \ MeO<^-\-A MeO OMe 8 0 8 1 MeO OMe Scheme 22. Synthesis of alcohols 80 and 81_ from d i o l 76^ . 39 product with petroleum ether. Evaporation of the a c e t o n i t r i l e , without heating, yielded the desired alcohol 81_ i n reasonable y i e l d . The easiest way to d i s t i n g u i s h between alcohols J}0_ and j!l_ i s by t h e i r 1H nmr spectra (see Spectral Appendix p. 191). The C-4 methine proton i n the desired alcohol 81^ has a chemical s h i f t s i m i l a r to the anomeric proton, and both protons appear as a multiplet at 6 4.70 - 5.10. This methine signal i n 80 i s s h i f t e d u p f i e l d r e l a t i v e to 81 and the C-6 methylene protons appear at approximately 6 4.3 - 4.7, consistent with the suggested structure. Attempted oxidation of alcohol jBl to aldehyde 69 with PCC (33) or with chromium(VI) oxide - pyridine (34) resulted i n t o t a l loss of the carbohydrate. The Swern oxidation (35), which uses trlethylamine, apparently resulted In elimination of the C-4 phosphonoacetate to y i e l d the corresponding a,8-unsaturated aldehyde (36). Fortunately, the Moffatt reaction under neutral (36) or a c i d i c (37) conditions i s known to be an e f f e c t i v e oxidation method for glucose derivatives with good leaving groups at C-4. As shown i n Scheme 23, a Moffatt oxidation using dimethyl-sulfoxide (DMSO), 1,3-dicyclohexylcarbodiimide (DCC) and a c a t a l y t i c amount of d i c h l o r o a c e t i c acid (38) yielded aldehyde 69. Freeze-drying the aqueous - DMSO layer a f t e r work-up afforded the aldehyde which was used without further p u r i f i c a t i o n . A Wadsworth-Emmons c y c l i z a t i o n of aldehyde 69_ with sodium hydride i n THF under r e f l u x (28) yielded the a,8-unsaturated urono-8,4-lactone 70 i n quantitative crude y i e l d . This product i s the second reported example of an a,B-unsaturated urono-8,4-lactone (36). It Is characterized by two 40 NaH, THF, A 50-57% Scheme 23. Preparation of a,8-unsaturated lactone 70 from alcohol 81. v i n y l i c signals in the AH nmr spectrum at 6 5.96 and 6 6.87, corresponding to H-7 and H-6, r e s p e c t i v e l y . Analysis of the crude product by % nmr indicated that the reaction was very clean, however, a l l of the methods used for separation of the product from the sodium phosphate ester s a l t s ( d i s t i l l a t i o n or chromatography on C e l i t e , F l o r i s i l , neutral alumina, or s i l i c a gel) resulted i n d r a s t i c a l l y reduced y i e l d s . Gel f i l t r a t i o n on 41 Sephadex was the most e f f e c t i v e method found, affording lactone 70^ i n y i e l d s of 50-57%. Martin and Szarek noted the unusual acid s e n s i t i v i t y of the f i r s t reported urono-8,4-lactone (36) and lactone 70_ appears to have s i m i l a r properties. I.B* Conjugate Addition to a,B-Unsaturated Lactone 70 Lipshutz has reported that the higher order mixed organocuprate, Me 2Cu(CN)Li 2, reacts r a p i d l y and e f f i c i e n t l y with a,B-unsaturated esters (39,40). This reagent reacted cleanly with a,B-unsaturated lactone 70^ to y i e l d a mixture of the a x i a l methyl lactone 82_ and the equatorial methyl lactone 83_ as shown i n Scheme 24. Temperature dependence studies were conducted to maximize the y i e l d of the major product, but from the r e s u l t s of several experiments i t appeared that temperature plays a minor role i n determining the product r a t i o . Under the best conditions (-78°C for 5 min, then -40°C for 4 h) the r a t i o of a x i a l to equatorial product was approximately 13:1. Work-up of this reaction mixture was a challenge because methyl lactones 82_ and 83_ are highly acid s e n s i t i v e . Quenching the reaction with an aqueous solution of ammonium chloride and ammonium hydroxide followed by standard aqueous work-up (39) afforded y i e l d s of product i n the range of 10-23%. Eventually, a work-up procedure was developed which involved quenching the reaction with g l a c i a l a c e t i c acid, followed by adding the disodium s a l t of ethylenediaminetetraacetic acid to complex the copper. Work-up with brine and aqueous sodium bicarbonate resulted In 75-100% y i e l d s of the lactone mixture. 42 a) Me 2 Cu(CN)Li 2 , E t 2 0 b) AcOH c) EDTA, disodium salt d) aqueous work-up 75-100% Scheme 24. Higher order mixed organocuprate reaction with a,8-unsaturated lactone 70 y i e l d i n g methyl lactones 82 and 83. I.C. Stereochemical Proof and Conformational Arguments f o r the Formation of the A x i a l Methyl Lactone 82 A pure sample of the a x i a l isomer 82_ was obtained by preparative g l c . The stereochemistry of the C-6 methyl group was proved by difference nuclear Overhauser enhancement (n.O.e.) experiments (41), the res u l t s of which are shown in Figure 3 and Table I. I r r a d i a t i o n of the C-methyl group resulted i n major enhancement of the H-4, H-6 and H-78 signals, but 4 4 T a b l e I. D i f f e r e n c e n.O.e. experiments on methyl l a c t o n e 82 ( 4 1 ) . I r r a d i a t e d protons and major through-space enhancement major n.O.e. minor n.O.e. MeO OMe H-7B H-6 H-4 H-7a H-5 H-2 H-1 H-7a U7P V6 O ^ H ^ ^ i h 6 MeO ^ l Z^A M e 0 OMe H-78 H-6 H-5 (H-2) H-5 Me M e O ^ ^ ^ ^ A 3 H ^ M e O OMe H-6 H-7a H-3 C-Me H-7B H-2 H-1 MeO-A^V-A M e 0 OMe C-Me H-2 H-78 H-7a H-1 45 only minor enhancement was seen for protons H-5 and H-7a. In a separate experiment, i r r a d i a t i o n of the H-4 methine proton resulted i n enhancement of the H-2 and the C-methyl group si g n a l s , but not the H-5 s i g n a l . Thus H-2, H-4 and the C_-methyl group are a l l c i s , confirming that the £-methyl assumes the a x i a l o r i e n t a t i o n at C-6. Additional experiments involving i r r a d i a t i o n of H-5 and H-7<x gave r e s u l t s which were consistent with the other experiments. The s t e r e o s e l e c t i v i t y of methyl addition to a,6-unsaturated lactone 7_0_ can be predicted using the rules of stereoelectronic c o n t r o l and the p r i n c i p l e of least conformational d i s t o r t i o n as proposed by Toromanoff (42). The rules of stereoelectronic control are: (a) addition must take place along the axes of the u o r b i t a l s i . e . addition must be perpendicular to the plane of the substituents on the double bond and (b) maximum o r b i t a l overlap must be maintained during the reaction. The arguments which Toromanoff used to explain the s t e r e o s e l e c t i v i t y of conjugate addition i n an enone system (43) can be extended to r a t i o n a l i z e our r e s u l t s . By analogy with a b i c y c l i c cyclohexenone (44), there are two conformations of the a,p-unsaturated lactone ring of compound 7_0_ with equally low energies, as shown i n Scheme 25. In the h a l f - c h a i r conformation 70a, C-5, C-6, C-7 and C-8 are co-planar. The ether oxygen of the lactone i s below this plane and C-4 i s above this plane. In the 1,2-diplanar conformation 70b, C-5, C-6, C-7, C-8 and the ether oxygen of the lactone are co-planar and C-4 i s above this plane. 46 82 protonation Me &4 84a 84b perpendicular addition perpendicular addition to top face to top face 5 6 70a 0 perpendicular addition to bottom face 6 7 70b =o protonation 83 Scheme 25. Conformational analysis of methyl group addition to a,8-unsaturated lactone 70. 47 Perpendicular cuprate addition to the top face of either conformation 70a or 70b y i e l d s the enolate 84a or 84b, r e s p e c t i v e l y . During the conversion of 70a to 84a, s i g n i f i c a n t conformational d i s t o r t i o n occurs to form a new half chair conformation. The ether oxygen of the lactone moves up to become co-planar with C-6, C-7 and C-8, C-4 stays above t h i s plane, and C-5 moves down below t h i s plane. During the conversion of 70b to 84b there i s l i t t l e conformational change. The o r i g i n a l ring conformation of 70b i s not d i s t o r t e d . According to the p r i n c i p l e of least conformational d i s t o r t i o n this l a t t e r pathway, proceeding through 1,2-diplanar intermediates, i s favoured (43). Enolates 84a and 84b both y i e l d the a x i a l methyl lactone 82_ a f t e r protonation. Perpendicular addition of the cuprate to the bottom face of eith e r 70a or 70b y i e l d s the 1,3-diplanar enolate 85a i n which the methyl group has an a x i a l - l i k e o r i e n t a t i o n (44). In this conformation C-6, C-7, C-8 and the ether oxygen are co-planar and both C-4 and C-5 l i e above t h i s plane. C l e a r l y , conformational d i s t o r t i o n occurs during the reaction from eit h e r 70a or 70b to 85a and hence this pathway i s disfavored. Protonation of 85a yi e l d s the equatorial methyl lactone 83. According to the above reasoning, the a x i a l product a r i s i n g v ia the 1,2-diplanar pathway should be the major product and our re s u l t s are consistent with t h i s . In addition, the r a t i o of a x i a l to equatorial product can be explained. Generally 1,2-diplanar enolates are lower i n energy than 1,3-diplanar enolates and i t can be assumed that the t r a n s i t i o n states leading to these enolates would exhibit the same 48 r e l a t i v e energy difference (43). The r a t i o of the a x i a l methyl lactone 82_ to the equatorial methyl lactone 83_ should, i n turn, r e f l e c t the energy difference between the t r a n s i t i o n states leading to enolates 84b and 85a. The mechanistic d e t a i l s of conjugate addition mediated by cuprate reagents are s t i l l unclear. Recently, Corey and Boaz have suggested that the reaction procedes v i a a r e v e r s i b l e d,u -complex, followed by copper(III) adduct formation (45). Their r e s u l t s suggest that i f a cuprate conjugate addition reaction i s conducted under r e v e r s i b l e conditions on a cyclohexenone with a y oxygen, the major product obtained w i l l be the one In which the new a l k y l group i s c i s to the oxygen f u n c t i o n a l i t y . In our major reaction product, the methyl group i s c i s to the pyranose oxygen - consistent with the re s u l t s of Corey and Boaz. A x i a l Introduction of a methyl group at C-6 of a,8-unsaturated lactone 7_0 i s therefore favoured following both the proposals of Toromanoff and of Corey and Boaz. 0. methyl group cis to oxygen at 7 position M e 0 OMe 8 2 49 I.D. Preparation of the Equ a t o r i a l Methyl Lactone 83 Unfortunately, we were unable to obtain sufficient quantities of the minor product, the equatorial methyl lactone 83, from the above cuprate reaction to be able to characterize It. Therefore, this isomer was prepared by a separate route as shown in Scheme 26. Although attempts were made to find optimal conditions for this reaction sequence, the instability and water soluble nature of certain intermediates resulted in some very low yields. Attempted additions of a methyl anion to aldehyde 69, using methyllithium (21) or methyltris(2-propoxy)titanium, Me(i_-Pr0)3Ti (46), were unsuccessful even when the crude reaction product was treated in situ with acetic anhydride, tert-butyldimethylsilyl t r i f l a t e (47) or Moffatt oxidation conditions in an attempt to trap the expected alkoxide product. We then tried using an active methylene complex, CH2Br2-Zn-TiCl^, developed by Takai, Hotta, Oshima and Nozaki, which is reported to be a mild and non-basic alternative to the WIttig carbonyl methylenation (48). Treatment of aldehyde 69 with this active methylene complex using a modified procedure developed by Lombardo (49) afforded olefin 86_ in moderate yield. A one-pot oxy—mercuratIon - Jones oxidation of the crude olefin following the procedure of Rogers, McDermott and Whitesides (50) afforded a crude product mixture of ketone _71_ in 50% weight balance. Analysis of the *H nmr spectrum by Integration of the methyl ketone signal at 6 2.23 (see Spectral Appendix p. 197), indicated that one-third of the crude 50 0 t (EtO) 2P 0 ( E t O ) 2 P x ) 0 ^ / H CH 2 Br 2 -Zn-TJCl4, ) 0=\ ^ \ n CH 2 CI 2 U = \ \ 0 ^ v ^ ^ 0 \ — - 0 MeO-X^T-A 42% MeO M e 0 OMe 6 9 8 6 a) Hg(OAc) 2 , H 2 0 , acetone b) H 2 S 0 4 , C r 0 3 , H 2 0 Y 1 17% ( E t 0 ) 2 P \ M p M e O ^ X - ^ ^ A MeO 0 M e 71 P t 0 2 , H 2 , MeOH 100% NaH, THF, A 39% Scheme 26. Synthesis of equatorial methyl lactone 83_ from aldehyde 69j 51 mixture consisted of the desired product. This suggests a y i e l d of about 17% for this r e a c t i o n . Longer reaction times f a i l e d to give a better y i e l d and attempts to e f f e c t the reaction under Wacker oxidation condi-tions (PdCl 2, CuCl, 0 2, H 20) (51) led only to recovered s t a r t i n g material. C y c l i z a t i o n of the crude methyl ketone product using sodium hydride i n THF under r e f l u x (28), followed by chromatography of the crude product on s i l i c a g e l , afforded a,8-unsaturated lactone 72_ i n 39% y i e l d . This y i e l d i s based on the amount of methyl ketone 71_ known to have been i n the s t a r t i n g material and although the y i e l d i s low, i t i s comparable to those obtained for a,8-unsaturated lactone 70. The *H nmr spectrum of lactone 12_ i s characterized by signals at 6 5.76 and 6 2.00 corresponding to the v i n y l i c proton and methyl group, r e s p e c t i v e l y . The equatorial methyl lactone 83_ was obtained by hydrogenation of a,8-unsaturated lactone 72 using platinum oxide i n methanol. There was no evidence by e i t h e r nmr or c a p i l l a r y glc for formation of the a x i a l methyl lactone 82. C a t a l y t i c hydrogenation of a,8-unsaturated carbonyl systems has been proposed to take place via a conjugate addition of hydride followed by protonation of the r e s u l t i n g enol or enolate (52). Therefore the arguments used e a r l i e r to r a t i o n a l i z e the preferred a x i a l attack of the cuprate on lactone 70_ can also be applied to this hydrogenation. Following the arguments of Toromanoff (42, 43, 44) the favoured reaction pathway i s through 1,2-diplanar intermediates. Conjugate addition of 52 hydride occurs to the top face of 72a such that the methyl group i s forced down into an e q u a t o r i a l - l i k e p o s i t i o n as shown i n Scheme 27. Protonation of enolate 85b y i e l d s the equatorial methyl lactone 83. Me"6 ° ~ T= 0 72a perpendlculor attack from top face Me' H .0 e protonation 83 85b Scheme 27. Hydride addition to the 1,2-diplanar conformation of a, 8-unsaturated lactone 12_ to y i e l d 83_ a f t e r protonation. The chemical s h i f t s of C-6 nmr signals of epimers B2_ and j53_ support the stereochemical assignments at C-6. In r i g i d six-membered rings, an a x i a l proton i s found 0.1 - 0.7 ppm further u p f i e l d than the corresponding equatorial proton on the same carbon (53). The a x i a l H-6 of 83 appears i n a multiplet at 6 2.04 - 2.17 - further u p f i e l d by about 0.25 ppm than the equatorial H-6 of 82, which appears at 6 2.31 - 2.40 (see Spectral Appendix p. 195). Evidence from * 3C nmr also gives credence to 53 the stereochemical assignments of 82_ and 83. A x i a l methyl groups i n cyclohexane rings normally have chemical s h i f t s of 6 15 - 18 whereas the corresponding equatorial methyl group signals are found at 6 18 - 25 (54). The proton decoupled * 3C nmr spectrum of a 77:13 mixture of methyl lactones 82_ and 83 shows only two signals u p f i e l d from 6 25 (see Spectral Appendix p. 196). A large signa l at 6 14.3 i s assigned to the a x i a l methyl group of j$2_ and a smaller peak at 6 18.5 to the equatorial methyl of 83, consistent with the known r a t i o of isomers i n the analyzed mixture. I.E. Preparation and I d e n t i f i c a t i o n of Isomeric By-Products Unfortunately, many of the products i n t h i s study were contami-nated with isomeric by-products which arose because of the f a c i l e 0-4 to 0-6 trans-acylation described e a r l i e r . On large scale, even though pure alcohol jft was used for the Moffatt oxidation some trans-acylation occurred, f a c i l i t a t e d by the a c i d i c and exothermic nature of the reaction, to y i e l d ketone 87_ as shown i n Scheme 28. Small amounts of ketone 87_ i n aldehyde 69_ could not be detected r e a d i l y by t i c or *H nmr. However, when the aldehyde-ketone mixture was c y c l i z e d , an Isomeric a,B-unsaturated lactone could be detected by *H nmr and c a p i l l a r y g l c . This contaminant also gave r i s e to by-products during the preparation of both the a x i a l and equatorial methyl lactones 82_ and 83. In order to prove the i d e n t i t i e s of these by-products, they were prepared v i a a separate route s t a r t i n g from alcohol 80 as shown i n Scheme 29. The *H nmr spectra and c a p i l l a r y glc retention times of the Isomeric lactones were i d e n t i c a l to the contami-nants detected en route to methyl lactones 82 and 83. 54 Scheme 28. Trans-acylation during the Moffatt oxidation of alcohol 8l_ y i e l d i n g ketone 87. The a,8-unsaturated lactone 88_ prepared from ketone 87_ i s charac-t e r i z e d by a single v i n y l proton s i g n a l at 6 6.13 i n the *H nmr spectrum. Methyl group addition to a,8-unsaturated lactone 88 using the higher order mixed organocuprate, Me 2Cu(CN)LI 2 (39), yielded a single product, lactone 89. In the XH nmr spectrum the angular methyl appeared as a s i n g l e t at 55 ? o (EtO) 2 P^A. 0 M e 0 OMe 8 0 DMSO, DCC, CI 2 HCC0 2 H 91% ? o ( E t O ^ P ^ A NaH, THF, A 50% M e 0 OMe 8 8 Me MeO Me 2 Cu(CN)Li 2 , E t 2 0 65% MeO OMe 8 9 H 2 , P t 0 2 , MeOH 80% M e 0 OMe 9 0 Scheme 29. Preparation of lactones 88, 89 and _90 which were seen as contaminants during the model study. 56 6 1.16 and the protons H-7 and H-7f appeared as an AB quartet at 6 2.42 and 6 2.69 (see Spectral Appendix p. 202). The coupling constants between H-5 and the two protons at H-6 were 3 Hz and 2 Hz. Hydrogenation of a,6-unsaturated lactone 88_ using platinum oxide i n methanol yielded only the cis-fused b i c y c l i c lactone 90. The *H nmr coupling constants between H-3 and H-4, H-4 and H-5, H-5 and H-6, and H-5 and H-6' were a l l equal to, or less than 5 Hz, i n d i c a t i n g that there were no t r a n s - d i a x i a l protons. For both lactones J59_ and 90_ large t r a n s - d i a x i a l coupling constants would have been expected i f the trans-fused b i c y c l i c systems shown below had been formed. The high s t e r e o s e l e c t i v i t y seen i n both the cuprate addition to, and the hydrogenation of, a, 8-unsaturated lactone j?8_ can be explained by the arguments which Toromanoff used to r a t i o n a l i z e conjugate additions of anions to cyclohexenones (55). Lactone 88_ can e x i s t in two 1,2-diplanar conformations 88a and 88b as shown i n Scheme 30. Nucleophilic attack from the top face in either conformation would involve a 1,3-diaxial i n t e r -action with H-2. On the other hand, n u c l e o p h i l i c attack from the bottom face experiences no such i n t e r a c t i o n . 57 nucleophile nucleophile 88a 88b Scheme 30. Preferred stereochemistry of n u c l e o p h i l i c attack on a,6-unsaturated lactone 88. For tuna te ly , the isomeric lactones 88, 89 and 90 were r e a d i l y d i s t ingu i shed from the desired lactones 70, 83 and JJ4_ by *H nmr and c a p i l l a r y g l c . The isomeric mixtures were general ly not p u r i f i e d because the only success ful method found for t h e i r separation was preparat ive glc - a tedious process . The isomers could not be separated by d i s t i l l a t i o n or by t i c . Even t i c using s i l v e r n i t r a t e impregnated s i l i c a gel (56) f a i l e d to separate the a,B-unsaturated lactones 7_0 and 88. Despite the problems of isomer formation because of the t r ans -a c y l a t i o n , and low y i e l d s during the synthesis of the equator i a l methyl lactone 83, the model study was succes s fu l . The syntheses of two a,8-unsaturated urono-8 ,4- lactones , 70 and 72, were achieved by a new route . Our tenet that a r i g i d trans-fused b i c y l i c a ,8-unsaturated lactone could be used to s t e r e o s e l e c t i v e l y introduce an a l k y l group at C-6 proved to be correct and furthermore, the major product, lactone 82, had p r e c i s e l y the stereochemistry desired for ionomycin. 58 I I . Synthesis of the Fragment A Precursor f o r Ionomycin The plan for the synthesis of fragment A of ionomycin was to use the chemistry developed by Sum and Weiler (18) to modify C-1 to C-4 of D-glucose and the chemistry developed i n the model study to Introduce the asymmetric centre at C-6. The f i r s t steps of this route are those used i n the synthesis of ( - ) - a - m u l t i s t r i a t i n (18). They concentrate on i n t r o -duction of the a x i a l methyl group at C-2 and deoxygenation at C-2 and C-3 as shown i n Scheme 31. II.A. Introduction of the A x i a l Methyl Group at C-2 No problems were encountered with this route u n t i l the cuprate reaction with epoxide 43. We were unable to obtain 44 i n y i e l d s greater than 63% using l i t h i u m dimethylcuprate and two by-products were detected by t i c instead of only one (57). I n t e r e s t i n g l y , a f t e r we had completed our work on t h i s part of the route, a report by Chapleur and co-workers appeared i n which they used a modified procedure for this reaction to obtain a y i e l d of 85% (58). Our attempt to improve the cuprate reaction centred around using the higher order mixed organocuprate, Me 2Cu(CN)Li 2, which i s reported to be milder and more e f f i c i e n t than l i t h i u m dimethylcuprate for ri n g opening reactions on epoxides (59). Use of t h i s cuprate reagent yielded the crude alcohol 44, which contained the same two by-products as above, although *H nmr indicated that they were produced i n lesser amounts (vide i n f r a ) . R e c r y s t a l l i z a t i o n of t h i s crude product afforded alcohol 44^  i n 76% y i e l d 59 MsCI, py 88% HO QM< 74 Me 2 Cu(CN)Li 2 , P h ^ o ^ A 2* X 1 A 78% HO OMe 44 a) NaH, E t 2 0 b) C S 2 c) Mel 99% r n \ T _ \ PhCH, — ^ 62% MeSCO OMe II S 92 OTr TrCI, py 76% \ 0 ^ ^ o M s O ^ ^ - - \ ^ | MsO OMe 91 NaOMe, MeOH, C H 2 C l 2 86% OMe 43 P h ~ - v O ^ \ 93 OMe TsOH, MeOH 98% • OMe Scheme 31. Synthesis of compound 95 following the route of Sum and Weiler (18). 60 and chromatography of the mother liquor increased the y i e l d by 2%, i n t o t a l , a 15% improvement over the previous method (57). The minor by-products obtained In both cuprate reactions were i d e n t i f i e d as enol ether 96_ (57) and a mixture of epimeric ketones 97, shown in Scheme 32. In the *H nmr spectra of the crude reaction products, the r a t i o s of 44:96;97 were 82:11:7 and 87:8:5 for the conventional cuprate reagent and the higher order mixed organocuprate reagent, respectively, i n d i c a t i n g that the l a t t e r gave a cleaner reaction product. HO OMe 4 4 (78%) 97(3%) Scheme 32. Higher order mixed organocuprate reaction with epoxide 43. 61 The mixture of ketones 97_ Is characterized by strong carbonyl, medium hydroxyl and strong geminal dimethyl group absorbances in the i n f r a -red spectrum and by c h a r a c t e r i s t i c isopropyl and benzylidene group signals i n the *H nmr spectrum. The *H nmr spectrum also shows separate peaks at 6 4.32 and 6 4.35 corresponding to the methine proton adjacent to the ketone i n each of the epimers (see Spectral Appendix p. 206). The ketones could have arisen by a sequence of steps as shown i n Scheme 33. Rearrangement of epoxide 43_ to 98_ (60), followed by elimination of methoxide would y i e l d the known hex-l-enopyrano-3-ulose _99_ (61). Epimeri-zation at C-4 (62) and conjugate addition of a methyl group to the enone mixture (61) would y i e l d the mixture of enolates 100. Elimination of the pyranose alkoxide (63) would give the enone mixture 101 and addition of a second methyl group to these enones would y i e l d the ketone mixture 97. II.B. Deoxygenation at C-3 Preparation of xanthate 92_ shown in Scheme 31 proceeded i n excellent y i e l d following the method of Sum and Weiler (18). During the subsequent Barton-McCombie deoxygenation using tri-n-butylstannane In toluene under r e f l u x (18), a number of d i f f i c u l t i e s were encountered. F i r s t , the reaction could not r e a d i l y be monitored by t i c because the R^ of the s t a r t i n g material was s i m i l a r to that of the product. Second, on large scale, the chromatographic work-up was unwieldy, re q u i r i n g large amounts of s i l i c a gel and solvent. F i n a l l y , by-products produced during the deoxygenation, and impurities a r i s i n g from by-products obtained during 62 cuprate reagent OMe 43 a) epimerization b) conjugate addition of methyl 100 O-M 101 9 8 9 9 a) conjugate addition of methyl b) protonation 9 7 Scheme 33. A possible mechanism for the formation of ketones epoxide 44 during a cuprate reaction. 63 the cuprate reaction resulted i n tedious chromatographic separations which generally had to be repeated. One of the i d e n t i f i e d by-products was enol ether 102 (64) which presumably arose v i a deoxygenation of enol ether 96^ as shown i n Scheme 34. Despite these d i f f i c u l t i e s , the desired deoxygenated compound _93_ was obtained i n moderate y i e l d as chunky white c r y s t a l s . Previously, compound 93_ was prepared i n good y i e l d but was reported to be an o i l (18). a) xanthate formation Scheme 34. Deoxygenation of enol ether 96_ to y i e l d compound 102. A deoxygenation procedure developed by Robins, Wilson, and Hansske i s reported to be milder, more e f f i c i e n t and cleaner than the Barton-McCombie procedure (65) and we f e l t that the new procedure might solve some of the problems encountered above. Accordingly, alcohol 44_ was treated with phenoxythiocarbonyl chloride (66), pyridine, and DMAP i n dichloromethane (65) to y i e l d phenoxythiocarbonate 103 as shown i n Scheme 35. The crude phenoxythiocarbonate usually contained 2-3% of phenoxycarbonate 104 which may have been due either to phenoxycarbonyl chloride i n the phenoxythiocarbonyl chloride reagent or to h y d r o l y t i c 64 HO OMe 4 4 PhOCCI, py, Ph-^V-0 DMAP, CH2CI2 \ > Ov 9 5 % PhOCO OMe II Y 1 0 3 , Y=s 1 0 4 , Y=O D-Bu3SnH, AIBN, PhCH3 62% based on recovered starting material Ph 9 3 OMe Scheme 35. Deoxygenation of a lcohol 44 fol lowing the procedure of Robins et a l . (65) . decomposition of phenoxythiocarbonate 103. An a n a l y t i c a l l y pure sample of 103 could not be obtained, suggesting that i t is not s t ab le . The Re of phenoxythiocarbonate 103 was greater than the deoxyge-nated compound 93_, so that monitoring the deoxygenation react ion by t i c was s t ra ight forward . Unfortunately , the deoxygenated product was obtained in only moderate y i e l d when we used this method for the large scale reac t ion en route to fragment A of ionomycin. 65 A c i d i c methanolysis of the benzylidene acetal of deoxygenated compound 93 afforded d i o l 94 i n excellent y i e l d as shown i n Scheme 31. Subsequent protection of the primary alcohol gave the t r i t y l ether 95. At th i s point In the synthesis we l e f t the route developed by Sum and Weiler (18) to follow the avenue of our model study. II.C. Preparation of <x,B-Unsaturated Lactone 110 As shown i n Scheme 36, alcohol J95_ was treated with bromoacetyl bromide, pyridine and DMAP i n ether (28) to y i e l d bromoacetate 105. Heating this bromoacetate with t r i e t h y l phosphite (28) gave the phosphonate 106 and a trace (2% y i e l d ) of chloroacetate 107. The l a t t e r product has the same R^ as the s t a r t i n g bromoacetate, but low and high r e s o l u t i o n mass spectrometry data support the suggested structure. Possibly, this by-product arose from traces of phosphorous t r i c h l o r i d e i n the t r i e t h y l phosphite reagent (67). The y i e l d from d i o l JJ4 to phosphonate 106 was 71% although the o v e r a l l y i e l d increased to 90% when the intermediate compounds were not p u r i f i e d . Hydrogenolysis of the t r i t y l ether 106 using palladium-on-charcoal and a trace of hydrochloric acid i n methanol, afforded alcohol 108 i n excellent y i e l d as shown i n Scheme 37. These mild conditions caused no 0-4 to 0-6 acyl migration. In f a c t , i n order to e f f e c t complete trans-a c y l a t i o n , i t was necessary to heat alcohol 108 In a c i d i c methanol under 66 Scheme 36. Synthesis of phosphonate 106 from alcohol 95. r e f l u x for 120 h. The trans-acylation reaction was never a problem during the synthesis of the fragment A precursor of ionomycin. In contrast to the model study, none of the expected by-products were ever detected by *H nmr or c a p i l l a r y g l c . It was unusual, but g r a t i f y i n g , that the reactions i n the actual synthesis were more e f f i c i e n t than those i n the model study! 67 106 o ( E t O ) 2 P v H 2 . Pd-C, 0 = ( HCI, MeOH 98% OMe 108 OMe DMSO, DCC, CI 2 HCC0 2 H 81% NQH, THF, A 4 2 % OMe 109 OMe Scheme 37. Synthesis of a,B-unsaturated lactone 110 from phosphonate 106, Alcohol 108 i s polar enough to be separated from triphenylmethane using the a c e t o n i t r i l e - petroleum ether l i q u i d - l i q u i d extraction method described e a r l i e r , although i t was more e f f i c i e n t to oxidize the crude alcohol mixture d i r e c t l y . During work-up of the Moffatt oxidation, the triphenylmethane was e a s i l y removed by ether extraction of the aqueous phase. On small scale, the Moffatt oxidation proceeded i n good y i e l d . Unfortunately, on large scale (25 mmol) aldehyde 109 decomposed during the long time period required to freeze-dry the aqueous layer a f t e r work-up. 68 The Wadsworth-Emmons c y c l i z a t i o n of aldehyde 109 afforded the crude a,8-unsaturated lactone 110 i n quantitative crude weight balance and i n greater than 90% p u r i t y as Indicated by c a p i l l a r y g l c . Like the model lactones 70_ and 72, lactone 110 i s very acid s e n s i t i v e . Gel f i l t r a t i o n on Sephadex separated most of the sodium phosphate ester s a l t s , affording lactone 110 i n 66% y i e l d , but subsequent chromatography on s i l i c a gel reduced the y i e l d to 42%. The second p u r i f i c a t i o n was necessary because cuprate reactions using the p a r t i a l l y p u r i f i e d a,8-unsaturated lactone gave y i e l d s i n the range of 40-65%. Yields of 85-91% using the pure a, 8-unsaturated lactone for the cuprate reaction compensated for the loss of lactone 110 on the s i l i c a gel column. During c y c l i z a t i o n of aldehyde 109, a by-product, aldehyde 111, was formed by base catalyzed elimination of the C-4 phosphonoacetate of 109. C a p i l l a r y glc and *H nmr of the crude c y c l i z a t i o n product Indicated that t h i s product was formed i n less than 10% y i e l d . Aldehyde 111 i s characterized by an aldehyde s i n g l e t at 6 9.15 and an o l e f i n multiplet at 6 5.85 - 6.05 i n the *H nmr spectrum. Aldehyde 111 was separated from the a,8-unsaturated lactone 110 by chromatography on s i l i c a gel but, because of i t s high v o l a t i l i t y , i t was d i f f i c u l t to i s o l a t e on small s c a l e . OMe 111 69 II.D. Introduction of the A x i a l Methyl Group at C-6 Conjugate addition to a,B-unsaturated lactone 110 using the higher order mixed organocuprate, Me2Cu(CN)LI 2, yielded the expected lactone 112 with an a x i a l methyl group as shown i n Scheme 38. A s l i g h t l y modified version of the a c e t i c acid - ethylenediaminetetraacetic acid work-up developed during the model study was used, r e s u l t i n g i n a very good y i e l d of product. A simple Kugelrohr d i s t i l l a t i o n of the crude product yielded an a n a l y t i c a l l y pure sample. a) Me 2 Cu(CN)Li 2 , E t 2 0 b) AcOH 0 c) EDTA, tetrasodium salt d) aqueous work-up - Q Q OMe 9 1 % 0 M e Scheme 38. Higher order mixed organocuprate reaction with a,8-unsaturated lactone 110 to y i e l d the methyl lactone 112. For the cuprate reaction, the reaction temperatures which had given the highest r a t i o of a x i a l to equatorial methyl lactones during the model study were used. F i f t e e n minutes a f t e r the s t a r t i n g material was added to the cuprate solution at -78°C, the temperature was raised to -40°C. C a p i l l a r y glc analysis indicated that the reaction was complete within 30 minutes at -40°C and i t also showed that the reaction was very clean. C a p i l l a r y glc and *H nmr data gave no evidence for formation of the equatorial methyl Isomer. 70 Data from the LE nmr spectrum of methyl lactone 112 support the stereochemical assignment at C-6. The H-5, H-7a and H-78 protons were assigned by t h e i r chemical s h i f t s and by c o r r e l a t i o n with the corresponding signals of the model a x i a l methyl lactone 82. As shown i n Figure 4, the coupling constants of the a x i a l protons H-5 and H-7cc with H-6 are only 5 and 7 Hz, r e s p e c t i v e l y . Trans- d i a x i a l proton coupling constants i n six-membered rings are t y p i c a l l y 8-10 Hz (68) and therefore we can assume that the a x i a l p o s i t i o n at C-6 i s occupied by the C-methyl group, not H-6. Figure 4. The coupling constants which allowed the stereochemical assignment of C-6 i n methyl lactone 112. The stereochemical outcome of the cuprate addition to a , 8 -unsaturated lactone 110 can be r a t i o n a l i z e d by the same stereoelectronic and conformational arguments which were discussed for the model system (see pp. 45-48). Since none of the equatorial methyl lactone was obtained i n the fragment A system, the energy difference between the t r a n s i t i o n states leading to the a x i a l and equatorial methyl lactones must be larger than i t was for the model system. 71 At this point i n the synthesis of fragment A we had completed the portion of the route which was based on the model study and we were w e l l on the way to modifying each of the six carbons of D-glucose. II.E. Introduction of the A x i a l Methyl Group at C-4 Following the l i t e r a t u r e precedent of Sum and Weiler (18), as discussed i n the Introduction, our plan was to introduce the C-4 methyl by hydrogenation of an exocyclic methylene group at C-4. In order to accom-p l i s h t h i s , i t was necessary to open the lactone ring while r e t a i n i n g the pyranoside r i n g . Reduction of la c t one 112 with diisobutylaluminum hydride (DIBAL) yielded the water soluble d i o l 113 as shown l n Scheme 39. The best work-up for this reaction was a procedure published by Trost, McDougal and Hall e r (69) i n which the aqueous washing of the organic layer was kept to an absolute minimum. D i o l 113 was treated with one molar equivalent of p i v a l o y l 2 chloride i n pyridine to y i e l d the monopivaloate ester 114. Even though p i v a l o y l chloride generally reacts s e l e c t i v e l y with primary alcohols (70), when excess p i v a l o y l chloride was used (e.g. 1.5 molar equivalents), the dipivaloate ester 115 was also formed. P i v a l o y l chloride i s a common name f o r 2,2-dimethylpropanoyl chloride or trlmethylacetyl c h l o r i d e . 72 115 Scheme 39. Preparation of pivaloate esters 114 and 115 from methyl lactone 112. 73 The C-4 hydroxyl group of 114 was oxidized using the Swern condi-tions (35) to y i e l d ketone 116 as shown i n Scheme 40. The C o l l i n s oxidation used by Sum and Weiler (18) gave lower y i e l d s than the Swern oxidation. Ketone 116 was then treated with the active methylene complex, CH 2Br 2-Zn-TiCli + (48,49), to y i e l d o l e f i n 117. H7 OMe Scheme 40. Preparation of o l e f i n 117 from alcohol 114. Following the precedent of Sum and Weiler (18), hydrogenation of the exocyclic o l e f i n using the homogeneous Wilkinson's c a t a l y s t , RhCl(PPh 3) 3, was anticipated to occur from the bottom face to y i e l d an a x i a l methyl group at C-4. The s t e r e o s e l e c t i v i t y was expected because a highly disfavoured 1,3-diaxial Interaction with the methyl at C-2 would occur i f the ca t a l y s t approached from the top face as shown i n Figure 5. 74 _ | _ C O ^ A . H = R 117 Figure 5. Catalyst approach to the two faces of o l e f i n 117. During several attempts to hydrogenate o l e f i n 117 using Wilkinson's c a t a l y s t , the reaction would proceed well for approximatley 1 h, and then the benzene sol u t i o n would turn black and the reaction would stop. The reaction seemed to be very clean by c a p i l l a r y g l c , but i t stopped at 45-67% completion. The s t a r t i n g material and product formed one spot on t i c and therefore i t would have been very d i f f i c u l t to p u r i f y the crude product. The reason for the ca t a l y s t f a i l u r e eluded us at this point, so a l t e r n a t i v e methods for hydrogenating the double bond were investigated. Hydrogenation using the heterogeneous catalyst rhodium-on-alumina i n methanol - e t h y l acetate, or benzene gave a mixture of products. Diimide reduction using p_-toluenesulfonyl hydrazide and sodium acetate i n wet THF under r e f l u x (71) seemed to be highly s t e r e o s e l e c t i v e . However, the reaction took i n excess of 16 h to go to completion and by this time other by-products were forming i n the reaction mixture. Hydroboration using an excess of borane i n THF, followed by an oxidative work-up yielded alcohol 118 i n good y i e l d , as shown i n Scheme 41. 75 a) B H 3 • THF b) H 2 0 2 , NaOH, H 2 0 HO 82% 117 OMe 118 OMe H = R Scheme 41. P r e p a r a t i o n of a l c o h o l 118 by h y d r o b o r a t i o n of o l e f i n 117. c o u l d be d e t e c t e d by c a p i l l a r y g l c or ^H nmr. P r o t o n nmr d e c o u p l i n g e x p e r i m e n t s e s t a b l i s h e d t h a t the c o u p l i n g c o n s t a n t between H-4 and H-5 i s 4 Hz, c o n s i s t e n t w i t h an e q u a t o r i a l - a x i a l r e l a t i o n s h i p between these p r o t o n s . Even though t h i s r e a c t i o n seemed p r o m i s i n g , we d i d not w i s h t o i n t r o d u c e a h y d r o x y l group which would have to be removed l a t e r . P r o t o n o -l y s i s of the i n t e r m e d i a t e a l k y l borane was a p o s s i b i l i t y , but the c o n d i -t i o n s f o r t h i s r e a c t i o n i n v o l v e h e a t i n g the s u b s t r a t e w i t h a c a r b o x y l i c a c i d (72) and we a n t i c i p a t e d t h a t t h i s would r e s u l t i n c l e a v a g e of the p y r a n o s i d e r i n g and e p i m e r i z a t i o n at C-2. c a t a l y s t , R h C l ( P P h 3 ) 3 . Study of an e a r l y paper by Osborn, J a r d i n e , Young and W i l k i n s o n ( 7 3 ) , i n d i c a t e d t h a t the d i f f i c u l t i e s we had e n c o u n t e r e d were c o n s i s t e n t w i t h the f o r m a t i o n of a b r i d g e d dimer, which i s c a t a l y t i -c a l l y i n a c t i v e . As shown i n Scheme 42, the c a t a l y s t i s b e l i e v e d to d i s s o c i a t e i n s o l u t i o n and then absorb one e q u i v a l e n t of hydrogen to y i e l d The h y d r o b o r a t i o n was h i g h l y s t e r e o s e l e c t i v e ; no o t h e r isomer T h e r e f o r e , we d e c i d e d to r e i n v e s t i g a t e the use of W i l k i n s o n ' s 76 the yellow, active hydrido species, RhCl(PPh 3) 2H 2. I f the sol u t i o n i s too concentrated, or i f there i s i n s u f f i c i e n t hydrogen dissolved i n the sol u t i o n , dimerization occurs to y i e l d the brown, inactive species, [ R h C l ( P P h 3 ) 2 ] 2 . During our f i r s t t r i a l reactions either of these scenarios could have caused the problem, because we were working on small scale, using 1 to 3 mL of solvent. The reaction mixture may have become too concen-trated due to evaporation of solvent or, more l i k e l y , the solvent was inadequately saturated with hydrogen due to i n e f f i c i e n t s t i r r i n g . R h C I ( P P h 3 ) 2 H 2 yellow H. R h C I ( P P h 3 ) 3 r e d b e n z e n e R h C I ( P P h 3 ) 2 + P P h 3 [ R h C I ( P P h 3 ) 2 ] 2 dark r e d - b r o w n Scheme 42. Various species a r i s i n g from Wilkinson's c a t a l y s t i n benzene under hydrogen. The problem of dimerization was suc c e s s f u l l y countered by using a gas dispersion tube to bubble hydrogen continuously through the reaction mixture and by increasing the molar equivalents of c a t a l y s t used. (The concentration of c a t a l y s t was kept at approximately 1 x 10~ 2 M.) Complete hydrogenation of o l e f i n 117 was effected, as shown i n Scheme 43, providing 77 the solution remained ei t h e r yellow or pale orange-red during the course of the reaction. C a p i l l a r y glc of the product indicated that i t consisted of a major product in 91% y i e l d , as well as a number of minor products, including one present i n 4% y i e l d . We were not able to i s o l a t e the minor products or i d e n t i f y them by *H or * 3C nmr, but allowing that any one of them may have been due to the C-4 eplmer, the s t e r e o s e l e c t i v i t y was at least 23:1. Scheme 43. Hydrogenation of o l e f i n 117 using Wilkinson's c a t a l y s t . The stereochemistry of the hydrogenated product 119, which was expected on mechanistic grounds, i s supported by the spectroscopic data. In the *H nmr spectrum, the one proton doublet at 6 4.26, with a coupling constant of 4 Hz, i s assigned to H-1 and c l o s e l y resembles H-1 of o l e f i n 117 i n both chemical s h i f t and coupling pattern, i n d i c a t i n g retention of the ^C^ chair conformation. The * 3C nmr spectrum of 119 showed only three signals u p f i e l d from 6 25 and two of these, peaks at 6 15.22 and 6 15.56, are a t t r i b u t e d to the a x i a l methyl groups at C-2 and C-4. (Recall the established rule that a x i a l methyl groups i n cyclohexane rings normally have 1 3 C nmr signals at 6 15 - 18 whereas the corresponding equatorial 78 methyl groups are usually found at 6 18 - 25 (54).) The calculated chemical s h i f t for the C-6 methyl i s 6 21.63 (74), and therefore the t h i r d s i g n a l at 6 19.14, i s at t r i b u t e d to th i s methyl group. At this stage of the synthesis, the three required methyl groups had been introduced. II.F. Opening the Pyranoside Ring The pyranose ri n g was no longer needed and could be opened to y i e l d the a c y c l i c chain. Thus treatment of compound 119 with 1,3-propane-d i t h i o l and boron t r i f l u o r i d e etherate i n dichlororoethane afforded dithiane 120 as shown i n Scheme 44. In keeping with the l i t e r a t u r e precedent (18), no epimerization of the C-2 methyl group was observed. Our objective to prepare a carbon chain with three pendent methyl groups having the correct r e l a t i v e and absolute stereochemistry for fragment A was achieved. Scheme 44. Opening the pyranoside r i n g to y i e l d hydroxy dithiane 120. II.G. Deoxygenation at C-5 Deoxygenation at C-5 was effected following a procedure developed by Fujimoto and Tatsuno (75) as shown i n Scheme 45. In order to prepare 79 124 (10%) Scheme 45. Deoxygenation at C-5 of hydroxy dithiane 120. the mesylate of the hindered alcohol at C-5, i t was necessary to treat hydroxy dithiane 120 with excess methanesulfonyl chloride and t r i e t h y l -amine i n methylene chloride overnight. A l l attempts to prepare the corresponding tosylate were unsuccessful. The crude mesylate 121 was 80 reduced using sodium iodide and fr e s h l y activated zinc dust i n wet dimethoxyethane, heated under r e f l u x . The desired product, compound 122, was i s o l a t e d i n about 25% y i e l d but the *H nmr spectrum indicated that i t was contaminated with about 15% of ol e f i n - c o n t a i n i n g material which i s presumed to be a mixture of double bond isomers 123. The low and high reso l u t i o n mass spectrometry data indicate molecular ions corresponding to both 122 and 123. In addition, the isomeric d i t h i o a c e t a l 124 was obtained i n 10% y i e l d . Less than 2 mg of 124 was i s o l a t e d , so i t s *"H nmr spectrum i s poor. However, i t d i f f e r s from that of 122 i n two s i g n i f i c a n t regions. F i r s t , the peaks u p f i e l d of 6 1.2, which correspond to the methyl groups, have a d i f f e r e n t shape and integration of this region indicates an extra methyl group i n compound 124. Second, inte g r a t i o n of the signals at approximately 6 2.5 - 3.0, which correspond to protons on a carbon adjacent to a sing l e s u l f u r , indicates only three protons for compound 124 i n contrast to four protons for dithiane 122. Additional support for the suggested structure i s given by mass spectrometry as both 122 and 124 have the same molecular weight, but only compound 124 shows a fragment ion at M+-75. This corresponds to the loss of an n-propylsulfide fragment, which i s expected for d i t h i o a c e t a l 124. The low y i e l d i n the deoxygenation reaction and the formation of d i t h i o a c e t a l 124 can both be at t r i b u t e d to an intramolecular displacement of the mesylate or iodide at C-5 by one of the dithiane s u l f u r s . This would r e s u l t i n the sulfonium s a l t 125 (76) as shown i n Scheme 46. 81 124 126 Scheme 46. A possible mechanism for the formation of d i t h i o a c e t a l 124 from mesylate 121. Nucleophilic attack at the least hindered carbon adjacent to the charged s u l f u r would lead to 126. Reduction of 126 would y i e l d 124. In support of t h i s hypothesis, the *H nmr spectrum of the crude reaction product shows a multiplet i n the range of 6 3.65 - 3.85, which agrees with published chemical s h i f t s of 6 3.80 - 3.85 for methylene protons adjacent to a p o s i t i v e l y charged s u l f u r (77). In addition, the weight balance of the crude reaction product was approximately 95% but 82 the r e c o v e r y of m a t e r i a l f o l l o w i n g the c h r o m a t o g r a p h i c p u r i f i c a t i o n was v e r y low. T h i s s u g g e s t s t h a t s a l t s , which d i d not e l u t e from the column, were p r e s e n t i n the crude p r o d u c t . We attempted to f i n d an a l t e r n a t i v e d e o x y g e n a t i o n p r o c e d u r e u s i n g , as a model, the a l c o h o l 2 , 4 - d i m e t h y l p e n t a n - 3 - o l (12 7 ) . T h i s a l c o h o l was OH 127 an a p p r o p r i a t e model because, l i k e a l c o h o l 120, i t s m e s y l a t e c o u l d be p r e p a r e d but the h y d r o x y l group was too h i n d e r e d f o r p r e p a r a t i o n of the t o s y l a t e . A t t e m p t s to p r e p a r e the t r i f l a t e from a l c o h o l 12 7 (78) or t o p r e p a r e the i o d i d e by t r e a t m e n t of the m e s y l a t e w i t h sodium i o d i d e i n acetone (79) y i e l d e d a v o l a t i l e p r o d u c t which was presumed to be the c o r r e s p o n d i n g o l e f i n . A n o t h e r attempt to p r e p a r e the i o d i d e from the a l c o h o l u s i n g N - m e t h y l - N , N ' - d i c y c l o h e x y l c a r b o d i i m i d i u m i o d i d e (80) f a i l e d to g i v e complete r e a c t i o n , even a f t e r 2 d a y s . We t h e r e f o r e c o n c e n t r a t e d our a t t e n t i o n on the m e s y l a t e . A number of p r o c e d u r e s f o r r e d u c i n g the m e s y l a t e were t r i e d and the r e a c t i o n s were m o n i t o r e d by c a p i l l a r y g l c u s i n g an i n t e r n a l s t a n d a r d . R e d u c t i o n of the m e s y l a t e u s i n g e i t h e r sodium b o r o h y d r i d e i n DMSO at 50-70°C o v e r n i g h t (81) or e x c e s s l i t h i u m t r i e t h y l b o r o h y d r i d e i n THF at room t e m p e r a t u r e o v e r n i g h t (82) was not s u c c e s s f u l . S c h r i e b e r and Wang 83 subsequently published t h e i r synthesis of a fragment A type molecule (9) i n which a deoxygenation was effected i n 95% y i e l d on a s i m i l a r mesylate using l i t h i u m aluminum hydride i n ether at 0°C for 2 days. The tri-n-butylstannane deoxygenation procedure of Robins, Wilson, and Hansske (65) was also t r i e d . The phenoxythiocarbonate ester of alcohol 127 was prepared (65,66) and complete deoxygenation proceeded smoothly. However, a separate competition reaction i n the presence of a model dithiane showed that the dithiane moiety would not withstand these reaction conditions. While not a l l of the possible deoxygenation methods were i n v e s t i -gated (83), we had established that several procedures were viable providing there was no dithiane moiety present i n the molecule. We there-fore decided that i t would be best to postpone the deoxygenation at C-5 u n t i l fragments A and B were coupled and the r e s u l t i n g d i t h i o k e t a l was hydrolyzed. The choice of protecting group for the C-5 hydroxyl group w i l l be discussed s h o r t l y . I I . H . Strategy for Homologation of the Fragment A Precursor We wished to accomplish one a d d i t i o n a l synthetic transformation on the fragment A precursor p r i o r to coupling i t with fragment B. As defined i n the Introduction, fragment A i s nine carbons long whereas the carbon backbone i s only eight carbons long at this stage of the synthesis. Our plan was to use the potassium s a l t of the anion of 2-cyano-l,3-dithiane (128) to e f f e c t a one carbon homologation. 84 a) KH OR n S S n n s s OR S S N = C N = C 128 Some advantages of this strategy are as follows: 1) the use of reagent 128 would allow us to introduce the carbon at the carboxylic acid oxidation l e v e l , 2) the alkylated product would have no a c i d i c protons which are known to i n t e r f e r e during the coupling of fragments A and B (12), 3) the cyanodithiane moiety can be hydrolyzed under mild conditions to y i e l d the carboxylic acid d i r e c t l y , and 4) hydrolysis of the cyanodithiane and dithiane moieties could be accom-plished simultaneously for an e f f i c i e n t double deprotection, a f t e r the coupling to fragment B. the cyano group In compound 129 to y i e l d the corresponding Imine 130 under the conditions required for coupling fragments A and B. Therefore, we chose to leave the one carbon homologation u n t i l a f t e r the coupling. Unfortunately, model studies showed that n-butyllithium adds to 85 We then checked the s t a b i l i t y of the p i v a l o a t e e s t e r p r o t e c t i n g group at C-8 to see i f i t would w i t h s t a n d the c o u p l i n g c o n d i t i o n s . D e s p i t e the f a c t t h a t the p i v a l o a t e e s t e r c a r b o n y l i s a n e o p e n t y l c e n t r e , i t i s s u s c e p t i b l e to a d d i t i o n o f n - b u t y l l i t h i u m . In model s t u d i e s , a p p r o x i m a t e -l y 40% of a model p i v a l o a t e e s t e r was d e s t r o y e d d u r i n g d e p r o t o n a t i o n of a model d i t h i a n e u s i n g the d e p r o t o n a t i o n c o n d i t i o n s d eveloped by S h e l l y ( 1 2 ) . T h e r e f o r e , t h i s p r o t e c t i n g group was u n s u i t a b l e and would have to be changed on the fragment A p r e c u r s o r . I I . I . P r o t e c t i o n o f the C-5 and C-8 H y d r o x y l Groups o f the Fragment A P r e c u r s o r The s e l e c t i o n o f p r o t e c t i n g groups f o r the C-5 and C-8 h y d r o x y l groups was made a f t e r l i t e r a t u r e s e a r c h e s and model s t u d i e s . We wanted to choose two p r o t e c t i n g groups f o r the h y d r o x y l groups at C-5 and C-8 of fragment A which c o u l d be s e l e c t i v e l y removed i n the presence of each o t h e r , and i n the p r e s e n c e of the t e r t - b u t y l d i m e t h y l s i l y l (TBDMS) e t h e r a l r e a d y p r e s e n t i n fragment B ( 1 2 ) . For C-5 we chose the 2-methoxyethoxy-m e t h y l (MEM) e t h e r (85) and f o r C-8 we chose the t e r t - b u t y l m e t h o x y p h e n y l -s i l y l (TBMPS) e t h e r ( 8 6 ) . The t e r t - b u t y l d i m e t h y l s i l y l group c o u l d be s e l e c t i v e l y h y d r o l y z e d under m i l d l y a c i d i c c o n d i t i o n s (85,86), the 2-methoxyethoxymethy1 e t h e r c o u l d be s e l e c t i v e l y removed u s i n g the Lewis a c i d c a t a l y s t z i n c bromide (85), and the t e r t - b u t y l m e t h o x y p h e n y I s i l y l e t h e r c o u l d be s e l e c t i v e l y c l e a v e d u s i n g f l u o r i d e ( 8 6 ) . Thus, at a l a t e r s t a g e we would have the o p t i o n of d e p r o t e c t i n g the t h r e e h y d r o x y l groups 86 i n any order, to accommodate changes in the synthet ic plan for ionomycin. The f i n a l steps in the synthesis of the fragment A precursor are out l ined in Scheme 47. Alcohol 120 was treated with 2-methoxyethoxymethy1 ch lor ide and N-ethyldi i sopropylamine in dichloromethane (85) to y i e l d compound 131. The pivaloate ester group was cleaved by reduct ion with l i th ium aluminum hydride and the r e s u l t i n g a lcohol 132 was treated with te r t -buty lmethoxyphenyl s i ly l bromide and tr iethylamine in dichloromethane (86) to y i e l d 133, the fragment A precursor . 120 MEMO TBMPSO MeO'VOvCI . o S S Et ( i -Pr)2N, CH 2 CI 2 , 11 - -f-co 100% OMe Ph-SiBr , P s E t 3 N - C H 2 C I 2 54% MEMO n S S 131 LiAIH 4 86% MEMO n S S 133 132 Scheme 47. Protect ion of the C-5 and C-8 hydroxyl groups to y i e l d the fragment A precursor 133. 87 Despite our apparently c a r e f u l planning i n choosing the three d i f f e r e n t protecting groups for fragments A and B, we made a poor decision i n choosing the tert-butylmethoxyphenylsilyl group. The y i e l d of 54% i n the l a s t step of Scheme 47 Is the p u r i f i e d y i e l d of s i l y l a c e t a l 133 a f t e r chromatography. No mention of the s i l y l acetal i n s t a b i l i t y on s i l i c a gel was mentioned i n the o r i g i n a l p u b l i c a t i o n (86) and we lo s t nearly half of our material during chromatography of the crude reaction product. None-t h e l e s s , we had approximately 35 mg of this material to use i n the coupling reaction. 88 I I I . Synthesis of Fragment B f o r Ionomycin Fragment B was prepared following the route developed by Shelly (12) although some minor changes were made i n the work-up and p u r i f i c a t i o n of some intermediates, as described i n the Experimental s e c t i o n . In addition, we resolved the intermediate acid ester b_ so that the o p t i c a l l y a ctive fragment B was prepared. The synthesis of fragment B was described b r i e f l y i n the Introduction (see pp. 9-12) and only s a l i e n t points w i l l be discussed here. Scheme 48 shows the f i r s t three steps of the synthesis. Meso-2,4-g l u t a r i c anhydride (5) was prepared i n 95% pu r i t y with the other 5% consi s t i n g p r i m a r i l y of the (±)-anhydride as indicated by c a p i l l a r y g l c . Methanolysis of anhydride 5_ gave an excellent y i e l d of acid ester 6_. This acid was then resolved by r e c r y s t a l l i z a t i o n of the diastereomeric s a l t s 0 0 0 E t O ^ Y ^ O E t + E t O ^ Y B r 1 3 4 1 3 5 ) NaOH, Et ) H + , H20, OH 0 20,A 0 97% HO 0 HO 6 OMe MeOH, A OH 1 3 6 a) Ac20, A b) recryst-allization from EtOAc 99% 2 8 % Scheme 48. Preparation of the racemic acid ester 6. 89 formed by treatment with (+)-a-methylbenzylamine, according to the procedure of Masamune (87). The o p t i c a l r o t a t i o n of the resolved acid was -4.2°. This value i s s l i g h t l y lower than the l i t e r a t u r e values of -5.2° (87) and -4.8° (88,89), but i s comparable to +4.0° reported f o r the enantiomer of 6_ (90). Preparation of o l e f i n 12, as shown i n Scheme 49, afforded a product which was 83% pure by c a p i l l a r y g l c . Of the remaining 17%, 11% consisted of a mixture of isomers which arose from the (i)-anhydride. During the r e s o l u t i o n of acid ester h_ the isomers a r i s i n g from the (±)-anhydride must have c o - c r y s t a l l i z e d with the desired o p t i c a l isomer r e s u l t i n g i n a concentration of these unwanted diastereomers. Ester 12_ was reduced to alcohol 1_3 which was then protected as the t e r t - b u t y l d i m e t h y l s i l y l ether 14. P u r i f i c a t i o n of this product by chroma-tography on s i l i c a g e l , using petroleum ether as eluant, e f f e c t i v e l y separated the unwanted diastereomers from the mixture. C a p i l l a r y g l c analysis of the p u r i f i e d product indicated that the proportion of the desired isomer had been increased to 98% and the unwanted diastereomers h a d been reduced to approximately 2%. The f i n a l step involved treatment of alkene 1_4 with m-chloroper-benzoic acid to y i e l d a 2:1 mixture of epimeric epoxides 15. These epimers could both be used since the epimeric centre would subsequently be oxidized to a f f o r d a ketone group. With the o p t i c a l l y active fragment B prepared, we were ready to couple i t with the fragment A precursor. 90 0 0 HO 6 resolved OMe (C0CI) 2 . DMF, benzene 69% Cl 0 0 OMe 0 OMe CH 2 Br 2 -Zn-T iC l4 f CH 2 C l 2 78% H 2 , P d - C 2,6-dimethyl-pyridine, THF 12 o o OMe 8 LiAIH 4, ether 54% 13 TBDMSOTf. CH 2 CI 2 , 2,6-dimethylpyridine 72% < ; : ; : Y N Y ^ 0 T B D M S 14 MCPBA, C H 2 C I 2 66% 0 H OTBDMS 15 Scheme 49. Preparation of fragment B from the resolved acid ester j6. 91 IV. C o u p l i n g o f the Fragment A P r e c u r s o r and Fragment B U s i n g models f o r fragments A and B, S h e l l y had found the r e a c t i o n c o n d i t i o n s f o r the s u c c e s s f u l c o u p l i n g of these two fragments (12) as d e s c r i b e d i n the I n t r o d u c t i o n . Our i n t e n t i o n was to ap p l y these c o n d i t i o n s t o the c o u p l i n g of 133 and 15. TBMPSO OTBDMS 133 15 IV.A. Attempted C o u p l i n g o f D i t h i a n e 133 w i t h Epoxide 15 D i t h i a n e 133 was t r e a t e d w i t h 1.1 molar e q u i v a l e n t s of n - b u t y l -l i t h i u m i n a s o l v e n t m i x t u r e of TMEDA, HMPA and THF to e f f e c t d e p r o t o n a -t i o n . A f t e r the p r e s c r i b e d amount of time at the a p p r o p r i a t e t e m p e r a t u r e s , 1.1 m o l a r e q u i v a l e n t s of the epo x i d e m i x t u r e 15 were added as a s o l u t i o n i n THF. Two and a h a l f hours l a t e r the r e a c t i o n was quenched, worked-up and the crude p r o d u c t was chromatographed but none of the d e s i r e d p r o d u c t was i s o l a t e d . I n s t e a d , as shown i n Scheme 50, a s m a l l amount of a b y - p r o d u c t , the n - b u t y l - t e r t - b u t y l p h e n y l s i l y l (NBTBPS) e t h e r 137 was i s o l a t e d , a l o n g w i t h s t a r t i n g m a t e r i a l . Once a g a i n , the t e r t - b u t y l m e t h o x y p h e n y l s i l y l e t h e r p r o t e c t i n g group proved to be a g r e a t d i s a p p o i n t m e n t . T h i s p r o t e c t i n g group r e a c t s w i t h n - b u t y l l i t h i u m d e s p i t e a m i s l e a d i n g s t atement to the c o n t r a r y i n the 92 TBMPSO 1 3 3 a) n-BuLi, HMPA, THF b) HMPA c) E^Y^OTBDMS 15 NBTBPSO - • • 1 3 7 (5%) 1 3 3 (40%) Scheme 50. Attempted coupling of the fragment A precursor 133 with the epoxide mixture 15. o r i g i n a l paper (86). To make matters worse, more than half of the fragment A precursor was lo s t during chromatography of the crude reaction product. We now had approximately 16 mg of the fragment A precursor. Even though less than 2 mg of s i l y l ether 137 was i s o l a t e d , i t could be i d e n t i f i e d . T i c shows i t to be less polar than s i l y l acetal 133, consistent with the fact that a methoxy group has been exchanged for an ii-butyl group. In the *H nmr spectrum three d i s t i n c t differences from the spectrum of s i l y l a c etal 133 are notable. For s i l y l ether 137 there i s no 93 methoxy peak att r i b u t e d to the s i l y l a c e t a l , the t e r t - b u t y l group i s sh i f t e d u p f i e l d by 0.08 ppm and integration of the spectrum shows a greater number of protons i n the a l i p h a t i c region. The mass spectrometry data show a very small molecular ion peak corresponding to the correct mass for 137. There i s l i t e r a t u r e precedent for n u c l e o p h i l i c attack of n-butyl-lithium on s i l y l acetals and a review has been published which discusses the mechanism of displacement at s i l i c o n (91). By analogy with examples given i n this review, the mechanism for our reaction could be envisaged as shown i n Scheme 51. Two pathways are shown because displacements with alky1lithiums generally show a lack of s e l e c t i v i t y and either alkoxide could act as the leaving group. Smaller leaving groups are displaced p r e f e r e n t i a l l y and therefore we would expect the pathway leading to 137 to be the major pathway. IV.B. Preparation of the Second Fragment A Precursor The tert-butylmethoxyphenylsilyl group was not suitable for the fragment A precursor so i t was exchanged for the t e r t - b u t y l d i m e t h y l s i l y l group. The s i l y l a c e t a l of 133 was s e l e c t i v e l y removed with tetra-n_-butylammonium f l u o r i d e i n THF (86) to y i e l d alcohol 132 as shown i n Scheme 52. Alcohol 132 was then treated with t e r t - b u t y l d i m e t h y l s i l y l t r i f l a t e and 2,6-dimethylpyridine i n dichloromethane (47) to y i e l d s i l y l ether 138. 94 + Ph MEMO -Si-0 + e 1 3 7 OMe Ph-Si-^O major pathway A(OMe MEMO 1 3 3 Ph i minor pathway MEMO Si-OMe + w O Scheme 51. Mechanism for the formation of s i l y l ether 137 from s i l y l a c e t a l 133. 95 MEMO TBMPSO Q-Bu 4 NF, THF 100% 1 3 3 MEMO 1 3 2 TBDMSO TBDMSOTf, 2,6-dimethyl-pyridine, CH2 CI2 87% MEMO 1 3 8 Scheme 52. Preparation of the second fragment A precursor 138. IV.C. Successful Coupling of Dithiane 138 and Epoxide 15. With the new fragment A precursor prepared, we were ready to attempt the coupling again. Studies with a model dithiane indicated that we would need to a l t e r the conditions which Shelly had used (12) because we had only 11 mg (0.022 mmol) of the new fragment A precursor. In p a r t i c u l a r , i t was best to omit the use of THF, and to use excess n-butyl-l i t h i u m ( i n hexanes), TMEDA and HMPA to eff e c t complete metallation on this small s c a l e . To check these conditions, dithiane 138 was treated 96 with 20 molar equivalents each of n-butyllithium (in hexanes) and TMEDA, and the c h a r a c t e r i s t i c amber colour of the dithiane anion was observed (12). After 1 h, the anion was quenched with deuterium oxide to af f o r d a quantitative y i e l d of the deuterated dithiane 139 as shown i n Scheme 53. The *H nmr spectrum of this product showed no peak at 6 4.15 proving that the dithiane proton had been completely exchanged for deuterium. The quantitative y i e l d Indicated that 138 was able to withstand the deprotonation conditions. The deuterated dithiane 139 was metallated again under i d e n t i c a l conditions, followed by the addition of excess HMPA and 12 molar equivalents of the neat epoxide mixture 15. Aft e r two days, work-up of the reaction mixture and chromatography of the crude product afforded an 80% recovery of the epoxide mixture 1_5_ and a 40% y i e l d of the hydroxy dithiane mixture 140. The product 140 i s characterized by a s l i g h t l y lower than dithiane 138 by t i c , as an t i c i p a t e d . The inf r a r e d data show a weak hydroxyl absorption and the *H nmr data show two t e r t - b u t y l peaks - one for each s i l y l ether. The most d e f i n i t e proof that coupling was achieved comes from the mass spectrometry data which show peaks at m/z_ 752 corresponding to the molecular ion, m/z_ 734 corresponding to the loss of water and m/z 695 corresponding to the loss of a t e r t - b u t y l group. 97 T B D M S O T B D M S O M E M O 1 3 8 a) n-BuLi, T M E D A b) D 2 0 100% M E M O 1 3 9 a) n-BuLi, T M E D A b) H M P A Q H c) ^ T o T B D M S 15 40% M E M O T B D M S O O T B D M S 1 4 0 Scheme 53. Deuteration of dithiane 138 and the subsequent coupling with fragment B to y i e l d the hydroxy dithiane mixture 140. 98 IV.D. Conclusion Coupling of the o p t i c a l l y active fragment A precursor and fragment B yielded the carbon frame work for C-2 to C-15 of ionomycin. In the course of the synthesis, f i v e pendent methyl groups were Introduced with the correct r e l a t i v e and absolute stereochemistry. To complete the carbon frame work, a one carbon homologation at the carboxylic acid oxidation l e v e l needs to be effected at the terminal end of the fragment A portion of the coupled product. The masked ketone needs to be deprotected and the r e s u l t i n g epimeric 8-hydroxy ketone moiety needs to be oxidized to y i e l d a B-diketone. F i n a l l y , the carbon backbone must be deoxygenated at "C-5". Model studies for a l l of these procedures have been c a r r i e d out In our laboratory. Hopefully, t h i s model study work can be applied to complete the synthesis of C-1 to C-15 of ionomycin. This portion could then be coupled to fragments C and D to achieve the t o t a l synthesis of our ultimate target, ionomycin. 99 EXPERIMENTAL I. General In this general section the following are described: p u r i f i c a t i o n methods for solvents and reagents, procedures for the set-up and the work-up of reactions, techniques for the analysis and the p u r i f i c a t i o n of products, the instruments used for spectroscopic c h a r a c t e r i z a t i o n of products, and the formats for reporting spectroscopic data. Dry solvents and pure reagents were prepared as described i n Table I I . If no d i r e c t comment i s made about p u r i f i c a t i o n , then a reagent was used as obtained from the su p p l i e r . Petroleum ether was of b o i l i n g range ca_. 30-60°C. Methyllithium ( i n ether) and n-butyllithium ( i n hexanes) were obtained from A l d r i c h Chemical Co. The a l k y l l i t h i u m s were standardized by t i t r a t i o n against 1,3-diphenyl-2-propanone p_-tosyl-hydrazone i n THF (92). Although a l l reactions should be c a r r i e d out i n the fume hood, attention i s drawn only to those i n which the reagents or products have high t o x i c i t y or stench. For a l l moisture s e n s i t i v e reactions, glassware was oven-dried and cooled under a stream of nitrogen before use. Nitrogen was dried by passing i t through a column of i n d i c a t i n g D r i e r i t e . Reactions were s t i r r e d at room temperature unless s p e c i f i c temperature conditions are mentioned. Cold temperature baths were prepared as follows: -78°C (dry i c e - acetone), -60°C (dry i c e - chloroform), -40°C 100 Table I I . Drying and p u r i f i c a t i o n of solvents and reagents Solvent or Reagent Method of P u r i f i c a t i o n a c e t o n i t r i l e d i s t i l l e d from P 2 0 5 Amberlite IR-120 and Amberlyst 15 washed with 1 M HC1, rinsed with d i s t i l l e d water and dried overnight at 0.05 Torr benzene d i s t i l l e d from L i A l H ^ boron t r i f l u o r i d e etherate treated with ether and d i s t i l l e d from CaH 2 at 67°C/43 Torr (93) copper(I) cyanide dried overnight at 0.05 Torr d i c h l o r o a c e t i c acid dried over anhydrous MgSO,^ decanted and f r a c t i o n a l l y d i s t i l l e d at 95°C/18 Torr dichloromethane d i s t i l l e d from P 2 0 5 1,3-dicyclohexylcarbodlimide (DCC) d i s t i l l e d at 122-124°C/6 Torr 2,6-dimethylpyridine d i s t i l l e d from CaH 2 dimethyl sulfoxide (DMSO) d i s t i l l e d from CaH 2 at 76°C/12 Torr ether d i s t i l l e d from Li A l H ^ or d i s t i l l e d from Na (benzophenone as i n d i c a t o r ) N-ethyldiisopropylamine d i s t i l l e d from CaH 2 hexamethylphosphoramide (HMPA) d i s t i l l e d from CaH 2 at 115°/15 Torr methanesulfonyl chloride d i s t i l l e d from P 2 0 5 at 60°C/21 Torr methanol d i s t i l l e d from Mg(0Me) 2 (93) pyridine d i s t i l l e d from CaH 2 tetrahydrofuran (THF) d i s t i l l e d from L i A l H H N,N,N',N*-tetramethylethylene diamine (TMEDA) d i s t i l l e d from K0H toluene d i s t i l l e d from CaH 2 triethylamine d i s t i l l e d from CaH 2 t r i e t h y l phosphite dried over Na, decanted and d i s t i l l e d at 52°C7 12 Torr (93) zinc dust s t i r r e d with 0.5 M HC1, f i l t e r e d , washed with more aci d , ethanol and ether, and dried at 0.05 Torr (93) 101 dry i c e - a c e t o n i t r i l e ) , -25°C and -10°C (dry i c e - aqueous C a C l 2 ) (94), and 0°C ( i c e - w a t e r ) . S o l v e n t s were evaporated under reduced p r e s s u r e u s i n g a Buchi r o t a r y e v a p o r a t o r f o l l o w e d by vacuum e v a p o r a t i o n (0.05 - 0.1 T o r r ) f o r at l e a s t 20 min. A n a l y t i c a l t h i n l a y e r chromatography ( t i c ) was c a r r i e d out u s i n g commercial, p r e - c o a t e d , aluminum-backed s i l i c a g e l p l a t e s ( s i l i c a g e l 60 F 25i +) s u p p l i e d by E. Merck Co. V i s u a l i z a t i o n was e f f e c t e d by u l t r a v i o l e t f l u o r e s c e n c e (UV), i o d i n e vapour ( l 2 ) , 2 , 4 - d i n i t r o p h e n y l h y d r a z i n e spray (2,4-DNP-hydrazine) (95) or 10% aqueous s u l f u r i c a c i d spray f o l l o w e d by h e a t i n g (H-^SO^). A n a l y t i c a l g l c was performed on a Hewlett Packard model 5880A gas chromatograph u s i n g a 0.2 mm x 12 m column of 3% OV-101 or 10% Carbowax 20M and a flame i o n i z a t i o n d e t e c t o r . F l a s h chromatography (96) was performed u s i n g s i l i c a g e l 230-400 mesh ASTM s u p p l i e d by E. Merck Co. Gums and s o l i d samples were adsorbed onto s i l i c a g e l b e f o r e chromatography. T h i s t e c h n i q u e i n v o l v e d d i s s o l v i n g the sample i n an a p p r o p r i a t e s o l v e n t , adding s i l i c a g e l (sample - s i l i c a g e l c a . 1:1 by weight) and e v a p o r a t i n g the s o l v e n t . Gel f i l t r a t i o n was performed on Sephadex LH-20 s u p p l i e d by Pharmacia. P r e p a r a t i v e gas l i q u i d chromatography ( g l c ) was c a r r i e d out on a V a r i a n Aerograph model 90-P equipped w i t h a 0.25 i n . x 10 f t s t a i n l e s s s t e e l column packed w i t h 5% 0V-17 on Supelco WHP (100-120 mesh). M e l t i n g p o i n t s were determined on a K o f l e r hot stage a p p a r a t u s . B o i l i n g p o i n t s are g i v e n as the a i r - b a t h temperatures r e q u i r e d f o r K u g e l r o h r d i s t i l l a t i o n . M e l t i n g p o i n t s and b o i l i n g p o i n t s are u n c o r -102 recced. O p t i c a l rotations were measured with a Perkin-Elmer 141 p o l a r i -meter at 20-25°C using sodium D l i g h t (589 nm). The solution concentra-tions (c) for s p e c i f i c r o t a t i o n s , la]^> are given i n grams of solute per 100 mL of s o l u t i o n . Infrared spectra were recorded on a Perkin-Elmer model 710B spectrophotometer. Solution spectra were obtained using sodium chloride s o l u t i o n c e l l s of 0.2 mm thickness and are ca l i b r a t e d by means of the 1601 cm - 1 band of polystyrene. The abbreviations used i n quoting the data are: s strong, m medium, w weak, and sh shoulder. A l l nuclear magnetic resonance spectra were taken i n deutero-chloroform s o l u t i o n . Proton nuclear magnetic resonance (*H nmr) spectra were recorded on a Varian EM 360L (60 MHz), a Bruker WP-80 (80 MHz), HXS-270 (270 MHz) or WH-400 (400 MHz) instrument. Signal positions are given i n parts per m i l l i o n downfield from i n t e r n a l tetramethylsilane (TMS) on the 6 scale for a l l compounds except those containing the t e r t - b u t y l -d i m e t h y l s i l y l group. In these cases the chemical s h i f t s are measured r e l a t i v e to chloroform (6 7.27). Signal m u l t i p l i c i t y , coupling constants and i n t e g r a t i o n r a t i o s are indicated i n parentheses. The abbreviations used i n quoting the data are: b broad, s s i n g l e t , d doublet, t t r i p l e t , q quartet, and m mu l t i p l e t . The chemical s h i f t s and coupling constants quoted for complicated coupling patterns are measured from the appropriate peaks i n the *H nmr spectra and hence may not exactly correspond to the true values (97). In cases where a mixture of isomers was obtained, the spe c t r a l data are reported only for the major isomer, unless otherwise stated. 103 Carbon-13 nuclear magnetic resonance ( l dC nmr) spectra were recorded on a Bruker WH-400 (100 MHz) and chemical s h i f t s are reported on the 6 scale r e l a t i v e to i n t e r n a l TMS. Low r e s o l u t i o n mass spectra were determined on either a Varian MAT model CH4B or a Kratos-AEI model MS 50 mass spectrometer. Only the parent peak and peaks having a r e l a t i v e i n t e n s i t y greater than twenty percent of the base peak are reported, unless peaks with lower i n t e n s i t y are s t r u c t u r a l l y diagnostic. The peak with the highest m/z_ i s assigned as either the molecular ion (M*) or as a fragment of the molecular ion. Relative i n t e n s i t i e s are reported in parentheses a f t e r the m/z_ value for each peak. Observed metastable peaks (m*) are reported, and the calculated values for the metastable peak r e s u l t i n g from the fragmentation process 2m^+ •* m2 + m3 are given i n parentheses, by the approximate formula m* = (m 2) 2/m 1. High res o l u t i o n mass measurements were made using a Kratos-AEI model MS 50 mass spectrometer. A l l instruments were operated at an i o n i z i n g p o t e n t i a l of 70 eV. Microanalyses were performed at either the M i c r o a n a l y t i c a l Laboratory, Un i v e r s i t y of B r i t i s h Columbia or the Canadian M i c r o a n a l y t i c a l Service Ltd., 5704 University Boulevard, Vancouver. 104 I I . Model Studies 3 Methyl 4,6-Oj-benzylidene-a-D-glucopyranoside (74) H O O M e This compound was prepared from methyl a-D-glucopyranoside (73) i n 68% y i e l d following the procedure of Richtmyer (98); mp 163.5-165.5°C ( l i t . (98) mp 163-164°C). Methyl 4,6-0-benzylidene-2,3-di-0-methyl-a-D-glucopyranoside (75) P h ^ s ^ 0 ^ \ o - V ^ ° \ M e O O M e To a solution of d i o l 74_ (23.4 g, 83.0 mmol) i n dry DMSO (500 mL) under nitrogen was added a so l u t i o n of sodium methylsulfinate anion i n DMSO (80.1 mL, 2.81 M, 225 mmol) (100). After s t i r r i n g f o r 1 h, the solu t i o n was cooled to 20°C and iodomethane (26.0 mL, 417 mmol) was added slowly so that the temperature did not r i s e above 25°C. A f t e r 45 min, the 3 Compounds containing the methyl pyranoside ring are named as carbohy-drates according to I.U.P.A.C. carbohydrate nomenclature (99). The nomenclature switches to I.U.P.A.C. substituted alkane nomenclature once the pyranoside ring i s opened. 1 0 5 r e a c t i o n w a s q u e n c h e d w i t h w a t e r ( 6 0 0 m L ) . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h e t h e r 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 w a s h e d w i t h 1 M h y d r o -c h l o r i c a c i d , 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 f i l t e r e d . E v a p o r a t i o n o f t h e s o l v e n t y i e l d e d d i m e t h y l e t h e r 7 5 ( 2 A . 9 g , 9 7 % ) a s w h i t e c r y s t a l s ; R f 0 . 3 0 ( p e t r o l e u m e t h e r - e t h y l a c e t a t e 3 : 1 , UV a n d H 2 S 0 1 + ) ; m p 1 2 1 - 1 2 3 ° C ( l i t . ( 1 0 1 ) 1 2 1 - 1 2 3 ° C ) ; i r ( C H C 1 3 ) : 1 0 9 0 ( s , C - 0 ) c m- 1 ; lE n m r ( 8 0 M H z , CDCI3) 6 : 3 . 2 9 ( d d , J = 9 , 4 H z , I H ) , 3 . 4 0 - 4 . 5 5 ( m , 5 H ) , 3 . 4 5 ( s , 3 H ) , 3 . 5 5 ( s , 3 H ) , 3 . 6 3 ( s , 3 H ) , 4 . 8 5 ( d , J = 4 H z , I H ) , 5 . 5 5 ( s , I H ) , 7 . 2 7 - 7 . 6 0 ( m , 5 H ) ; m s m/z: 3 1 0 ( M + , 3 ) , 2 7 9 ( 4 ) , 1 6 1 ( 5 3 ) , 1 0 5 ( 3 2 ) , 1 0 1 ( 6 4 ) , 8 8 ( 9 5 ) , 7 5 ( 1 0 0 ) , 4 3 ( 3 1 ) . Methyl 2,3-di-O-iaethyl-o-D-glucopyranoside (76) m e t h a n o l ( 4 5 0 m L ) w a s a d d e d p _ - t o l u e n e s u l f o n i c a c i d m o n o h y d r a t e ( 0 . 9 5 g , 5 . 0 m m o l ) ( 1 8 ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 3 h , a n d t h e n s o l i d s o d i u m c a r b o n a t e ( c a . 1 g ) w a s a d d e d t o n e u t r a l i z e t h e a c i d . A f t e r s t i r r i n g f o r 1 0 m i n , t h e r e a c t i o n m i x t u r e w a s f i l t e r e d a n d c o n c e n t r a t e d . T h e r e s u l t i n g r e s i d u e w a s d i l u t e d w i t h w a t e r ( 2 0 0 m L ) a n d e t h e r ( 2 0 0 m L ) . OH MeO OMe T o a s o l u t i o n o f b e n z y l i d e n e a c e t a l 7 5 ( 2 4 . 9 g , 8 0 . 3 m m o l ) i n 106 The ether layer was extracted with d i s t i l l e d water (2 x 100 mL) and the combined aqueous extracts were concentrated. The residue was dissolved in dichloromethane (900 mL), dried over anhydrous magnesium sulfate, and f i l t e r e d . Evaporation of the solvent yielded white crystals (17.1 g). Recrystallization of the crude product from benzene - petroleum ether yielded diol 76 (16.5 g, 92%) as white crystals; Rf 0.50 (ethyl acetate - 1-propanol - water 65:23:12, H2S0^); mp 83.5-85.0°C ( l i t . (101) mp 81-84°C); i r (CHC13): 3590 (m, free OH), 3550-3200 (m, H-bonded OH), 1065 (s, C-0) cm-1; *H nmr (80 MHz, CDCI3) 6: 2.50 (bs, IH, D20 exchangeable), 2.82 (bs, IH, D20 exchangeable), 3.08-3.70 (m, 4H), 3.42 (s, 3H), 3.48 (s, 3H), 3.62 (s, 3H), 3.72-3.90 (m, 2H), 4.82 (d, J = 3 Hz, IH); ms m/zj 191(M+-0Me, 1), 88(100), 87(30), 75(87), 73(29), 45(22). Methyl 2,3-di-O-methyl-6-0-triphenylmethyl-o-D -g lucopyrano8 ide (77) H0-MeO-MeO OMe To a solution of diol 76_ (3.00 g, 13.5 mmol) in dry pyridine (30 mL) under nitrogen ln the fume hood was added triphenylmethyl chloride (5.65 g, 20.3 mmol) (18) and the resulting mixture was stirred for 42 h. The reaction mixture was poured into an ice-cold mixture of water (25 mL) and dichloromethane (20 mL) and then was acidified with ice-cold 1 M 107 hydrochloric acid (15 mL). The aqueous layer was extracted with d i c h l o r o -methane and the combined extracts were washed with saturated aqueous sodium bicarbonate, brine, and water, dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded the crude product (8.32 g) as a s o l i d . P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - e t h y l acetate 2:1, 1:1, and then neat ethyl acetate as eluant yielded t r i t y l ether 77 (5.73 g, 92%) as white c r y s t a l s , which were pure enough for the next reacti o n . A small sample was r e c r y s t a l l i z e d from ethanol for char a c t e r i z a t i o n ; R f 0.50 (petroleum ether - e t h y l acetate 1:1, UV and HgSO^); mp 172.0-174.5°C ( l i t . (101) mp 172-174°C); i r (CHC1 3): 3580 (w, free OH), 3550-3200 (w, H-bonded OH), 3020 1610 1495 1450 (m, aromatic C-H), 1060 1070 (s, C-0) cm - 1; XH nmr (80 MHz, CDCI3) 6: 2.55 (bs, IH, D 20 exchangeable), 3.10-3.85 (m, 6H), 3.45 (s, 3H), 3.50 (s, 3H), 3.62 (s, 3H), 4.85 (d, J = 3 Hz, IH), 7.10-7.60 (m, 15H); ms m/£t 464(M+, 1), 244(27), 243(100), 165(28), 161(28), 105(21), 88(66), 75(64), 45(25), 43(20). 108 Methyl 4-0-bromoacetyl-2,3-di-0-methyl-6-0-triphenylmethyl-a -Dj-gluco-pyranoside (78) To a solu t i o n of alcohol 77_ (50.5 g, 110 mmol), dry pyridine (17.5 mL, 218 mmol), and DMAP (1.3 g, 11 mmol) i n dry THF (600 mL) at 0°C under nitrogen i n the fume hood was added over 0.5 h a solution of bromoacetyl bromide (14.2 mL, 160 mmol) i n dry THF (300 mL). The ice bath was removed and the reaction mixture was s t i r r e d f o r 3 h, while warming to room temperature. The reaction mixture was di l u t e d with ether (350 mL), f i l t e r e d through a sintered glass f i l t e r , and the p r e c i p i t a t e was rinsed with ether. The combined f i l t r a t e was washed with saturated aqueous sodium bicarbonate, 1 M hydrochloric acid, brine, dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded the crude product (63.8 g) as yellow c r y s t a l s which were then dissolved i n ethy l acetate. F i l t r a t i o n of the r e s u l t i n g solution through a short column of s i l i c a gel and evaporation of the solvent yielded bromoacetate 78 (62.9 g, 99%) as off-white needles which were pure enough to use i n the next r e a c t i o n . A small sample was r e c r y s t a l l i z e d from ethanol to y i e l d a n a l y t i c a l l y pure, off-white needles for characterization; R f 0.55 (petroleum ether - ethyl acetate 1:1, UV and HjSO^); mp 161.5-163.5°C; [ a ] D +72.7 (£0.400, CHC1 3); 109 i r (CHCI3): 1750 (s, C=0), 1100 1030 (s, C-0) cm - 1; XH nmr (80 MHz, CDCI3) 6: 3.05-3.20 (m, 2H), 3.22-3.45 (dd, J -10, 4 Hz, IH), 3.45-4.10 (m, 3H), 3.51 (s, 6H), 3.55 (s, 3H), 4.77-5.10 (m, 3H), 7.10-7.60 (m, 15H); ms m/z: 586( 8 1Br: M+, 0.1), 584( 7 9Br: M+, 0.1), 554(0.4), 552(0.4), 244(30), 243(100), 165(47), 88(65), 77(95). Exact mass: calcd. for C 3 0 H 3 3 7 9 B r O 7 : 584.1410; found (ms): 584.1404. Anal, calcd. for C 3 0 H 3 3 B r O 7 : C 61.54, H 5.68, Br 13.65; found: C 61.39, H 5.76, Br 13.51. Methyl 4-0-(diethyl phosphonoacetyl)-2,3-di-O-methyl-6-0-triphenyl-methyl-a-D-glucopyranoslde (79) 0 t To neat bromoacetate 78_ (9.20 g, 15.7 mmol) under a stream of nitrogen i n the fume hood was added dry t r i e t h y l phosphite (5.38 mL, 31.4 mmol). Aft e r about one eighth of the t r i e t h y l phosphite had been added, the reaction mixture was heated to 150°C (28). The remaining t r i e t h y l phospite was added dropwise at a rate s u f f i c i e n t to keep the reaction mixture under r e f l u x . The bromoethane produced was d i s t i l l e d out of the reaction mixture. Af t e r a l l of the t r i e t h y l phosphite had been 110 added, the reaction mixture was s t i r r e d at 150°C for 1 h and then was allowed to cool to room temperature. The excess t r i e t h y l phosphite and ethy l bromide were removed under vacuum to y i e l d a pale amber gum. P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel In the fume hood using the sequence of solvents: petroleum ether - ethyl acetate 1:1 and then eth y l acetate - methanol 9:1 as eluant yielded d i e t h y l phosphonate T9_ (10.5 g, 104%) as a pale amber gum; R f 0.80 (ethyl acetate - 1-propanol - water 65:23:12, UV and H ^ ) ; i r (CHC1 3): 1750 (s, C=0), 1300-1200 (s, P=0), 1035 (s, C-0) cm - 1; *H nmr (80 MHz, CDC1,) 6: 1.30 ( t , J = 7 Hz, 6H), 2.62 (d, J_ _„ = 22 Hz, 2H), 2.80-3.20 (m, 2H), 3.33 (dd, J - 10, 3 Hz, IH), 3.45-3.80 (m, 2H), 3.48 (s, 3H), 3.53 (s, 6H), 3.80-4.35 (m, 4H), 4.77-5.10 (m, 2H), 7.00-7.55 (m, 15H); ms m/zi 642(M+, 0.1), 565(1), 399(29), 244(29), 243(100), 179(55), 165(58), 139(33), 88(88), 75(45). Exact mass: calcd. for C 2 8 H 3 8 0 1 Q P (M^-CgHg): 565.2202; found (ms): 565.2195. I l l Methyl 6-0-(diethyl pho8phonoacetyl)-2,3-dl-0-methyl-a-£-glucopyranoslde To a so l u t i o n of t r i t y l ether 79_ (0.76 g, 1.2 mmol) i n methanol (20 ml) was added a spatula t i p f u l l of Amberlite IR-120. A f t e r s t i r r i n g for 44 h, the reaction mixture was f i l t e r e d and concentrated. The gummy residue was p u r i f i e d by f l a s h chromatography on s i l i c a gel using e t h y l acetate to elute methyl triphenylmethyl ether and then methanol to elute the product. Evaporation of methanol, with heating, yielded alcohol 80 (0.44 g, 91%) as a pale amber gum; R f 0.56 (ethyl acetate - 1-propanol - water 65:23:12, H 2S0 1 +); l r (CHC1 3): 3600 (m, free OH), 3575-3275 (m, H-bonded OH), 1740 (s, C=0), 1300-1200 (s, P=0), 1020 (s, C-0) cm - 1; XH nmr (80 MHz, CDC1 3) 6: 1.35 ( t , J = 7 Hz, 6H), 3.04 (d, J_ = 22 Hz, 2H), 3.10-3.90 (m, 5H), 3.43 (s, 3H), 3.51 (s, 3H), 3.64 (s, 3H), 3.90-4.70 (m, 6H), 4.82 (d, J = 3 Hz, IH); ms m/z: 369(M+-OMe, 1), 368(1), 101(42), 83(100), 75(55), 73(20), 45(25). Exact mass: calcd. for C^H-^OgP (M+-Me0H): 368.1235; found (ms): 368.1213. ( 8 0 ) 0 M e 0 OMe 112 Methyl 4-0-(diethyl phosphonoacetyl)-2,3-dl-O-methyl-o-D-glucopyranoslde methanol (15 mL) was added 5% palladium-on-charcoal (0.240 g) and 2 drops of 12 M hydrochloric a c i d . The reaction mixture was s t i r r e d overnight under hydrogen at atmospheric pressure (30). The cat a l y s t was recovered by f i l t r a t i o n and washed with methanol. Concentration of the f i l t r a t e , without heating, yielded a mixture of alcohol J51_ and triphenylmethane as a white semi-solid which was subsequently p u r i f i e d by continuous l i q u i d -l i q u i d e x t r a c t i o n . The crude product mixture was dissolved i n a c e t o n i t r i l e and the r e s u l t i n g s o l u t i o n was extracted continuously with petroleum ether. A f t e r 8 h, t i c of the a c e t o n i t r i l e layer showed no triphenylmethane. The a c e t o n i t r i l e layer was f i l t e r e d through a pad of C e l i t e to remove traces of palladium c a t a l y s t . Evaporation of the solvent, without heating, yielded alcohol 80_ (0.546 g, 72%) as a pale amber gum. A f t e r s i x weeks the product c r y s t a l l i z e d to y i e l d the a n a l y t i c a l l y pure monohydrate of alcohol 80 as white c r y s t a l s ; (81) 0 t To a so l u t i o n of t r i t y l ether 79 (1.22 g, 1.90 mmol) i n dry R f 0.45 (ethyl acetate - 1-propanol - water 3:1:0.2, R^SO^); mp 34-38.5°C; [ a ] D +79.9 (£0.568, CHC1 3); 113 i r ( C H C I 3 ) : 3670 (w, free OH), 3625-3200 (w, H-bonded OH), 1740 (m, C=0), 1200-1300 (s, P=0), 1025 (s, C-0) cm - 1; XH nmr (80 MHz, C D C 1 3 ) 6 : l l 3 5 ( t , J - 7 Hz, 6H), 2.70 (bs, IH, D 20 exchangeable), 3.02 (d, J_ _ = 22 Hz, 2H), 3.29 (dd, J = 10, 3 Hz, IH), 3.40-3.85 (m, 4H), 3.43 (s, 3H), 3.52 (s, 3H), 3.54 (s, 3H), 3.93-4.50 (m, J = 7 Hz, 4H), 4.70-5.10 (m, 2H); ms m/z: 400(M+, 0.5), 369(4), 368(4), 179(37), 103(23), 88(100), 75(26). Exact mass: calcd. for C 1 5 H 2 9 0 1 Q P : 400.1498; found (ms): 400.1487. Anal, calcd. for C 1 5 H 2 9 O 1 0 P « H 2 O : C 43.06, H 7.47, 0 42.06; found: C 43.05, H 7.31, 0 42.0. Methyl 4-0-(diethyl phosphonoacetyl)-2,3-dl-O-aethyl-a-D-gluco-hexodialdo-1,5-pyranoside (69) ~~ 0 t To a solu t i o n of alcohol 81^  (2.22 g, 5.55 mmol) and f r e s h l y d i s t i l l e d DCC (3.40 g, 16.5 mmol) i n dry DMSO (20 mL) under nitrogen i n the fume hood was added dry di c h l o r o a c e t i c acid (0.23 mL, 2.8 mmol) (38). Aft e r s t i r r i n g for 1 h, the cloudy white reaction mixture was f i l t e r e d This reaction was exothermic. Cooling the reaction mixture to 0°C might help to prevent the formation of by-products (see p. 53). 114 through a sintered glass f i l t e r , and the p r e c i p i t a t e was rinsed with d i s t i l l e d water. The combined aqueous f i l t r a t e was extracted repeatedly with ether and then frozen using a dry i c e - acetone bath. Freeze-drying under vacuum for 2 days yielded aldehyde 69_ (2.00 g, 91%) as a colourless semi-solid; 0.54 (ethyl acetate - 1-propanol - water 3:1:0.2, H 2S0 l t and 2,4-DNP-hydrazlne); i r (CHC1 3): 3575 (w, free OH) 3550-3150 (m, H-bonded OH of hydrated aldehyde), 1750 (s, C=0), 1200-1300 (s, P=0), 1030 (s, C-0) cm - 1; lE nmr (80 MHz, CDC1 3) 6: 1.35 ( t , J = 7 Hz, 6H), 3.02 (d, J L -22 Hz, 2H), 3.28 (dd, J = 9, 3 Hz, IH), 3.40-3.85 (m, IH), 3.45 (s, 3H), 3.53 (s, 3H), 3.55 (s, 3H), 3.90-4.40 (m, 5H), 4.93 (d, J = 3 Hz, IH), 4.98 (dd, J = 10, 9 Hz, IH), 9.57 (d, J = 2 Hz, IH); ms m/z: 398(M+, 0.1), 367(1), 179(43), 101(20), 88(100), 75(33), 45(24). Exact mass: calcd. for C 1 5H 2 7O 1 0P: 398.1342; found (ms): 398.1339. (Methyl 6,7-dideoxy-2,3-di-Q-methyl-a-D-gluco-oct-6-eno-l,5-pyranosid)-urono-8,4-lactone^ (70) 7 6 MeO oMe Sodium hydride (0.275 g, 60% dispersion i n mineral o i l , 6.86 mmol) Uronolactones are named according to the convention developed by Martin and Szarek (36). 115 was washed free of o i l with dry ether ( 3 x 5 mL) under nitrogen and then dry THF (10 mL) was added to the sodium hydride. The r e s u l t i n g s l u r r y was added via pipette to a s o l u t i o n of aldehyde 69_ (2.75 g, 6.86 mmol) i n dry THF (250 mL) under nitrogen which resulted i n immediate evolution of hydrogen. The reaction mixture was s t i r r e d for 5 min, heated under r e f l u x for 1 h and then was allowed to cool to room temperature (28). Amberlite IR-120 (several spatula t i p s f u l l ) was added to n e u t r a l i z e any excess base. Af t e r s t i r r i n g for 10 min, the reaction mixture was f i l t e r e d and concentrated to y i e l d a dark amber o i l . P u r i f i c a t i o n by gel f i l t r a t i o n on Sephadex LH-20 using methanol - chloroform 1:1 as eluant, followed by p a r t i a l l y d i s s o l v i n g the r e s u l t i n g residue i n ether, decanting and concentrating the s o l u t i o n , yielded a 9:1 mixture of a,8-unsaturated lactones 7_0_ and 88_ (0.910 g, 54%) as a pale amber o i l . Kugelrohr d i s t i l l a t i o n yielded a 9:1 mixture of the a,B-unsaturated lactones as a white semi-solid; R f 0.29 (petroleum ether - e t h y l acetate 1:1, UV and H 2S0 4); bp 195°C/0.25 Torr; i r (CHC1 3): 3020 (m sh, C=C-H), 1745 (s, C=0), 1090 (s, C-0) cm - 1; XH nmr (400 MHz, CDC1 3) 6: 3.25 (dd, J.2 3 " 9 H z » -1 2 ** 3 * 5 H z > IH, H-2), 3.47 (s, 3H), 3.55 (s, 3H), 3.66 (s, 3H), 3.70 ( t , £ 2 3 = -3 4 = 9 Hz, IH, H-3), 3.98 (dd, 5 = 10 Hz, £ 3 4 = 9 Hz, IH, H-4), 4.48 (ddd, £4 5 = 10 Hz, J_5 7 = 3 Hz, J_5 6 = 2 Hz, IH, H-5), 4.87 (d, 2 = 3.5 Hz, IH, H - l ) , 5.96 (dd, ? = 10 Hz, J_5 ? = 3 Hz, IH, H-7), 6.87 (dd, £ 5 7 = 10 Hz, J 5 6 = 2 Hz, IH, H-6); 116 ms m/z: 244(M+, 0.3), 213(1), 88(100), 73(22), 60.5(m* - (73) 2/88), 55(21), 45(23). Exact mass: calcd. for C n H 1 6 0 6 : 244.0947; found (ms): 244.0972; cal c d . f or C 1 0 H 1 3 0 5 (M+-0Me): 213.0762; found (ms): 213.0764. (Methyl 6 >7-dldeoxy-6-C-methyl-2 >3-dl-0-methyl-D-glycero-tt-D-gluco-octo-1,5-pyrano8ld)urono-8,4-lactone (82) To a suspension of copper(I) cyanide (32 mg, 0.36 mmol) i n dry ether (5 mL, d i s t i l l e d from sodium) at -78°C under nitrogen i n the fume hood was added a sol u t i o n of methyllithium In ether (0.42 mL, 1.7 M, 0.72 mmol). Aft e r s t i r r i n g f o r 5 min at -78°C, the mixture was allowed to warm to 0°C. The mixture was s t i r r e d at 0°C for 10 min by which time the copper(I) cyanide had a l l reacted to give a cloudy tan so l u t i o n of the cuprate Me 2Cu(CN)Li 2 (39). The cuprate so l u t i o n was cooled to -78°C and a so l u t i o n of a,8-unsaturated lactone 7_0 from above (77 mg, 0.30 mmol) i n dry ether ( d i s t i l l e d from sodium) (2 mL) was added dropwise. The r e s u l t i n g bright yellow reaction mixture was s t i r r e d at -78°C for 30 min and at -25°C for 1 h. The reaction was quenched by adding g l a c i a l a c e t i c a c i d (0.04 mL, 0.72 mmol) and was d i l u t e d with ethyl acetate. The mixture became a c l e a r , pale green so l u t i o n containing a small amount of a fin e 1 1 7 white p r e c i p i t a t e . The cold bath was removed and the mixture was allowed to warm to room temperature. Disodium ethylenediaminetetraacetic acid dihydrate (0.13 g, 0.36 mmol) was added and the r e s u l t i n g mixture was s t i r r e d for 10 min. Brine (6 drops) and water (6 drops) were added and immediately a f l o c c u l a n t , white p r e c i p i t a t e formed. The aqueous layer containing the p r e c i p i t a t e was extracted with ethyl acetate and the combined organic solvents were dried over anhydrous magnesium su l f a t e and f i l t e r e d . Evaporation of the solvent yielded a pale green o i l (78 mg, 100%). P u r i f i c a t i o n of a small sample by preparative glc yielded lactone 82 as a colourless o i l ; R f 0.28 (petroleum ether - e t h y l acetate 1:1, H 2S0 H); i r (CHC1 3): 1730 (s, C=0), 1055 (s, C-0) cm - 1; 1E nmr (400 MHz, CDCI3) 6: 1.07 (d, g = 7 Hz, 3H, Me), 2.31-2.40 (A part of ABX system plus a d d i t i o n a l couplings, IH, H-6), 2.42 (B part of ABX system, J ? a 7 Q = 17 Hz, ? ^ = 4 Hz, IH, H-78), 2.78 (X part of ABX system, J ? a y ^ - 17 Hz, J a - 7 Hz, IH, H-7oc), 3.20 (dd, J_2 3 = 9 Hz, J L 2 = 3.5 Hz, IH, H-2), 3.43 (s, 3H), 3.53 (s, 3H), 3.61 ( t , -2 3 * -3 4 = 9 H z ' 1 H > H - 3 ) » 3 , 6 3 (s» 3 H ) ' 3 , 8 7 ( d d» ^4 5 = 1 0 , 5 H z » -5 6 6 Hz, IH, H-5), 4.05 (dd, £ 4 5 = 10«5 Hz, £ 3 4 - 9 Hz, IH, H-4), 4.83 (d, J j 2 = 3.5 Hz, IH, H - l ) ; 1 3 C nmr 6 (100 MHz, CDCI3) 6: 14.29 (Me), 27.63 (C-6), 36.93 (C-7), 55.52 59.26 61.10 (OMe), 65.64 76.27 80.78 81.24 (CH), 98.31 ( C - l ) , 169.54 (C-0); 6 This 1 3 C nmr spectrum was obtained from a sample which consisted of a 73:13:10 mixture of methyl lactones 82, 83 and a,B-unsaturated lactone 88. Only the major peaks are reported. 118 ms m/z: 260(M+, 0.3), 229(1), 88(100), 73(12), 60.5(m* = (73) 2/88). Exact mass: calcd. for C 1 2H 2 0O 6: 260.1260; found (ms): 260.1245. Active Methylene Complex To a s t i r r e d s l u r r y of zinc dust (11.5 g, 176 mmol), dibromo-methane (4.04 mL, 56 mmol) and dry THF (100 mL) at -40°C under nitrogen i n the fume hood was added dropwise, over 0.5 h, titanium(IV) chloride (4.6 mL, 42 mmol) (12, 49). The reaction was extremely vigorous and a copious amount of green gas was produced. Af t e r the addition of titanium(IV) chlo r i d e , the reaction mixture became a grey s l u r r y and was s t i r r e d at -40°C f o r 2 h, at 2°C for a least 24 h and then was stored between 0°C and 5°C u n t i l use. The complex could be stored for up to two weeks without d e t e r i o r a t i o n . Methyl 6,7-dideoxy-A-0-(diethyl phosphonoacetyl)-2,3-di-0-methyl-o-D-gluco-hept-6-eno-l,5-pyranoalde (86) 0 t To a s t i r r e d solution of aldehyde 69_ (0.80 g, 2.0 mmol) i n dry dichloromethane (20 mL) at 0°C under nitrogen was added i n portions, via 119 pipette, the active methylene complex prepared above (20 x ca. 1.5 mL), u n t i l t i c analysis of the reaction mixture (2,4-DNP-hydrazlne) indicated that a l l of the aldehyde had been consumed. The black reaction mixture was poured into a s l u r r y of sodium bicarbonate i n saturated aqueous sodium bicarbonate (100 mL) and the r e s u l t i n g s l u r r y was dilu t e d with ethyl acetate (200 mL). The mixture was s t i r r e d for 1 h giving a c l e a r , colourless organic layer and a pale grey-green aqueous layer. The aqueous layer was extracted with ethyl acetate and the combined organic solvents were dried over anhydrous magnesium sul f a t e and f i l t e r e d . Evaporation of the solvent yielded o l e f i n J 3 6 _ (0.34 g, 42%) as an amber gum; R f 0.50 (ethyl acetate - 1-propanol - water 3:1:0.2, I 2 ) ; i r (CHC1 3): 1740 (s, C=0), 1660-1640 (m, C=C), 1300-1200 (s, P=0), 1035 (s, C-0) cm - 1; lE nmr (80 MHz, CDCI3) 6 : 1.35 ( t , J = 7 Hz, 6H), 2.75-3.85 (m, 3H), 2.95 (d, Jj, C H = 22 Hz, 2H), 3.43 (s, 3H), 3.52 (s, 3H), 3.53 (s, 3H), 3.90-4.50 (m, 4H), 4.60-5.20 (m, 5H); ms m/z: 396(M+, 1), 365(4), 179(100), 151(30), 123(37), 110(23), 109(35), 101(51), 97(20), 88(31), 75(73), 73(27), 45(50), 41(20). Exact mass: calcd. for C 1 5H 2 60gP (M+-0Me): 365.1365; found (ms): 365.1363. 120 Methyl 7-deoxy-4-0-(diethyl phosphonoacetyl)-2,3-di-O-methyl-a-D-gluco-hepto-l,5-pyranosld-6-ulo8e (71) 0 t To a so l u t i o n of mercuric acetate (96 mg, 0.30 mmol) i n acetone (5 mL) and water (10 drops) was added a solution of alkene j$6_ from above (86 mg, 0.21 mmol) i n acetone (2 mL) and the r e s u l t i n g s o l u t i o n was s t i r r e d for 40 min. To the clear yellow solution was added Jones reagent (102) (0.21 mL, 1.4 M, 0.30 mmol) and the r e s u l t i n g red mixture was s t i r r e d for 4.5 h (50). The brown reaction mixture was f i l t e r e d and the green chromium s a l t s were washed with ethyl acetate. The combined organic solvents were evaporated and the r e s u l t i n g residue was redissolved i n ethyl acetate. The organic s o l u t i o n was washed with saturated aqueous sodium bicarbonate (6 x 10 drops), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . The solvent was evaporated to y i e l d crude methyl ketone 71_ (45 mg, 50%) as an amber gum. A l l traces of acetone and ethyl acetate were then removed by coevaporation with carbon t e t r a c h l o r i d e . The y i e l d of methyl ketone 7_1 i s approximately 17% based on integ r a t i o n of the methyl ketone s i g n a l at 6 2.23 i n the *H nmr spectrum. The crude mixture was characterized by the following: R, 0.55 (ethyl acetate - 1-propanol - water 3:1:0.2, H-SO^ and 121 2,4-DNP-hydrazine); i r (CHCI3): 1740 (m, C=0), 1375 (w, methyl ketone), 1300-1200 (s, P=0), 1030 (s, C-0) cm - 1; lE nmr (80 MHz, CDCI3) 6: 1.35 ( t , J - 7 Hz, 6H), 2.23 (s, IH, methyl ketone), 2.75-3.18 (m, 2H), 3.18-3.80 (m, 11H), 3.80-4.50 (m, 5H), 4.50-5.05 (m, 2H), 5.05-6.05 (m, re s i d u a l o l e f i n ) ; ms m/z: 412(M+, 0.8), 179(53), 101(21), 88(100), 75(29). Exact mass: calcd. for c i 6 H 2 9 ° 1 0 P : 4 1 2«1498; found (ms): 412.1489. (Methyl 6,7-dideoxy-6-C-methyl-2,3-dl-0-methyl-a-D-gluco-oct-6-eno-l,5-pyrano8id)urono-8,4-lactone (72) was washed free of o i l with dry ether ( 3 x 1 mL) under nitrogen and then dry THF (2 mL) was added to the sodium hydride. The r e s u l t i n g s l u r r y was added v i a pipette to a so l u t i o n of methyl ketone J_l_ from above (0.171 g, 33% pure, 0.133 mmol) l n dry THF (20 mL) under nitrogen. The reaction mixture was s t i r r e d for 5 min, heated under r e f l u x for 2 h and then was allowed to cool to room temperature (28). Amberlite IR-120 (several spatula t i p s f u l l ) was added to neut r a l i z e any excess base. Af t e r s t i r r i n g f o r 10 min, the reaction mixture was f i l t e r e d and concentrated to Me MeO OMe Sodium hydride (16 mg, 60% dispersion i n mineral o i l , 0.4 mmol) 122 y i e l d a brown gum. P u r i f i c a t i o n by f l a s h chromatography on s i l i c a g e l using petroleum ether - e t h y l acetate 1:1 as eluant yielded a 4:1 mixture of <x,B-unsaturated lactones 7_2_ and 88_ (13 mg, 39%) as a white semi-solid; R f 0.25 (petroleum ether - e t h y l acetate 1:1, UV and HjSO,^; mp 70-108°C; i r (CHC1 3): 1730 (s, C=0), 1650 (w, C=C), 1070 (s, C-0) cm - 1; XH nmr (80 MHz, CDCI3) 6: 2.00 ( t , J = 1 Hz, 3H), 3.25 (dd, £ = 9, 3 Hz, IH), 3.40-4.70 (m, 3H), 3.47 (s, 3H), 3.60 (s, 3H), 3.67 (s, 3H), 4.90 (d, J • 3 Hz, IH), 5.76 (m, IH); ms m/z: 258(M+, 0.2), 227(0.5), 88(100), 73(14), 60.5(m* = (73) 2/88). Exact mass: calcd. for C u H 1 5 0 5 (M+-OMe): 227.0920; found (ms): 227.0926. (Methyl 6,7-dideoxy-6-C-methy1-2,3-di-0-methyl-L-glycero-a-D-gluco-octo-1,S-pyranosid)urono-8,4-lactone (83) A suspension of platinum oxide (2 mg) i n methanol (1 mL) was pre-hydrogenated at atmospheric pressure for 1 h to give elemental platinum as black granules. To this mixture was added a sol u t i o n of a,8-unsaturated lactone 7_2_ from above (4 mg, 0.01 mmol) i n methanol (0.25 mL). Af t e r s t i r r i n g under hydrogen at atmospheric pressure for 3.5 h, the reaction mixture was f i l t e r e d and the catalyst was rinsed with methanol. 123 Evaporation of the solvent yielded a 72:17:11 mixture of lactones 83 and 90, and an u n i d e n t i f i e d product (4 mg, 100%) as a colourless o i l ; R f 0.26 (petroleum ether - ethyl acetate 1:1, HjSO^); i r (CHC1 3): 1740 (m, C=0), 1055 (s, C-0) cm - 1; XH nmr (400 MHz, C D C I 3 ) 6: 1.10 (d, g = 7 Hz, 3H, Me), 2.04-2.17 (A part of ABX system plus a d d i t i o n a l couplings, IH, H-6), 2.26 (B part of ABX system, J.. -,Q = 18 Hz, J . , = 9 Hz, IH, H-7B), 2.90 (X —/ Q, / p —o , / p part of ABX system, J ? a y ^ = 18 Hz, ? a = 8 Hz, IH, H-7a), 3.25 (dd, J . ,= 9 Hz, J, 0 = 3.5 Hz, IH, H-2), 3.33-3.52 (m, IH), 3.44 (s, 3H), 3.54 (s, 3H), 3.60 ( t , J = 9 Hz, IH), 3.64 (s, 3H), 3.88 ( t , J = 9 Hz, IH), 4.84 (d, Jjy 2 ** 3 , 5 H z » 1 H » H - 1 ) 5 ms m/zj 260(M+, 0.1), 229(3), 168(78), 88(100), 75(49), 73(13), 60.5(m* = (73) 2/88). Exact mass: calcd. for C 1 1 H 1 ? 0 5 (M+-0Me): 229.1076; found (ms): 229.1078. 124 Methyl 6 - 0 - ( d i e t h y l phosphonoacety1)-2,3-dl-O-methyl-g-D-xylo-hexo-l,5-pyranosid-4-ulose (87) d i s t i l l e d DCC (0.45 g, 2.2 nmol) i n dry DMSO (3 mL) under nitrogen i n the fume hood was added dry d i c h l o r o a c e t i c acid (0.029 mL, 0.36 mmol) (38). After s t i r r i n g for 4 h, the cloudy white reaction mixture was f i l t e r e d through a sintered glass f i l t e r and the p r e c i p i t a t e was rinsed with d i s t i l l e d water. The combined aqueous f i l t r a t e was extracted with ether ( 6 x 4 mL) and then frozen using a dry Ice - acetone bath. Freeze-drying under vacuum for 1.5 days yielded ketone 87 (0.22 g, 91%) as an amber gum; 0.63 (ethyl acetate - 1-propanol - water 3:1:0.2, HjSO^ and 2,4-DNP-hydrazine); i r (CHC1 3): 1750 (s, C=0), 1300-1200 (s, P=0), 1030 (s, C-0) cm - 1; lE nmr (80 MHz, CDC1 3) 6: 1.35 ( t , J = 7 Hz, 6H), 3.00 (d, JL, = 22 Hz, 2H), 3.35-3.80 (m, IH), 3.54 (s, 3H), 3.56 (s, 3H), 3.60 (s, 3H), 3.90-4.80 (m, 8H), 5.02 (d, J = 3 Hz, IH); ms m/z: 398(M+, 2), 367(2), 101(51), 88(100), 75(44). Exact mass: calcd. for C 1 5 H 2 7 0 1 Q P : 398.1342; found (ms): 398.1343. M e 0 O M e To a s o l u t i o n of alcohol 80 (0.29 g, 0.72 mmol) and f r e s h l y 125 [Methyl 4-€-(carboxymethine)-4-deoxy-2,3-dl-0-methyl-tt-D-xylo-hex-4( 7 )-eno-1,5-pyranosid]-8,6-lactone (88) To a sol u t i o n of ketone 87_ (0.180 g, 0.45 mraol) i n dry THF (18 mL) under nitrogen was added sodium hydride (0.018 g, 60% dispersion i n o i l , 0.45 mmol). The reaction mixture was s t i r r e d f o r 5 min, heated under r e f l u x for 1 h and then was allowed to cool to room temperature (28). Amberlite I R - 1 2 0 (several spatula t i p s f u l l ) was added to neu t r a l i z e any excess base. Af t e r s t i r r i n g for 1 0 min, the reaction mixture was f i l t e r e d and concentrated. P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using petroleum ether - eth y l acetate 1 : 1 as eluant yielded a,8-unsaturated lactone 88 (55 mg, 50%) as a cl e a r , colourless gum. Kugelrohr d i s t i l l a t i o n yielded an a n a l y t i c a l l y pure sample; R f 0.29 (petroleum ether - ethyl acetate 1 : 1 , UV and HjSO^); bp 130-135°C /0.05 Torr; [ct]D +182° (£ 0.406, C H C 1 3 ) ; i r ( C H C 1 3 ) : 3005 (m sh, C=C-H), 1730 (s, C = 0 ) , 1 1 0 0 (s, C - 0 ) cm - 1; *H nmr (400 MHz, C D C I 3 ) 6: 3.34 (dd, J_2 3 = 1 0 Hz, J 1 2 = 3.5 Hz, IH, H - 2 ) , 3.50 (s, 3H), 3.57 (s, 3H), 3.62 (s, 3H), 4 . 11-4.24 (m, 2 H ) , 4.48-4.57 (m, 2 H ) , 4.92 (d, J . = 3.5 Hz, IH, H-l), 6.13 (dd, J - 2.5, I»^ 1 Hz, IH, H-7); 126 ms m/z: 244(M +, 0.8), 213(2), 141(48), 140(100), 139(23), 125(23), 124(38), 111(47), 109(30), 97(24), 88(53), 75(42), 73(22), 69(32), 53(25), 45(68), 43(34), 41(36), 39(35). Exact mass: c a l c d . f o r C u H 1 6 0 6 : 244.0947; found (ms): 244.0945. A n a l , c a l c d . f o r C u H 1 6 0 6 : C 54.10, H 6.60; found: C 54.10, H 6.60. [Me thy 1 4-C_-( carboxyme thy 1) -4 -deoxy-4 -Cme thy 1 -2,3-d i -0-me thy 1 -a-D-g a l a c t o - h e x o - 1 , 5 - p y r a n o s i d ] - 8 , 6 - l a c t o n e (89) To a s u s p e n s i o n o f c o p p e r ( I ) c y a n i d e (26 mg, 0.29 mmol) i n d r y e t h e r (4 mL, d i s t i l l e d from sodium) at -78°C under n i t r o g e n i n the fume hood was added a s o l u t i o n o f m e t h y l l i t h i u m i n e t h e r (0.45 mL, 1.3 M, 0.58 mmol). A f t e r s t i r r i n g f o r 5 min at -78°C, the m i x t u r e was a l l o w e d to warm t o 0°C. The m i x t u r e was s t i r r e d at 0°C f o r 5 min by which time the c o p p e r ( I ) c y a n i d e had a l l r e a c t e d to g i v e a c l o u d y , tan s o l u t i o n of M e 2 C u ( C N ) L i 2 ( 3 9 ) . The c u p r a t e s o l u t i o n was c o o l e d to -78°C and a s o l u t i o n of a, 8 - u n s a t u r a t e d l a c t o n e _8_8 (60 mg, 0.25 mmol) i n d r y e t h e r (2 mL, d i s t i l l e d from sodium) was added d r o p w i s e . The r e s u l t i n g b r i g h t y e l l o w r e a c t i o n m i x t u r e was s t i r r e d at -78°C f o r 30 min and at 0°C f o r 1.75 h. The r e a c t i o n was quenched by a d d i n g g l a c i a l a c e t i c a c i d (25 dr o p s ) 127 u n t i l the reaction mixture became a clear pale green solution containing a very small amount of a fin e white p r e c i p i t a t e . Disodium ethylenediamine-t e t r a a c e t i c acid dihydrate (0.11 g, 0.29 mmol) was added and the r e s u l t i n g mixture was s t i r r e d for 10 min while warming to room temperature. Brine (10 drops) was added and a f l o c c u l a n t white p r e c i p i t a t e formed. The mixture was f i l t e r e d through a sintered glass f i l t e r and the f i l t r a t e was washed with saturated aqueous sodium bicarbonate (4 x 10 drops), dried over magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded a pale green residue which was then suspended in chloroform. F i l t r a t i o n of the suspension and concentration of the f i l t r a t e yielded lactone 89_ (42 mg, 65%) as a pale amber o i l ; R f 0.22 (petroleum ether - e t h y l acetate 1:1, H 2S0 4); i r (CHC1 3): 1740 (s, C=0), 1085 (s, C-0) cm - 1; XH nmr (400 MHz, CDC1 3) 6 : 1.16 (s, 3H, Me), 2.42 (A part of AB quartet, J y j, = 18 Hz, IH, H-7), 2.69 (B part of AB quartet, 7 , = 18 Hz, IH, H-7'), 3.22 (d, £ 2 3 = 9 H z » l H » H - 3 > » 3 * 3 6 <dd> ±2 3 = 9 H z ' -1 2 = 4 Hz, IH, H-2), 3.44 (s, 3H), 3.51 (s, 3H), 3.57 (s, 3H), 3.69 (X part of ABX system, J c ,, = 3 Hz, J c = 2 Hz, IH, H-5), 4.39 (B part of ABX system, J , ,, =13 Hz, J c , = 2 Hz, IH, H-6), 4.54 (A part of ABX system, —O , O — J , o J , = 13 Hz, J_ ,, = 3 Hz, IH, H-6'), 4.91 (d, J, = 4 Hz, IH, H-1); -o, o —J, o — 1 , L ms m/z^ : 260(M+, 1), 229(2), 88(53), 75(100), 73(12), 60.5(m* = (73) 2/88), 45(24). Exact mass: ca l c d . for C 1 2 H 2 0 0 6 : 260.1260; found (ms): 260.1256. 128 [Methyl 4-C-(carboxymethyl)-4-deoxy-2,3-di-0-methyl-a-D-galacto-hexo-l,5-pyranosid]-8,6-lactone (90) A suspension of platinum oxide (2 mg) i n methanol (1 mL) was pre-hydrogenated at atmospheric pressure for 1 h to give elemental platinum as black granules. To this mixture was added a solu t i o n of a,B-unsaturated lactone J38 (10 mg, 0.02 mmol) i n methanol (0.25 mL). Aft e r s t i r r i n g under hydrogen at atmospheric pressure f o r 3 h, the reaction mixture was f i l t e r e d and the cata l y s t was rinsed with methanol. Evaporation of the solvent yielded lactone 90_ (8 mg, 80%) as a colourless semi-solid; R f 0.20 (petroleum ether - e t h y l acetate 1:1, HjSO^); mp 51-68°C; bp 140°C/0.01 Torr; i r (CHC1 3): 1740 (s, C=0), 1100 (s, C-0) cm - 1; lE nmr (400 MHz, CDCI3) 6: 2.61-2.67 (m, 2H), 2.68-2.78 (m, IH), 3.37 (dd, J 2 3 » 10 Hz, J_x 2 = 4 Hz, IH, H-2), 3.43 (s, 3H), 3.46 (s, 3H), 3.52 (s, 3H), 3.73 (dd, £ 2 3 = 10 Hz, £ 3 4 = 5 Hz, IH, H-3), 4.08 (X part of ABX system plus a d d i t i o n a l couplings, IH, H-5), 4.41 (B part of ABX system, ftt = 13 Hz, £ 5 6 = 3 Hz, IH, H-6), 4.49 (A part of ABX system, £g 6 , = 13 Hz, J 5 6 , = 2 Hz, IH, H-6*), 4.91 (d, 2 = 4 Hz, IH, H- l ) ; ms m/z_: 246(0.4), 215(3), 88(88), 75(100), 73(23), 60.5(m* = (73) 2/88), 58(31), 45(26). Exact mass: calcd. for C U H 1 8 0 6 : 246.1104; found (ms): 246.1104. 129 I I I . Preparation of the Fragment A Precursor Methyl 4>6-0j-benzylldene-2,3-dl-O-methanesulfonyl-a-D_-glucopyrano8lde This compound was prepared from methyl 4,6-O-benzylidene-oc-D-glucopyranoside (74) i n 88% y i e l d following the procedure of Sum and Weiler (18); mp 187-189°C ( l i t . (18) mp 186-188°C). Methyl 2 t3-anhydro-4,6-0-benzylidene-o-p_-allopyranoside (43) This compound was prepared from dimesylate 91_ i n 86% y i e l d following the procedure of Sum and Weiler (18); mp 199-201°C ( l i t . (18) mp 198-200°C). (91) MsO OMe 130 Methyl 4>6-0-benzylldene-2-deoxy-2~C-methyl--a-P-altro-pyrano8lde (44) HO OMe Method A: This compound was prepared from epoxide 43_ i n 63% y i e l d following the procedure of Hicks and Fraser-Reid (57); mp 111.5-112.5°C ( l i t . (57) mp 111-113 0C). Method B: To a s l u r r y of copper(I) cyanide (20.1 g, 224 mmol) i n dry ether (525 mL, d i s t i l l e d from sodium) at -78°C under nitrogen i n the fume hood was added a solution of methyllithium i n ether (320 mL, 1.4 M, 448 mmol). Afte r s t i r r i n g for 5 min at -78°C, the mixture was allowed to warm to 0°C. The mixture was s t i r r e d at 0°C for 25 min at which time the copper(I) cyanide had a l l reacted to give a cloudy pale green solution of the cuprate, Me 2Cu(CN)Li 2 (59). The cuprate so l u t i o n was cooled to -78°C and epoxide 43 (49.2 g, 186 mmol) was added. The r e s u l t i n g s l u r r y was s t i r r e d at -78°C f o r 15 min and at 0°C for 4 h. The reaction was quenched c a r e f u l l y with a solu t i o n of saturated aqueous ammonium chloride - 16 M ammonium hydroxide 9:1 ( N H ^ l - NH^OH 9:1) (100 mL). The mixture was transferred to a separatory funnel and dil u t e d with ether (1100 mL) and NH^Cl - NH^OH 9:1 (50 mL). The ether layer was washed with NH4C1 - NH^OH 9:1 (4 x 50 mL), brine (3 x 100 mL), dried over anhydrous magnesium 131 s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded alcohol 4_4 (51.1 g, 98%) as white c r y s t a l s which could be used In the next reaction without p u r i f i c a t i o n . R e c r y s t a l l i z a t i o n of the crude product from ether -petroleum ether yielded pure alcohol kk_ (39.8 g, 76%) i n two crops; mp 112-114°C ( l i t (57) mp 111-113°C). P u r i f i c a t i o n of the mother liquo r material by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - e t h y l acetate 3:1, 2.5:1, 2:1 and then 1:1 as eluant yielded a number of compounds. a) A 1:1 mixture of ketones 97_ (1.55 g, 3.1%) was i s o l a t e d as a n a l y t i c a l l y pure white c r y s t a l s ; R f 0.69 (petroleum ether - e t h y l acetate 1:1, UV and HjSO^); mp 68.5-80.0°C; i r ( C H C 1 3 ) : 3650-3350 (m, H-bonded OH), 1705 (s, C=0), 1395 1375 (s, gem-dimethyl), 1085 (s, C-0) cm - 1; *H nmr (400 MHz, CDCI3) 6: 0.93 (d, J = 7 Hz, 3H), 0.94 (d, J = 7 Hz, 3H), 2.19 (X part of ABX system plus a d d i t i o n a l couplings, x = J„ ^ = J„ „ =7 Hz, IH), 2.56 (B part of ABX system, J . = 17 Hz, J D v = — B , A —A,Me —A,n — D , A 7 Hz, IH, H-B), 2.62 (A part of ABX system, ^ g = 17 Hz, ^ x = 7 Hz, IH, H-A), 3.55 (bs, IH, D 20 exchangeable), 3.58-3.69 (m, IH), 3.87-3.98 (m, 2H), 4.32 ( t , J = 3 Hz, 0.5H), 4.35 (d, J = 5 Hz, 0.5H), 5.54 (s, IH), 7.32-7.45 (m, 3H), 7.45-7.55 (m, 2H); ms m/z: 264(M+, 0.1), 263(0.8), 180(12), 179(100), 107(85), 132 91(23), 85(13), 79(45), 77(32), 57(23). Anal, calcd. for C 1 5H 2 0O 4: C 68.18, H 7.63; found: C 68.30, H 7.73. b) A 4:1 mixture of hydroxy enol ether 96_ and an un i d e n t i f i e d product (1.05 g, 2.4%) was i s o l a t e d as white c r y s t a l s ; R f 0.55 (petroleum ether - ethyl acetate 1:1, UV and HjSO^); mp 70-76°C ( l i t . (103) mp 84.0-84.5°C); i r (CHC1 3): 3595 (w, free OH), 1640 (m, C=C), 1080 (s, C-0) cm - 1; 1E nmr (80 MHz, CDC1 3) 6: 2.55 (bs, IH, D 20 exchangeable), 3.60-4.30 (m, 2H), 4.04-4.60 (m, 3H), 5.03 ( t , J = 6 Hz, IH), 6.58 (s, IH), 6.46 (d, J = 6 Hz, IH), 7.25-7.65 (m, 5H); ms m/z: 234(12), 107(30), 106(21), 105(100), 77(26), 71(25). c) The desired alcohol 44_ (0.94 g, 1.8%) was i s o l a t e d as white c r y s t a l s and the sp e c t r a l data were i n agreement with those reported above. The t o t a l y i e l d of pure alcohol 44_ was 40.8 g (78%). Methyl 4 t6^-benzylidene-2-deoxy-2-C-methyl-3-0-[ (thiomethyl)-thiocarbonyl]-a-D-altro-pyranoside (92) following the procedure of Hicks and Fraser-Reid (57) and could be used MeSCO OMe II S This compound was prepared from alcohol 44_ i n 99% crude y i e l d 133 d i r e c t l y i n the next reacti o n . P u r i f i c a t i o n of a small amount by f l a s h chromatography on s i l i c a gel using carbon t e t r a c h l o r i d e - ether 5:1 as as eluant yielded xanthate 92_ as a very pale amber o i l ; R f 0.45 (carbon tet r a c h l o r i d e - ether 5:1, UV and HjSO^); i r (CHC1 3): 1070 (s, C=S and C-0) cm - 1; *H nmr (80 MHz, CDCI3) 6: 1.20 (d, J = 7 Hz, 3H), 2.57 (s, 3H), 2.60 (dq, J = 8, 2 Hz, IH), 3.38 (s, 3H), 3.60-4.10 (m, 2H), 4.15-4.55 (m, 2H), 4.47 (s, IH), 5.60 (s, IH), 5.82 ( t , J = 3 Hz, IH), 7.30-7.60 (m, 5H); ms m/z: 370(M+, 8), 262(37), 149(100), 125(21), 121(33), 113(38), 105(26), 97(27), 91(50), 85(75), 69(41), 59(28), 55(42), 45(20), 43(53), 41(38). Methyl 4,6-0-benzylidene-2^eoxy-2-C-TBethyl-3-0-phenoxythiocarbonyl-a-D-altro-pyranoside (103) PhOCO OMe II S To a solu t i o n of crude alcohol 44_ (50.0 g, 178 mmol) i n dry dichloromethane (800 mL) under nitrogen i n the fume hood was added dry pyridine (50.2 mL, 623 mmol) and DMAP (4.4 g, 36 mmol). The s t i r r e d s o l u t i o n was cooled to 0°C and phenoxythiocarbonyl chloride (65, 66) (29.6 mL, 214 mmol) was added dropwlse over 30 min. The ice bath was removed and the reaction mixture was s t i r r e d for 4 h, while warming to room 134 temperature. The reaction mixture was concentrated and the r e s u l t i n g residue was suspended i n ethyl acetate (500 mL). The suspension was f i l t e r e d on a sintered glass f i l t e r and the p r e c i p i t a t e was rinsed with e t h y l acetate (3 x 100 mL). The combined organic solvents were washed with 1 M hydrochloric acid (4 x 150 mL), saturated aqueous sodium bicarbonate (3 x 150 mL), brine (2 x 150 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded phenoxythiocarbonate 103 (70.5 g, 95%) as an amber semi-solid which could be used i n the next reaction. P u r i f i c a t i o n of a small amount by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - ethyl acetate 19:1, 9:1, 8:2, 1:1 and then neat ethyl acetate as eluant yielded two compounds. a) The desired phenoxythiocarbonate 103 was i s o l a t e d as white c r y s t a l s which were then r e c r y s t a l l i z e d from petroleum ether - ether; R f 0.88 (petroleum ether - ethyl acetate 1:1, UV and HgSO^); mp 149.0-150.5°C; i r (CHC1 3): 1105 (s, C=S and C-0) cm - 1; lE nmr (80 MHz, CDCI3) 6: 1.23 (d, J = 7 Hz, 3H), 2.70 (dq, J = 8, 2 Hz, IH), 3.33 (s, 3H), 3.50-4.40 (m, 4H), 4.46 (s, IH), 5.45-5.68 (m, 2H), 7.00-7.65 (m, 10H); ms m/z_: 416(M+, 1), 157(90), 149(42), 125(27), 121(100), 113(22), 97(31), 91(25), 85(49), 77(24), 69(39), 43(23). Exact mass: calcd. for C 2 2H 2 l 40 6S: 416.1294; found (ms): 416.1276. 135 b) Phenoxycarbonate 104 was i s o l a t e d i n trace amounts as an amber gum; R f 0.83 (petroleum ether - e t h y l acetate 1:1, UV and HjSO^; i r (CHC1 3): 1755 (s, C=0), 1275 (s, C-0), 1105 (s, C=S and C-0) cm - 1; XH nmr (80 MHz, CDCI3) 6: 1.25 (d, J = 7 Hz, 3H), 2.52 (dq, J = 8, 2 Hz, IH), 3.42 (s, 3H), 3.45-4.10 (m, 2H), 4.15-4.55 (m, 3H), 5.08 ( t , J = 2 Hz, IH), 5.63 (s, IH), 7.00-7.65 (m, 10H); ms m/_z: 400(M+, 0.5), 263(32), 157(79), 149(20), 125(30), 121(100), 113(38), 105(37), 97(34), 91(34), 85(78), 77(40), 69(60), 59(29), 55(40), 43(54), 41(28). Exact mass: ca l c d . for C 2 2 H 2 H 0 7 : 400.1522; found (ms): 400.1524. Methyl 4,6-0-benzylidene-2,3-dldeoxy-2-C-methyl-tt-D-arabino-hexopyranoside (93) OMe Method A v i a deoxygenation of xanthate 92; To a solu t i o n of tri-n-butylstannane (104) (27.9 g, 106 mmol) i n dry toluene (150 mL) at re f l u x under nitrogen i n the fume hood was added a solut i o n of crude xanthate 92_ (19.6 g, 53.0 mmol) i n dry toluene (200 mL) (18). The yellow s o l u t i o n was heated under r e f l u x overnight to af f o r d a very pale mixture. The reaction mixture was allowed to cool to room temperature and then was concentrated. The residue was p a r t i a l l y p u r i f i e d 136 by f l a s h chromatography on s i l i c a gel i n the fume hood using the sequence of solvents: neat petroleum ether, petroleum ether - ether 19:1, 7:1 and then 1:1 as eluant. Evaporation of solvent from the purest f r a c t i o n s yielded a semi-solid which was then r e c r y s t a l l i z e d from petroleum ether to y i e l d the pure deoxygenated compound 93_ (4.4 g) as large white c r y s t a l s . The other chromatography f r a c t i o n s and the mother liquo r were combined and concentrated. The *H nmr of this material indicated the presence of s t a r t i n g material. The whole experimental procedure was repeated on this crude material to y i e l d a d d i t i o n a l product (4.1 g), bringing the t o t a l y i e l d of deoxygenated compound 93_ to 8.5 g (62%) as white c r y s t a l s ; R f 0.34 (petroleum ether - ether 7:1, UV, HjSO^ and I 2 ) ; mp 71.0-72.5°C ( l i t . (18) reported as an o i l ) ; i r (CHC1 3): 1100 1055 (s, C-0) cm - 1; lE nmr (80 MHz, CDC1 3) 6: 1.16 (d, J = 7 Hz, 3H), 1.50-2.35 (m, 3H), 3.38 (s, 3H), 3.60-4.10 (m, 3H), 4.13-4.30 (m, IH), 4.38 (s, IH), 5.56 (s, IH), 7.25-7.65 (m, 5H); ms m/z_: 264(M+, 15), 233(7), 115(100), 105(21), 82(32), 73(25), 55(29). Occasionally enol ether 102 was also i s o l a t e d by chromatography i n small amounts as a white semi-solid (see p. 63). R e c r y s t a l l i z a t i o n from petroleum ether yielded pure enol ether 102 as white c r y s t a l s ; R f 0.58 (petroleum ether - ether 7:1, UV and H 2S0 1 +); mp 108-110°C ( l i t . (64) mp 113-114°C); i r (CHC1 3): 1645 (m, C=C), 1085 (s, C-0) cm - 1; 137 XH nmr (80 MHz, CDC1 3) 6: 2.10-2.45 (m, 2H), 3.55-4.60 (ra, 4H), 4.60-4.85 (m, IH), 5.62 (s, IH), 6.32 (dt, J - 6, 2 Hz, IH), 7.25-7.65 (m, 5H); ms m/z_: 218(M+, 84), 112(53), 106(20), 105(100), 84(39), 83(93), 81(42), 77(47), 51(23). Exact mass: calcd. for C 1 3H l i +0 3: 218.0943; found (ms): 218.0943. Method B v i a deoxygenation of phenoxythiocarbonate 103; To a so l u t i o n of the crude phenoxythiocarbonate 103 (5.0 g, 12 mmol) i n dry toluene (150 mL) under nitrogen i n the fume hood was added tri-n-butylstannane (104) (5.25 g, 18 mmol) and AIBN (0.39 g, 0.2 mmol). The reaction mixture was heated at 75°C for 3 h (65), changing from deep amber to pale yellow. The mixture was allowed to cool to room temperature and then was concentrated. P u r i f i c a t i o n of the residue by f l a s h chromatography twice on s i l i c a gel i n the fume hood using the sequence of solvents: neat petroleum ether, petroleum ether - ether 19:1, 7:1, 1:1 and then neat ether as eluant yielded a number of compounds. a) The desired deoxygenated compound j>3_ (1*65 g, 52%) was is o l a t e d as white c r y s t a l s and the sp e c t r a l data were l n agreement with those reported above. b) The s t a r t i n g material, phenoxythiocarbonate 103 (0.52 g, 16%) was Isolated as white c r y s t a l s and the s p e c t r a l data were i n agreement with those reported above. 138 Methyl 2,3-dldeoxy-2-C-methyl-tt-D-arabino-hexopyranoslde (94) OMe This compound was prepared from benzylidene acetal 93 i n 98% y i e l d following the procedure of Sum and Weiler (18); R f 0.10 (petroleum ether - ether 1:1, HjSO^); i r (CHC1 3): 3600 (m, free OH), 3570-3100 (m, H-bonded OH), 1055 (s, C-0) cm - 1; lE nmr (80 MHz, CDC1 3) 6: 1.07 (d, J = 7 Hz, 3H), 1.50-2.20 (m, 3H), 2.80-3.15 (bs, 2H, D 20 exchangeable), 3.35 (s, 3H), 3.25-4.00 (m, 4H), 4.35 (s, IH); ms m / z i 145(M+-0Me, 19), 86(28), 84(44), 83(23), 74(65), 72(100), 71(21), 61(23), 57(31), 56(36), 55(36), 43(34), 41(26). Methyl 2,3-dldeoxy-2-C-methyl-6-0-trlphenylmethyl-a-D-arabino-hexopyranoside (95) OMe This compound was prepared from d i o l 9h_ i n 76% y i e l d following the procedure of Sum and Weiler (18); mp 146-147°C ( l i t . (18) 147-149°C). 139 Methyl 4-0-bromoacetyl-2,3-dideoxy-2-C-raethyl-6-0-triphenylmethyl-a-D-arabino-hexopyrano8lde (105) OMe To a sol u t i o n of alcohol 95_ (17.1 g, 41 mmol), dry pyridine (13.2 mL, 164 mmol), and DMAP (0.50 g, 4.1 mmol) i n dry ether (250 mL) at 0°C under nitrogen i n the fume hood was added bromoacetyl bromide (7.1 mL, 82 mmol) over 5 min (28). The reaction mixture was s t i r r e d at 0°C for 10 min and then at room temperature f o r 17 h. The orange reaction mixture was f i l t e r e d through a sintered glass f i l t e r and the p r e c i p i t a t e was washed with ether (50 mL). The f i l t r a t e was washed with 1 M hydrochloric acid (3 x 50 mL), saturated aqueous sodium bicarbonate (3 x 50 mL), brine (3 x 50 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evapo-ra t i o n of the solvent yielded crude bromoacetate 105 (19.7 g, 90%) as a yellow semi-solid which could be used d i r e c t l y i n the next reacti o n . P u r i f i c a t i o n of a small sample by fl a s h chromatography on s i l i c a gel using petroleum ether - ethyl acetate 8:1 as eluant yielded bromoacetate 105 as a colourless gum which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from ethanol afforded an a n a l y t i c a l l y pure sample of off-white c r y s t a l s ; R f 0.34 (petroleum ether - ethy l acetate 8:1, UV and H 2S0^); mp 90-92°C; 140 [ a ] D +66.2° (c 1.20, CHC1 3); i r ( C H C 1 3 ) : 1740 (s, C=0), 1075 (s, C-0) 965 (s, C-0) cm - 1; XH nmr (80 MHz, CDCI3) 6: 1.13 (d, J = 7 Hz, 3H), 1.70-2.20 (m, 3H), 3.00-3.28 (m, 2H), 3.28-3.67 (m, 2H), 3.44 (s, 3H), 3.67-4.00 (m, IH), 4.43 (d, J = 2 Hz, IH), 4.80-5.20 (m, IH), 7.15-7.60 (m, 15H); ms m/z_: 540( 8 1Br: M+, 1), 538( 7 9Br: M+, 1), 258(24), 244(29), 243(100), 165(30). Exact mass: calcd. for C 2 9 H 3 1 8 1 B r 0 5 : 540.1335; found (ms): 540.1338. Anal, calcd. for C 2 9 H 3 1 B r 0 5 : C 64.57, H 5.79, Br 14.81, 0 14.83; found C 64.71, H 5.83, Br 14.69, 0 14.71. Methyl 2,3-dideoxy-4-0-(diethyl phosphonoacetyl)-2-C-methyl-6-0-triphenylmethyl-tt -D-arabino-hexopyranoslde (106) nitrogen i n the fume hood was added dry t r i e t h y l phosphite (9.5 mL, 56 mmol). The reaction mixture was heated to 135-140°C and the bromo-ethane produced was d i s t i l l e d out of the reaction mixture (28). Af t e r 4 h, the reaction mixture was allowed to cool to room temperature and was 0 t OMe To neat bromoacetate 105 (3.0 g, 5.6 mmol) under a stream of 141 p u r i f i e d by f l a s h chromatography on s i l i c a gel i n the fume hood using the sequence of solvents: petroleum ether - eth y l acetate 1:1 and neat ethyl acetate as eluant. Evaporation of solvent from the appropriate f r a c t i o n s yielded two compounds. a) Chloroacetate 107 (0.07 g, 2%) was i s o l a t e d from the petroleum ether -ethyl acetate solvent as white c r y s t a l s which were then r e c r y s t a l l i z e d from ethanol; R f 0.88 (petroleum ether - ethyl acetate 1:1, UV and HjSO^); mp 104-106°C; i r (CHC1 3): 1760 (s, C=0), 1740 (sh, C=0), 1075 (s, C-O), 960 (s, C-O) cm - 1; *H nmr (80 MHz, CDCI3) 6: 1.15 (d, J = 7 Hz, 3H), 1.50-2.25 (m, 3H), 3.00-3.30 (m, 2H), 3.43 (s, 3H), 3.60-4.05 (m, 3H), 4.43 (d, J = 2 Hz, IH), 4.85-5.27 (m, IH), 7.10-7.65 (m, 15H); ms m/zj 4 9 6 ( 3 7 C 1 : M+, 0.2), 494 ( 3 5C1: M+, 0.2), 258(23), 244(26), 243(100), 165(22). Exact mass: calcd. for C 2 9 H 3 1 3 7 C 1 0 5 : 496.1830; found (ms): 496.1789; calcd. for C 2 9 H 3 1 3 5 C 1 0 5 : 494.1860; found (ms): 494.1857. b) Phosphonoacetate 106 (3.5 g, 104%) was i s o l a t e d from the ethyl acetate as a gum which c r y s t a l l i z e d on standing. A small sample was r e c r y s t a l l i z e d repeatedly from ether - petroleum ether to y i e l d a n a l y t i -c a l l y pure f i n e white needles; 142 R f 0.15 (petroleum ether - ethyl acetate 1:1, UV and HjSO^); mp 85-86°C; [ a ] D +50.2° (£0.804, CHC1 3); i r (CHCI3): 1740 (m, C=0), 1320-1200 (m, P=0), 1020 (s, C-0) cm - 1; lE nmr (80 MHz, CDCI3) 6: 1.10 (d, J = 7 Hz, 3H), 1.28 ( t , J = 7 Hz, 6H), 1.55-2.20 (m, 3H), 2.70 (d, J n _ =22 Hz, 2H), 2.95-3.35 (m, —T y LH 2 2H), 3.45 (s, 3H), 3.70-4.35 (m, 5H), 4.43 (d, J - 2 Hz, IH), 4.80-5.25 (m, IH), 7.05-7.65 (m, 15H); ms m/z: 596(M+, 0.1), 321(70), 244(29), 243(100), 197(27), 179(32), 165(31), 127(36). Exact mass: calcd. for C 2 7H 3 60gP (M" 1"-^^): 519.2148; found (ms): 519.2143. Anal, calcd. for C 3 3H 4 10gP: C 66.43, H 6.93, 0 21.45; found: C 66.22, H 6.93, 0 21.25. Methyl 2,3-dideoxy-4-0-(diethyl pho8phonoacety l)-2-C-methyl-a-D-arabino-hexopyranoside (108) t OM To a sol u t i o n of t r i t y l ether 106 (0.50 g, 0.84 mmol) in methanol (10 mL) was added 5% palladium-on-charcoal (0.1 g) and a trace of 12 M 143 hydrochloric a c i d . The reaction mixture was s t i r r e d under hydrogen at atmospheric pressure for 8 h (30), f i l t e r e d through a pad of C e l i t e , and concentrated, without heating, to give a white semi-solid residue which consisted of triphenylmethane and alcohol 108. Although the crude material could be used d i r e c t l y i n the next reaction, this sample was p u r i f i e d by continuous l i q u i d - l i q u i d extraction. The crude product mixture was dissolved i n a c e t o n i t r i l e and the r e s u l t i n g s o l u t i o n was extracted continuously with petroleum ether. After 2.5 h, t i c of the a c e t o n i t r i l e layer showed no triphenylmethane. The a c e t o n i t r i l e layer was f i l t e r e d and concentrated, without heating, to y i e l d alcohol 108 (0.29 g, 98%) as a pale amber o i l ; R f 0.12 (ethyl acetate, H 2S0 4); i r (CHC1 3): 3650-3250 (w, H-bonded OH), 1740 (m, C=0), 1320-1200 (s, P=0), 1050 (s, C-0) 1025 (s, C-0) cm - 1; :H nmr (80 MHz, CDCI3) 6: 1.10 (d, J = 7 Hz, 3H), 1.35 ( t , J = 7 Hz, 6H), 1.70-2.25 (m, 3H), 2.83 (bs, IH, D 20 exchangeable), 2.95 (d, J D = 22 Hz, 2H), 3.38 (s, 3H), 3.50-3.95 (m, 3H), 3.95-4.31 (m, 4H), 4.40 (bs, IH), 4.80-5.25 (m, IH); ms m/z_: 323(M+-OMe, 9), 223(20), 197(100), 179(83), 151(29), 127(22), 123(25), 115(27), 72(41). Exact mass: calcd. for C 1 3H 2 1 +0 7P (M+-0Me): 323.1259; found (ms): 323.1256. 144 Methyl 2,3-dideoxy-4-0-(diethyl phosphonoacetyl)-2-C-methyl-a-D-arablno-hexodlaldo-1,5-pyranoside (109) 0 t OMe To a so l u t i o n of alcohol 108 (0.29 g, 0.8 mmol) and f r e s h l y d i s t i l l e d DCC (0.51 g, 2.4 mmol) i n dry DMSO (3.5 mL) under nitrogen i n the fume hood was added dry di c h l o r o a c e t i c acid (0.03 mL, 0.4 mmol) (38). After s t i r r i n g for 1.75 h, the cloudy white reaction mixture was f i l t e r e d through a sintered glass f i l t e r and the p r e c i p i t a t e was rinsed with d i s t i l l e d water. The combined aqueous f i l t r a t e was extracted with ether (6 x 10 mL) and then frozen using a dry ice - acetone bath. Freeze-drying under vacuum overnight yielded aldehyde 109 (0.24 g, 81%) as a pale amber o i l ; R f 0.70 (ethyl acetate - 1-propanol 3:1, I^SO^ and 2,4-DNP-hydrazine); i r (CHC1 3): 1740 (s, C=0), 1320-1200 (s, P=0), 1045 (s, C-0), 1025 (s, C-O) cm - 1; *H nmr (80 MHz, CDC1 3) 6: 1.05 (d, J = 7 Hz, 3H), 1.35 ( t , J = 7 Hz, 6H), 1.50-2.25 (m, 3H), 2.98 (d, ± . .„ =22 Hz, 2H), 3.45 (s, 3H), 3.90-4.39 (m, 5H), 4.42 (d, J - 3 Hz, IH), 5.00-5.40 (m, IH), 9.71 (s, IH); ms m/z: 323(M+-CHO, 20), 197(39), 179(100), 151(50), 128(20), 145 127(86), 125(28), 123(54), 115(39), 109(27), 97(23), 95(36), 85(32), 83(31), 81(25), 73(26), 72(72), 59(33). Exact mass: c a l c d . for C 1 3 H 2 1 t 0 7 P (M+-CH0): 323.1260; found (ms): 323.1265. (Methyl 2,3,6,7-tetradeoxy-2-C-methyl-a-D-arablno-oct-6-eno-l,5-pyranosld)-urono-8,4-lactone (110) OMe Sodium hydride (0.13 g, 60% dispersion i n o i l , 3.3 mmol) was washed free of o i l with dry THF under nitrogen and then dry THF (5 mL) was added to the sodium hydride. The r e s u l t i n g s l u r r y was added v i a pipette to a solu t i o n of aldehyde 109 (0.99 g, 2.8 mmol) i n dry THF (120 mL) under nitrogen. The reaction mixture was s t i r r e d for 5 min, heated under r e f l u x for 1 h and then was allowed to cool to room temperature (28). Amberlyst-15 (several spatula t i p s f u l l ) was added to neutralize any excess base. Af t e r s t i r r i n g for 10 min, the reaction mixture was f i l t e r e d and concentrated to y i e l d an amber gum (1.1 g). P a r t i a l p u r i f i c a t i o n by gel f i l t r a t i o n on Sephadex LH-20 using chloroform - methanol 1:1 as eluant yielded a pale amber gum (0.36 g). P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using petroleum ether - eth y l acetate 3.5:1 as eluant yielded a,8-unsaturated lactone 110 (0.23 g, 42%) as a cl e a r , colourless o i l which c r y s t a l l i z e d overnight. A small amount was Kugelrohr d i s t i l l e d to y i e l d an a n a l y t i c a l l y pure sample; 146 R f 0.25 (petroleum ether - ethyl acetate 3.5:1, UV and H 2S0 l +); mp 56.5-58.0°C; bp 61-63°C/0.01 Torr; [ a ] D +135° (£0.088, CHC1 3); i r (CHCI3): 1745 (sh), 1730 (s, C=0), 1060 (s, C-O) cm - 1; *H nmr (400 MHz, CDCI3) 6: 1.12 (d, J = 7 Hz, 3H), 2.80-2.88 (m, IH), 3.13-3.25 (m, 2H), 3.39 (s, 3H), 4.29 (dt, J - 11, 5 Hz, IH), 4.40-4.48 (m, 2H), 5.97 (dd, J = 10, 3 Hz, IH), 6.88 (d, J = 10 Hz, IH); ms m/_z: 198(M+, 1), 167(11), 96(100), 83(56), 73(32), 68(49), 55(90), 45(32), 41(30), 39(50). Exact mass: calcd. for C 9 H u 0 3 (M+-0Me): 167.0708; found (ms): 167.0704. Anal, calcd. for C 1 0H 1 1 +0 4: C 60.59, H 7.12; found: C 60.33, H 7.29. Occasionally aldehyde 111 was i s o l a t e d from this reaction. When the p a r t i a l l y p u r i f i e d c y c l i z a t i o n product was subjected to f l a s h chroma-tography, as described above, evaporation of solvent from the appropriate f r a c t i o n s afforded aldehyde 111 as a v o l a t i l e , colourless o i l ; R f 0.34 (petroleum ether - ethyl acetate 3.5:1, UV); i r (CHCI3): 2750 (w, aldehyde C-H), 1695 (s, C=0), 1655 (m, C=C) cm - 1; XH nmr (80 MHz, CDCI3) 6: 0.97 (d, J = 7 Hz, 3H), 1.70-2.35 (m, 2H), 2.40-2.85 (m, IH), 3.50 (s, 3H), 4.81 (d, J = 2 Hz, IH), 5.85-6.05 (m, IH), 9.15 (s, IH); ms m/z: 156(M+, 10), 72(100), 71(41), 57(35), 55(77), 53(23), 41(37). Exact mass: calcd. for C 8 H 1 2 0 3 : 156.0787; found (ms): 156.0792. 147 (Methyl 2,3,6,7-tetradeoxy-2,6-di-C-methyl-a-D-altro-octo-l,5-pyranosld)-urono-8,4-lactone (112) 0 OMe To a suspension of copper(I) cyanide (0.178 g, 1.99 mmol) i n dry ether (20 mL, d i s t i l l e d from sodium) at -78°C under nitrogen i n the fume hood was added a solu t i o n of methyllithium i n ether (2.65 mL, 1.5 M, 3.98 mmol). Aft e r s t i r r i n g for 5 min at -78°C, the reaction mixture was allowed to warm to 0°C. The mixture was s t i r r e d at 0°C for 20 min by which time the copper(I) cyanide had a l l reacted to give a cloudy so l u t i o n of Me 2Cu(CN)Li 2 (39). The cuprate so l u t i o n was cooled to -78°C and a solut i o n of a,B-unsaturated lactone 110 (0.328 g, 1.66 mmol) i n dry ether (12 mL, d i s t i l l e d from sodium) was added dropwise. The r e s u l t i n g bright yellow reaction mixture was s t i r r e d at -78°C for 15 min, at -40°C for 30 min and then was allowed to warm to 0°C. The reaction was di l u t e d with ether and quenched with g l a c i a l a c e t i c acid (6 mL) to give a clear pale turquoise s o l u t i o n containing a small amount of a fine white p r e c i p i t a t e . Tetrasodium ethylenediaminetetraacetate trihydrate (0.86 g, 2.0 mmol) was added and the r e s u l t i n g mixture was s t i r r e d f o r 15 min while warming to room temperature. Brine (5 mL) was added and a floc c u l a n t white p r e c i p i t a t e formed. The mixture was s t i r r e d f o r an a d d i t i o n a l 5 min and then was f i l t e r e d on a sintered glass f i l t e r . The f i l t r a t e was washed 148 with a so l u t i o n of saturated aqueous sodium carbonate - brine 1:1 (5 x 4 mL), brine ( 2 x 4 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded lactone 112 (0.32 g, 91%) as a very pale amber o i l which was pure enough to use i n the next reaction. A small amount was Kugelrohr d i s t i l l e d to y i e l d an a n a l y t i c a l l y pure sample as a colourless o i l ; R f 0.45 (petroleum ether - ethyl acetate 2:1, HgSO^); bp 70-73°C/0.01 Torr; [ a ] D +37° (c_ 0.070, CHC1 3); i r (CHC1 3): 1735 (s, C=0), 1055 (s, C-0) cm - 1; 1E nmr (400 MHz, CDCI3) 6: 1.10 (d, J = 7 Hz, 3H), 1.13 (d, J = 7 Hz, 3H), 1.83-1.92 (m, IH), 2.01-2.18 (m, 2H), 2.24-2.36 (m, IH), 2.48 (dd, £ 7 a ) 7 p = 18 Hz, J ^ 7 p = 3.5 Hz, IH, H-78), 2.82 (dd, £ 7 a > 7 p = 18 Hz, = 7 Hz, IH, H-7a), 3.38 (s, 3H), 3.84 (dd, J . c = 10 Hz, J c , = —6,7a * ' ' ' ' ' —4,5 ' —5,6 5 Hz, IH, H-5), 4.34-4.44 (m, 2H); ms m/z_: 214(M+, 1), 183(10), 112(100), 84(42), 72(58), 69(33), 56(46), 43(26), 41(28). Exact mass: calcd. for C 1 1 H 1 8 0 4 : 214.1205; found (ms): 214.1204. Anal, calcd. for C 1 1H 1 80 1 +: C 61.66, H 8.47; found: C 61.52, H 8.55. 149 Methyl 2,3,6,7-tetradeoxy-2,6-dl-C-methyl-a-D-altro-octo-l,5-pyranoside (113) OMe To a s o l u t i o n of l a c t o n e 112 (0.323 g, 1.51 mmol) l n dry e t h e r (10 mL) under n i t r o g e n was added a s o l u t i o n of d i i s o b u t y l a l u m i n u m h y d r i d e i n hexanes (9.3 mL, 1.0 M, 9.3 mmol). A f t e r s t i r r i n g o v e r n i g h t , the r e a c t i o n m i x t u r e was c o o l e d to 0°C, d i l u t e d w i t h e t h y l a c e t a t e (30 mL) and quenched w i t h s a t u r a t e d aqueous sodium s u l f a t e (5 mL). The g e l a t i n o u s aqueous phase was 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 (3 x 15 mL) and the combined o r g a n i c s o l v e n t s were washed w i t h 10% aqueous sodium b i s u l f a t e (1 x 25 mL, 1 x 5 mL), 10% aqueous potas s i u m c a r b o n a t e (1 x 5 mL), b r i n e ( 2 x 5 mL), d r i e d over anhydrous magnesium s u l f a t e , and f i l t e r e d . E v a p o r a t i o n of the s o l v e n t y i e l d e d d i o l 113 (0.308 g, 94%) as a c o l o u r l e s s o i l which c o u l d be used i n the next r e a c t i o n . P u r i f i c a t i o n of a s m a l l sample by f l a s h chromatography on s i l i c a g e l u s i n g neat e t h y l a c e t a t e as e l u a n t , f o l l o w e d by K u g e l r o h r d i s t i l l a t i o n , y i e l d e d a n a l y t i c a l l y pure d i o l 113 as a white s e m i - s o l i d ; R f 0.29 ( e t h y l a c e t a t e , H 2 S 0 4 ) ; bp 105-110°C/0.01 T o r r ; [<x] D +112 (c 0.460, CHC1 3); 150 i r (CHCI3): 3640 (w, free OH), 3600-3100 (m, H-bonded OH), 1055 (s, C-0) cm - 1; XH nmr (80 MHz, CDCI3) 6: 1.04 (d, J = 7 Hz, 3H), 1.07 (d, J = 7 Hz, 3H), 1.15-2.40 (m, 6H), 3.20-4.00 (m, 6H, 2H are D 20 exchangeable), 3.35 (s, 3H), 4.33 (bs, IH); ms m/z_: 187(M+-0Me, 1), 169(5), 72(100), 55(20). Exact mass: calcd. for C 1 Q H 1 9 0 3 (M+-0Me): 187.1334; found (ms): 187.1319. Anal, calcd. for C u H 2 2 0 1 + : C 60.52, H 10.16; found: C 60.72, H 10.24. Methyl 2,3,6,7-tetradeoxy-2,6-di-C-methyl-8-0-pivaloyl-g-D-altro-octo-l,5-pyranoside (114) OMe To a so l u t i o n of d i o l 113 (0.216 g, 1.00 mmol) and dry pyridine (2 mL) at 0°C under nitrogen was added p i v a l o y l chloride (0.123 mL, 1.00 mmol) over 5 min and the r e s u l t i n g mixture was s t i r r e d at 0°C for 3 h. Ice was added to quench the reaction, the mixture was s t i r r e d for 1 h and then was d i l u t e d with dichloromethane (10 mL) and water (5 mL). The aqueous layer was extracted with dichloromethane (2 x 10 mL) and the combined organic solvents were washed with 1 M hydrochloric acid (4 x 151 10 mL), saturated aqueous sodium bicarbonate (2 x 10 mL), brine (2 x 10 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded pivaloate ester 114 (0.222 g, 74%) as a colourless 011 which could be used i n the next reaction. P u r i f i c a t i o n of a small amount by f l a s h chromatography on s i l i c a gel using petroleum ether - e t h y l acetate 3:1 as eluant, followed by Kugelrohr d i s t i l l a t i o n , yielded an a n a l y t i c a l l y pure sample; R f 0.70 (petroleum ether - et h y l acetate 1:1, HjSO,^; bp 105-110°C/0.1 Torr; [ a ] D +88.1 (£ 0.520, CHC13); Ir (CHC13): 3625 (w, free OH), 3600-3300 (w, H-bonded OH), 1720 (s, C=0), 1160 (s, C-0) cm - 1; *H nmr (80 MHz, CDCI3) 6: 1.03 (d, J_ = 7 Hz, 3H), 1.06 (d, J = 7 Hz, 3H), 1.20 (s, 9H), 1.40-2.25 (m, 7H, IH i s D 20 exchangeable), 3.25-3.50 (m, IH), 3.35 (s, 3H), 3.55-3.95 (m, IH), 3.95-4.25 (m, 2H), 4.30 (d, J = 2 Hz, IH); ms m/z: 302(M+, 0.1), 271(3), 98(25), 85(75), 83(56), 73(40), 72(97), 71(44), 69(41), 57(100), 56(23), 55(64), 43(40). Exact mass: calcd. for C 1 5H 2 ?0 l t (M+-0Me): 271.1909; found (ms): 271.1912. Anal, calcd. for C 1 6H 3 ( )0 5: C 63.55, H 10.00; found: C 63.36, H 10.00. When excess p i v a l o y l chloride was used l n this reaction, the dip i v a l o a t e ester 115 was also produced. Separation of the two products 152 by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - eth y l acetate 20:1, 15:1 and then 3:1 as eluant yielded d i p i v a l o a t e ester 115 as a cl e a r , colourless o i l . A small amount was Kugelrohr d i s t i l l e d to y i e l d an a n a l y t i c a l l y pure sample; R f 0.93 (petroleum ether - ethyl acetate 3:1, H 2S0 l t); bp 100-110°C/0.05 Torr; [ct]D +87.7° (£ 0.618, CHC13); i r (CHCI3): 1720 (s, C=0), 1160 (s, C-0) cm - 1; lE nmr (80 MHz, CDCI3) 6: 1.02 (d, J = 7 Hz, 3H), 1.07 (d, J = 7 Hz, 3H), 1.18 (s, 9H), 1.20 (s, 9H), 1.55-2.15 (m, 6H), 3.38 (s, 3H), 3.63 (dd, J = 9, 3 Hz, IH), 4.02-4.22 (m, 2H), 4.32 (d, J = 2 Hz, IH), 4.75-5.25 (m, IH); ms m/z: 355(M+-OMe, 1), 95(20), 85(29), 72(100), 57(73), 55(21). Anal, calcd. for C 2 1 H 3 8 0 6 : C 65.26, H 9.91; found: C 65.17, H 10.01. Methyl 2,3,6,7-tetradeoxy-2,6-dl-C-methyl-8-0-plvaloyl-a-D-arabino-octo-l,5-pyranosid-4-ulose (116) OMe To a solu t i o n of ox a l y l chloride (34 n l , 0.40 mmol) in dry d i c h l o -153 chloromethane (2 mL) at -60°C under nitrogen was added DMSO (55 uL, 0.80 mmol) and the r e s u l t i n g s o l u t i o n was s t i r r e d at -60°C for 5 min. To th i s and the r e s u l t i n g s o l u t i o n was s t i r r e d at -60°C for 5 min. To th i s mixture was added a solution of alcohol 114 (98 mg, 0.32 mmol) i n dry dichloromethane (3 mL) and the r e s u l t i n g s o l u t i o n was s t i r r e d at -60°C f o r 20 min. Triethylamine (225 uL, 1.6 mmol) was added slowly and the reaction mixture was s t i r r e d at -60°C for 5 min and then at room tempera-ture for 5 h (35). Ice was added to quench the reaction and the mixture was s t i r r e d for 20 min. The r e s u l t i n g s o l u t i o n was di l u t e d with d i c h l o r o -methane (20 mL) and the organic layer was washed with 1 M hydrochloric acid ( 1 x 2 mL, 2 x 1 mL), saturated aqueous sodium bicarbonate ( 1 x 2 mL), brine ( 2 x 2 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded an amber o i l (89 mg) which was p u r i f i e d by f l a s h chromatography on s i l i c a gel using petroleum ether - e t h y l acetate 12:1 as eluant to y i e l d ketone 116 (76 mg, 78%) as a c l e a r , colourless o i l . A small amount was Kugelrohr d i s t i l l e d to y i e l d an a n a l y t i c a l l y pure sample; R f 0.32 (petroleum ether - e t h y l acetate 8:1, HjSO^); bp 100-105°C/0.09 Torr; [ a ] D +208° (£ 0.884, CHClj); i r (CHC1 3): 1720 (s, C=0), 1160 (s, C-O) cm - 1; lR nmr (80 MHz, CDC1 3) 6: 1.07 (d, J = 7 Hz, 3H), 1.10 (d, J = 7 Hz, 3H), 1.20 (s, 9H), 1.45-1.85 (m, 2H), 1.85-2.55 (m, 4H), 3.44 (s, 3H), 3.88-4.18 (m, 3H), 4.53 (d, J - 4 Hz, IH); 154 ms m/z_: 300(M+, 1), 269(2), 72(100), 57(34), 41(26). Exact mass: calcd. for C 1 6 H 2 8 0 5 : 300.1937; found (ms): 300.1942. Anal, calcd. for C 1 6 H 2 a 0 5 : C 63.97, H 9.40; found: 64.10, H 9.40. Methyl 2,3,4,6,7-pentadeoxy-2,6-di-C-methyl-4-C-methylene-8-0-pivaloyl-a-D-arablno-octo-1,5-pyranoside (117) OMe To a s o l u t i o n of ketone 116 (66 mg, 0.22 mmol) in dry d i c h l o r o -methane (5 mL) was added i n portions, via pipette, the active methylene complex (see p. 118) (9 x ca. 1.5 mL) u n t i l t i c analysis Indicated that the reaction was complete. The black reaction mixture was poured into a s l u r r y of sodium bicarbonate i n saturated aqueous sodium bicarbonate (15 mL) and the r e s u l t i n g s l u r r y was d i l u t e d with ethyl acetate (25 mL). The mixture was s t i r r e d for 40 min giving a c l e a r , colourless organic layer and a pale grey aqueous layer. The aqueous layer was extracted with ethyl acetate ( 3 x 10 mL) and the combined organic solvents were dried over anhydrous magnesium s u l f a t e and f i l t e r e d . Evaporation of the solvent yielded an o i l (84 mg) which was p u r i f i e d by f l a s h chromatography using petroleum ether - e t h y l acetate 8:1 as eluant to y i e l d alkene 117 (55 mg, 83%) as a c l e a r , colourless o i l . A small amount was Kugelrohr d i s t i l l e d 155 to y i e l d an a n a l y t i c a l l y pure sample; 0.48 (petroleum ether - et h y l acetate 8:1, R^SO^); bp 85-90°C/0.1 Torr; [ a ] D +122 (£ 0.560, CHC1 3); i r (CHCI3): 1720 (s, C=0), 1650 (w, C=C), 1160 (s, C-0) cm - 1; ln nmr (400 MHz, CDCI3) 6: 0.98 (d, J = 7 Hz, 3H), 1.02 (d, J = 7 Hz, 3H), 1.20 (s, 9H), 1.41-1.52 (m, IH), 1.73-1.82 (m, IH), 1.95 (dd, J - 13, 8 Hz, IH), 2.02-2.13 (m, 2H), 2.42 (dd, J = 13, 5 Hz, IH), 3.40 (s, 3H), 4.02 (bd, J = 4 Hz, IH), 4.08-4.20 (m, 2H), 4.36 (d, J = 4 Hz, IH), 4.77 (bs, IH), 4.85 (bs, IH); ms m/z_: 298(M+, 0.2), 269(3), 141(99), 121(24), 109(100), 107(23), 85(43), 81(44), 72(59), 71(22), 57(50). Exact mass: calcd. for C^HggO^: 298.2144; found (ms): 298.2159. Anal, calcd. for C 1 7H 3 0O l +: C 68.42, H 10.13; found: C 68.64, H 10. Methyl 2,3,4,6,7-pentadeoxy-4-C-hydroxymethylene-2,6-di-C-nethyl-8-0-pivaloyl-a-D-manno-octo-1,5-pyranoside (118) To a s o l u t i o n of alkene 117 (11 mg, 0.037 mmol) i n dry THF (1 mL) at 0°C under nitrogen was added a solution of borane i n THF (0.20 mL, 1.0 M, 0.20 mmol). After s t i r r i n g at room temperature overnight, the H, OMe 156 reaction was c a r e f u l l y quenched with water. Then 3 M sodium hydroxide (10 drops) and 30% hydrogen peroxide (10 drops) were added and the r e s u l t i n g mixture was heated at 35-40°C for 1 h. The mixture was cooled and poured into ether (10 mL). The aqueous layer was extracted with ether (2 x 10 mL) and the combined organic solvents were washed with brine (4 x 2 mL), dried over anhydrous magnesium sul f a t e and f i l t e r e d . Evaporation of the solvent yielded an o i l (11 mg). P u r i f i c a t i o n by f l a s h chromato-graphy using the sequence of solvents: petroleum ether - e t h y l acetate 2.5:1, and then 1.5:1 as eluant yielded alcohol 118 (9 mg, 82%) as a colourless o i l ; R f 0.50 (petroleum ether - e t h y l acetate 2:1, I^SO^); i r (CHC1 3): 3650 (w, free OH), 3600-3300 (w, H-bonded OH), 1720 (s, C=0), 1160 (s, C-0) cm - 1; lR nmr (270 MHz, CDCI3) 6: 0.94 (d, J = 7 Hz, 3H), 1.03 (d, J = 7 Hz, 3H), 1.19 (s, 9H), 1.10-1.50 (m, 2H), 1.50-1.96 (m, 4H), 1.96-2.09 (X part of ABX system plus a d d i t i o n a l couplings, IH, H-4), 2.10-2.25 (m, IH), 3.39 (s, 3H), 3.53 (dd, 5 = 10 Hz, J_5 g = 4 Hz, IH, H-5), 3.71 (B part of ABX system, B = 11 Hz, B = 4 Hz, IH, H-B), 3.75 (A part of ABX system, R = 11 Hz, A = 6 Hz, IH, H-A), 4.17 (dd, J = 8, 6 Hz, 2H), 4.27 (d, J x 2 - 6 Hz, IH, H - l ) ; ms m/z_: 284(M+-HOMe, 0.1), 266(0.1), 85(28), 72(100), 57(42). Exact mass: calcd. for C 1 6 H 2 8 0 4 (M+-H0Me): 284.1987; found (ms): 284.1991. 157 Methyl 2,3,4,6,7-pentadeoxy-2,4,6-tri-C-methy1-8-0-pivaloyl-g-D-manno octo-l,5-pyrano8ide (119) OMe A so l u t i o n of fr e s h l y prepared Wilkinson's ca t a l y s t (73) (0.310 g, 0.33 mmol) In dry benzene (25 mL) was prehydrogenated by bubbling hydrogen through the s t i r r e d s o l u t i o n for 1.5 h. To the r e s u l t i n g pale orange-red mixture^ was added a solu t i o n of alkene 117 (0.100 g, 0.336 mmol) i n dry benzene (10 mL) (18). Hydrogen was continuously bubbled through the s t i r r e d mixture and the reaction was monitored by c a p i l l a r y g l c . A f t e r 6.5 h, the reaction mixture was dil u t e d with petroleum ether - ethy l acetate 4:1 and the r e s u l t i n g suspension was f i l t e r e d through a pad of s i l i c a g e l . Evaporation of the solvent yielded compound 119 (75 mg, 75%) as a pale amber o i l ; R f 0.70 (petroleum ether - ethy l acetate 6:1, HjSO^); i r (CHC1 3): 1720 (s, C=0), 1160 (s, C-0) cm - 1; *H nmr (400 MHz, CDC1 3) 6: 0.86 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H), 1.02 (d, J = 7 Hz, 3H), 1.19 (s, 9H), 1.31-1.42 (m, IH), 1.61-1.79 (m, 3H), 1.81-1.98 (m, 2H), 2.12-2.23 (m, IH), 3.37 (s, 3H), 3.40 Complete hydrogenation i s effected providing the solu t i o n i s either yellow or pale orange-red during the entire course of the reaction (see p. 76). 158 (dd, J - 11, 4 Hz, IH), 4.15 (dd, J = 8, 6 Hz, 2H), 4.26 (d, J = 4 Hz, IH); 1 3 C nmr (100 MHz, CDC1 3) 6: 15.22 15.56 19.14 (CH3), 27.23 ( t e r t - b u t y l ) , 28.86 31.38 31.79 (CH), 32.52 34.36 (CH 2), 38.69 (C), 55.08 (OCH3), 63.19 (CH 2), 73.75 (CH), 105.91 (CH), 178.53 (C=0); ms m/z: 269(M+-OMe, 6), 268(10), 109(29), 96(80), 95(57), 85(36), 81(56), 72(75), 69(29), 57(100), 55(48). Exact mass: calcd. for C 1 6 H 2 9 0 3 (M+-0Me): 269.2116; found (ms): 269.2104. (2St 4R,5£, 6R)-5-Hydroxy-2,4,6-trlmethyl-8-[(pivaloyl)oxy J-l,l-(propane-l',3*-dithlo)octane (120) To a solution of acetal 119 (70 mg, 0.23 mmol) i n dry d i c h l o r o -methane (4 mL) at 0°C under nitrogen i n the fume hood was added 1,3-propanedithiol (6 drops, ca. 0.7 mmol) and boron t r i f l u o r i d e etherate (56 uL, 0.47 mmol) (18). Aft e r s t i r r i n g for 2.5 h at 0°C, the reaction mixture was d i l u t e d with ethyl acetate (30 mL). The organic layer was washed with 3 M sodium hydroxide ( 3 x 4 mL), brine ( 3 x 5 mL), dried over anhydrous magnesium s u l f a t e , f i l t e r e d , and concentrated to give an o i l (93 mg). P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel i n the fume hood using petroleum ether - ethyl acetate 6:1 as eluant yielded hydroxy dithiane 120 (74 mg, 84%) as a cl e a r , colourless gum; 159 0.16 (petroleum ether - ethyl acetate 6:1, UV and H^O^); i r (CHC1 3): 3650 (w, free OH), 3600-3300 (w, H-bonded OH), 2980 (s, C-H), 1720 (s, C=0), 1165 (s, C-O) cm"1; lE nmr (400 MHz, CDCI3) 6: 0.88 (d, J = 7 Hz, 3H), 0.91 (d, J = 7 Hz, 3H), 1.10 (d, J = 7 Hz, 3H), 1.20 (s, 9H), 1.42-1.53 (m, IH), 1.59 (bs, IH, D 20 exchangeable), 1.65-1.91 (m, 5H), 1.93-2.16 (m, 3H), 2.82-2.97 (m, 4H), 3.21 (b d, J = 7 Hz, IH), 4.08-4.23 (m, 3H); ms m/z_: 376(M +, 3), 358(2), 159(26), 146(26), 119(100), 85(29), 57(72), 55(28). Exact mass: calcd. for C 1 9H3 60 3S 2: 376.2106; found (ms): 376.2114. (2£, 4R,5S, 6R)-5-[(Methanesulfonyl)oxy ]-2,4,6-trimethyl-8-[(pivaloyl)oxy]-1,l-(propane-l 1,3'-dithio)octane (121) To a s o l u t i o n of alcohol 120 (25 mg, 0.066 mmol) i n dry d i c h l o r o -methane (2 mL) at 0°C under nitrogen was added methanesulfonyl chloride (36 uL, 0.46 mmol) and dry triethylamine (110 uL, 0.79 mmol). The reaction mixture was s t i r r e d at 0°C for 5 h and then was stored at 2°C overnight. Ice was added to quench the reaction and the r e s u l t i n g mixture was s t i r r e d for 1 h. The sol u t i o n was d i l u t e d with dichloromethane (10 mL) and the aqueous layer was extracted with dichloromethane ( 2 x 3 mL). 160 The combined organic extract was washed with 1 M hydrochloric acid ( 2 x 3 mL), brine ( 1 x 3 mL), saturated aqueous sodium bicarbonate ( 2 x 3 mL), brine ( 3 x 3 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded mesylate 121 (30 mg, 100%) as a pale amber o i l ; R f 0.35 (petroleum ether - et h y l acetate 3:1, UV and H 2S0^); i r (CHC1 3): 1720 (s, C=0), 1170 (s, C-O) cm - 1; *H nmr (80 MHz, CDC1 3) 6: 0.90-1.15 (m, 9H), 1.20 (s, 9H), 1.25-2.25 (m, 9H), 2.75-3.02 (m, 4H), 3.08 (s, 3H), 4.00-4.25 (m, 3H), 4.48 (dd, J = 6, 4 Hz, IH); ms m/z: 454(M+, 1), 374(5), 159(24), 149(43), 135(20), 123(33), 121(25), 119(60), 109(28), 107(41), 94(41), 93(23), 87(22), 81(22), 67(32), 58(21), 57(100), 55(40). Exact mass: calcd. for C 2 0H 3 8O 5S 3: 454.1881; found (ms): 454.1881. (2£, 4S_, 6S)-2,4,6-Trimethyl-8- [ ( p i v a l o y l )oxy ] - l , l-(propane-l *, 3 • - d i t h i o )-octane (122) To a so l u t i o n of crude mesylate 121 (30 mg, 0.066 mmol) i n 1,2-dimethoxyethane (2 mL) was added f r e s h l y activated zinc dust (43 mg, 0.66 mmol), sodium iodide (49 mg, 0.33 mmol) and water (2 drops) (75). The deep amber mixture was heated to r e f l u x and within 10 min the colour 161 had disappeared. A f t e r 4 h at r e f l u x , the reaction mixture was cooled to 0°C, d i l u t e d with ether (5 mL), f i l t e r e d through a sintered glass f i l t e r , and the p r e c i p i t a t e was rinsed with ether (20 mL). The f i l t r a t e was evaporated to give a gum (53 mg) which was then suspended i n deutero-chloroform. Decantation and evaporation of the solvent yielded a gum (29 mg). P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using petroleum ether - eth y l acetate 45:1 as eluant yielded two products. a) Thioacetal 124 (2.5 mg, 10%) was Isolated as a colourless o i l ; R f 0.28 (petroleum ether - e t h y l acetate 30:1, UV and HjSO^); i r (CHC1 3): 1720 (m, C=0), 1165 (s, C-0) cm - 1; lE nmr (80 MHz, CDCI3) 6 : 0.63-1.03 (m, 12H), 1.20 (s, 9H), 1.35-2.40 (m, 9H), 2.40-3.00 (m, 3H), 3.80-4.40 (m, 3H); ms m/z_: 360(M+, 2), 359(3), 358(12), 285(2), 284(2), 183(36), 159(100), 119(20), 85(24), 57(26). Exact mass: calcd. for C i gH3 502S 2: 360.2157; found (ms): 360.2160; calcd. for C 1 6 H 2 9 0 2 S (M+-SC 3H 7): 285.1888; found (ms): 285.1873. b) An 85:15 mixture of dithiane 122 and o l e f i n mixture 123 (6 mg, 25%) was i s o l a t e d as a colourless o i l ; R f 0.22 (petroleum ether - e t h y l acetate 30:1, UV and HjSO^); i r (CHCI3): 1720 (s, C=0), 1165 (s, C-0) cm - 1; XH nmr (400 MHz, CDC1 3) 6 : 0.86 (d, J = 7 Hz, 3H), 0.88 (d, J = 7 Hz, 3H), 1.08 (d, J_ - 7 Hz, 3H), 1.20 (s, 9H), 1.25-2.40 (m, 11H), 2.80-2.98 (m, 4H), 4.09 ( t , J - 7 Hz, 2H), 4.13 (d, J = 4 Hz, IH); 162 ms m/z: 360(M+, 5), 358(4), 183(23), 159(83), 148(37), 146(64), 121(75), 120(46), 119(100), 107(45), 106(44), 95(49), 93(24), 85(51), 83(22), 81(29), 75(20), 73(35), 69(40), 67(25), 57(80), 55(60). Exact mass: calcd. for C i g H 3 6 0 2 S 2 : 360.2157; found (ms): 360.2143; calcd. for C 1 9H 3 1 +0 2S 2: 358.2000; found(ms): 358.1973. (2£, 4R,5S,6R)-5-[(2•-Methoxyethoxymethyl)oxy J-2,4,6-trimethy1-8-[(pivaloyl)-oxy]-l,l-(propane-l",3"-dlthio)octane (131) To a solu t i o n of alcohol 120 (12 mg, 0.032 mmol) i n dry d i c h l o r o -methane (1 mL) at 0°C under nitrogen was added 2-methoxyethoxymethyl chloride (11 uL, 0.096 mmol) and N-ethyldiisopropylamine (25 uL, 0.144 mmol) (85). The reaction mixture was s t i r r e d at 0°C for 30 min and at room temperature overnight. A f t e r 18 h, t i c analysis indicated that the reaction was about 30% complete. The reaction mixture was cooled to 0°C, ad d i t i o n a l 2-methoxyethoxymethyl chloride (54 uL, 0.48 mmol) and N-ethyl-diisopropylamine (83 uL, 0.48 mmol) were added and the reaction mixture was s t i r r e d overnight at room temperature. After a t o t a l of 42 h, t i c analysis indicated that the reaction was complete. The reaction mixture was d i l u t e d with ether (25 mL) and the combined organic solvents were washed with 0.5 M hydrochloric acid ( 3 x 3 mL), saturated aqueous sodium bicarbonate ( 2 x 5 mL), brine ( 2 x 5 mL), dried over anhydrous magnesium 163 s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded 2-methoxy-ethoxymethyl ether 131 (15 mg, 100%) as an amber o i l which could be used i n the next reaction. P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using petroleum ether - eth y l acetate 6:1 as eluant yielded 131 (9 mg, 61%) as a cl e a r , colourless o i l ; R f 0.22 (petroleum ether - e t h y l acetate 6:1, UV and H 2S0 1 +); i r (CHC1 3): 1710 (s, C=0), 1040 (s, C-0) cm - 1; lE nmr (270 MHz, CDCI3) 6: 0.93 (d, J_ = 7 Hz, 3H), 0.96 (d, J = 7 Hz, 3H), 1.09 (d, J = 7 Hz, 3H), 1.20 (s, 9H), 1.22-2.18 (m, 9H), 2.80-2.95 (m, 4H), 3.12 (dd, J = 6, 4 Hz, IH), 3.40 (s, 3H), 3.53-3.60 (AA' part of AA'BB' system, 2H), 3.72-3.79 (BB' part of AA'BB' system, 2H), 4.07-4.19 (m, 3H), 4.77 (s, 2H); ms m/z_: 464(M +, 0.6), 388(52), 307(21), 273(22), 231(20), 161(31), 159(56), 149(20), 148(22), 147(29), 146(31), 125(35), 121(21), 119(100), 89(88), 59(82), 57(39). Exact mass: calcd. for C23 Hi»4°5 S2 : 464.2630; found (ms): 464.2634. (2£,4R,5S_,6R)-8-Hydroxy-5-[(2 ,-methoxyethoxymethyl)oxy]-2,4,6-trimethyl-l,l-(propane-l",3"-dithio)octane (132) MEMO n To a s l u r r y of li t h i u m aluminum hydride (8.5 mg, 0.22 mmol) i n dry 164 ether (5 mL) at 0°C under nitrogen was added a solution of crude pivaloate ester 131 (71 mg, 0.15 mmol) i n ether (5 mL) and the r e s u l t i n g mixture was s t i r r e d at 0°C. After 1 h, t i c indicated that the reaction was not com-plete so a d d i t i o n a l l i t h i u m aluminum hydride (12 mg, 0.32 mmol) was added. After a further 30 rain, the reaction was complete and was quenched with 0.5 M hydrochloric acid (10 mL). The aqueous layer was extracted with ether (1 x 25 mL, 2 x 25 mL) and the combined organic extract was washed with 0.5 M hydrochloric acid (2 x 5 mL), saturated aqueous sodium bicarbonate ( 1 x 5 mL), brine ( 2 x 5 mL), dried over anhydrous magnesium s u l f a t e , f i l t e r e d and concentrated to y i e l d a colourless o i l (62 mg). P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using ether as eluant yielded alcohol 132 (50 mg, 86%) as a c l e a r , colourless o i l . A small amount was Kugelrohr d i s t i l l e d to y i e l d an a n a l y t i c a l l y pure sample; R f 0.50 (ether, UV and H 2S0 H); bp 130-140°C/0.1 Torr; [ a ] D +15° (£0.020, CHC1 3); Ir (CHCI3): 3675 (w, free OH), 3625-3300 (w, H-bonded OH), 1040 (s, C-0) cm - 1; *H nmr (270 MHz, CDCI3) 6: 0.92 (d, J = 7 Hz, 3H), 0.94 (d, J = 7 Hz, 3H), 1.08 (d, J = 7 Hz, 3H), 1.10-2.25 (m, 10H), 2.80-3.00 (m, 4H), 3.15 (d, J = 6, 4 Hz, IH), 3.38 (s, 3H), 3.50-3.90 (m, 6H), 4.15 (d, J = 3 Hz, IH), 4.78 (s, 2H); ms m/z: 380(0.2), 159(33), 146(29), 125(21), 119(100), 89(51), 85(27), 59(67). 165 Exact mass: calcd. for C 1 8H 3 6O t tS 2: 380.2055; found (ms): 380.2054. Anal, calcd. for C 1 8 H 3 6 0 i t S 2 : C 56.80, H 9.53; found: C 57.00, H 9.60. (2S,4R, 5 J 5 , 6 R ) - 8 - [ (tert-Butylmethoxyphenylslly1 )oxy ] - 5 - [ ( 2 '-methoxyethoxy-methy1)oxy]-2,4,6-trimethyl-1,l-(propane-l",3"-dlthio)octane (133) TBMPSO To a solu t i o n of alcohol 132 (32 mg, 0.084 mmol) i n dry d i c h l o r o -methane (1.5 mL) under nitrogen was added triethylamine (0.175 mL, 1.26 mmol) and tert-butylmethoxyphenylsilyl bromide (0.135 g, 0.49 mmol) (86). A f t e r s t i r r i n g for 26 h, the reaction was quenched with water (2 mL) and di l u t e d with ether (15 mL). The combined organic solvents were washed with 0.5 M hydrochloric acid (2 x 2.5 mL), saturated aqueous sodium bicarbonate (2 x 2.5 mL), brine (3 x 2.5 mL), dried over anhydrous magnesium s u l f a t e , f i l t e r e d , and concentrated to y i e l d a pale amber o i l (0.106 g). P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - eth y l acetate 15:1 and then 6:1 as eluant yielded s i l y l acetal 133 (26 mg, 54%) as a pale amber o i l ; R f 0.46 (petroleum ether - e t h y l acetate 6:1, UV and H 2S0 l +); i r (CHC1 3): 2950 (m, C-H), 1090 (s, Si-0), 1035 (m, C-0) cm - 1; XH nmr (270 MHz, CDC1 3) 6: 0.85-1.00 (m, 6H), 0.95 (s, 9H), 166 1.02-1.12 (m, 3H), 1.12-2.15 (m, 9H), 2.77-2.97 (m, 4H), 3.12-3.18 (m, IH), 3.38 (s, 3H), 3.52-3.58 (AA' part of AA'BB' system, 2H), 3.63 (s, 3H), 3.72-3.78 (BB' part of AA'BB' system, 2H), 3.80-3.95 (m, 2H), 4.15 (d, J - 4 Hz, IH), 4.76 (s, 2H), 7.30-7.40 (m, 3H), 7.55-7.65 (m, 2H); ms m/z_: 572(M+, 0.4), 515(2), 439(39), 211(54), 167(32), 161(32), 159(41), 153(59), 149(54), 147(23), 146(38), 125(21), 123(35), 121(46), 119(97), 109(21), 107(49), 95(23), 93(20), 91(29), 89(100), 69(20), 59(99), 55(23). Exact mass: calcd. for C 2 9 H 5 2 0 5 S 2 S i : 572.3025; found (ms): ( 2£, 4R,5S, 6R)-8-Hydroxy-5-[(2'-methoxyethoxymethyl)oxy]-2,4,6-trimethy1-l,l-(propane-l",3"-dithio)octane (132) v i a deprotection of s i l y l a c e t a l 133 To neat s i l y l a c e t a l 133 (15 mg, 0.027 mmol) was added a s o l u t i o n o f tetra-n_-butylammonium f l u o r i d e i n THF (0.27 mL, 1.0 M, 0.27 mmol) (86). A f t e r s t i r r i n g f o r 2 h, the r e a c t i o n m i x t u r e was d i l u t e d w i t h e t h e r (20 mL). The combined o r g a n i c s o l v e n t s were washed w i t h b r i n e ( 3 x 2 mL), d r i e d over anhydrous magnesium s u l f a t e , f i l t e r e d , and c o n c e n t r a t e d to y i e l d an o i l (22 mg). P u r i f i c a t i o n by f l a s h chromatograpy on s i l i c a g e l u s i n g e t h e r as e l u a n t y i e l d e d a l c o h o l 132 (10 mg, 100%) as a c o l o u r l e s s o i l , and the s p e c t r a l data were i n agreement w i t h those r e p o r t e d above. 572.3023. MEMO n 167 (2£,4R,5 S ,6R)-8-[(tert-Butyldlmethyl8llyl)oxy]-5-[(2 ,-methoxyethoxy-methyl)oxy]-2,4,6-trimethyl-l,l-(propane-l",3"-dithio)octane (138) n TBDMSO To a sol u t i o n of alcohol 132 (15 mg, 0.039 mmol) i n dry d i c h l o r o -methane (1 mL) at 0°C under nitrogen was added t e r t - b u t y l d i m e t h y l s i l y l t r i f l a t e (30 p,L, 0.13 mmol) and dry 2,6-dimethylpyridine (20 uL, 0.16 mmol) (47). After s t i r r i n g at 0°C for 15 min, the reaction mixture was allowed to warm to room temperature f o r 15 min. The reaction mixture was di l u t e d with ether (15 mL) and the combined organic solvents were washed with brine ( 3 x 3 mL), dried over anhydrous magnesium s u l f a t e , f i l t e r e d , and concentrated to y i e l d an o i l (21 mg). P u r i f i c a t i o n by f l a s h chromatography on s i l i c a gel using petroleum ether - ether 3:1 as eluant yielded s i l y l ether 138 (17 mg, 87%) as a pale amber o i l ; R f 0.30 (petroleum ether - ether 3:1, UV and R^SO^); i r (CHC13): 2945 (s, C-H), 1095 (s, Si-0), 1040 (s, C-O) cm - 1; XH nmr (80 MHz, CDCI3): 0.02 (s, 6H), 0.75-0.98 (m, 6H), 0.87 (s, 9H), 0.98-1.15 (m, 3H), 1.45-2.30 (m, 9H), 2.72-3.02 (m, 4H), 3.12 (dd, J = 6, 3 Hz, IH), 3.38 (s, 3H), 3.44-3.84 (m, 6H), 4.15 (d, J = 3 Hz, IH), 4.76 (s, 2H); ms m/z: 494(M+, 0.1), 437(1), 159(24), 133(59), 119(51), 89(100), 75(28), 73(26), 59(75). Exact mass: calcd. for C ^ H ^ O ^ S i : 494.2920; found (ms): 494.2892. 168 IV. Preparation of Fragment B 2,4-Dimethylglutaric a c i d (136) This compound was prepared from d i e t h y l methylmalonate (134) and et h y l 2-bromoisobutyrate (135) i n 97% y i e l d according to the procedure of Shelly (12); 8 i r (CHC1 3): 3600-2450 (m, COOH), 1720 (s, C=0), 1460 (m, CH 3) cm - 1; *H nmr (60 MHz, CDC1 3) 6: 1.20 (d, J = 7 Hz, 6H), 1.63-2.87 (m, 4H), 11.46 (bs, 2H, D 20 exchangeable). ate80-2,4-Dlmethylglutarlc anhydride (5) This compound was prepared from d i a c i d 136 i n 28% y i e l d according g to the method of Shelly (270). C a p i l l a r y glc indicated that this product was 95% pure; This experiment was performed by A. Schwerdtfeger, r e c i p i e n t of an N.S.E.R.C. Undergraduate Summer Research Award - 1985. 169 i r (CHCI3): 1810 (m, C=0), 1765 (s, C=0), 1070 (s, C-0), 1015 (s, C-O) cm - 1; XH nmr (270 MHz, CDCI3) 6: 1.37 (d, J = 7 Hz, 6H), 1.58 (q, J = 11 Hz, IH), 2.05 (dt, J = 11, 5 Hz, IH), 2.63-2.80 (m, 2H). Methyl (2£* >4R*)-2,A-dimethylglutarlc a c i d ester (6) This compound was prepared from anhydride 5_ i n 99% crude y i e l d 9 according to the procedure of Shelly (12). The crude product was used, without d i s t i l l a t i o n , i n the next reaction; i r (CHCI3): 3600-2450 (w, COOH), 1735 (s, C00R), 1715 (s sh, COOH) lK nmr (60 MHz, CDCI3) 6: 1.18 (d, J = 7 Hz, 6H), 1.40-2.90 (m, 4H), 3.67 (s, 3H), 10.93 (s, IH, D 20 exchangeable). Methyl (2£,4R)-2,4-dimethylglutaric acid ester (6) To a hot sol u t i o n of racemic acid 6_ (16.03 g, 921 mraol) i n 2-propanol (29.25 mL) was added (+)-a-methylbenzylamine (11.15 g, 921 mmol) and ether (29.25 mL) and the r e s u l t i n g solution was stored at 9 2°C overnight (87). F i l t r a t i o n of the r e s u l t i n g s l u r r y yielded white 9 This experiment was performed by A. Schwerdtfeger. 0 0 cm -1. 170 c r y s t a l s (13.61 g) which were then r e c r y s t a l l i z e d from hot 2-propanol (50.8 mL) and ether (25.A mL) to y i e l d white needles (6.54 g). The s a l t was r e c r y s t a l l i z e d again from hot 2-propanol (40.8 mL) and ether (10.2 mL) to y i e l d long white needles (4.24 g). The c r y s t a l s were dissolved i n water (52 mL) and the so l u t i o n was a c i d i f i e d to pH 2 by the addition of 1 M hydrochloric a c i d . The aqueous sol u t i o n was extracted with ether (6 x 30 mL) and the combined extract was washed with brine (3 x 50 mL), dried over anhydrous magnesium s u l f a t e , f i l t e r e d , and concentrated to y i e l d an o i l (2.76 g). Kugelrohr d i s t i l l a t i o n yielded the resolved acid 6_ (2.34 g, 29%) as a c l e a r , colourless o i l ; bp 95-110°C/0.75 Torr ( l i t . (87) bp 75-80°C/0.75 Torr); [ c t ] D -4.2° (c 13.44, CHC1 3) [ l i t (87) -5.22° (£ 2.585, CHC13)] • Methyl (2J[,4R)-4-chloromethanoyl-2-methylpentanoate ( 7 ) 0 0 c l' JS /Y^ 0 M e This compound was prepared from the resolved acid 6_ i n 69% y i e l d according to the procedure of Shelly ( 1 2 ) ; ^ bp 47°C/0.2 Torr ( l i t (12) bp 52°C/0.2 Torr); i r ( C H C I 3 ) : 1795 (s, C0C1), 1740 (s, COOR) cm - 1; 1E nmr (270 MHz, CDC1 3) 6: 1.22 (d, J = 7 Hz, 3H), 1.32 (d, J = This experiment was performed by A. Schwerdtfeger. 171 7 Hz, IH), 1.40-1.65 (m, IH), 2.17-2.31 (m, IH), 2.47-2.62 (ra, IH), 2 . 8 7 - 3 . 0 0 (m, IH), 3.70 (s, 3H). Methyl (2R,4S)-2,4-dimethyl-5-hexenoate (12) 0 This compound was prepared from acid chloride 1_ according to the procedure of Shelly ( 1 2 ) with the following modifications i n the work-up and p u r i f i c a t i o n * * . After removal of the magnesium s u l f a t e by f i l t r a t i o n , the s o l u t i o n was concentrated on the rotary evaporator to a volume of 50 mL. The remaining solvent was removed by d i s t i l l a t i o n at 80°C to y i e l d alkene 12_ ( 0.91 g, 78%) as a pale amber o i l which could be used i n the next reaction. Kugelrohr d i s t i l l a t i o n of a small sample ( 0 . 2 g) yielded alkene 1 2 ( 0 . 1 2 g) as a cl e a r , colourless o i l . C a p i l l a r y glc indicated that this sample was 83% pure; bp 70-75°C/35 Torr; [ a ] D -15.4° (£ 1.87, C H C 1 3 ) ; i r ( C H C 1 3 ) : 1725 (s, C = 0 ) , 1640 (w, C=C) cm"1; lE nmr (80 MHz, C D C I 3 ) 6: 0.75 -2.75 (m, 1 0 H ) , 3.68 (s, 3H), 4.80-5.15 (m, 2 H ) , 5.35-5.90 (m, IH). This experiment was performed by A. Schwerdtfeger. 172 (2St4R)-2,4-Dimethyl-5-hexen-l-ol (13) This compound was prepared from ester \2_ according to the procedure of Shelly (12) with the following modifications i n the work-up 12 and p u r i f i c a t i o n . A f t e r removal of the magnesium sulfate by f i l t r a t i o n , the solvent was removed by d i s t i l l a t i o n at 50-60°C. Kugelrohr d i s t i l l a t i o n of the residue yielded alcohol 1^ (0.30 g, 54%) as a c l e a r , colourless o i l ; bp 80-85°C/37 Torr ( l i t (12) bp not reported); [<x]D +25.2° (c_ 2.16, CHC1 3); i r (CHC1 3): 3650 (m, free OH), 3600-3350 (w, H-bonded OH), 2990 (s, C-H), 1655 (m, C=C) cm - 1; XH nmr (80 MHz, CDCI3) 6 : 0 , 9 0 (<*, J = 7 Hz, 3H), 0.98 (d, J = 7 Hz, 3H), 0.75-1.95 (m, 2H), 1.95-2.50 (m, IH), 3.30-3.55 (m, 2H), 4.80-5.15 (m, 2H), 5.35-6.00 (m, IH). (2S >4R)-l-[(tert-Butyldimethylsllyl)oxy]-2,4-dlmethyl-hex-5-ene (14) < ^ Y ^ T ^ 0 T B D M S This compound was prepared from alcohol 13^  according to the method of Shelly (12) with some modifications i n the work-up and p u r i f i c a t i o n . This experiment was performed by A. Schwerdtfeger. 173 Afte r removal of the magnesium sul f a t e by f i l t r a t i o n , the s o l u t i o n was concentrated on the rotary evaporator and the crude residue was p u r i f i e d by f l a s h chromatography on s i l i c a gel using neat petroleum ether as eluant. Evaporation of solvent from the purest f r a c t i o n s , at 6 0 Torr for 1 . 5 h, yielded s i l y l ether 1 4 _ ( 0 . 1 5 g, 72%) as a cl e a r , colourless o i l . C a p i l l a r y glc indicated that this product was 98% pure; i r (CHC1 3): 2950 (s, C-H), 1640 (w, C=C), 1090 (s, Si- 0 ) , 835 (s, Si-C) cm - 1; XH nmr (80 MHz, CDC13) 6: 0.02 (s, 6H), 0.70-1.85 (m, 9H), 0.90 (s, 9H), 2.00-2.35 (m, IH), 3.27-3.47 (m, 2H), 4.77-5.20 (m, 2H), 5.32-6.00 (m, IH). (2S t4R)-l-[(tert-Butyldimethylsllyl)oxy]-5,6-epoxy-2,4-dimethylhexane (15) This compound was prepared from alkene £4_ according to the method of Shelly (12) with some modifications. To a solution of alkene £4_ (0.217 g, 0.90 mmol) i n dry dichloromethane (5 mL) at 0°C under nitrogen was added m-chloroperbenzoic acid (0.464 g, 2.70 mmol) and the r e s u l t i n g mixture was s t i r r e d at 0°C for 30 min and at room temperature for 6 h. The reaction mixture was di l u t e d with ether (25 mL) and the combined 0.36 (petroleum ether, l 2)» [ a ] D +6.66° (£2.00, CHC1 3); 174 organic solvents were washed with saturated aqueous sodium bicarbonate ( 1 x 5 mL), saturated aqueous sodium t h i o s u l f a t e ( 3 x 5 mL), saturated aqueous sodium bicarbonate ( 2 x 5 mL), brine ( 2 x 5 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . The sol u t i o n was concentrated on the rotary evaporator and then at 50 Torr f or 20 min to y i e l d a semi-s o l i d (0.238 g). P u r i f i c a t i o n by f l a s h chromatography using petroleum ether - ether 19:1 as eluant, followed by solvent evaporation at 60 Torr, yielded the epimeric epoxides 1_5 (0.152 g, 66%) as a clea r , colourless o i l ; R f 0.43 (petroleum ether - ether 19:1, H 2S0 4); i r (CHC1 3): 1260 (m, Si-C), 1095 (s, Si-0), 835 (s, Si-C) cm - 1; XH nmr (80 MHz, CDCI3) 6 : ° * 0 2 ^s> 6 H ^ » 0 , 8 6 9 H ^ » °-75-1.95 (m, 10H), 2.35-2.85 (m, 3H), 3.15-3.50 (m, 2H). 175 V. Coupling of the Fragment A Precursor with Fragment B Attempted coupling with s i l y l a c e t a l (133) To a s o l u t i o n of s i l y l a c etal 133 (35 mg, 0.061 mmol) In dry THF (0.2 mL) at -40°C under nitrogen i n the fume hood was added a s o l u t i o n of n-butyllithium i n hexanes (45 \iL, 1.5 M, 0.068 mraol) and TMEDA (11 uL, 0.073 mmol). The pale yellow reaction mixture was s t i r r e d at -40°C for 1 h and then HMPA (16 \iL, 0.091 mmol) was added. After s t i r r i n g for an ad d i t i o n a l 15 min at -40°C, the pale amber reaction mixture was cooled to -78°C, and a s o l u t i o n of the epoxide mixture JL5_ (18 mg, 0.067 mmol) i n dry THF (0.2 mL) was added. The reaction mixture was s t i r r e d at -78°C for 30 min, at -40°C for 30 min, at -10°C for 2 h (12) and then the reaction was quenched with water (3 drops). The r e s u l t i n g mixture was d i l u t e d with ether (15 mL) and the organic solvents were washed with saturated aqueous ammonium chloride ( 3 x 1 mL), brine ( 3 x 1 mL), dried over anhydrous magnesium s u l f a t e , and f i l t e r e d . Evaporation of the solvent yielded an o i l (47 mg) which was p u r i f i e d by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - ethyl acetate 10:1 and then 3:1 as eluant. Evaporation of solvent from the appropriate f r a c t i o n s yielded two compounds. a) S i l y l ether 137 (1.8 mg, 5%) was Isolated as an o i l ; R f 0.28 (petroleum ether - ethyl acetate 10:1, UV and H 2S0 l t); i r (CHC1 3): 2975 (s, C-H), 2940 (s, C-H), 1095 (s, Si-0) cm - 1; 1 7 6 1H nmr (270 MHz, CDC13) 6: 0.87 (s, 9H), 0.75-2.05 (m, 27H), 2.72-2.92 (m, 4H), 3.10-3.17 (m, IH), 3.37 (s, 3H), 3.30-3.85 (m, 6H), 4.15 (d, J - 3.5 Hz, IH), 4.77 (s, 2H), 7.30-7.40 (m, 3H), 7.45-7.55 (m, 2H); ms m/zj 598(M+, 0.1), 465(23), 237(100), 137(24), 123(24), 121(20), 119(26), 107(21), 89(64), 59(67). Exact mass: calcd. for 0 3 2 ^ 3 0 ^ 8 2 8 ! : 598.3546; found (ms): b) The s t a r t i n g m a t e r i a l 133 (14 mg, 40%) was i s o l a t e d as a p a l e amber o i l and the s p e c t r a l d a t a were i n agreement w i t h those r e p o r t e d above. (2£,4R,5S_, 6R)-8-[(tert-Butyldlmethyl8llyl)oxy]-5-[(2'-methoxyethoxy-methyl)oxy]-2,4,6-trimethyl-l,l-(propane-l",3"-dithio)-[1- 2H]octane (139) To neat d i t h i a n e 138 (11 mg, 0.022 mmol) a t -40°C under n i t r o g e n i n the fume hood was added a s o l u t i o n of n - b u t y l l i t h i u m i n hexanes (0.30 mL, 1.5 M, 0.44 mmol) and TMEDA (67 uL, 0.44 mmol) and the r e s u l t i n g amber mixture was s t i r r e d a t -40°C f o r 1 h ( 1 2 ) . The r e a c t i o n was quenched by the a d d i t i o n of de u t e r i u m o x i d e (20 drops) and the amber c o l o u r d i s a p p e a r e d . The mi x t u r e was d i l u t e d w i t h e t h e r (5 mL) and the aqueous l a y e r was e x t r a c t e d w i t h e t h e r ( 2 x 5 mL). The combined e t h e r 5 9 8 . 3 5 2 6 . MEMO n 177 extract was dried over anhydrous magnesium sul f a t e and f i l t e r e d . Evapo-r a t i o n of the solvent yielded deuterodithiane 139 (13 mg, 100%) as a pale amber o i l ; R f 0.30 (petroleum ether - ether 3:1, UV and HjSO^); i r ( C H C 1 3 ) : 2945 (s, C-H), 1095 (s, Si-0), 1040 (s, C-0) cm - 1; XH nmr (270 MHz, CDCI3) 6: 0.03 (s, 6H), 0.88 (s, 9H), 0.90 (d, J = 7 Hz, 3H), 0.91 (d, J = 7 Hz, 3H), 1.08 (d, J = 7 Hz, 3H), 1.10-2.15 (m, 9H), 2.75-2.97 (m, 4H), 3.08-3.16 (m, IH), 3.39 (s, 3H), 3.50-3.75 (m, 6H), 4.77 (s, 2H); ms m/z_: 495(M +, 0.1), 438(1), 159(20), 133(59), 120(24), 89(100), 75(26), 73(24), 59(69). Exact mass: calcd. for C 2 1 +H l + 9D0 l 4S 2Si 1: 495.2982; found (ms): 495.2998. (3R, 4£, 5R,7S,1IR,13S)-1,14-{D1[(tert-butyldimethylsilyl)oxy]}-10-hydroxy-4-[(2'-methoxyethoxymethyl)oxy J-3,5,7,11,13-pentaraethyl-8,8-(propane-l",3"-dithio)tetradecane (140) TBDMSO OTBDMS To neat deuterodithiane 139 (10 mg, 0.020 mmol) at -40°C under nitrogen i n the fume hood was added a solu t i o n of n-butyllithium i n hexanes (0.270 mL, 1.5 M, 0.40 mmol) and TMEDA (61 uL, 0.40 mmol) and the r e s u l t i n g amber mixture was s t i r r e d at -40°C for 1 h. Then HMPA (70 uL, 178 0.40 mmol) was added and the r e s u l t i n g deep amber suspension was s t i r r e d at -40°C for 15 min and then was cooled to -78°C. To the reaction suspen-sion was added neat epoxide 1_5 mixture (68 uL, 0.24 mraol), i n portions, v i a syringe. The reaction mixture was s t i r r e d at -78°C for 30 min, at -40°C for 30 min and at -10°C for 2 h and then the pale yellow so l u t i o n was stored at 2°C for 40 h (12). The sol u t i o n was quenched with water (20 drops) and the colour disappeared. The mixture was di l u t e d with ether (5 mL) and the aqueous layer was extracted with ether ( 2 x 5 mL). The combined ether extract was dried over anhydrous magnesium sulfate and f i l t e r e d . Evaporation of the solvent yielded a pale amber o i l which was p u r i f i e d by f l a s h chromatography on s i l i c a gel using the sequence of solvents: petroleum ether - ether 19:1, 10:1, 6:1 and then neat ether as eluant. Evaporation of solvent from the appropriate f r a c t i o n s yielded two compounds. a) Epoxide 15_ (43 mg, 80% recovery) was Isolated as a colourless o i l and the spectral data were i n agreement with those reported above. b) The desired alcohol 140 (6 mg, 40%) was is o l a t e d as a pale amber o i l ; R f 0.27 (petroleum ether - ether 3:1, UV and HjSO^); l r (CHC1 3): 3675 (w, free OH), 3600-3350 (w, H-bonded OH), 2945 (s, C-H), 1095 (s, S i - 0 ) , 1040 (s, C-0), 835 (s, Si-C) cm - 1; XH nmr (400 MHz, CDCI3) 6: 0.05 (s, 12H), 0.80-1.10 (m, 12H), 0.89 (s, 9H), 0.90 (s, 9H), 1.16 (d, J - 7 Hz, 3H), 1.20-2.25 (m, 15H), 179 2.75-2.92 (m, 4H), 3.18-3.22 (m, IH), 3.31-3.42 (m, IH), 3.38 (s, 3H), 3.45-3.82 (m, 8H), 4.05 (b d, J - 8 Hz, IH), 4.75-4.83 (m, 2H); ms m/£: 752(M+, 1), 734(1), 695(1), 377(24), 246(20), 245(100), 187(30), 133(35), 113(63), 95(26), 89(67), 75(50), 73(42), 59(51). Exact mass: calcd. for C 3 8 H 8 n 0 6 S 2 S i 2 ! 752.4935; found (ms): 752.4946. 180 REFERENCES 1. 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Res. 11, 497 (1969). 102. See reference 67. p. 142. 103. A.A.J. Feast, W.G. Overend, and N.R. Williams. J . Chem. Soc. 7378 (1965); see also reference 57. 104. H.G. K u i v i l a and O.F. Beumel, J r . J . Am. Chem. Soc. 83_, 1246 (1961). 187 SPECTRAL APPENDIX 1 3 * Generally, i r and 80 MHz H^ nmr spectra were recorded for each compound and these spectra can be found together on one page. For some compounds, higher f i e l d *H and * 3C nmr spectra were also recorded. In these cases, the H^ nmr spectrum can be found on the page d i r e c t l y following the i r and 80 MHz *H nmr spectra, and the 1 3C nmr spectrum can be found on the subsequent page. 188 681 191 192 193 J ii t----i i^f":"]"^....!---.-.^-.-..!.!--^ .... o 761 195 196 1 9 8 199 200 1" -1-4-2 0 1 203 204 205 208 603 2 1 0 TIZ 212 214 216 L\Z 218 219 c GO' X O ' o 0 = 0 I!! 220 221 223 224 226 227 228 2 2 9 0£Z 231 

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