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Model studies directed towards ionomycin Shelly, Kevin Paul 1984

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MODEL STUDIES DIRECTED TOWARDS IONOMYCIN by KEVIN PAUL SHELLY B . S c , University College Galway, 1981 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept this thesis as conforming to the required standard The University of B r i t i s h Columbia October, 1984 © Kevin Paul Shelly, 1984 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 f o r scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date IS O C T ff*f-DE-6 (3/81) - i i -ABSTRACT This work i s concerned with model studies directed towards the synthesis of the polyether a n t i b i o t i c ionoraycin (2). HOjC This involved the synthesis of: (a) a model of the A portion of _2, namely 30a (b) a precursor to the B portion of 2, namely 31 30a 31 Both of these racemic subunits were prepared from meso-2,4-diraethylglutaric anhydride (25). 25 Subsequent work comprised of in v e s t i g a t i n g the coupling reaction of these two portions. Model studies using the simpler moieties 17 and - i i i -.39b The use of the epoxide 40a proved more successful, providing 43a and 43b in a 39% y i e l d . 40a 43b - i v -The conditions found for oxidation of 20 to 21. proved f r u i t l e s s with 43a and 43b. However, dithiane hydrolysis followed by an oxidation 21 yielded the 6-diketones 44a and 44 b. 44a 44 b - v -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF FIGURES v i LIST OF TABLES v i i LIST OF ABBREVIATIONS v i i i ACKNOWLEDGEMENTS x INTRODUCTION A. Natural Product Synthesis.... 1 B. Polyether A n t i b i o t i c s 2 C. Ionoraycin 3 D. Synthesis 4 DISCUSSION 1. Model Studies.. 19 2. Synthesis of a Common Intermediate Leading to Subunits 25 3. Dithiane Subunit 30 31 4. Epoxide Subunit 3_1_ 33 5. Dithiane Metallation 36 6. A l k y l a t i o n Reaction 39 7. Route to 3-Diketones 44a and 44b 44 EXPERIMENTAL 54 BIBLIOGRAPHY 78 SPECTRAL INDEX 81 - v i -LIST OF FIGURES Figure T i t l e Page 1 Retrosynthetic plan leading from ionoraycin (2_) 12 2 Percent product vs. time i n oxidation of alcohol 20 using PCC and PCC • AI2O3 22 3 Percent product vs. time i n oxidation of alcohol 20 using PDC in DMF 24 4 Co r r e l a t i o n of ^-nmr and gc data of various crops of anhydride c r y s t a l s . . . . . . . . . . . . . . . . . . . . . . 27 - v i i -LIST OF TABLES Table T i t l e Page I A l k y l a t i o n of dithiane 17_ with 1,2-epoxybutane (19)... 20 II Oxidation of alcohol 20_ using PDC in DMF 23 III Elemental analysis of anhydride 25_ containing one water of hydration 29 IV M e t a l l a t i o n studies on dithiane 30a using _t-butyl lithium 37 V Metallation studies on dithiane 30a using n-butyllithiura 39 - v i i i -LIST OF ABBREVIATIONS AC2O acetic anhydride n-BuLi n_-butyllithium j:-BuLi _t-butyllithium °C degrees Celsius cone. concentration DCC dicyclohexylcarbodilmide DMF dimethylformamide DMSO dimethylsulfoxide equiv. equivalent(s) ethyl ether d i e t h y l ether gc • gas l i q u i d chromatography h hour ^H-nmr proton nuclear magnetic resonance HMPA hexamethylphosphoramide i r i n f r a - r e d LAH lithium aluminum hydride MCPBA meta-chloroperoxybenzoic acid min minute(s) PCC pyridinium chlorochrornate PCC«Al203 pyridinium chlorochrornate on alumina (1:4) PDC pyridinium dichromate rbf round bottom f l a s k S03*Py pyridine s u l f u r t r i o x i d e complex - ix -TBDMS _t-butyldiraethylsilyl TEA triethylamine THF tetrahydrofuran THP 2-tetrahydropyranyl t i c thin layer chromatography TMEDA tetraraethylethylenediaraine abbreviations for m u l t i p l i c i t i e s of ^-nrar signals s s i n g l e t bs broad s i n g l e t d doublet t t r i p l e t q quartet m m u l t i p l e t dt doublet of t r i p l e t s ddd doublet of doublets of doublets - x -ACKNOWLEDGEMENTS I wish to express my sincere thanks to Dr. Larry Weiler for his exc e l l e n t guidance and invaluable suggestions throughout the course of my research and the preparation of this t h e s i s . Numerous discussions with members of the research group, past and present, have been most b e n e f i c i a l and valuable. To them I extend my thanks and best wishes. The assistance of the elemental analysis, nmr, and mass spectroscopy s t a f f , as well as the other s t a f f i n the department, i s appreciated. - x i -To My Parents - 1 -INTRODUCTION A. Natural Product Synthesis "One should always be drunk, thats a l l that matters. . . . but what with? . . . " Following on this advice from the French poet Baudelaire (1821 -1867), synthetic organic chemists seek out a natural product to ( synthesize and i n e f f e c t get "drunk with". As organic chemistry develops and provides more synthetic methods, more natural product syntheses are attainable. While organic chemists can debate the merits of various syntheses, they can only a l l o c a t e the s i l v e r and bronze medals. Nature, while providing the target, also usually provides the best s o l u t i o n . Indeed, some syntheses follow guidelines prompted by the biosynthetic pathway used by nature, and often the building blocks used i n syntheses are supplied by nature, such as carbohydrates and amino acids. Nevertheless, once a synthesis has been achieved, the group involved w i l l r i g h t l y f e e l a sense of achievement. As well as d i r e c t gains possible from the synthesis of a natural product such as an a n t i b i o t i c or an insect pheromone, a r e a l value l i e s i n the experience gained by a l l involved i n the project. Apprenticeship, the oldest of educational methods, i s the basic concept i n the learning process. Techniques, methods, and the planning s k i l l s learned in one synthesis can be ever so useful i n subsequent work and - 2 -thus are an investment, a v a i l a b l e only through d i r e c t experience. There are a l o t more ways to get drunk than by synthesizing a natural product. Baudelaire had these thoughts about the why and how; "One should always be drunk thats a l l that matters. So as not to f e e l Time's h o r r i b l e burden that breaks your shoulders and bows you down, You must get drunk without ceasing. But what with? With wine, with poetry or with v i r t u e as you please." B. Polyether A n t i b i o t i c s The polyether a n t i b i o t i c s are members of a much larger class of compounds ca l l e d ionophores. Ionophores can complex an ion and transport i t through a l i p o p h i l i c i n t e r f a c e . Westley defines eight s t r u c t u r a l groups of ionophores based on chemical structure (1). The polyether a n t i b i o t i c group i s distinguished by a l i n e a r carbon framework, containing tetrahydrofurans and tetrahydropyrans, numerous asymmetric centres and often a terminal carboxylic a c i d . The f i r s t polyether a n t i b i o t i c to be is o l a t e d was n i g e r i c i n 0_) i n 1951, i t ' s s t r u c t u r a l determination was r e a l i z e d 17 years l a t e r (2). These a n t i b i o t i c s are an ever growing class of ionophores, with more than 30 having been recognized by 1978; while only 6 years l a t e r , 40 - 3 -more polyether a n t i b i o t i c s had been reported (3,4). A h •Me 1 Economically, polyether a n t i b i o t i c s have been applied in the treatment of c o c c i d i o s i s , a poultry disease. They have not gained any use i n human therapy because of the i r high t o x i c i t y when administered p a r e n t e r a l l y . A number of laboratories are investigating other possible uses for the polyether a n t i b i o t i c s . C. Iononycin L i u et a l . in 1978 (3) reported the production and i s o l a t i o n of the polyether a n t i b i o t i c ionomycin (2). The a n t i b i o t i c was is o l a t e d as i t s calcium s a l t from a broth concentrate which had been adjusted to pH 12 with aqueous sodium hydroxide. The high a f f i n i t y for calcium ions i l l u s t r a t e s an in t e r e s t i n g property of ionomycin. This polyether a n t i b i o t i c chelates d i p o s i t i v e ions as a dibasic a c i d , whereas the few other known ionophores which chelate such divalent cations do so as monobasic acids. - 4 -2 The s t r u c t u r a l determination of _2 resulted from i r , nmr, x-ray and mass spectroscopic data as detailed by Toeplitz et a l . i n 1978 ( 5 ) . The molecular structure of the calcium and cadmium s a l t s of ionoraycin contain a c i s o i d B-diketone anion that together with a carboxylate group and three other oxygen atoms are octahedrally coordinated to the central divalent cation as shown by an x-ray structure (5). D. Synthesis Some of the d i f f i c u l t i e s involved i n the synthesis of ionoraycin include s e t t i n g up a 32 carbon l i n e a r skeleton containing 14 asymmetric centres and a var i e t y of functional groups. While Evans has r e a l i z e d the synthesis of four subunits of ionomycin (6), the total synthesis of ionoraycin has not been reported to date. The synthesis planned by our group c o i n c i d e n t a l l y involves a four part convergent synthesis. A convergent synthesis i s inherently more e f f i c i e n t than a l i n e a r one (7). The linkage points chosen In such a plan are very important. We planned a strategy based on the bond disconnections shown In 3. - 5 -A_ _B_ _C_ .D 3 This thesis i s concerned with model studies towards l i n k i n g the A and B portions of ionoraycin, as well as preparing the groundwork for the synthesis of the B portion. A retrosynthetic analysis prompted us to consider dithiane chemistry to l i n k the A and B subunits. A l k y l a t i o n of the metallated dithiane with an epoxide and subsequent transformations might y i e l d the desired B-diketone. - 6 -Applying the methods of Corey and Seebach, developed since 1965, a l k y l a t i o n of dithiane anions with various e l e c t r o p h i l e s i s possible (8). Since regeneration of the carbonyl function can be achieved by a va r i e t y of methods, the thioacetal carbanions are equivalent to acyl anions and can be used e f f e c t i v e l y to reverse the c h a r a c t e r i s t i c e l e c t r o p h i l i c i t y of a carbonyl carbon. In 1972 Seebach proposed the use of the terra "urapolung" for this inversion of r e a c t i v i t y (9). - 7 -The use of dithiane chemistry i n natural product synthesis i s well documented. Seebach in his 1977 review, c i t e s numerous appl i c a t i o n s (9). Recent examples involve the t o t a l synthesis of aplasraomycin (10) and (+)-phyllanthocin (11). aplasmomycin (+)-phyl lanthocin - 9 -We were s p e c i f i c a l l y interested In the a l k y l a t i o n of dithianes with an epoxide, one of the slower reactions of dithiane anions. Seebach and Corey noted that epoxides "are opened very slowly" by dithiane anions and suggested storage of the reaction vessel at sub-zero temperatures for up to one week (7). This retardation i n epoxide opening allowed them to achieve the cheraoselectivity shown i n equation ( i ) , using epichlorohydrin as an a l k y l a t i n g agent. The desired product 4_ was obtained i n 64% y i e l d . There are examples of successful epoxide openings by dithiane carbanions i n natural product synthesis. Redlich et a l . , in their synthesis of the pheromone l i n e a t i n , alkylated the dithiane _5 and obtained the 3-hydroxy dithiane 6^  i n 88% y i e l d (12). (i ) - 10 -- 11 -In the synthesis of jaborosalactone A, B and D, Hirayama et a l . , employed the dithiane 7_ to extend the side chain on the steroid nucleus (13) . A l k y l a t i o n of _7 with the epoxide 8^  followed by dithiane hydrolysis afforded the B-hydroxy ketone 9_ i n 76% o v e r a l l y i e l d . While these reactions were successful, each involved either a simple epoxide or a simple dithiane moiety. We planned to employ both a complex dithiane and a complex epoxide. The B subunit i n our synthesis, the epoxide, would consist of a seven-carbon chain with two asymmetric centres. This work involves preparing a precursor to this subunit and studying the coupling reaction between this subunit and a suitable model for subunit A. The dithiane model needed in these studies should be as s t r u c t u r a l l y s i m i l a r to the eventual A portion of ionomycin as possible. Studies directed towards the synthesis of the A portion, a nine-carbon chain with three asymmetric centres, are currently being carried out in our laboratory (14) . The retrosynthetic plan, shown in F i g . 1, i l l u s t r a t e s that a model for A and a precursor for B can both be prepared from a common 2,4 -dimethyl substituted hexane intermediate _10_. We considered three possible routes to t h i s intermediate. I. Carbohydrates I I . (R)-3-hydroxyisobutyraldehyde (11) I I I . 2,4-dimethylglutaric acid (12) Figure 1. Retrosynthetic plan leading from ionomycin (2) - 13 -I . Carbohydrates The use of carbohydrate precursors in the synthesis of natural products i s well documented (15,16). The concept i s simple and involves the use of one of nature's sources of c h i r a l organic compounds to provide another natural product. Thereby, the synthetic chemist uses the inherent c h i r a l i t y and f u n c t i o n a l i t y of carbohydrates to provide target subunits or molecules. When used elegantly, these building OMe •> ( - ) - c x - m u l t i s t r i a t i n OMe - 14 -blocks are a superb source of such targets. Care must be taken so as not to get involved i n a route to the desired molecule, I n i t i a t e d from carbohydrates, which i s long, c i r c u i t o u s and i n e f f i c i e n t . Synthesis directed towards polyether a n t i b i o t i c s with carbohydrate s t a r t i n g materials include a n t i b i o t i c A23187 (17) and l a s a l o c i d A (18). Sum and Weiler could prove useful i n providing a 2,4-diraethyl six-carbon chain (19). This route would provide us with the two portions required for our proposed coupling studies, each with the correct absolute stereochemistry. The synthesis of the same natural product by Plaumann et a l . , would also provide the required carbon skeleton (20). I I . (R)-B-hydroxyisobutyraldehyde ( 1 1 ) Another possible route to the two target subunits involves the aldehyde 1J_ a v a i l a b l e from (+)-S-hydroxyisobutric acid (13) (21). The synthesis of (-)-ce-raultistriatin from D-glucose achieved by 13 11 - 15 -Collum et a l . , synthesized the lactone 1_4_ from the s t a r t i n g aldehyde JL1_ i n the synthesis of monensin (22). 11 XX XX 14 THPO>. J s . v s ^ ^ C 0 2 E t H" T HPO COoEt OH > monens in The lactone could, i n a series of steps, lead to the aldehyde 10a, an intermediate which might be used to prepare the two required substrates. 10a - 17 -III. 2,4-dimethylglutaric acid (12) The acid-ester 1_5_ i s r e a d i l y available from 2,4-dimethylglutaric acid (12) with chemistry developed by Auwers and Thorpe (23) and modified by A l l i n g e r (24). products (25) including ot-multistriatin (26) and Prelog-Djerassi lactone (27). The ot-multistriatin synthesis achieved by B a r t l e t t and Myerson produced the racemic natural product. The synthesis of ot-multistriatin from D-glucose by Weiler and Sum (15) provides the (-)-ot-isomer of the natural product and obviously has an advantage over the racemic synthesis. Since Chen et a l . , have described a microb i o l o g i c a l method for the preparation of J5_ i n >98% enantiomeric p u r i t y , the acid-ester 1_5 can be used e f f e c t i v e l y i n non-racemic syntheses (28). Conversion of _15_ to the aldehyde-ester 16 would provide us with a common intermediate from which both subunits could be derived. This l a t t e r route was favoured over the f i r s t two schemes because of the ready a v a i l a b i l i t y of large amounts of the d i a c i d 12. hydrolysis and oxidation in e i t h e r order would afford the desired B-diketone. 12 15 The acid-ester 1_5_ has been used in the synthesis of natural Once the coupling of the two units had been r e a l i z e d , subsequent - 19 -DISCUSSION 1. Model Studies 1.1. The dithiane _17_ was obtained from isobutyraldehyde (18) following the general procedure of Seebach and Corey (8). I n i t i a l attempts at the a l k y l a t i o n of the dithiane with 1,2-epoxybutane (19) were not too successful. A gc analysis of the crude product indicated that It contained about 60% of product alcohol 20. This resulted i n a 42% i s o l a t e d y i e l d of 20. Increasing the amount of epoxide used produced no change i n these r e s u l t s . 18 17 1. n-BuLi 19 20 - 20 -When the raetallation time with n-butyllithium was increased, a higher y i e l d of product was obtained. Doubling of the d i thiane concentration afforded the product 20 in almost quantitative y i e l d . These re s u l t s are summarized i n Table I. Table 1. A l k y l a t l o n of dith i a n e V7_ with 1,2-epoxybutane (19) Equlv, of J_7 Cone. In THP Temp •c Equlv. of n-BuLl H e t a l a t l o n Conditions Equlv. of ,19/ Tenp i .17:20 gc A n a l y s i s aolated Y i e l d 20 1 0.1 M -30 • 1.1 3 h/-30°C 1/0'C 40:60 20-40 h 421 1 0.1 M -30 1.1 3 h/-30'C 1.5/0*C 40:60 20 h -1 0.1 M -20 1.1 3 h/-20°C 16 h/-10*C 1/0*C 10:90 5 h -1 0.2 M -20 1.1 3 h/-20*C 16 h/-10°C 1/0°C -:>95 5 h 91X We observed no change by gc in the yi e l d s of product obtained with longer reaction times. Further gc investigations showed the a l k y l a t i o n to be complete within minutes of adding the epoxide at 0°C. The ease of this reaction was encouraging, though we r e a l i z e d i t was achieved employing both a very simple dithiane and a very simple epoxide as models. 1.2. The f i r s t choice of oxidizing agents to convert the alcohol 20 into the corresponding ketone 21. w a s pyridinium chlorochroraate (PCC) (29). I n i t i a l studies were deceptively promising. Using PCC with sodium acetate and sometimes with 4A molecular sieves i n methylene chloride produced some of the desired ketone 21, but varying amounts of the s t a r t i n g alcohol were always evident. Crude yields were not very - 21 -high, due to the d i f f i c u l t i e s i n extracting product from the black tar produced i n the oxidations. The use of excess PCC with sodium acetate lead to the formation of some sulfoxide as evidenced by mass spectroscopic data. We needed to modify the a c t i v i t y of the PCC and avoid the infamous black tar. PCC on alumina (1:4) was found to be a milder but e f f e c t i v e o x i d i z i n g agent (30). Four reactions were monitored by gc analysis using the oxidation with 3 equiv. of PCC as the reference. The r e s u l t s are presented i n F i g . 2. The reaction time with PCC on alumina Is slower by a factor of six or more when compared to the reference PCC oxidation. While the oxidation reaction mixture contained only ketone and no s t a r t i n g material, crude y i e l d s r a r e l y reached 40%. This resulted from the l o g i s t i c a l problem of extracting, t y p i c a l l y 1 g of product from 25 g of a granular s o l i d . A 74% crude y i e l d obtained using 5 equiv. of PCC*Al20 3 was the r e s u l t of many washings of the s o l i d residue and was not very reproducible. We t r i e d a few varia t i o n s with the work-up including kugelrohr d i s t i l l a t i o n and soxhlet extraction.. The former resulted i n product - 22 -1 * 1 — t 1 e i — # Time (h) Figure 2 - Percent product vs. time in oxidation of alcohol 20_ using PCC and PCC«A1 203. decomposition and the l a t t e r only afforded crude yields of 50% to 55%. Obviously PCC on alumina was not s a t i s f a c t o r y in t h i s oxidation. PCC was adsorbed onto F l o r o s i l and we attempted the oxidation of 20 using 5 equivalents of t h i s oxidant. The result was worse than before, y i e l d i n g very impure product. - 23 -1.3 We then turned our attention to pyridinium dichroraate (PDC) which Corey and Schmidt used to oxidize a secondary alcohol when a dithiane moiety was also present in the molecule as shown by equation ( i i ) (31). They found that 7 equiv. of PDC, 1.2 M in DMF, proved successful in the oxidation. The results of our studies u t i l i z i n g PDC i n DMF are summarized in Table I I . Table I I . Oxidation of alcohol 20 using PDC i n DMF Equiv. PDC Cone. PDC i n DMF Temp/Time Crude Y i e l d Ketone 21 P u r i t y («c) 1.1 M 25'C/l h 58Z 91Z 0.3 M 25"C/4 h 68Z 97Z 0.2 M 0*C/96 h 831 93Z 0.2 M 0"C/24 h 66Z 99Z 1.2 M 0°C/11 h 84 Z > 95X 1.2 M 0*C/7 h 74X > 98Z The work-up involved with these oxidations was cleaner than with PCC, r e s u l t i n g i n reasonable crude yields varying between 66% and 84%. At 0°C, the purity of the f i n a l product was generally higher than that obtained from reactions at room temperature. The monitoring of four reactions by gc analysis yielded a similar plot to that obtained with PCC on alumina, F i g . 3. The optimal conditions for the oxidation appear to be the use of 7 to 9 equivalents of PDC, 1.2 M i n DMF at 0°C, s t i r r e d f o r 7 to 11 h, affording crude y i e l d s i n the 80% range. - 24 -A > A . A • A . A . A / / A , • * AL. 2 4 6 8 1 0 12 v 24 4 8 72 96 Time (h) Figure 3 - Percent product vs. time i n oxidation of alcohol 2Q using PDC i n DMF. 1.3 The hydrolysis of the S-keto dithiane 21_ was achieved using mercuric chloride and mercuric oxide i n r e f l u x i n g aqueous a c e t o n i t r i l e (19, 32). The desired 8-diketone 12_ was obtained i n 52% p u r i f i e d y i e l d . As there are numerous techniques to hydrolyse dithianes we did not spend time improving this y i e l d on our simple model. - 25 -2. Synthesis of a Common Intermediate Leading to Subunits The common intermediate we envisaged using in the synthesis of both the dithiane and epoxide subunits was the aldehyde 16. the reported route to this compound started with the d i a c i d 12_ and C^Me 16 following anhydride formation, methanolysis, acid chloride formation and Rosenmund reduction afforded the aldehyde 16_ (27). The d i a c i d _12_ was prepared by a modification of the method used by Auwers and Thorpe in 1895 (23). Condensation of d i e t h y l ( i i i ) V ^ / C C ^ E t COoEt X C 0 2 E t 23 24 1. NaOEt 2. H + , A HO, 12 - 26 -methylmalonate (23) and ethyl-2-bromoisobutyrate (24), followed by subsequent hydrolysis and decarboxylation of the t r i a c i d provided 2,4-dimethylglutaric acid (12) in almost quantitative y i e l d as shown by equation ( i i i ) . The mixture of meso- and d l - d i a c i d s _12_ was converted to the corresponding anhydrides from which the meso-2,4-dimethylglutaric anhydride (25) could be isolated by c r y s t a l l i z a t i o n following the procedure developed by A l l i n g e r (24). By a c o r r e l a t i o n of nmr and gc data we found the f i r s t crop of c r y s t a l s to be 99.3% meso-anhydride, F i g . 4. Subsequent crops were mixtures of meso- and dl-anhydrides, with the percentage of d l ever increasing. The nmr data for the meso-anhydride (25) and the d l anhydride 26^  were very d i f f e r e n t . The two protons on C-3 in the case of 25 2 6 25 are non-equivalent, both chemically and magnetically. On the other hand, with the dl-anhydride 26^ , the two protons on C-3 are equivalent. - 27 -These facts are evident i n the 270 MHz H-nmr of each anhydride. One si g n a l i s observed for the two H c protons of 26_ while two signals are observed f o r the two H a and H^ protons of 25. C r o p No. 2 7 0 M H z Vl-nmr g c d a t a Jl ill L L U 9 9 . 3 0 .7 % 3 7 . 5 6 2 . 5 % T o I T 1.9 9 8 . 1 % p p m Figure 4 - Correlation of *H-nmr and gc data of various crops of anhydride c r y s t a l s . - 28 -Heating the anhydride to r e f l u x i n dry methanol provided only 30% to 40% of the desired mono-ester J_5_ with the d i a c i d 12_ c o n s t i t u t i n g the other product. Zamojski had reported this procedure affording y i e l d s of greater than 90% (33). When we treated s u c c i n i c anhydride (27) to the same experimental conditions, we obtained the acid-ester _28 i n 87% y i e l d . 28 Why did this model work but not the r e a l anhydride? A po t e n t i a l source of the problem would be the presence of water i n the reaction but the only difference i n the two experiments was the difference i n anhydride's used. Could the anhydride 25_ contain water of hydration? Elemental analysis of the anhydride provided affirmative evidence that one water of hydration had c r y s t a l l i z e d with the anhydride, Table I I I . This problem was overcome by kugelrohr d i s t i l l a t i o n of the hydrated anhydride. Subsequent raethanolysis of the d i s t i l l e d anhydride afforded the desired acid-ester J_5 i n 91% d i s t i l l e d y i e l d . - 29 -Table I I I . Elemental a n a l y s i s of anhydride 23 containing one water of hydration Coopound Z C Z H Calcd f o r 25_ 59.14 7.09 Calcd f o r 25_ • H 20 52.4 9 7.55 Found 52.45 7.73 We decided not to resolve the acid ester 15. Once the pathway to the B portion of ionomycin has been developed a subsequent synthesis using one enantioraer of compound 1_5 would be straightforward. The acid could be resolved using an enantioraerically pure, amine or as we alluded to e a r l i e r , by using the microbiological method developed by Sih (28). 15 29 The conversion of racemic 1_5 to the acid chloride 29. w a s r e a l i z e d using the procedure of Burgstahler, et a l . (34). 29 _16 I n i t i a l l y we hoped to use the crude acid chloride In the next step, which i s the aldehyde formation. The reaction work-up of _29_ involved removal of the solvent and excess reagents under reduced pressure. The crude acid chloride obtained i n this fashion f a i l e d to - 30 -give reasonable y i e l d s of aldehyde _16_ in the subsequent Rosenmund reduction. For the reduction we employed the modification as d e t a i l e d by Burgstahler et a l . i n 1976 (34) and recommended by B a r t l e t t and Adams in t h e i r synthesis of Prelog-Djerassi lactone (27). I n i t i a l l y we associated the poor y i e l d s with the suspect s t a b i l i t y of the acid c h l o r i d e . As we had more dealings with both the acid chloride 29_ and the aldehyde _16_, we found the aldehyde to be the more unstable compound of the two. In f a c t , the crude acid chloride could be d i s t i l l e d at reduced pressure affording a colourless o i l i n 92% y i e l d . Once d i s t i l l e d , i t could be stored for up to a month before conversion to the aldehyde _16_ i n 60% y i e l d . The i n s t a b i l i t y of the aldehyde lead us to consider employing the acid chloride 29_ as the common intermediate to the dithiane 30 and epoxide 31 subunits. 29 / \ We w i l l discuss l a t e r the steps leading to the epoxide, after we describe our route to the dithiane 30. - 31 -3. Dithiane Subunit 30 The dithiane 32_ can be obtained d i r e c t l y from the aldehyde _16_ by treatment of in chloroform with 1,3-dithiolpropane in the presence of boron t r i f l u o r i d e etherate. The i n s t a b i l i t y of the neat aldehyde i n v a r i a b l y led to low y i e l d s of the p u r i f i e d dithiane 32_* As long as the aldehyde _16_ was i n solut i o n , i t s s t a b i l i t y was greatly enhanced. So we attempted to overcome the problem of the decomposition of the neat aldehyde by combining two steps in one. Hydrogenation of the acid chloride for 8 h, followed by a care f u l work up provided the aldehyde in a chloroform s o l u t i o n . Without any time delay, the aldehyde was converted to the dithiane 32_ in a p u r i f i e d y i e l d of over 60%. Reduction of the ester in 32 was achieved using lithium aluminum hydride, affording us the alcohol 33 in high y i e l d . _ t-butyldimethylsilyl moiety. It needed to survive dithiane metallation, Involving a strong base, and dithiane hydrolysis conditions. Using t - b u t y l d i m e t h y l s i l y l chloride with imidazole in DMF, af t e r 3 days at 16 32 Our choice of a protecting group for 33 was the - 32 -LAH 33 room temperature, only 50% of pure product 30a was obtained. S t a r t i n g alcohol was also i s o l a t e d . The use of _t-butyldimethylsilyl trifluoromethane sulfonate with 2,6-diraethylpyridine i n methylene chloride (35) provided the subunit 30a i n much shorter time and much higher y i e l d (97%). .33 30a - 33 -4. Epoxide Subunit 31 Our plan for the synthesis of the epoxide subunit 31_ involved a Witt i g reaction of the aldehyde 16, followed by an epoxidation as shown i n equation ( i v ) . (iv) Attempted methylenation by adding the aldehyde to the y l i d , from methyltriphenylphosphonium bromide and rv-butyllithiura, i n a THF s o l u t i o n Invariably gave the desired alkene 34_ i n yields of 30% or l e s s . The same unsatisfactory r e s u l t s were observed when the y l i d was added to the aldehyde, using ether as solvent, or at lower reaction temperatures. We suspected two problems. One was the i n s t a b i l i t y of the s t a r t i n g aldehyde _16_. I t was f e l t that this factor alone could not account for the low y i e l d s . The base s e n s i t i v i t y of the ester raoity could also be a - 34 -cause of the low y i e l d . This p o s s i b i l i t y was supported by the loss of the methyl ester s i n g l e t i n the ^-nrar of the crude product obtained when 3.5 equivalents of y l i d were used. These problems were solved by the u t i l i z a t i o n of a d i f f e r e n t methylenating agent. In 1978, Takai et a l . developed two methods for terminal o l e f i n synthesis (36). They found that reaction of CH 2I 2-Zn-Me 3Al o r a CH 2Br 2-Zn-TiCLi t mixture with a ketone or aldehyde could provide the desired methylene product in good y i e l d . Lombardo, i n his work on g i b e r e l l i n syntheses 4 years l a t e r , reacted the highly e l e c t r o p h i l i c CH2Br2-Zn-TiCli+ reagent with the ketone 35_ and found i t destroyed the substrate before reacting (37). He prepared a more active reagent by using neat titanium tetrachloride instead of a 1.0 M solution and changing the temperature and time of the procedure. The desired transformation was achieved in 90% i s o l a t e d y i e l d using the more active reagent with no evidence of epimerization of the adjacent c h i r a l centre. Upon applying this reagent to cyclododecanone (36), we obtained the terminal o l e f i n 37 in quantitative y i e l d s . - 35 -3 6 37 Reaction of this reagent with the aldehyde 1_6 afforded the o l e f i n 34 i n p u r i f i e d y i e l d s varying between 50% and 60%, a doubling of the y i e l d obtained with the W i t t i g reaction. The o v e r a l l y i e l d from the acid chloride 29_ to the o l d e f i n 34, with i s o l a t i o n of the aldehyde was now i n the range of 30% to 36%. By not i s o l a t i n g the aldehyde, but rather treating a methylene chloride solution of same with the methylene reagent, we obtained the o l e f i n 34 i n a 40% p u r i f i e d y i e l d from the acid chloride 29. Thus the problem of aldehyde decomposition was eliminated. Epoxidation of 34_ was r e a l i z e d by treatment of the alkene i n methylene chloride with 2 equivalents of meta-chloroperoxybenzoic acid (MCPBA) providing a 75% y i e l d of epoxide 31. 2. C H 2 ' c o m p l e x 29 3 4 31 - 36 -Now we were ready to i n i t i a t e a study of the metallation of the dithiane 30a and subsequent coupling with the epoxide 41. 5. Dithiane M e t a l l a t i o n The dithiane 30a was metallated and reacted with epoxide 3J_ under the same conditions as were successful in the case of our model dithiane 17 and the epoxide 19. Unfortunately no product was obtained. 30a 1. n - B u L i 2 31 no product The problem was traced to the lack of formation of the metallated dithiane of 30a as shown by a deuterium oxide quench of an aliquot of the solution containing 30a and n-butyllithiura. The percentage deuterium incorporated into the substrate was determined from the ^-nrar spectrum by integration of the d i t h i o a c e t a l hydrogen. - 37 -Our attention was then directed to generation of the dithiane anion using d i f f e r e n t bases, solvent, reaction times and temperatures. Using the stronger base _ t - b u t y l l i thiura with THF as solvent f a i l e d to show any deuterium incorporation, over both short and long metallation times. When we changed the solvent to _n-heptane, we found no improvement. However, with the addition of tetraraethylethylenedfamine (TMEDA), up to 58% anion formation was shown to occur. Varying the solvent, amount of TMEDA, metallation time and temperature gave the r e s u l t s shown i n Table IV. Table TV. Me t a l l a t i o n studies on dithiane 30a using _ c - b u t y l l l thium Solvent Equlv. TMEDA Temp •c Time h X D rr- heptane - -70 2 0 ir- heptane 1.1 -70 2 50 tt-heptane 3 -70 2 50 tj- heptane 5 -70 2- 49 n-heptane 1.5 -35 2 45 ether 2 -70 1 42 vr heptane 2 -30 1.5 -20 21 0 From the percentage deuterium incorporated into 30a, we seem able to obtain only about 50% anion formation with _ t - b u t y l l i thiura. Longer metallation times, more TMEDA and a solvent change f a i l e d to produce increased amounts of raetallated dithiane. These r e s u l t s did show the very b e n e f i c i a l e f f e c t of TMEDA i n anion formation though. Next we turned our attention to employing ri-butyllithiura and TMEDA in either THF or n-heptane to metallate 30a. A double-check on - 38 -anion formation was determined by reaction with 1,2 epoxy butane (19) to give 3_8, as well as deuterium incorporation of an al i q u o t . Some results are given i n Table V and they show an improvement in anion formation over previous methods. Longer metallation times, as in the cases using _t-butyllithium showed no improvement over these r e s u l t s . S i m i l a r l y using more TMEDA proved f r u i t l e s s . While anion formation could be achieved i n about 70%, the y i e l d s of alkylated dithiane 38_ were In the 35% to 45% range. Hexamethylphosphoramide (HMPA) might increase the n u c l e o p h i l i c i t y of the anion or r e s u l t In Improved anion formation and hence higher y i e l d i n the reaction with the epoxide. Indeed, we found this to be so, re s u l t i n g i n 75% yie l d s by gc of 3_8. Only 20% of the s t a r t i n g dithiane 30a remained under the conditions. This r e s u l t was achieved by treatment of 30a i n THF with n-butyllithium and TMEDA at -35°C for 0.5 h, followed by addition of HMPA and the epoxide 19_ at -20°C for 48 h. We were now prepared to attempt the a l k y l a t i o n using epoxide 31. 30a 1. n-BuLi 19 •Si' 38 - 39 -Table V. M e t a l l a t i o n studies on d i t h i a n e 30a using rr-bu t y l l l thlum Solvent Equiv. TMEDA Equivalent i i Temp •c Time h X D A l i q u o t Z Product 38 THF 1.2 3 -30 -30 -20 1 0.5 40 50» 30-40* THF 1.1 - -30 2 75' -1.2 -20 24 - 3 7 b n-heptane 1.1 3 -30 -30 -20 0.5 0.5 72 55 a 30-40 8 tj-heptane 1.2 3 -30 -30 -20 1.25 0.5 72 a 70 40° * H-msr a n a l y s i s b i s o l a t e d y i e l d c g c a n a l y s i s 6. A l k y l a t l o n Reaction Reaction of epoxide 3_1_ with the anion from 30a under s i m i l a r conditions which had proved successful with 1,2-epoxybutane (19) only yielded 13% of iso l a t e d products 39a and 39b. The reaction was repeated. Before addition of the epoxide 31_, an al i q u o t of the solu t i o n was quenched with deuterium oxide. Analysis of the ^-nrar spectrum revealed almost 100% deuterium incorporation. Subsequent reaction with 31_ at -20°C for 4 days showed no improvement in the y i e l d of 39a and 39b. - 41 -The deuteration r e s u l t s indicated that the a l k y l l i t h i u r a base was abstracting the d i t h i o a c e t a l proton providing the raetalated dithiane in high y i e l d . Once the epoxide-ester 31_ was added, the l i t h i o d i t h i a n e moiety might abstract a proton from the carbon alpha to the ester and thus compete with the reaction of the epoxide. This would r e s u l t i n a poor y i e l d of products 39a and 39b, as shown i n equation ( v ) . This 3 1 39a 3 9 b 30a + - 42 -hypothesis could be tested by H-nrar or gc analysis of recovered epoxide 31 showing racemization of the methyl group alpha to the ester. As the epoxide 3_1_ was v o l a t i l e at reduced pressure and had a very s i m i l a r Rf value to the products 39a and 39b t we could never recover 3_1_ to test this postulate. As a r e s u l t of this possible deprotonation we considered a l k y l a t i o n of the dithiane with the epoxide 40_ i n which the ester was reduced and protected. A route to this substrate was developed from the 4 0 alkene-ester 34. Reduction of the ester with lithium aluminum hydride, followed by treatment with _t-butyldimethylsilyl trifluoromethane sulfonate afforded the alkene 42_ i n j u s t under 55% o v e r a l l y i e l d . Epoxidation of kl^ using 3 equivalents of raeta-chloroperoxybenzoic acid (MCPBA) gave the epoxide 40a i n 86% y i e l d . The r a t i o of epoxide - 43 -30a 1, n -BuU,TMEDA 2. HMPA 4 0 a 4 3 b diastereoraers was 65:35 as determined by gc analysis. This asymmetric centre present in 40a was not a concern, as i t would be destroyed subsequently. Generation of the dithiane anion of 30a was achieved using - 44 -n-butyllithium, TMEDA and HMPA i n THF. The epoxide 40a was added and a f t e r 40 h the reaction was worked up. The long reaction time did not improve product formation as shown by t i c analysis a f t e r 3 h and 43 h. The desired (3-hydroxy dithianes 43a and 43b were obtained i n 39% p u r i f i e d y i e l d . We recovered 43% of the s t a r t i n g dithiane 30a, which could be recycled. The y i e l d while three times that obtained with the epoxide-ester 3J_ was not as high as we had hoped. Our attention was then directed to the two f i n a l steps which would provide the 3-diketones 44a and 44b. 7. Route to B-Diketones 44a and 44b 7 4 4 b The model studies on the B-hydroxy dithiane 20_ provided the ketone 2jL_ in crude yields of about 80% using PDC i n DMF. Treatment of the S-hydroxy dithiane 38_ to the same conditions gave the ketone 4_5 in a crude y i e l d of only 26%. - 45 -P D C , D M F V Because of this poor y i e l d we decided to hydrolyse the dithiane, and unmask a B-hydroxy ketone and then oxidize this substrate to a B-dike tone. The a l k y l a t i v e hydrolysis of dithianes developed by Fetizon and J u r i o n (38) involving methyl iodide, and used by Markezich et a l . (39), appealed to us because I t was neither strongly a c i d i c nor basic. The dithiane 3_8_ was treated with methyl iodide in r e f l u x i n g aqueous a c e t o n i t r i l e with calcium carbonate present, and provided a good y i e l d of the B-hydroxy ketone 46_. We were pleased to observe that the TBDMS group was not cleaved. The B-hydroxy dithianes 43a and 43b were - 46 -Mel hydrolysed under the same conditions to provide the desired products 47a and 47b i n 54% p u r i f i e d y i e l d . Evans et a l . , had used the sul f u r trioxide pyridine complex (S0 3*Py) to oxidize a B-hydroxy Imide 48_ as shown by Equation ( v i ) (40). The desired product 49_ was obtained i n 90% y i e l d . (vi) This oxidation method was a modification of that developed by Parikh and Doering (41). - 48 -47b S 0 3 - P y , TEA ? The 8-hydroxy ketones 47a and 47b were treated with triethylamine (TEA) and s u l f u r trioxide pyridine complex while being s t i r r e d i n a methylene chloride:diraethylsulfoxide s o l u t i o n . After 20 h no change was evident by t i c analysis. However, the crude product obtained exhibited spectroscopic data consistent with formation of the desired 6-diketone. 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 provided a quantitative y i e l d of the s t a r t i n g B-hydroxy ketones 47a and 47b, as shown by ^H-nmr, i r and mass spectroscopy. The use of the 3-hydroxy ketone 50 gave a s i m i l a r r e s u l t . - 49 -' ( C H 2 ) 1 2 C H 3 5 0 We speculate that a c y c l i c s u l f i t e _51_ or su l f a t e 5_2_ may be the crude product obtained which hydrolyses on s i l i c a gel to regenerate the B-hydroxy ketones 47a and 47b. With the f a i l u r e of this oxidation, we carried out a Moffat oxidation on the 3-hydroxy ketone 5_0_ (42), using dicyclohexylcarbodiimide (DCC), dimethylsulfoxide and d i c h l o r o a c e t i c acid for 1.5 h at room temperature. Although some dehydration of 50, affo r d i n g a,B-unsaturated ketone, was apparent the major reaction product which was i s o l a t e d was the desired S-diketone 53_ i n over 50% p u r i f i e d y i e l d . 51 52 - 50 -( C H 2 ) 1 2 C H 3 D C C . H * DMSO ( C H 2 ) 1 2 C H 3 The substrates 47a and 47b were subjected to the same oxidative method, and the desired B-diketones 44a and 44b were iso l a t e d i n 25% p u r i f i e d y i e l d . About 50% of the unreacted 3-hydroxy ketones 47a and 47b were recovered. Longer reaction times did not increase the amount of product formed, nor did the addition of more reagents. The use of methylene chloride and diraethylsulfoxide as solvent was also f u t i l e i n improving the y i e l d . - 52 -The s t r u c t u r a l proof of the S-diketones 44a and 44 b came from 400 MHz ^-nmr, i r , high and low re s o l u t i o n mass spectroscopy. The r a t i o of diastereoraers could not be determined and their separation was not possible. However, with the use of one enantiomer of the acid-ester 1_5_ with the correct absolute stereochemistry, the B portion of ionomycin can be produced with the correct absolute stereochemistry. The A portion of ionomycin which our group i s deriving from carbohydrate precursors w i l l also have the correct absolute stereochemistry (14). Subsequent coupling of these two units would provide one half of ionomycin (2), with the correct absolute stereochemistry. The model studies reported in this thesis have provided a viable pathway for the coupling of these two units in the synthesis of ionomycin. 15 B portion - 53 -- 54 -EXPERIMENTAL General Unless otherwise stated the following are implied. Melting points were determined on a Kofler micro heating stage and are uncorrected. Kugelrohr d i s t i l l a t i o n s were performed by means of a Buchi Kugelrohr thermostat. Infrared spectra were recorded on a Perkin-Elmer model 710B spectrophotometer. Solution spectra were performed using a sodium chloride solution c e l l of 0.2 mm thickness. Absorption positions are given i n cm - 1 and are calibrated by means of the 1601 cm - 1 band of polystyrene. The proton nuclear magnetic resonance spectra were taken i n deuterochloroform solution and recorded on a Bruker WP-80 (80 MHz) instrument unless otherwise s p e c i f i e d . The 400 MHz spectra were recorded on a Bruker WH-400 instrument, and the 270 MHz spectra were recorded on a home-built unit consisting of an Oxford instrument 63.4 KG superconducting magnet and a Nicolet 32K computer. Signal positions are given i n parts per m i l l i o n downfield from tetramethylsilane using the 6 scale. The signal positions were determined r e l a t i v e to chloroform. Signal m u l t i p l i c i t y , coupling constants, and integrated areas are indicated i n parentheses. Low reso l u t i o n mass spectra were determined on either a Varian MAT CH4B or Kratos MS50 mass spectrometer. Spectra quoted as m/z values. The major ion fragmentations are reported as percentages of the base peak. High r e s o l u t i o n mass measurements were determined using a Kratos MS50 mass spectrometer. Gas-liquid chromatography was performed on a Hewlett - 55 -Packard model 5880A gas chromatograph using a 12 m x 0.2 mm column of OV-101 or Carbowax 20M. The flow rate for the 5880A model was 1.0 mL/min or 2.4 mL/min and helium was used as the c a r r i e r gas. In a l l cases a flame i o n i s a t i o n detector was used. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of B r i t i s h Columbia, Vancouver. S i l i c a gel PF254+366 supplied by E. Merck Co. was used for preparative t i c . The plates were ca. 1 mm in thickness. A n a l y t i c a l t i c was performed on commercial, pre-coated s i l i c a gel plates ( s i l i c a gel 60 F25O supplied by E. Merck Co. V i s u a l i s a t i o n was effected by a combination of UV fluorescence, iodine vapour, or a 2 M sulphuric acid spray. Flash chromatography (43) was performed using s i l i c a gel 60, 230-400 mesh ASTM, supplied by E. Merck Co. A l l reactions involving a i r or moisture s e n s i t i v e reagents were performed under an atmosphere of dry nitrogen using either oven of flame-dried glassware. A l l reaction products were dried by allowing the solutions to stand over anhydrous magnesium sulphate. The petroleum ether used was of b o i l i n g range ca. 30°-60°C. Dry solvents and reagents were prepared as follows: a c e t o n i t r i l e and methylene chloride by d i s t i l l a t i o n from phosphorus pentoxide; benzene, boron t r i f l u o r i d e etherate, dimethylsulfoxide, 2,6-dimethylpyridine, d i e t h y l methylmalonate (23), 1,2-epoxybutane (19), eth y l 2-bromoisobutyrate (24), n-heptane and hexamethylphosphoramide by d i s t i l l a t i o n from calcium hydride; d i c h l o r o a c e t i c acid by storage over anhydrous magnesium s u l f a t e - 56 -followed by a f i l t r a t i o n and d i s t i l l a t i o n ; diraethylforraaraide by d i s t i l l a t i o n from barium oxide followed by storage over 4A molecular sieves; dicyclohexylcarbodiiraide and oxalyl chloride were d i s t i l l e d before use; ethanol by r e f l u x i n g over magnesium ethoxide followed by d i s t i l l a t i o n ; ethyl ether and tetrahydrofuran by re f l u x i n g over l i t h i u m aluminum hydride followed by d i s t i l l a t i o n ; methanol by r e f l u x i n g over magnesium raethoxide followed by d i s t i l l a t i o n ; tetramethylethylenediamine by d i s t i l l a t i o n from potassium hydroxide. n-Butyllithium and _t-butyllithium were obtained from A l d r i c h Chemical Company, Inc. The a l k y l l i t h i u m solutions were standardised by t i t r a t i o n against 1,3-diphenyl-2-propanone tosylhydrazone i n THF (44). - 57 -1,1 (Propane-1',3' dlthlo)-2-methyl propane (17) 17 A 1-L f l a s k was charged with 36 mL isobutyraldehyde (18) (0.4 mole), 800 mL chloroform and 40 ml 1,3-dithiolpropane (0.4 mole). The s o l u t i o n was s t i r r e d for 1 h under an atmosphere of nitrogen, then cooled to -20°C. Boron t r i f l u o r i d e etherate (24*6 mL, 0.2 mole) was added, and the reaction was allowed to warm to room temperature overnight. The organic layer was washed three times each with water, potassium hydroxide sol u t i o n and water and was dried over anhydrous magnesium s u l f a t e . Removal of the solvent under reduced pressure yielded a yellow o i l . D i s t i l l a t i o n at reduced pressure (90°C/3 Torr) gave 51 g of compound 1_7_ (71% yield) as a pale yellow o i l ; i r (CHCI3): 1460, 1415, 1280, 1190, and 910 cm - 1; ^-nmr (CDCI3) 6: 1.03 (d, J_ - 7 Hz, 6H), 1.67-2.23 (m, 3H), 2.70-2.93 (m, 4H), 3.98 (d, = 6 Hz, IH); mass spectrum: a) high res o l u t i o n calcd for C 7 H 1 1 + S 2 : 162.0537 amu; found: 162.0535. b) low reso l u t i o n m/z ( r e l I n t e n s i t y ) : 162(M +, 41), 121(12), 119(100), 55(14), 45(18), and 41(22). - 58 -5,5 (Propane-1',3' dithio)-6-methyl heptan-3-ol (20) 20 A 50-mL rbf was charged with 0.81 g of the dithiane _17_ (5.0 mmole) and 25 mL THF. The s t i r r e d solution was cooled to -20°C under a nitrogen atmosphere and 4.0 mL jv-butyllithiura (1.4 M in hexane, 5.6 mmole) were added dropwise. After s t i r r i n g for 2.5 h at -20°C, the reaction f l a s k was stored at -10°C for 16 h. The sol u t i o n was then warmed to 0°C, and 0.43 mL of 1,2-epoxybutane (19) (5.0 mmole) was added. After 5 h, the mixture was concentrated under reduced pressure. Water was added and the aqueous phase was extracted three times with ethyl ether. The combined organic extracts were washed with water, brine solution and water, dried over anhydrous magnesium s u l f a t e and f i l t e r e d . Removal of the solvent under reduced pressure afforded 1.06 g of the alcohol 20_ (90% yield) as a white c r y s t a l l i n e s o l i d . Preparative t i c of a small amount of t h i s material using petroleum ether: ethyl acetate (6:1) gave 20_ as white powdery c r y s t a l s ; mp: 65-66°C; i r (CHC13): 3425, 1460, 1420, 1385, 1130, 1060 and 990 cm - 1; ^-nmr (CDC1 3) 6: 1.03 ( t , J = 7 Hz, 3H), 1.06 (d, J = 7 Hz, 3H), 1.24 (d, J_= 7 Hz, 3H), 1.35-2.55 (m, 7H), 2.75-3.00 (ra, 4H), 3.75 (bs, IH, exchangeable with D 20), 3.75-4.10 (m, IH); - 59 -mass spectrum: a) high resolution calcd for CHH22OS2'. 234 .1112 amu; found: 234.1108; b) low resolution m/z ( r e l i n t e n s i t y ) : 234 (M +, 24), 191(79), 161(18), 135(12), 133(100), 107(13), 73(13), 69(20), 59(25), 57(29) and 41(40). 5,5(Propane-l',3' dithio)-6-methyl heptan-3-one (21) 21 A 100-mL rbf was charged with 11.3 2 g pyridinium dichromate (30.0 mmole) and 25 mL DMF. The r e s u l t i n g solution was cooled to 0°C and the alcohol _20 (1.0 g, 4.3 mmole) was added to this s o l u t i o n . After 11 h at 0°C, the reaction mixture was poured into 150 mL water. The aqueous phase was extracted several times with ethyl ether. The combined organic phases were washed four times with water, dried over anhydrous magnesium sul f a t e and the solvent was removed under reduced pressure giving 0.84 g of the crude ketone (85% y i e l d ) . Preparative t i c of a small amount of this material using petroleum ether: ethyl acetate (8:1) gave 21_ as a colourless o i l ; i r (CHCI3): 1710, 1460, 1355, 1230, 1140 and 1110 cm - 1; hl-nmr (CDCI3) 270 MHz 6: 1.04 ( t , J_ = 7 Hz, 3H), 1.22 (d, J_ = 6.5 Hz, 6H), 1.79-2.12 (ra, 2H), 2.41 - 2.56 (m, 1H), 2.59 (q, 2H), 2.73 - 3.01 (m, 4H), 3.16 (s, 2H); - 60 -mass spectrum: a) high r e s o l u t i o n calcd for Ci ^ n C ^ J 232.0955 amu; found: 232.0942; 22), 189(72), 175(13), 133(29), 107(18), 69(16), 57(100), 41(37) and 29(66). 2,4-Dimethylglutaric acid (12) The d i a c i d 1_2_ was prepared by a modified method of that employed by Auwers and Thorpe (23). A 3-necked 1-L rbf f i t t e d with an addition funnel, condenser and nitrogen i n l e t , was charged with 200 mL ethanol. Sodium (11.5 g, 0.5 mole) was added, portionwise, followed by an a d d i t i o n a l 50 mL ethanol. The mixture was heated u n t i l the so l u t i o n was homogeneous. After the solution was cooled, a mixture of 100 mL d i e t h y l methylmalonate (23) (0.58 mole) and 71.1 mL ethyl 2-bromoisobutyrate (24) (0.485 mole) were added In two portions. The reaction was heated to reflux gently and then s t i r r e d overnight at room temperature. Most of the ethanol was removed by d i s t i l l a t i o n . Then 200 mL g l a c i a l a c e t i c a c i d : water (1:3) were added to the cooled f l a s k . The organic layer was separated and the aqueous phase was washed four times with et h y l ether. The combined organic extracts were dried over anhydrous magnesium sul f a t e and solvent removed under reduced pressure to y i e l d b) low r e s o l u t i o n m/z ( r e l i n t e n s i t y : 232(M +, 12 - 61 -163 g of a pale yellow o i l . This material was heated to ref l u x for 10 h with 270 mL concentrated hydrochloric acid and 200 mL water. The small organic layer which was s t i l l present was separated from the aqueous phase and recycled. The water i n the aqueous phase was removed under reduced pressure and the r e s u l t i n g l i q u i d was heated under nitrogen, f i r s t to 120°C, then to 160°C. After 30 min, the f l a s k was cooled and the o i l obtained was dissolved i n water and extracted f i v e times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium s u l f a t e , f i l t e r e d and concentrated to give 53.3 g of the diac i d \2_ as a white s o l i d . A further 20.2 g was obtained from r e c y c l i n g the organic layer i s o l a t e d e a r l i e r to give a total crude y i e l d of 95%. This material was converted, without further p u r i f i c a t i o n , to the anhydride 25. A small amount of the dia c i d _12 was r e c r y s t a l l i z e d from benzene; mp: 103-105°C ( l i t . (23)rap 105-107°C); i r (CHC1 3): 2980, 1720 and 1460 cm"1; 'H-nmr (CDC1 3) 6: 1.20 (d, _J = 7 Hz, 3H), 1.23 (d, J = 7 Hz, 3H), 1.78-2.93 (m, 4H), 8.85 (bs, 2H, exchangeable with D 20); mass spectrum: a) high resolution calcd for C 7H 1g0 3 (M +-H 20): 142.0630 amu; found: 142.0624; b) low resolution _m/_z ( r e l i n t e n s i t y ) : 142(M +-H 20, 11), 118(11), 114(56), 100(17), 87(17), 74(54), 69(100), 56(79), 45(54), 44(76) and 41(68). - 62 -Meso-2,4-dlaethylglutaric anhydride (25) The d i a c i d _12 (8.14 g, 0.05 mmole) was heated to 100°C with 10.8 mL acetic anhydride for 2 h. Removal of the v o l a t i l e materials under reduced pressure, followed by kugelrohr d i s t i l l a t i o n of the r e s u l t i n g 011 (80°C-140°C/0.1 Torr) afforded 7 g (97% yield) of a mixture of meso-and dl-anhydrides. This material was dissolved in 10 mL warm ethyl acetate and f i l t e r e d . The f i l t r a t e was washed six times with 10 mL portions of ethyl acetate. The combined ethyl acetate washings were reduced to a volume of 50 mL. C r y s t a l l i z a t i o n by allowing the s o l u t i o n to stand afforded 2.76 g meso-anhydride 25 (38% y i e l d from d i a c i d 12) as a white c r y s t a l l i n e s o l i d ; mp: 93.5-94°C ( l i t . ( 2 3 ) mp 94-95°C); i r (CHC1 3): 1818, 1770, 1080 and 1020 cm - 1; JH-nmr (CDC 13) 270 MHz 6: 1.37 (d, J = 8 Hz, 6H), 1.59 (q, = 12 Hz, J = 12 Hz, J_ = 12 Hz, 1H), 2.04 (dt, J = 6 Hz, J = 6 Hz, J = 12 Hz, 1H), 2.65-2.81 (m, 2H); mass spectrum: a) high resolution calcd for C7H10O3: 142.0630 amu; found: 142.0636; b) low r e s o l u t i o n m/z ( r e l i n t e n s i t y ) : 98(M+-COO, 11) 70(10), 56(100), 55(17), 41(13), 39(13) and 28(28). - 63 -Mono-methyl 2S*, 4R*-2,4-dimethyl glutarate (15) 15 A 50 mL rb f , f i t t e d with a ref l u x condenser, was charged with 3.07 g (21.6 mmole) 25_ and 15 mL dry methanol. The r e s u l t i n g s o l u t i o n was heated to reflux and s t i r r e d overnight, a f t e r which the methanol was removed under reduced pressure. Vacuum d i s t i l l a t i o n (102°C/0.2 Torr) yielded 3.41 g of the monoacid _15_ (91% y i e l d ) , as a colourless o i l ; i r (CHC1 3): 2990, 1735, 1715, 1460, 1280 and 1175 cm - 1; ^-nmr (CDC1 3) 6: 1.18 (d, J - 6 Hz, 3H), 1.20 (d, J - 6 Hz, 3H), 1.53 (q, IH), 2.10 (q, IH), 2.38-2.78 (m, 2H), 3.67 (s, 3H), 11.33 (bs, IH); mass spectrum: a) high resolution calcd for CgHi 20 3 (M +-H20): 156.0787 amu; found: 156.0784. b) low resol u t i o n m/z ( r e l i n t e n s i t y ) : 156(M +-H 20, 7) 143(32), 142(21), 128(47), 115(33), 114(45), 101(39), 88(49), 69(100), 59(50), 57(36), 56(71), 45(62) and 41(67). Methyl 2R*, 4j5*-4-chloromethanoyl-2-me thyl pen tanoate (29) 29 The monoacid _15 (3.21 g, 18.5 mmole) was s t i r r e d i n 15 mL of dry - 64 -benzene i n a 3-necked 100-mL rbf f i t t e d with an equal pressure addition funnel and a nitrogen i n l e t . A c a t a l y t i c amount of DMF was added (5 ML), followed by 2.42 mL oxalyl chloride (27.7 mmole) i n 5 mL benzene over 30 min. After 3 h, the benzene was removed by d i s t i l l a t i o n . Vacuum d i s t i l l a t i o n (52°C/0.2 Torr) afforded 3.26 g of the acid chloride 29 (92% y i e l d ) as a colourless o i l ; i r (CCli,): 1800, 1745, 1460, 1200, 1180 cm - 1; JH-nmr (CDC1 3) 6: 1.21 (d, J = 6 Hz, 3H), 1.32 (d, J = 6 Hz, 3H), 1.58 (q, IH), 2.21 (q, IH), 2.48 (q, IH), 2.94 (q, IH), 3.70 (s, 3H); mass spectrum: a) high resolution calcd for C7HJQ02C1 (M+-0CH3): 161.0370 amu; found: 161.0361; b) low resolution _m/z_ ( r e l i n t e n s i t y ) : 16KM+-OCH3, 10), 157(35), 129(31), 128(32), 73(25), 69(100), 59(41), 56(48) and 41(56). Methyl 2S*, 4R*-2,4-dimethy1-5,5 (propane-1',3'dithio) hexanoate (32) A 50-mL 2-necked rbf was charged with 80 mg 9% Pd/C ca t a l y s t (15 mg per mmole acid c h l o r i d e ) , 18 mL THF, 0.6 mL 2,6 dimethylpyridine (5 mmole). The acid chloride 29_, 0.985 g (5.1 mmole), in 7 mL THF was added and the system was hydrogenated for 8 h at atmospheric pressure. - 65 -The reaction was f i l t e r e d through C e l i t e , and the s o l i d was washed with ethyl ether. The f i l t r a t e was reduced to a volume of 10 to 15 mL. Then 50 mL ethyl ether was added and the organic layer was washed three times with cold 0 . 2 N hydrochloric acid, three times with sodium bicarbonate s o l u t i o n , ammonium chloride solution twice, brine and water. The organic phase was dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent removed under reduced pressure to a volume of 5 to 10 mL. This solution was transferred to a 50-mL rbf f i t t e d with a nitrogen i n l e t . Chloroform (15 mL) was added, followed by 0.51 mL 1 , 3-dithiolpropane (5 . 1 mmole). After 1 h s t i r r i n g at room temperature the so l u t i o n was cooled to - 2 0 ° C . Boron t r i f l u o r i d e etherate (0.315 mL, 2.56 mmole) was added and the reaction was allowed to warm to room temperature overnight, a f t e r which chloroform was added. The organic layer was washed with water, three times each with potassium hydroxide s o l u t i o n and water. The organic layer was dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure to give a yellow o i l . Flash chromatography ( 3 : 1 , petroleum ether: ethyl acetate) provided 787 mg of the dithiane _32_ (62% y i e l d ) as a pale yellow o i l ; i r (CHC13): 1735, 1460, 1390, 1280, 1180 and 1150 cm - 1; ^-nmr ( C D C 1 3 ) 6 : 1.15 ( t , 6 H ) , 1 .33-1.60 (m, 1 H ) , 1 . 6 8 - 2.23 (m, 4 H ) , 2 . 3 4 - 2.70 (m, 1 H ) , 2.78-3.03 (m, 4 H ) , 3 . 6 8 (s, 3 H ) , 4.13 (d, J = 3 Hz, 1 H ) ; mass spectrum: a) high r e s o l u t i o n calcd for C 1 1 H 2 0 O 2 S 2 : 248.0905 amu; found: 248.0905; - 66 -b) low reso l u t i o n jn/jz ( r e l i n t e n s i t y ) : 248(M +, 26), 121(17), 119(100), 106(10), 73(15), 59(15), 45(21) and 41(32). 2S* f 4R*-2,4-dimethyl-5,5 (propane-1' ,3' d i t h i o ) hexan-l-ol (33_) 33 A 50-mL 2-neck.ed rbf was charged with 191 mg lithium aluminum hydride (5 mmole) and 8 mL ethyl ether, under a nitrogen atmosphere. The suspension was cooled to 0°C, and then 635 mg of the ester 32 (2.56 mmole) in%7 mL ethyl ether was added. After 30 min at 0°C and 90 rain at room temperature, the reaction was c a r e f u l l y quenched with d i l u t e hydrochloric acid. Ethyl ether was added and the organic layer was separated. The aqueous phase was washed three times with ethyl ether. The combined ether extracts were dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure to give a yellow o i l . Flash chromatography (1:1, petroleum ether: ethyl acetate) provided 492 mg of the alcohol 33_ (87% yield) as a pale yellow o i l ; i r (CHC1 3): 3475, 1460, 1420, 1380, 1275 and 1015 cm - 1; 'H-nmr (CDC1 3) 6: 1.00 (d, J = 9 Hz, 3 H ) , 1.05 (d, J_ = 9 Hz, 3 H ) , 1.58-2.33 (m, 6 H ) , 2.15 (bs, 1H, exchangeable with D 20), 2.73-3.05 (m, 4 H ) , 3.28-3 .68 (ra, 2 H ) , 4.15 (d, J_ = 3 Hz, 1H); mass spectrum: a) high r e s o l u t i o n calcd for C 1 1 H 2 0 O S 2 : 220.0956 - 67 -arau; found: 220.0957; b) low resolution m/,z ( r e l i n t e n s i t y ) : 220(M +, 23), 121(15), 120(10), 119(100), 73(14), 55(13), 45(22) and 41(35). 2$*, 4R*-2,4-dimethyl-5,5 (propane-1',3* dithio)-l-[(t-butyldiraethyl-silyl)oxy]-hexane (30a) To a solution of the alcohol 33_ (0.48 g, 2.2 ramole) i n 3 mL methylene chloride was added 2,6-diraethylpyridine (0.51 mL, 4.4 mmole) at 0°C under nitrogen. After 5 min, _t-butyldimethylsilyl trifluororae thane sulfonate (0.75 mL, 3.3 mmole) was added and the reaction was s t i r r e d for 30 min at 0°C and 2.5 h at room temperature. The reaction was d i l u t e d with ethyl ether, washed with 0.2 N hydrochloric acid twice, sodium bicarbonate solution twice, ammonium chloride s o l u t i o n and water. The organic layer was dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure giving a yellow o i l . Kugelrohr d i s t i l l a t i o n (140°C/0.2 Torr) afforded 0.708 g 30a as a colourless o i l (97% y i e l d ) ; i r (CHC1 3): 1465, 1455, 1240, 920 and 825 cm - 1; LH-nmr (CDC1 3) 270 MHz 6: 0.07 (s, 6H), 0.95 (s, d, 12H), 1.13 (d, J - 6 Hz, 3H), 1.63-2.22 (m, 6H), 2.84-3.05 (m, 4H), 3.35-3.59 (ddd, -2°a - 68 -2H), 4.20 (d, J = 4 Hz, 1H); mass spectrum: a) high resolution calcd for C 16H34OS2Si: 334.1820 amu; found: 334.1825; b) low resolution m/z_ ( r e l i n t e n s i t y ) : 334(M +, 2), 319(2), 279(12), 278(19), 277(91), 171(22), 165(25), 149(11), 129(10), 119(77), 113(37), 95(23), 91(11), 75(100), 73(46) and 41(20). The active methlene complex was prepared by a s l i g h t modification of Lombardo's method (37). A 500-mL 2-necked rbf, f i t t e d with an equal pressure addition funnel, was charged with 11.5 g zinc dust, 100 mL THF and 4.04 mL methylene bromide under nitrogen. The sl u r r y was cooled to -40°C. Titanium tetrachloride (4.6 mL) was poured into the addition funnel and dropwlse, over 30 min, was added to the s l u r r y . As the addition of the titanium tetrachloride i s very vigorous, i t i s recommended to leave the addition funnel stopperless. After 2 h s t i r r i n g at -40°C, the grey s l u r r y was warmed to 0°C, and s t i r r e d for 24 h. The active methylene complex can be stored between 0°C and 5°C for up to 2 weeks. Methyl-2R*, 4j5*-2,4-dime thyl-5-hexenoate (34) Methylenation reagent 34 A 100-mL 3-necked rbf was charged with 0.18 g 9% Pd/C ca t a l y s t - 69 -(15 mg per mmole acid c h l o r i d e ) , 40 mL THF, 1.35 mL 2,6-dimethylpyridine (11.6 mmole). The acid chloride 29, 2.25 g (11.7 mmole), i n 15 mL THF was added and the system was hydrogenated for 8 h at atmospheric pressure. The reaction was f i l t e r e d through C e l i t e and the s o l i d was washed with methylene c h l o r i d e . The f i l t r a t e was reduced to a volume of 10 to 15 mL. Then 50 mL methylene chloride was added and the organic layer was washed three times with cold 0.2 N hydrochloric acid, three times with sodium bicarbonate sol u t i o n , ammonium chloride solution twice, brine and water. The organic phase was dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent removed under reduced pressure to a volume of 50 mL. The methylene complex (37) s t i r r e d at 0°C was added portionwise, using a pipette, to this methylene chloride s o l u t i o n of the aldehyde 16. Conversion to the alkene 34_ i s instantaneous and can be monitored by gc or t i c analysis. After complete conversion, the black s o l u t i o n was poured into 150 mL super-saturated solution of sodium bicarbonate and 300 mL ethyl ether. The mixture was s t i r r e d for 2 h u n t i l the solu t i o n was white with a black s o l i d evident. The organic layer was separated and the aqueous layer was washed a few times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure to give a yellow o i l . Flash chromatography (methylene chloride) provided 729 mg of the alkene 34_ as a pale yellow o i l (40% y i e l d ) ; i r (CHC13): 1735, 1650, 1460, 1170 and 920 cm - 1; ^-nmr (CDC1 3) 6: 1.03 (d, J = 7 Hz, 3H), 1.11 (d, J - 7 Hz, - 70 -3H), 1.28-2.65 (m, 4H), 3.65 (s, 3H), 4.83-5.13 (ra, 2H), 5.38-5.88 (m, IH); mass spectrum: a) high resolution calcd for C9H16O2 (M+-0CH3): 125.0966 amu; found: 125.0974; 5), 125(10), 124(8), 101(12), 97(20), 96(13), 88(100), 81(12), 69(26), 57(27), 55(63), 41(36) and 29(24). 2R*. 4j>*-2,4-dime thy 1-5-hexen-l-ol (41) Lithium aluminum hydride (0.185 g, 4.9 mmole) was s t i r r e d i n 8 mL ethyl ether at 0°C. The alkene 34_ (0.38 g, 2.4 mmole) in 7 mL ethyl ether was added. After 30 min at 0°C and 90 min at room temperature, the reaction was c a r e f u l l y quenched with d i l u t e hydrochloric a c i d . E t h y l ether was added and the organic layer was separated. The aqueous phase was washed three times with ethyl ether. The combined ether extracts were dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure to give a yellow o i l . Flash chromatography (methylene chloride) afforded 0.174 g of the alcohol 41_ (56% y i e l d ) as a yellow o i l ; b) low res o l u t i o n m/z ( r e l i n t e n s i t y ) : 156(M +, 41 i r (CHCI3): 3480, 1650, 1460, 1380, 1020 and 920 cm -1 1 H-nmr (CDCI3) 6: 0.90 (d, J_ = 6 Hz, 3H), 0.98 (d, J_ =• 6 Hz, - 71 -3H), 1.13-1.88 (in, 2H), 2.03-2.49 (m, 2H), 2.45 (bs, 1H, exchangeable with D 20), 3.30-3.63 (ra, 2H), 4.80-5.15 (ra, 2H), 5.40-5.90 (ra, 1H); 97.1017 amu; found: 97.1021; b) low resolution m/_z ( r e l i n t e n s i t y ) : 128(M +, 1), 97(18), 95(41), 71(47), 70(29), 69(22), 68(42), 58(43), 57(21), 56(35), 55(100), 43(33), 41(54), 39(22), 31(30) and 29(36). 2R*, 4S^*-2,4-Dimethyl-l-[(t-butyldimethylsilyl)oxy]-hex-5-ene (42) To a solution of the alcohol 41 (159 mg, 1.24 mmole) i n 1.5 mL methylene chloride was added 2,6-dimethylpyridine (0.29 mL, 2.5 mmole) at 0°C under nitrogen. After 5 min _t-butyldimethylsilyl trifluororaethane sulfonate (0.43 mL, 1.9 mmole) was added and the reaction was s t i r r e d for 30 min at 0°C and 2.5 h at room temperature. The reaction was dilu t e d with ethyl ether, washed with 0.2 N hydrochloric acid twice, sodium bicarbonate solution twice, ammonium chloride s o l u t i o n and water. The organic layer was dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure giving a yellow o i l . Flash chromatography (10:1, petroleum ether: ethyl acetate) afforded 270 mg of the ether 4_2_ (90% y i e l d ) as a colourless o i l ; mass spectrum: a) high resolution calcd for C7H 1 3(M +-CH 2OH): - 72 -i r (CHCI3): 1650, 1480, 1260, 950 and 840 cm - 1; 1H-nmr (CDCI3) 400 MHz 6: 0.09 (s, 6H), 0.92 (d, J = 6 Hz, 3H), 0.95 (s, 9H), 1.02-1.11 (m, IH), 1.05 (d, J_ = 6 Hz, 3H), 1.39-1.48 (m, IH), 1.63-1.75 (m, IH), 2.23-2.34 (m, IH), 3.37-3.51 (ddd, 2H), 4.92-5.05 (m, 2H), 5.61-5.72 (m, IH); mass spectrum: a) high r e s o l u t i o n calcd for C i o H 2 l O S i (M^-tBu): 185.1376 amu; found: 185.1369; lSSCM+^Bu, 57), 115(14), 76(12), 75(100), 73(27), 55(11) and 41(11). 2R*, 4 S * - 2 t 4 - D i m e t h y l - l - [ ( t - b u t y l d i m e t h y l 8 i l y l ) o x y ] - 5 , 6 - e p o x y hexane To a s t i r r e d solution of the alkene kl_ (253 mg, 1.04 mmole) in 6 mL methylene chloride at 0°C, was added 543 mg (3.14 mmole) meta-chloroperbenzoic acid (MCPBA). The reaction was allowed to warm to room temperature slowly and was l e f t s t i r r i n g overnight. The reaction was d i l u t e d with methylene chloride and washed once with sodium bicarbonate so l u t i o n , sodium t h i o s u l f a t e s o l u t i o n , three times with sodium bicarbnate s o l u t i o n and f i n a l l y water. The organic layer was dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under b) low r e s o l u t i o n m/z ( r e l i n t e n s i t y ) : (40a) 40a - 73 -reduced pressure, giving a yellow o i l . Flash chromatography (3:1, petroleum ether: ethyl ether) provided 231 mg of the epoxide 40a (86% y i e l d ) as a pale yellow o i l ; i r (CHC1 3): 1460, 1255, 1090, 830 and 770 cm"1; ^-nmr (CDC1 3) 6: 0.05 (s, 6H), 0.83-1.13 (m, 8H), 0.93 (s, 9H), 1.38-1.93 (m, 2H), 2.40-2.85 (m, 3H), 3.33-3.48 (m, 2H); mass spectrum: a) high r e s o l u t i o n calcd for CiQH 2i02Si (M +- tBu): 201.1335 amu; found: 201.1323; b) low r e s o l u t i o n m/z ( r e l i n t e n s i t y ) : 201(M +- tBu, 16), 171(30), 145(22), 129(13), 115(28), 109(22), 105(12), 89(20), 75(100) and 73(26). 2S*, 4R*, 8S*, lORjfc-Z^.S.lO-Tetramethyl-l.ll-IdiCt^butyldlmethylsilyl) oxy]-7,7 (propane—1',3' dithio) undec-5-ol (43a) and i t s diastereomer (43b) 43b The dithiane 30a (114 mg, 0.34 mmole) was s t i r r e d i n 1 mL THF at -40°C. n-Butyllithium (0.17 mL, 2.2 M i n hexane, 0.37 mmole) was added, followed by tetramethylethylenediamine (TMEDA, 0.06 mL, 0.41 mmole), - 74 -producing a f a i n t yellow coloured s o l u t i o n . After 1 h, hexamethylphosphoramide (HMPA, 0.09 mL, 0.51 mmole) was added and a deep yellow coloured solution was observed. After 15 min, the reaction was cooled to -78°C. The epoxide 40a (96 mg, 0.37 mmole) in 1 mL THF was added dropwise. The reaction was s t i r r e d for 30 min at -78°C, 30 min at -40°C, 2 h at -10°C and was stored at -2°C for 40 h. The reaction was di l u t e d with water and ethyl ether. The organic layer was washed with sodium chloride s o l u t i o n , ammonium chloride s o l u t i o n , dried over anhydrous magnesium sulfate and f i l t e r e d . Removal of the solvent under reduced pressure afforded on orange o i l . Flash chromatography (methylene chloride) gave the following compounds i n order of e l u t i o n : (a) dithiane 30a (49 mg, 43%); (b) B-hydroxy dithianes 43a and 43b as a pale yellow o i l (79 mg, 39% y i e l d , 69% based on recovered s t a r t i n g dithiane 30a); i r (CHC1 3): 3450, 1470, 1260, 1050, 910, 820 cm - 1; ^-nmr (CDC1 3) 6: 0.05 (s, 12H), 0.80-1.27 (m, 16H), 0.93 ( s , 18H), 1.30-2.33 (m, 8H), 2.60-2.95 (m, 4H), 3.20-3.65 (m, 5H), 3.73-4.05 (m, IH); mass spectrum: a) high r e s o l u t i o n calcd for C 3oHg^0 3S2Si2'• 592.3834 amu; found: 592.3834; b) low r e s o l u t i o n m/z_ ( r e l i n t e n s i t y ) : 592(M +, 3), 535(10), 377(20), 359(15), 246(19), 245(100), 187(29), 185(26), 165(16), 145(11), 133(19), 115(15), 113(99), 109(22), 107(13), 95(27), 75(58), 73(41) and 55(15). - 75 -2R*, 4S*, 8R*, lO^-Z^.S.lO-tetraaethyl-l^U-tdl-Ct-butyldlmethylstlyl) oxy]-7 hydroxy-undec—5-one (47a) and i t s diastereomer (47b) 47a + 47b The 0-hydroxy dithianes 39a and 39b (39 mg, 0.07 mmole) and 18 mg calcium carbonate (0.4 mmole) were s t i r r e d i n 5 mL a c e t o n i t r i l e and 2 mL water. Methyl iodide (1 mL) was added and the reaction was heated to r e f l u x " f o r 17 h. The solvents were removed under reduced pressure and water was added to the residual material. The aqueous phase was washed three times with ethyl ether. The combined organic extracts were dried over anhydrous magnesium s u l f a t e , f i l t e r e d and the solvent was removed under reduced pressure to give a yellow o i l . Flash chromatography (4:1, petroleum ether: ethyl ether) provided 18 mg of the 3-hydroxy ketones 47a and 47b (54% y i e l d ) ; i r (CHC1 3): 1710, 1460, 1390, 1260, 1110 and 840 cm - 1; ^-nmr (CDC1 3) 6: 0.05 (s, 12H), 0.80-2.15 (m, 20H), 0.93 (s, 18H), 2.48-2.70 (m, 2H), 3.33-3.53 (m, 5H), 3.80-4.05 (m, 1H); mass spectrum: a) high resolution calcd for 023^0,0^51 2(M +- tBu) 445.3170 amu; found: 445.3170; - 76 -b) low resolution m/z_ ( r e l i n t e n s i t y ) : 445(M +- tBu, 11), 427(9), 313(5), 295(6), 287(7), 246(10), 245(57), 243(12), 221(15), 203(17), 201(24), 188(12), 187(94), 185(30), 113(100), 109(37), 95(49), 85(43), 83(31), 75(86), 73(59) and 57(47). 2R*, 4S*, 8R*, 10S*-2,4,8,10-tetramethyl-l,ll-ldi(_t-butyldimethylsilyl) oxy]-undec-5,7-dione (44a) and i t s diastereomer (44b) 44b The B-hydroxy ketones 47a and 47b (10 mg, 0.02 mmole) were s t i r r e d i n 0.2 mL dimethylsulfoxide and 0.2 mL methylene chloride. Dicyclohexylcarbodiimide (DCC, 25 mg, 0.12 mmole) was added and a f t e r i t dissolved, 0.8 uL (0.01 mmole) di c h l o r o a c e t i c acid was added. Petroleum ether was added, and the organic layer was washed with water and aqueous oxa l i c acid. The combined aqueous layers were washed once with petroleum ether. A l l the organic extracts were dried over anhydrous magnesium s u l f a t e , f i l t e r e d and concentrated affo r d i n g a pasty s o l i d . Flash chromatography (40:1, petroleum ether: ethyl ether) provided i n order of el u t i o n : - I l -ia) product B-diketones 44 a and 44b (2.5 rag, 25% y i e l d , 75% based on recovered s t a r t i n g material); (b) s t a r t i n g B-hydroxy ketone 47a and 47b (5 mg, 50%). The B-diketones 44a and 44b were characterized by the following s p e c t r a l data; i r (CHC1 3): 1600, 1460, 1260, 1060 and 1020 cm"1; 1H-nrar(CDCl 3) 400 MHz 6: 0.03 (s, 12H), 0.90 (d, s, 24H), 1.08-1.18 (ra, 2H), 1.14 (d, J = 8 Hz, 6H), 1.56-1.66 (m, 2H), 1.72-1.81 (m, 2H), 2.40-2.50 (m, 2H), 3.34-3.46 (m, 4H), 5.47 (s, 1H); mass spectrum: a) high resolution calcd for C27H560i*Si2: 500.3719 amu; found: 500.3718; b) low resolution m/_z_ ( r e l i n t e n s i t y ) : 500(M +, 2), 485(4), 445(12), 444(33), 443(100), 311(40), 244(14), 243(71), 185(49), 115(11), 109(11), 95(11), 83(30), 75(74), 73(57), 69(21) and 55(16). - 78 -BIBLIOGRAPHY 1. J.W. Westley. Adv. Appl. M i c r o b i o l . J22, 177 (1977). 2. L.K. Steinrauf, M. Pinkerton, and J.W. Charaberlin. Biochera. Biophys. Res. Commun. 33_, 29 (1968). 3. W. L i u , D.S. Slusarchyk, G. Astle , W.H. Trejo, W.E. Brown, and E. Meyers. J . An t i b i o t . 31_, 815 (1978). 4. D.E. Cane, W.D. Celmer, and J.W. Westley. J . Am. Chera. 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Pergamon Press, New York. 1983. 17. Y. Nakahara, K. Beppu, and T. Ogawa. Tetrahedron L e t t . 22_, 3197 (1981). 18. B. Nader, R.W. Franck, and S.M. Weinreb. J . Am. Chem. Soc. 102, 1155 (1980). - 79 -19. P.E. Sura, and L. Weiler. Can. J. Chera. 60, 327 (1982). 20. D.E. Plaumann, B.J. FitzSimmons, B. M. R i t c h i e , and B. Fraser-Reid. J . Org. Chem. 4_7_, 941 (1982). 21. C.T. Goodhue,- and J.R. Schaeffer. Biotechnol. Bioeng. _13_, 203 (1971). 22. D.B. Collum, J.H. McDonald, and W.C. S t i l l . J. Am. Chem. Soc. 102, 2118 (1980). 23. K. von Auwers, and J.F. Thorpe. Ann. 285, 310 (1895). 24. N.L. A l l i n g e r . J . Am. Chera. Soc. 81_, 232 (1959). 25. D.M. Walba, and M.D. Wand. Tetrahedron L e t t . 23_, 4995 (1982). 26. P. B a r t l e t t , and J . Myerson. J . Org. Chem. 44_, 1625 (1979). 27. P.A. B a r t l e t t , and J.L. Adams. J . Am. Chem. Soc. 102, 337 (1980). 28. C.S. Chen, Y. Fujimoto, and C.J. Sih. J . Am. Chem. Soc. 103, 3580 (1981). 29. E.J. Corey, and J.W. Suggs. Tetrahedron L e t t . 2647 (1975). 30. Y.S. Cheng, W.L. Siu, and S. Chen. J . Chera. Soc. Chem. Commun. 223 (1980). 31. E.J. Corey, and G. Schmidt. Tetrahedron L e t t . 399 (1979). 32. E.J. Corey, and D. Crouse. J . Org. Chem. 33_, 298 (1968). 33. A. Zamojski. Roczniki Chem. 40_, 451 (1966). 34. A.W. Burgstahler, L.O. Weigel, and C.G. Shaeffer. Synthesis, 767 (1976). 35. E.J. Corey, H. Cho, C. Rucker, and D.H. Hua. Tetrahedran L e t t . 22_, 3455 (1981). 36. K. Takai, Y. Hotta, K. Oshima, and H. Nozaki. Tetrahedran L e t t . 2417 (1978). 37. L. Lombardo. Tetrahedran Lett. 23_, 4293 (1982). 38. M. Fetizon, and M.Jurion. J . Chem. Soc. Chem. Commun. 382 (1972). 39. R.L. Markezich, W.E. W i l l y , B.E. McCarry, and W.S. Johnson. J . Am. Chera. Soc. 95, 4414 (1973). - 80 -40. D.A. Evans, M.D. Ennis, and T. Le. J . Am. Chera. Soc. 106, 1154 (1984). 41. J.R. Parikh, and W. von E. Doering. J . Am. Chem. Soc. 89, 5505 (1967). 42. G.H. Jones, and J.G. Moffatt JLn Methods i n Carbohydrate Chemistry. Vol. VI. Edited by R.L. Whistler, and J.N. BeMiller. Academic Press, New York. 1972. pp. 315-336. 43. W.C. S t i l l , M. Kahn, and A. Mitra. J . Org. Chem. 43_, 2923 (1978). 44. A l f a . J . Org. Chera. 46(9), 2A (1981). - 81 -SPECTRAL INDEX - 88 -- 89 -- 91 -

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