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UBC Theses and Dissertations

Synthetic studies towards the prostaglandins Rickards, Gordon E. 1978

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SYNTHETHIC STUDIES TOWARDS THE PROSTAGLANDINS by Gordon E. Rickards B . S c , 1974 U n i v e r s i t y of B r i t i s h Columbia A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES DEPARTEMENT OF CHEMISTRY We accept t h i s t h e s i s as conforming to the req u i r e d standards THE UNIVERSITY OF BRITISH COLUMBIA October, 1977 © Gordon Rickards , 19?8 In presenting th i s thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f ree ly ava i l ab le for reference and study. I fur ther agree that permission for extensive copying of th is thesis for scho lar ly purposes may be granted by the Head of my Department or by his representat ives. It is understood that copying or pub l i ca t ion of th is thes is for f inanc ia l gain sha l l not be allowed without my written permission. Depa rtment The Univers i ty of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 - i -ABSTRACT The synthesis of an important intermediate (36) in a total synthesis of the prostaglandins was undertaken. Treatment of the monoanion of the pyrrolidine enamine of methyl acetoacetate with cis-4,5-epoxy-2(E)-decen-1-yl mesylate (42) followed by addition of one equivalent of lithium diisopropylamide and then hydrolysis yielded the desired intermediate 36. This intermediate contains the correct r e l i t i v e stereochemistry between the C-12 and C-15 carbons which has turned out to be the most d i f f i c u l t problem associated with the synthesis of the prosta-glandins. Alkylation with trans-4,5-epoxy-2(E)-decen-1-yl mesylate (67) produced the intermediate with the unnatural stereochemistry. - i i -The two mesylates were produced stereospecifically, the f i r s t starting from propargyl alcohol. In the process of making these two mesylates, two natural products were synthesized, ethyl 2(E),4(Z)-decadienoate (79), isolated from Bartlett pears, and 2(E),4(Z)-decadien-1-yl isovalerate (41), isolated from the essential oils of Cyprus. - i v -TABLE OP CONTENTS Abstract i Table of Contents iv Table of Abbreviations v Acknowledgements v i Introduction: Isolation & Structure 1 Nomenclature 3 Biosynthesis 10 Synthesis 14 The present Approach 28 Results & Discussion: Model Compound 34 Mesylate 67 46 Mesylate 42 49 Experimental: 59 Bibliography: 78 Spectral Index 85 -V-ABBREVIATIONS Following is a l i s t of the abbreviations used in the context of this work. LDA lithium diisopropylamide DBN diazabicyclo[4.3.0]nonene ACgO acetic anhydride Py pyridine DCC dicyclohexylcarbodiimide THE tetrahydrofuran DMSO dimethylsulfoxide Bu^SnH tri-n-butyltin hydride Bz benzene THP tetrahydropyran DMBS dimethyl-t-butylsilane n-BuLi n-butyllithium TsOH toluenesulfonic acid Et20 ethyl ether MsCl methanesulfonyl chloride DIBAH diiosbutylaluminum hydride Et^N triethyl amine NMR nuclear magnetic resonance d doublet (NMR) d d doublet of doublets (NMR) m multiplet (NMR) s singlet (NMR) t tr i p l e t (NMR) IR infrared GC gas chromatography - v i -ACKNOWLEDGEMENTS I would like to thank Dr. Larry Weiler for his guidence and understanding in the period i t took to complete this work. I would also like to thank Dr. Prank W. B. Skinner Mr. Sam Sum, Mrs. P. E. Sum and Dr. Akash Chopra for their help in many discussions. And f i n a l l y , I would like to thank Mrs. G. Rickards for typing this thesis. INTRODUCTION (A) Isolation and Structure It has been known for many years that the extracts of seminal f l u i d and of the prostate gland produce a number of physiological reactions in mammalian tissue. For example, the extracts of seminal fluids have been used by certain tribes in Africa as a method of inducing labour. The effective agent however, had not been isolated u n t i l quite recently. p Von Euler in 1936 established that the active agents in the seminal fluids were a new and distinct class of compounds. He found that they were soluble in l i p i d s o l -vents and in alkaline media, similar to fatty acids.. With the use of electrophoresis he was able to determine that these compounds were new and distinct. To make reference to them more convenient, he gave them the name "prostaglandins". This name arises from his assumption that they originated in the prostate gland. In 1949, Bergstrom"^ u t i l i z i n g a Craig countercurrent method, showed that the prostaglandins were similar to un-saturated hydroxy fatty acids. He was also able to show that there was more than one compound in this group. In 1957, 4 Bergstrom and Srjovall isolated two prostaglandins in crystalline form. These would later be given the names PG-E.J and PGFj. By 1959 the name prostaglandin had been so firmly established, that the name was not changed even,when Eliasson showed that the compounds which Von Euler had described, in fact did not originate in the prostate gland but rather in the seminal vesicles. In 1962 Bergstrom and coworkers determined the structure of three prostaglandins using the results of micro-analysis, mass spectral analysis and a series of degradations, these would later be given the names PGE1, PGF1 and PGF2« The stereochemistry of PGF^ was determined by 7 Abrahamsson e_t a l . in 1962 u t i l i z i n g x-ray analysis of the bromo- and iodobenzoate derivative. By this time i t was obvious to a number of people that the prostaglandins bore some resemblance to, and might originate from, certain fatty acid precursors. The relation-ship between the fatty acids and the prostaglandins was g shown by two groups independently. In 1964 Bergstrom et a l . 9 and Van Trop e_t a l . simultaneously showed that when tritium labeled arachidonic acid was incubated with whole homogenates of sheep vesicular glands, tritium labeled PGEg could be isolated. It was later determined that PGE-j and PGE-^  were obtained from dihomo-y-linolenic acid and 5,8,11,14,17-eicosapentenoic acid, respectively. The correct absolute stereochemistry was f i r s t 10 determined by Nugteren et_ a l . in 1966, when he measured the optical activity of the 2-hydroxyheptanoate formed in oxidative ozonolysis of PGE^  and found i t to have the S configuration. In 1968 the f i r s t synthesis of a natural prostaglandin was published. Since then there has been extensive research in not only the problems associated with the synthesis of -3-the prostaglandins, but in their physiological effects as well. This interest has resulted because of their high potency (3-10 ng/ml) and also because of their wide range of effects on mammalian tissue. The prostaglandins act as vasodilators, decongestants, and they have the a b i l i t y to improve platelet mobility and st a b i l i t y . They have also been found to be useful in the treatment of stomach ulcers and as abortificants or birth control agents. "It is impossible to make any general statement of the occurrence and physiological effects of the prostaglandins except to note that they appear to be ubiquitous and to have some physiological role in almost every mammalian tissue. Different prostaglandins appear to have different and even opposite action in the same target tissue of one species and the same compound may have different actions in different species or even different tissue of the same (B) Nomenclature A l l the prostaglandins possess the same basic 20 carbon sleleton as that found in prostanoic acid (1). The numbering sequence is that found in a l l the fatty acids, with the acid carbon designated as C-1. species. ti Reference 1(a), p 119 10 -4-A l l of the natural prostaglandins possess an E double bond in the 13,14 position as well as a hydroxyl group (with an S configuration) at the 15 position as shown in 2. O H - 2 -There are four basic prostaglandin classifications (Figure 1). They are prostaglandin E (3) and prostaglandin F (4), which are considered to be primary prostaglandins, and prostaglandin A (5) and'prostaglandin B (6). -5-Figure 1 b. The E and P series are called primary because they are obtained directly from the fatty acids and are non-interconvertable. The A and B series are obtained through metabolization of the E series. As can be seen, the PGE series possesses a (i-hydroxy ketone in the cyclopentane ring, with a keto group at carbon 9 and the hydroxyl group at carbon 11 (R configuration). The PGP series contains a 1 , 3 - d i o l i n the cyclopentane ring, one hydroxyl group at carbon 11 as in the E series' and the other at carbon 9 . The hydroxyl group at carbon 9 has been found in two enant-iomeric forms. If i t has an R configuration, i t is denoted by the subscript (Figure 2 ) and similarly the enantiomer -6-is denoted as the o£-form. F i gu re 2. The PGA and PGB series are a dehydrated form of PGE. The difference l i e s in the position of the double bond. In PGA the double bond is between carbons 10 and 11, and in PGB i t is between carbons 8 and 12. Some additional variations in the series result from the presence or absence of double bonds or hydroxyl groups in the side chains. The number of double bonds in the side chains are denoted by a numeric subscript. There-fore, a l l prostaglandins possess at least the numeral 1. If the prostaglandin possesses two double bonds, the f i r s t being the E double bond between carbons 13 and 14, the second is -7-always a Z double bond between carbons 5 and 6. For example, PGE2 (9) possesses two double bonds. If the prostaglandin possesses three double bonds, the f i r s t two are as in PGE2 (9) and the third is a Z double bond between carbons 17 and 18, for example PGE^ (10). As mentioned before the prostaglandin might also possess an additional hydroxyl group. If i t does, this hydroxyl group w i l l be at carbon 19 with an S configuration and this is denoted by the prefix 19-0H. 19-OH-PGE 2 -8-Following is a l i s t of the 16 natural prostaglandins found in mammals. -9-P G F 2 O O H H O P G B 2 O O H H 6 P G A 2 O O H H O H O 1 9 O H P G E 2 O O H H O H O 1 9 O H P G B 2 O O H H 6 H O 1 9 O H P G A 2 H O H 6 P G E . H Q P G F ' -10-(C) Biosynthesis o As mentioned previously, Bergstrom e_t a l . and q Van Trop e_t a l . showed that PGE2 was derived from arachidonic acid. Eventually a l l 16 natural prostaglandins were proven to be derived from one of three 20-carbon poly-unsaturated fatty acids. Each of these three were shown in turn to be derived from an 18-carbon fatty acid -lin o l e i c acid (Scheme 1). It has also been shown that the lack of li n o l e i c acid in one's diet w i l l lead to .a number of adverse physiological effects related to the absence of the prostaglandins. 10 9 5,8,1114,17 eicosapentenoic acid The proposed biosynthetic sequence for the prostaglandins from the three fatty acids is as shown in Scheme 2. linolejc acid (dietary) dihomo-tf-linolenic acid — 19-OH-PGE, / \ P G F ^ PGB-r^-PGA-p*-19 0 H PGB.,—19 OH PGA-j arachidonic acid P G E 2 19 OH P G E 2 I / \ / \ PGF 2 o c PGBg—PGAg—19 OH PGB 2 —19 OH PGA. 5,8,11,14,17eicosapentenoic acid *~PGE^ i P G F ^ Scheme 2. The actual biosynthetic pathway (Scheme 3) was determined in the years between 1965 and 1967 and presented in a number of 11 b r i l l i a n t papers by Hamberg and Samuelsson. The f i r s t paper dealt with tracer studies of tritium labelled fatty acids. Prom this study, i t was determined that the i n i t i a l step involved a lipoxygenase-like reaction in which the 13-pro S hydrogen was removed. The second paper studied the incbrpOra.' *l 8 "16 tion of O2 and 0^ into the prostaglandins. By analysis of the mass spectral data, the authors were able to show that the two oxygen atoms on the cyclopentane ring were obtained from the same 0 2 molecule and that the oxygen at the C-15 position was obtained from a different molecule. It was observed that there was no interconversion between the PGE's and the PGP's so that different processes are suggested for the biosynthesis of these two prostaglandins. -13-1 2 In 1973 Hamberg and Samuelsson and Nugteren and 1 ^  Hazelhoff isolated the two intermediate endoperoxides and gave them the names PGG9 and PGH0. An interesting note is the fact that these two prostaglandins were found to have much higher potency than PGEg. They found that P G G 2 was 50 - 200 times more potent and P G H 2 was 100 - 450 times more potent towards platelet aggregation than was PGEg. This would indicate that these two prostaglandins may not be mere biosynthetic intermediates. - 1 4 -(D) Synthesis In the past ten years there has been an increasing interest in the synthesis of prostaglandins. A number of reviews 14 of these syntheses have been published. A brief discussion of the main steps in some of the more important synthetic sequences w i l l be given here. At a casual glance, the synthetic problem in the prostaglandins does not appear to be too demanding. However, taking a closer look w i l l show a large assortment of interesting and synthetically challenging problems. Fi r s t to be considered is the introduction of a number of asym-metric centers. In the E-series there are four asymmetric centers, three being contiguous asymmetric centers. In the F-series, there are five asymmetric centers, four of which are contiguous. This problem is then compounded by the presence of an acid group, a labile |3-hydroxy ketone (PGE), a secondary a l l y l i c alcohol with an E double bond, and as many as two additional Z double bonds. -15-Of a l l these synthetic hurdles, the one which has turned out to be the most challenging is that of setting up the relative stereochemistry of the 15(S)-0H group. This 15(S)-0H group has been shown to be essential for substantial antagonist activity regardless of what changes are made in other parts of the molecule. (a) Synthesis before Setember, 1974 1 5 In 1967, Just et a l . published a communication which reported the synthesis of prostaglandins PGE-j and PG-p^ . The major step of this synthesis (Scheme 4) involved a stereospecific opening of a cyclopropyl epoxide which led to the formation, in one step, of the E double bond as well as the two hydroxyl groups found at C-11 and C-15. C5H11 C5H11 C5H11 -16-Two major problems arose in this synthesis however. Fir s t , the direction of attack could not be controlled in the epoxidation step and thus the ring opening would lead to both isomers at C-15. Secondly, this work was found to be non-reproduceable by other workers. They found a pre-dominance of the 1,2-diol resulting from opening of the 1 7 epoxide. This diol was later used by Schneider and coworkers ' to produce PG-E2 by way of a mesylate of the diol. 1 8 Corey et_ a l . in 1969 published two different routes to the key intermediate (12). The f i r s t synthesis (Scheme 5) u t i l i z e d an aldol cyclization to set up the cyclopentane ring. This was followed by reduction.of the C-13 keto group with sodium borohydride and dehydration. Scheme 5. The second synthesis (Scheme 6) u t i l i z e d a v i n y l -ogous aldol condensation to construct the cyclopentane ring. 5 Hn It may be observed that in both of these syntheses the reduction of the C-15 ketone gave two epimers in approx-imately equal amounts. 19 In 1969 Corey erb a l . developed a stereospecif ic method to reach the key intermediate 13. This method (Scheme 7) involved an alkylation of sodium cyclopentadienide (1.4) with chloromethyl methyl ether in tetrahydrofuran at -55° to give 15. This was then subjected to a Diels-Alder reaction with 2-chloroacrylonitrile at 0° in the presence of cupric fluoroborate. The chloro n i t r i l e 16 was then hydrolysed to afford 17. Note that these two steps are equivalent to a ketene addition in a Diels-Alder sense and the cupric fluoro-borate is present to catalyze the Diels-Alder reaction at a much lower temperature than usually required. The ketone 17was then subjected to a Baeyer-Villiger oxidation, sapon-i f i c a t i o n and resolution to form the acid alcohol 18. Treatment of 18 with aqueous KI^ produced the crystalline iodo lactone 19. -19-At this point the basic skeleton had been set up and now a l l that was required to complete the synthesis of 13 was protection of the alcohol with acetic anhydride, removal of the iodine with tri-n-butyltin hydride, removal of the methyl ether with boron tribromide and oxidation of the resulting alcohol to the aldehyde 13. -20-20 Corey and Gneco were later able to use this inter-mediate in a large number of different prostaglandin syntheses. The entire sterochemistry of the cyclopentane ring is controlled in the Diels-Alder step. In Corey's f i r s t synthesis of a prostaglandin from this intermediate 13 the reduction of the C-15 carbonyl in 20 was s t i l l a problem. I n i t i a l l y using zinc borohydride as a reducing agent a 1:1 mixture of the two C-15 alcohols was obtained. Eventually Corey 21 et a l . were able to improve this step by changing the reducing agent to the lithium trialkylborohydride 21 and the protecting group for the C-11 hydroxyl to p-phenylbenzoate. - 2 1 -Using this modification the desired alcohol 22 was obtained in a ratio of 4.5:1 over the undesired product. Realizing that this reduction of the C-15 ketone was the limiting 22 factor in his synthesis, in 1971 Corey and coworkers once again used his intermediate 13, but this time they u t i l i z e d the Wittig reagent 23 which had the 15(S)-hydroxyl group already present. In doing this they bypassed the need for reduceing the C-15 keto group which had plagued a l l the previous syntheses of prostaglandins. This idea was quickly adopted by a number of other 2 3 groups. In 1972, Sih _et a l . reacted the lithium cuprate 24 OH containing the 15(S)-0H with an -unsaturated ketone. £ 5 H n } y SR. <5R' O z Me 6RX CO,Me -24-24 That same year Pried and coworkers used the aluminum r derivative 26 to open the epoxide 25 in a regiospecific sense. QH \ Al QH UH - 2 6 -25 5 H11 OH In 1973 Corey and Mann reported a cuprate addition to the lactone 27. QDMBS ^ N ^ O O H 5 H11 Up to this point the emphasis in prostaglandin synthesis had been to set up the stereochemistry of the cyclopentane ring at an early point in the synthesis. The biosynthesis of the prostaglandins, which involves the formation of the cyclopentane ring late in the sequence, suggested a number of alternate ways in which a prostaglandin Of. skeleton could be built. In 1972 Martel et_ a l . were able to set up the proper stereochemistry at the C-12 and C-15 position by a stereospecific ring opening of the epoxide 28 OH Scheme 8. -24-This was the f i r s t synthesis which resembled the natural biosynthetic pathway. By changing the stereochemistry of the double bond or the epoxide they found they could get either isomer of the 15-OH group. R Figure 4. It was reported that by using the proper stereochemical relationship between the double bond and epoxide one could obtain the desired relative stereochemistry of the C-12 and -25-C-15 carbons f o r the prostaglandins. 27 In 1973 Corey e_t a l . also published a synthesis based upon the biosynthetic route, i n which the key reaction involved the c y c l i z a t i o n of the epoxide 29 with a Lewis acid, This reaction however resulted i n equal amounts of the lactones 30, epimeric at C-15. (b) Synthesis a f t e r September 1974 2 8 In 1976 Stork and Raucher started a synthesis with a simple sugar 2,3-isopropylidine-L-erythrose (31). Using the absolute stereochemistry inherent i n the sugar, they were able to produce an o p t i c a l l y pure natural prostaglandin. The s p e c i f i c route also included the use of two.Claisen rearrangements. The f i r s t was used to produce the necessary E geometry of a double bond and the second as a means of t r a n s f e r r i n g the c h i r a l i t y of a carbon oxygen bond to that of a non-adjacent carbon-carbon bond (Scheme 9). -27-pq 30 In 1977, Kendo et_ a l . and Taber independently synthesized a prostaglandin, u t i l i z i n g a sulfoxide-sulfenate 31 rearrangement. In this synthesis the sulfoxide is produced "by oxidation of the sulfide formed by attack of thiophen-. oxide on the cyclopropyl ring of 32 (Scheme 10). Scheme 10. Thus, they were able to set up the relative stereochemistry at C-8, C-12, C-13, and C-15. (E) The Present Approach For a number of years, our laboratory has been involved in a study of the alkylation of the dianions of £-keto esters. Generation of the dianion was accomplished by the i n i t i a l addition of one equivalent of sodium hydride in tetrahydrofuran to methyl acetoacetate, followed by add-it i o n of one equivalent of n-butyllithium to generate the dianion 33. JUL. JUL. ^AA - 3 3 -It was found that the dianion could be reacted with an assortment of alkylating agents to give exclusively the IT-alkylated product. Attempts to dialkylate the dianion with dihaloalkanes proved promising. For example, when the dianion 33 was reacted with either excess 1,3-dibromo-propane or under high dilution conditions, a predominance of the cyclic product 34 was obtained. -29-The idea was advanced that one might have an e f f i c i e n t prostaglandin synthesis i f cyclopentanone rings could be set up i n t h i s fashion. The a l k y l a t i n g agent, i n this case, would have to d i f f e r from the dihaloalkanes. An e f f i c i e n t synthesis would involve the formation of the 13-E double bond as well as control of the r e l a t i v e stereochemistry of C-12 and C-15. The proposed synthesis would involve i n i t i a l T T-alkylation of dianion 33 with 35 followed by i n t e r n a l c y c l i z a t i o n at the°C-carbon to give 36. This would give us a key intermediate i n a prostaglandin synthesis. In f a c t t h i s intermediate has been used i n a number of recent syntheses of prostaglandins. ^ ' 30»61 It was found that the c y c l i z a t i o n step did not -30-proceed to form the desired cyclopentanone ring. This was further confirmed by our failure to obtain other types of cyclopentane rings in related cyclizations. In most cases the only product was derived from i n i t i a l V -alkylation of ~. 33 followed by exclusive O-alkylation instead of the desired 32 C-alkylation. An example of this 0-cyclization is shown below. OOH Also the alkylation of the dianion 33 with 1,4-dibromo-2(Z)-butene gave a mixture of the dimer 37 and of the cyclohept-32 anone 38, but no cyclopentanone product. - 3 1 -It was later pointed out "by Baldwin^ that such alkylations were governed by stereoelectronic factors. He studied the ring closures of a number of keto enolates (Scheme 11) and found that endocyclic alkylations (path A) of these enolates depend c r i t i c a l l y upon the size of the ring formed and that six- but not five-membered cyclic ketones can be synthesized in this fashion. The "ft-halo enblates instead undergo exocyclic 0-alkylation (path B). In light of these facts a slight modification of our proposed synthesis was attempted. It had already been shown by Martel et_ a l . that cyelization of the enamine 28 could be accomplished using sodium amide to give the cyclopentanone product after hydrolysis. The pyrrolidine enamine 39 of methyl acetoacetate - 2 8 -was synthesized. 1) N a N H 2 2) H 3 0 + C 5 H 1 1 Me TsOH Bz OH Me -39-,34 It is known that the monoanion of the enamine 39 behaves similarly to the dianion of the £ -keto esters in that ex-clusive Y-alkylation is obtained. Therefore using the same intermediate 35 and the enamine of methyl acetoacetate one can obtain the prostaglandin intermediate 36. In the process of making intermediate 36, two additional natural products were synthesized. These natural products, were ethyl 2(E),4(Z)-decadienoate (40) which was identified as part of the odoriferous principle of Bartlett 35 pears and 2(E),4(Z)-decadien-1-yl isovalerate (41) which is a compound isolated from the essential o i l of the Cyprus. 36 -33-RESULTS and DISCUSSION The synthesis of the desired intermediate 36 was planned in two phases as follows. The f i r s t phase (Part 1) would involve the use of a model compound to test the feas-i b i l i t y of our planned route. The second phase (Part 2) would involve the synthesis and reaction of compound 42 to form the intermediate 36. Part 1 A model compound which contains a l l the desired features of compound 42 is the unsaturated epoxide 46. The route to the model intermediate 47 was planned as shown in Scheme 12. - 3 5 --47-37 The readily available 4,5-epoxy-2(E)-pentenal ( 4 4 ) was reduced with sodium borohydride in methanol in a slightly alkaline media to yield the alcohol 45 in 7 4 $ yield. Neither the aldehyde nor any side products (which could include reduction of the epoxide) were present in the crude mixture as judged by NMR. The relatively low yield i s attributed to the moderate solubility of the product in water. A number of very mild procedures for the conversion of a l l y l i c alcohols to a l l y l i c halides were attempted. T O Corey et_ a l . described a procedure to replace an hydroxyl group by halogen under neutral conditions which is selective for a l l y l i c alcohols and also extremely mild. This method involves the use of the complex 48 formed between N-bromo-succinimide and dimethyl sulfide. It was found that using -36-s-/ Br" - 4 8 -this procedure on alcohol 45, the epoxide also reacted, as confirmed by the loss of the epoxide protons in the NMR. A different procedure was developed by Hooz and G i l a n i . ^ The complex formed from the reaction of tri-n-octyl-phosphine and carbon tetrabromide is trapped by reaction with an alcohol to provide complex 49 which then collapses to the alkyl bromide 50. (n-octyl)-^P + CBr^ .(n-octyl)^PBr CBr-^  + - + (n-octyl^PBr CBr^ + R-OH ^_(n-octyl)-jP-OR + HCBr-j — — Br - 4 9 -(n-octyl)^P-O-R -Br R-Br+ (n-octyl)-^PO - 5 0 - . When this reaction was carried out on alcohol 45 the crude product, once again, showed the loss of the epoxide protons in the NMR. It was decided at this point to abandon the synthesis -37-of the a l l y l i c halide and try a different leaving group. 40 Crossland and Servis developed a method of converting an a l l y l i c alcohol to the mesylate under very mild conditions. This method involves dissolving the alcohol in methylene chloride at 0° and to this solution is added a 50$ excess of triethylamine followed by a 10$ excess of methanesulfonyl chloride. This solution is l e f t for ten minutes and then washed with dilute acid, base, and f i n a l l y with brine. In an attempt to avoid the use of either acid or base to wash the product, i t was decided that only one equivalent of both triethylamine and methanesulfonyl chloride would be used. It wa.s also decided that dry THP would be used in place of methylene chloride. This would permit removal of the i n -soluble triethylamine hydrochloride by f i l t r a t i o n . The f i l t r a t i o n would be followed by washing the product with a small amount of brine to remove residual quantities of starting materials and by-products. This procedure yielded M s C E t 3 N - 4 5 - V E t 2 ° _ 4 6 _ the mesylate 46 in 78$ yield. The alcohol reacted very clearly as shown by NMR. The epoxide protons were unchanged and -38-there was a shift of the a l l y l i c methylene protons from 4.17 for the alcohol to 4.72 for the mesylate. The difference in reaction mechanisms between the formation of the halide and the formation of the mesylate is very important. In the synthesis of the halide the f i r s t step involves the formation of a complex between the alcohol and dimethylsulfide in the case of Corey's reagent or t r i -n-octylphosphine in the case of Hooz's reagent. This complex is then displaced in a S^2 reaction with the free halide ion. It should be noted that in 45 there are two oxygens present for complexing. The mesylation step, however, involves the 41 i n i t i a l formation of the sulfene 51 from reaction of triethylamine and methanesulfonyl cholride. The alcohol then acts as a "sulfene trap" to afford the mesylate 52. Et.N + CHv-S-Cl -Et.N-HCl + CFL, ' S - b l ' 3 3 b ^ R-OH R-O-S-CH3 -52-When the dianion of methylacetoacetate was alkyl-ated with the mesylate 46, i t was found that the product was not the cyclized product 53, but rather the monoalkyl-ated product 54. - 3 9 -Two reasons can "be proposed for the failure of the system to undergo cyclization. First the monoanion of -keto esters is quite stable and is slow to react with most electrophiles. Secondly, the d i f f i c u l t y in the formation of five-membered 3 3a rings in this fashion was later rationalized by Baldwin (Scheme 13). In this study the ketobromide 55 was converted into either the potassium or the lithium enolate. In both cases, the sole reaction product was the enol ether 56 whereas under the same conditions the ketobromide 57 yielded only the cyclohexanone,58. -40-- 5 8 --C^ V Sir -57-Baldwin states that the remarkable difference between these two cyclizations results from stereoelectronic control of the cyclization of the ambident nucleophile (the enolate anion). For such an Ion (59), carbon alkylation requires approach of the electrophile perpendicular to the plane of the enolate, whereas oxygen alkylation requires approach in the plane of the enolate. C - 5 9 --41-Consequently, in the five-membered ring case, approach of the alkylation site to the carbon in the O-metalated enolate as in Scheme 14 is sterically d i f f i c u l t compared to i t s approach to the oxygen. The cyclization of ft -keto ester 54 can be considered to involve an endocyclic enolate, similar to that from ketone 55. What was needed was a substitute for methyl aceto-acetate. F i r s t , one needs a species that is more reactive than the very stable monoanion of the P -keto esters. Secondly, one needs a species that does not involve the less favored endocyclization. The enamine of the -keto ester 2 6 was found to f u l f i l l these c r i t e r i a . Martel et a l . were able to cyclize 28 to form a five membered ring by treating i t with one equivalent of sodium amide to form the anion -42-which cyclized and after acid hydrolysis yielded 38. In 1)NaNH 2) H 3o + -28- -38 - OH light of Baldwin's rules one can see two points. F i r s t , the keto group is no longer available for C—cyclization, and secondly, the anion cyclization can be considered to proceed via a 5-exo-cyclization as shown in 60. It is known that the anion of an enamine of a -keto ester reacts in a similar fashion to the dianion of the ^-keto ester in that exclusive -alkylation is obtained. With these facts, we could then use our model compound to set up the five membered ring of the prosta-glandins . -43-Me -61-To the enamine of methyl acetoacetate 42 in tetra-hydrofuran at -60°, one equivalent of n-butyllithium is added to produce the anion 61. Then the model compound 46 is added, The reaction is l e f t overnight at room temperature and to this mixture is added one equivalent of lithium diisopropyl-amide to regenerate the anion which is l e f t at room tempera-ture overnight. After hydrolysis, the product obtained was the desired cyclopentanone 62. -62-The presence of a CB^ -OH at 4.12, vinyl protons at 5.7, loss of the -methylene protons of a ^ -keto ester and presence of a multiplet between 1.8 and ' 3.4 corresponding to six protons in the NMR is consistant with structure 62. This spectrum agrees closely with the NMR spectra for the inter-- 4 4 -p q mediate 36 supplied by Kondo. We have now established that our synthetic route can be u t i l i z e d to construct the basic structure 6 2 . Now the problem is to establish the actual lower half of the prostaglandins. Part 2 In the model compound there was no stereochemistry at the potential 15-OH group in relation to the C-12 carbon. The question that arises is can the stereochemistry in the epoxide and the double bond control the stereochemistry ? f of the 15-hydroxyl group. Martel et_ a l . accomplished his -cyclization on a number of isomers. Of the four possible isomers, he found that only two gave the correct relative stereochemistry of the prostaglandins,; Neither compound 63 nor 64 gave the proper stereochemistry on cyclization. The two isomers which gave the correct stereochemistry were compounds 65 and 6 6 . - 4 5 -C5 H11 We decided to synthesize one isomer with the correct relative stereochemistry and one isomer with the opposite stereochemistry. Therefore the two required mesylates were 42 for the natural prostaglandin and 67 for i t s isomer. M : - 4 2 - -67--46-Mesylate 67 The commercially available 2(E),4(E)-decadienal (68) was easily oxidized to the ethyl ester 69 using the 43 method of Corey _et a l . This ester was obtained in high yield and purity and was compared to the same ester prepared 44 by Burden et_ a l . Oxidation of the ester was necessary because epoxidation of the aldehyde 68 did not proceed cleanly to the epoxy aldehyde 70. It is known that ^ fS- t f i -unsaturated esters undergo 4 epoxidation in high yield to give H -epoxides exclusively. The ester 69 was epoxidized with meta-chloroperbenzoic acid i n methylene chloride to give the desired epoxide 71 in 99$ yield. The ratio of the trans to cis epoxides was 93:7 as -47-determined by gas chromatographic analysis. This ratio was found to be the same in the starting aldehyde 68, so i t is apparent that no isomerization took place during the epoxidation step. In the reduction of this ester, a selective reducing agent which w i l l reduce esters in the presence of epoxides is required. Prom our studies on the model compound 44 i t was known that an aldehyde may be reduced in the presence of an epoxide with sodium borohydride. It is also A f known that diisobutylaluminum hydride (DIBAH) w i l l reduce esters to aldehydes under very mild conditions. Masamune 47 et a l . m the synthesis of methymycin used DIBAH to reduce a 2,3-epoxy ester to the aldehyde without reducing the epoxide. Conditions for this reduction involved the addition of one equivalent of DIBAH, in benzene, to an ether solution of the ester at -60°. The aldehyde could then be reduced with sodium borohydride to the alcohol. The Masamune procedure when applied to ester 71 was found to'yield only a small amount of the desired aldehyde 72. The other products were a mixture of starting material arid products resulting from over reduction of the aldehyde 72. The best yield of aldehyde 72 was obtained by addition of one equivalent of DIBAH to -48-a solution of the ester in toluene at -60°. However, i t was found that under these conditions, the epoxide could also be reduced and in fact when two equivalents of DIBAH were used at -78° for two hours, a substantial amount of AO the epoxide was reduced. Lenox and Katzenellenbogen reduced the epoxide 74 with DIBAH yielding an assortment of products depending upon solvent and temperature (Scheme 15). Scheme 15. The suggested mechanism for this reduction involved either complexing to the epoxide and hydride delivery to the double bond, or direct hydride transfer to the double bond as shown. -49-It was found that i n the DIBAH reduction of the ester 71 a small amount of the desired alcohol 73 was also present. Thus we decided to attempt to reduce the ester directly to the alcohol 73. Reduction of ester 71 in ether at -20° for one hour using two equivalents of DIBAH produces the alcohol 73 in 70$ yield with l i t t l e reduction of the epoxide. The f i n a l step before alkylation and cyclization involved the conversion of the alcohol into a mesylate. Using the method developed for the model compound 45, the alcohol 73 was converted into mesylate 67 in 75$ yield. Mesylate 42 The synthesis of mesylate 42 is shown in Scheme 16. - 5 0 --50-42 two equivalents of lithium amide were added to propargyl alcohol (75) to produce the dianion 82, which was then alkylated with 1-bromopentane to produce the alcohol 76 according to 49 the procedure of Edwards. Lithium amide was used to generate the dianion since i t is known^^ that the sodium salt of the dianion w i l l give mostly O-alkylation. The yield of this reaction was 50$, and no attempt was made to maximize the yield. The acetylenic alcohol 76 was oxidized to the aldehyde 77 in 83$ yield using active manganese dioxide (NtaX^). 52 The anion of triethylphosphonoacetate was condensed with the acetylenic aldehyde 77 to yield ester 78 in 97$ yield. The stereochemistry of the double bond was found to be E from the 16 Hz coupling of the vinyl protons in the NMR at —1 6.03 and 6.67, and the 970 cm band in the,IR due to the C-H bending of an E disubsituted alkene. This was the expected 5 3 configuration for the Emmons-Wadsworth modification of the Wittig reaction. Gas chromatographic analysis showed one product plus starting aldehyde ( 5 $ ) . Hydrogenation of the ester 78 was f i r s t attempted with palladium on barium sulfate as a catalyst and quinoline / \ 54 as a poison (Pd-BaS0 A-quinoline). -82--52-In this reaction the predominant product was the desired E,Z_ isomer 79 obtained in 55.7$ yield, but contaminated by 22.7$ over-hydrogenated product 83 and a 21.6$ mixture of the E,E isomer 69 and starting material 78. Hydrogenation of 78 using freshly prepared Lindlar's catalyst (Pd-CaCO-^-PbO)'^ yielded 94.4$ of the desired E,Z isomer 79 as determined by gas chromatographic analysis and only 1.7$ of the E,E isomer 69 plus 3.9$ starting material. The NMR spectrum of 79 was -7 8-Pd-BaSO. R + -79-5 5 . 7 % > >Et R + •83-2 2 . 9 % , Pd-CaCO-PbO 9 4 4 c / o 0°/c 1.7°/o ( 6 9 ) 3 . 9 % ( 7 8 ) 56 found to be identical to those supplied by Naf for the E,Z_ isomer. The overall yield of this reaction was 96$ (94$ pure). This method for obtaining ethyl 2(E),4(Z)-decadien-oate (79) can be compared with two recent•methods of synthes-56 izing this compound. Naf and Decorzant reacted the Grignard reagent 8 4 with enamine 8 5 and obtained the desired ester 7 9 in 3 2 $ yield with 8 9 $ isomeric purity. K r i e f 5 ' treated the Wittig reagent 8 6 with the cx, ^  -unsaturated aldehyde 8 7 to yield the desired ester in 6 5 $ yield with 6 8 $ isomeric purity. As can he seen, the method developed in this work yields the desired ester in much higher yields and isomeric purity. The conditions for the epoxidation of 79 were identical to those used for the trans isomer 71• In this case the yield of epoxide 8 0 was 72$. Comparison of the NMR data for this epoxide with i t s isomer 71 is given below. Prom the NMR data and gas chromatographic analysis i t was concluded that - 5 4 -H-1 6 6.04(d,J=15Hz) H-2 6 6.63(d d, J=15 l 7Hz) H-3 & 3.15(dd, J=2 , 7Hz) H-4 o 2.83(m) s 6.14(d, J=16Hz) s 6.84(dd, J=16, 7Hz) s 3.51 (d d, J = 4 , 7Hz) 6 3.19(m) there was l i t t l e or no isomerization during this epoxidation. The trans isomer may he distinguished by the proton-proton coupling for the protons on the epoxide which i s 2 Hz f o r *trans protons i n 71, and i n the c i s isomer 80 th i s coupling i s 4 Hz f o r c i s protons. The ester 80 was reduced by the same method as the reduction of epoxide 71. Two equivalents of DIBAH at -20°C reduced the ester i n 80 to the alcohol 81 i n 60$ y i e l d , 83$ y i e l d based upon recovery of s t a r t i n g material. Once again the epoxide was e s s e n t i a l l y unreduced. The NMR spectra of the two isomers 73 and 81 are given below. The mesylation step was carr i e d out using the same procedure as f o r the model compound 50, to produce the desired isomer 42. -55-H1 *6.01(d t > 1 5 , 5Hz) H2 «5.3 8(dd,J=15 l 7H Z ) H3 s3.08(d d,J = 7, 2Hz) H4 52.83(m) 5 6.11 (d t J = 1 5 , 5 H z ) s 5.61 (d d , J=15 ,8Hz) 6 3.45(d d, J«4» 8Hz) 8 3.01 (d t, J=4> 6Hz) The procedure for the alkylation step with the two mesylates was the same as for the model compound 50. To the enamine of methyl acetoacetate in tetrahydrofuran at -60°C, one equivalent of n-butyllithium was added to produce the monoanion. To this solution the mesylate 42 or 67 was added. The reaction was l e f t overnight at room temperature and then one equivalent of lithium diisopropylamide was added to generate the monoanion which was again l e f t at room temperature overnight. After hydrolysis, the product obtained was the desired cyclopentanone 36 or 88. The cis isomer 42 gave the intermediate 36 with the natural relative stereochemistry of C-12 and C-15 and the trans isomer 67 yielded the intermediate 88 with the unnatural stereochemistry. The spectra of these intermediates were compared to the spectra of a sample of 36 obtained from Kondo. The IR and NMR were identical for the two intermediates 36 and 88 and the stereochemistry could not he distinguished from the IR and NMR spectra. However, gas chromatographic analysis showed that the product from the mesylate 42 was identical to 29 that of a sample of 36 supplied "by Kondo , whereas the product from the mesylate 67 was not identical with the product 36 and was assigned the unnatural stereochemistry in 88. A number of methods have already been used to convert the key intermediate 36 into the prostaglandin series. 2 6 Martel et_ a l . synthesized prostaglandins PGA0 and PGB9 from the ethyl ester of 36. Kondo ejt a l . ^ converted 36 into the 11-deoxyprostaglandin . Taber3<^ synthesized PG>A2 from 61 36 and Toru synthesized PGAg from 36. Thus we can claim a new, stereospecific synthesis of these prostaglandins. However, of greater importance is the demonstration that this route to the prostaglandins is feasible and this establishes the ground work for a new and very convergent synthesis of the prostaglandins as shown below. Part 3. In the studies related to the synthesis of mesylate 42 two other natural products were synthesized. The' f i r s t was ester 79 which was found to exist in the odoriferous fraction 3 5 in Bartlett pears , and the second was 2(E),4(Z)-decadien-1-yl isovalate 41 which has been isolated from the cypress -58-essential o i l s . The pear ester 79 synthesis can be found in Part 2. The ester 79 was reduced with diisobutylaluminum hydride to afford the ahcohol 90 followed by esterification to yield the product 41 as shown in the following scheme. -41-The NMR spectrum of 90 was identical to the spectra reported by Tabacchi et_ a l . ^ The alcohol 90 and isovaleryl c h l o r i d e ^ were combined with triethylamine in tetrahydrofuran. The reaction yielded the isovalerate ester 41 in 98$ and the resultant spectral data were identical to those of the natural product. - 5 9 -EXPERIMENTAL Spectral Data A l l IR spectra were taken in chloroform solution unless otherwise noted. They were recorded on a Perkin-Elmer Model 700 spectrophotometer and were calibrated with the 1601 cm band of polystyrene. The assignment of each band is noted in parenthesis after i t . A l l absorptions were -1 given m cm i The H-NMR spectra were taken in deuterochloroform unless otherwise noted and were recorded on a Varian Model T-60 or Model XL-100 spectrometer. Tetramethylsilane was used as an intermal standard. Chemical shifts are reported on the scale. Coupling constants are quoted in Hz. and the multiplicity of the signal is designated as singlet (s), doublet (d), t r i p l e t (t), quartet (q) and multiplet (m). The mass spectra were recorded with either an Atlas CH-4b or, for high resolution on AEI-MS-50 mass spectrometer. In both cased, the spectra were obtained at 70 eV. The value in parenthesis after each mass is i t s relative intensity. The ultraviolet absorption spectra were recorded on Unicam Model SP800 spectrophotometer in ethanol solvent. Physical Data Elemental analysis were performed by Mr. Peter, Borda, U.B.C. Chromatography Preparative thin layer chromatography (TLC) was carried out using 0.9 mm thickness s i l i c a gel ( E. Merck ) -60-on either 20 x 20 cm or 5 x 20 cm glass plates. Small analytical plates were prepared by dipping microscope slides into a stirred solution of s i l i c a gel in chloroform. Column chromatography was carried out with s i l i c a gel finer than 200 mesh. Gas chromatography was carried Out on either a Varian Aerograph Model 90P or a Hewlett Packard Model 5830A using Helium as the carrier gas and OV-1 and OV-17 as the columns. Solvents Solvents termed "dry" have been treated as follows: ethyl ether and tetrahydrofuran (THP) were dried by refluxing over lithium aluminum hydride. Toluene and benzene were dried over sodium. Methanol was dried by refluxing over magnesium methoxide and ethanol over magnesium ethoxide. Techniques Anhydrous magnesium sulfate was used to dry organic solutions and was removed by f i l t r a t i o n . A l l stir r i n g , unless otherwise stated, was carried out using teflon-coated magnetic s t i r r i n g bars. Trans-4,5-epoxy-2-pentenol (45) To a solution of 0.523 g (5.33 mM) of trans-4,5-epoxy-2-pentenal (44) in.5 ml methanol at 0°C was added a solution of 0.07 g (1.9 mM) sodium borohydride in one ml of 0.1 M aqueous NaOH. This solution was l e f t for 30 min. at 0°C. The methanol was then removed under reduced pressure. The resulting o i l was diluted with 25 ml brine and extracted with 3 x 25 ml of ethyl ether. Then the organic layer was -61-dried and the solvent removed to y i e l d 0.395 g (74$) of crude 45. A small sample was p u r i f i e d by preparative TLC ( s i l i c a gel, EtOAc:CH 2Cl 2 =1:1) and the band at Rf .55 was removed and extracted with ethyl acetate. IR: 3200-3700 (OH), 1620 (C=C). NMR: 6.16 (d t, J=15 & 5, 1H), 5.42 (m, J=7, 15 & 2, 1H), 4.16 (d, J=5, 2H), 3.2-3.6 (m, 2H), 2.98 ( t , J=5, 1H), 2.67 (d d, J=2 & 5, 1H) Analysis: calculated f o r C^HgOg: C, 59.98; H, 8.01. Pound: C, 59 . 7 0 ; H, 8.20. Mass Spectrum: 100 (9) , 82(100), 81(57), 70(27), 69(51), 68(15), 66(30), 57(13), 55(16), 54(43), 53(73), 51(18), 44(16), 43(19), 41(38), 40(19), 39(65). Trans-4,5-epoxy-2-penten-1-yl mesylate (46) To a solution of 0.0891 g (0.90 mM) of 45 i n 10 ml dry ethyl ether at 0°C was added 0.208 ml (1.49 mM) of t r i -ethylamine. To the r e s u l t i n g solution was added 0.085 ml (1.09 mM) of methanesulfonyl chloride. This solution was then allowed to s t i r f o r 30 min. at 0°C and then the r e s u l t i n g mixture was washed with 5 ml brine and the brine washed with 10 ml ethyl ether. The organic layer was dried and the solvent removed under reduced pressure to y i e l d 0.123 g (78$) of the mesylate 46. On TLC (EtOAc:CH 2C1 2 =1:1) the mesylate has an Rf of . 9 . IR: 1682 (C=C), 1360 & 1180 (-SOy), 980 & 940 (c=C) NMR: 6.04 (d t, J=19 & 6, 1H), 5.53 (d d, J=7 & 16, 1H), 4.65 (d, J=6, 2H), 3.2-3.5 (m, 1H), 3.0 (s + m, 4H), 2.6 (d d, J=3 & 6, 1H). Mass Spectrum: 178(1), 169(2), 159(13), 114(3), 113(5), 109(6), 82(100), 81(42), 71(16), 69(18), 54(17), 53(65). 2-Methoxycarbonyl-3-(3-hydroxy-1-propenyl)cyclopentan-1-one (47). A 2.537 g (15 mM) sample of the pyrrolidine enamine of methyl acetoacetate"^ was dissolved in 60 ml dry tetra-hydrofuran. This solution was then cooled to -60°C ( CHCl^ and dry ice ) under a Ng atmosphere. To this solution was added 9.25 ml (14.8 mM) of 1.6 M n-butyllithium in hexane. The solution was l e f t for 30 min. at -60°C and then for 1 hr. at room temperature. This solution was then cooled to -60°C and to i t was added 2.928 g (16mM) of the mesylate 46. The mixture was l e f t at -60°C for 30 min and then at room temperature for 24 hr. The solution was then cooled to -60°C and a solution made from 1.81 ml diisopropylamine and 8.1 ml of 1.6 M n-butyllithium was added. After 30 min. at -60°C the mixture was again l e f t at room temperature for 24 hr. The resulting enamine was then hydrolysed with a mixture of 5 ml HgO, 5 ml acetic acid and 0.5 g'sodium acetate. This mixture was l e f t at room temperature for 4 hr. The acetic acid was neutralized with saturated NaHCO-^  solution and the resulting solution was extracted with 3 x 100 ml of ethyl ether. - 6 3 -The organic layer was dried and the solvent removed under reduced pressure yielding 1 .78 g (60$). A small sample was purified by preparative TLC (EtOAc) and the band between Rf . 3 and . 5 was removed and extracted with ethyl acetate. - \ IR: 3 2 0 0 - 3 7 0 0 (-0H), 1 7 4 0 (cyclopentanone), 1 7 2 0 (COOMe), 1 6 4 0 (C=C). NMR: 5.71 (m, 2 H ) , 4 . 1 1 (m, 2H), 3 . 7 3 (s, 3H), 1.6 - 3 . 0 (m, 5H). Analysis calculated for C^H^O^: C, 60 . 5 9 ; H, 7 . 1 2 Pound: C, 60 . 3 8 ; H, 7.30 Mass Spectrum: 199(11), 1 9 8 ( 5 0 ) , 192(24); 1 8 0 ( 9 ) , 167(29), 166(19) , 138(14), 137 (59) , 136 (22) , 1 2 5 ( 5 4 ) , 1 2 1 ( 7 9 ) , 113 (38) , 1 1 1 ( 1 0 0 ) , 1 0 7 ( 4 4 ) , 1 0 5 ( 9 2 ) , 101(64), 99(24), 9 8 ( 2 2 ) , 97(41), 96(26), 9 5 ( 4 9 ) , 9 4 ( 2 1 ) . Ethyl 2(E),4(E)-decadienoate (69). To 25 ml of ethanol was added 0.164 g (1.08 mM) of 2(E) ,4(E)-decadienal, 1 . 9 5 2 g of Mn0 2 5 1, 0 . 2 7 7 g ( 1 2 mM) of sodium cyanide and 0.098 ml acetic acid. This mixture was allowed to s t i r at room temperature overnight. The Mn02 was then f i l t e r e d off and the ethanol was removed under reduced pressure. The resulting solid was dissolved in 25 ml water and this solution was extracted with.3 x 25 ml ethyl ether. The organic layer was dried and the solvent removed under ~* reduced pressure giving 0.143 g (80$) of ester 6 9 . GC analysisishowed this ester to be 9 5 $ pure with no trace of -64-starting aldehyde. A small quantity was isolated by gas chromat ography. IR: 1710 (COOEt), 1640 & 1620 (C=0). NMR: 6.9-7.4 (m, 1H), 5.5-6.2 (m, 3H), 3.70 (s, 1H), 4.13 (q, J=7, 2H), 2.0-2.4 (m, 1H), .7-1.6 (m, 9H). UV: 257 nm Analysis calculated for C 1 2H 2 00 2: C, 73.43; H, 10.27 Pound: C, 73.29; H, 10.29 Mass Spectrum: 197(8), 196(43), 151(28), 128(11), 127(15), 126(13), 125(100), 123(13), 122(13), 121(8), 114(8), 112(6), 111(10), 109(6), 108(10), 107(8), 99(18), 98(30), 97(53), 96(13), 95(13), 94(10), 93(10), 84(6), 83(10), 82(10), 81(50). Ethyl trans-4,5-epoxy-2(E)-decenoate (71). Ethyl 2(E),4(E)-decadienoate ( 69, 0.794 g, 4.05 mM) was dissolved in 25 ml methylene chloride and this was cooled to 0°C.-~ To this solution was added 1.240 g (6.09 mM) of m-chloroperbenzoic acid. The mixture was l e f t for 30 min. at 0°C and then overnight at room temperature. After a few hours, the solution turned a cloudy white ( the m-chloro-benzoic acid percipitates out). To this mixture was added aqueous saturated sodium bisu l f i t e to remove the excess peracid and then the organic layer was washed with sodium bicarbonate to remove the acid. The aqueous layers were extracted twice with ethyl ether and the combined organic layers were dried and the solvent removed under reduced pressure yielding 0.848 g (99$) of crude product. This crude mixture was analysed by GC and found to be 93$ of the E alkene 71 and 7$ of the Z alkene 80. This is the same isomer ratio as the starting aldehyde. A small portion was purified by TLC (EtOAc:CH2C12 = 9:1) and the band at Rf .75 was removed and eluted with ether. IR: 1725 (COOEt), 1680 (C=C).' NMR: 6.63 (d d, J=7 & 15, 1H), 6.04 (d, J=15, 1H), 4.18 (q, J=7, 2H), 3.15 (d d, J=7 & 2, 1H), 2.83 (m, 1H), .9-1.6 (m, 9H), .5-.9 (m, 3H). Analysis calculated for C 1 2H 2 00 3: C, 67.89; H, 9.50 Pound: C, 67.71; H, 9.32 Mass Spectrum: 212(.1), 196(5), 183(15), 167(4), 166(3), 157(4), 155(6), 151(4), 140(2), 139(23), 129(10), 125(10), 114(3), 113(4), 112(37), 111(2), 110(6), 99(6), 97(8), 85(13), 84(100), 83(19), 81(9), 73(7), 71(5), 69(23), 67(12). Trans-4,5-epoxy-2(E)-decen-1-ol (73). A 0.211 g (1.0 mM) sample of ester 71 was dissolved in 25 ml of dry ethyl ether (N 2 atmosphere). This solution was cooled to -20°C (CCl^ and dry ice) and 2.1 ml (2.0 mM) of 20$ diisobutylaluminum hydride in hexane were added over a period of 7 min. and the solution l e f t at -20°C for 1 hr. To this solution was added 2 ml of aqueous saturated ammonium chloride and the resulting mixture was allowed.to warm to -66-room temperature. This mixture was stirred for two hours. Anhydrous magnesium sulfate and Celite were added and the mixture was fi l t e r e d . The f i l t r a t e s were dried and the solvent removed under reduced pressure to yield 0.113 g ( 7 0 $ ) of the alcohol 7 3 . A small sample was purified by TLC (EtOAcrCHgClg = 1:9) and the band at Rf . 3 3 was removed and eluted with ether. IR: 3200-3700 (-0H), 1620 (C=C). NMR: 6.01 (d ,t, J=5 & 15, 1H), 5 .38 (d d, J=15 & 7, 1H), 4.10 (d, J=5, 2H), 3.08 (d d, J= 7 & 2, 1H), 2.5-2.9 (m, 2H), 1 .2-1 .7 (m, 8H), 1.0 (m, 3H). Mass Spectrum: 170(1), 169(2), 153 (3) , 140(2), 139(22), 129(4), 99(15), 97(9), 95(8), 87(4), 86(7), 85(4), 84(5), 83(24), 82(5), 81(29), 79(6), 71(18), 70(100), 69(28). High Resolution: Calculated for C^H^Og: 170.1307. Pound: 170.1311. Trans-4,5-epoxy-2(E)-decen-1-yl mesylate (67). A solution of 0 . 2 9 8 g (1.75 mM) of alcohol 73 in 24 ml of dry tetrahydrofuran was cooled to 0°C. To this solution was added 0.36 ml (2.6 mM) triethylamine and then 0.149 ml (1.91 mM) of methanesulfonyl chloride. The mixture was l e f t for 30 mid. and then the triethylamine hydrochloride was f i l t e r e d off. The ether layer was washed with 10 ml of brine, dried and the solvent removed under reduced pressure yielding 0.400 g of product. IR: 1360 & 1180 ( - S 0 3 - ) , 980 & 930 (C=C). NMR: 5.8-6.0 (m, 2H), 4.63 (d, J=6, 2H), 2.6-3.1 (m+s, 5H), .7-1.6 (m, 11H). 2-Octyn-1-ol (76). In a 2 - l i t r e f l a s k was condensed 1 l i t r e of ammonia and a c a t a l y t i c amount of Fe(NO^)^ was added. To the solution was slowly added 12.55 g (1.8 moles) of lithium. After the blue colour had disappeared, 54.6 ml (.92 moles) of propargyl alcohol i n 200 ml tetrahydrofuran was added over 15 min. The mixture was l e f t f o r 1 hr. and then 124 ml (1.0 moles) of 1-bromopentane dissolved i n 100 ml dry tetrahydrofuran was added. After 45 min. the reaction was quenched with s o l i d ammonium chloride. The ammonia was evaporated and the r e s u l t i n g s o l u t i o n was washed with brine, dried and the solvent removed under reduced pressure. The 2-octyne-1-ol d i s t i l l e d at 90°C (8 mm) y i e l d i n g 57.2 g (50$) product. IR: 3700 & 3500 (-0H), 2330 & 2250 (CSC). NMR: 4.16 (m, 2H), 3.67 (s, 1H), 2.0-2.36 (m, 2H), 1.0-1.8 (m, 6H), .7-1.0 (m, 3H). Analysis calculated f o r CgH^O: C, 76.14; H, 11.18 Pound: C, 76.33; H, 11.10 Mass Spectrum: 126(1), 95(39), 93(44), 91(13), 83(52), 82(17), 81(30), 79(39), 77(22), 70(74), 69(48), 68(22), 67(83), 66(13), 65(17), 57(26), 55J91 ), 54(22), 53(355, 52(30), 51(22), 43(44), 42(39), 41(100), 40(22), 39(78), 31(13), 29(74), 38(44), 27(52). -68-2-Octynal (77). In a 500 ml flask was placed 250 ml of methylene chloride, 25 g of active Mn0 2 5 1 and 3.64 g (28.9 mM) of 2-octyne-1-ol (76). The mixture was l e f t at room temperature - for 4 hr. The Mn02 was f i l t e r e d off and the solvent removed under reduced pressure yielding 2.963 g (83$) of 2-octynal (77) which d i s t i l l e d at 49°C (0.1 mm). IR: 2250 ( C S C ) , 1676 (C=0). NMR: 9.08 (s, 1H), 2.36 (t, J=6, 2H), 1.2-1.8 (m, 6H), .7-1.2 (m, 3H). Analysis calculated for CgH^O: C, 77.38; H, 9.74 Pound: C, 77.45; H, 9.90 Mass Spectrum: 124(1), 123(9), 109(33), 96(10), 95(100), 81(38), 70(19), 68(43), 67(48), 57(19), 56(14), 55(52), 54(14), 53(24), 41(86), 39(57), 29(90), 28(29), 27(43). Ethyl (E)-dec-2-ene-4-.ynoate (78). A 0.957 g (19.9 mM) sample of NaH (50$ mineral oil) was stirred in 50 ml dry tetrahydrofuran. To this mixture was added 4.64 g (19.9 mM) of triethyl phosphonoacetate. When the evolution of H 2 stopped, the mixture was cooled to -20°C (CC14 and dry ice) and 2.47 g (19.9 mM) of 2-octynal was added slowly and the reaction was l e f t at -20°C for"2 hr. The mixture was then extracted with ethyl ether and the ether layer dried. The solvent was removed under reduced pressure yielding 3.77 g (97$) of the desired ester 78. IR: 2250 (C=C), 1725 (C=0), 1631 (C=C), 970 (C=C). NMR: 6.67 (d t, J=16 & 2, 1H), 6.03 (d, J=16, 1H), 4.15 (q, J=7, 2H), 2.2-2.5 (m, 2H), 1.0-1.6 (m, 9H), .6-1.0 (m, 3H). Analysis calculated for C- |2 H 18°2 : C ' 74.19; H> 9«34 Found: C, 74.10; H, 9.43 Mass Spectrum: 194(2), 179(17), 169(5), 166(12), 165(48), 151(21), 149(55), 148(17), 147(21), 138(5), 137(21), 133(21), 125(7), 124(10), 123(41), 121(48), 120(36), 119(59), 111(10), 110(43), 109(55), 107(17), 106(17), 105(45), 98(19), 96(26), 95(21), 94(69), 93(38), 92(35), 91(62), 83(17), 82(35), 81(52), 80(14), 79(71), 78(19), 77(50), 57(17), 55(83), 53(27), 51(28), 41(78), 39(58), 29(100), 28(55), 27(50). Ethyl 2(E),4(Z)-decadienoate (79). In a 50-ml flask was placed 0.115 g of freshly 5 4 prepared Lindlar's catalyst, 2 drops of quinoline, 0.906 g (4.67 mM) of ester 78, and 25 ml of hexane. A'slight positive pressure of hydrogen was applied to the flask. When 1 equiv-alent (103 ml) of was taken up the catalyst was fi l t e r e d off. The solution was washed with mild acid, dried and the solvent was removed-under reduced pressure yielding 0.900 g of product shown to be 94$ pure by GC analysis. A small sample was isolated by gas chromatography. -70-IR: 1720 (C=0), 1640 & 1620 (C=C). NMR: 7.55 (d d, J=16 & 10, 1H), 5.80 (d, J=16, 1H), 5.5-6.3 (m, 2H), 4.18 (q, J=7, 2H), 2.0-2.2 (m, 2H), 1.0-1.7 (m, 9H), .7-1.0 (m, 3H). Analysis calculated for C 1 2H 2 00 2: C, 73.45; H, 10.27 Pound: C, 73.50; H, 10.20 Mass Spectrum: 197(9), 196(61), 167(6), 151(42), 129(48), 128(26), 127(29), 126(16), 125(100), 123(19), 122(32), 121(16), 114(10), 108(19), 98(26), 97(29), 81(61), 79(32), 67(68), 55(29), 53(23), 41(42), 29(90). 2(E),4(Z)-Decadien-1-ol (90). To 4.66 ml (4.5 mM) of DIBAH (20$ in hexanes) was added to 15 ml hexane and this solution was cooled to 0°C (N 2 atmosphere) with sti r r i n g . Then 0.378 g (1.92 mM) of ethyl 2(E),4(Z)-decadienoate (79) dissolved in 5 ml hexane was slowly added to the DIBAH solution. The reaction was l e f t at 0°C for 2 hr. To the reaction was added 3 ml methanol and after 10 min. 10 ml aqueous dilute HC1 was added and the mixture was l e f t for 1 hr. The resulting solution was then extracted with ethyl ether and the organic layer was dried and the solvent removed yielding 0.266 g (90$) of the alcohol 90. The spectral data of the crude alcohol 90 were identical to that reported hy Tabacchi et a l . ^ for 2(E),4(Z)-decadien-l IR: 3400 (-0H), 980 (C=C) NMR: 5.2-6.7 (m, 4H), 3.79 (d, J=6, 2H), 1.9-2.4 (m, 3H, one exchanges on addition of DgO), 1.0-1.8 (m, 9H), 0.7-1.0 (m, 3H). 2(E),4(Z)-Decadien-1-yl isovalerate (41). In a 25-ml f l a s k was placed 0.235 g (1.53 mM) of 2(E),4(Z)-decadien-1-ol (90) dissolved i n 10 ml dry t e t r a -hydrofuran. To the alcohol solution was added 0.22 ml (1.6 mM) of triethylamine and then 0.30 ml (2.5 mM) of 5 9 i s o v a l e r y l chloride. The solution was refluxed f o r 2 hr. and l e f t at room temperature f o r 12 hr. Then 25 ml ethyl ether was added and the r e s u l t i n g solution extracted with aqueous saturated NaHCO^. The organic layer was dried and the solvent removed under reduced pressure y i e l d i n g 0.364 g (98$) of the desired ester 41. IR: 1730 (COOR), 1579 (COOR), 980 (C=C). NMR: 6.4-6.8 (d d, J=7.5 & 5 .5, 1H), 5.4-6.2 (m, 3H), 4.57 (d, J=6, 2H), 1.8-2.4 (m, 4H), 1.1-1.7 (m, 7H), 0.7-1.0 (d, J=3, 9H). Analysis calculated f o r C^^E2602: C, 75.58; H, 11.00 Pound: C, 75.53; H, 10.80 Mass Spectrum: 238(6), 137(5), 136(5), 111(4), 110(8), 99(4), 85(100), 83(7), 82(8), 81(12), 80(14), 79(20), 77(7), 71(8), 69(13), 68(10), 67(22),, 57(79), 55(18), 54(104), 43(29), 42(7), 41(40), 39(12), 29(26). -72-Ethyl cis - 4 , 5-epoxy-2(E)-decenoate (80). A 6 . 8 8 . g (35 mM) sample of ethyl 2(E),4(Z)-decadienoate was dissolved i n 200 ml of methylene chloride. This mixture was cooled to 0°C and to i t was added 10.59 g of 8 5 $ m-chloroperbenzoic acid over a period of 10 min. The mixture was then l e f t at 0°C fo r 2 hr. and then at room temperature fo r 12 hrs. The mixture was washed with 50 ml of saturated NaHSO^ to remove excess peracid and then with 2 x 50 ml of aqueous saturated NaHCO^ to remove the acid. The organic layer was dried and the solvent removed y i e l d i n g 5.34 g (72$) a f t e r d i s t i l l a t i o n at 79°C (.05 mm). The crude mixture was found to contain 8 5 $ of the desired product hy TLC (CCl^cEtgO = 4:2) and the band at Rf .75 was removed and eluted with ethyl ether. IR: 1700 (COOEt), 1660 (C=C), 980 (C=C). NMR: 6.84 (d d, J=16 & 7, 1H), 6.14 (d, J=16, 1H), 4.23 (q, J=7, 2H), 3.51 (d d, J=7 & 4, 1H), 3.19 (d t, J=4 & 5, 1H), 1.2-1 .8 (m, 11H), 0.7-1.1 ( t , J=6, 3H). Analysis calculated f o r C ^ H ^ O y C, 67.89; H, 9.50 Pound: C, 68.12; H, 9 . 5 5 Mass Spectrum: 212(.6), 194(1 . 5 ) , 183(.8), 177 ( 5 ) , 155(6), 139(29), 129(23), 113 ( 9 ) , 1 12(755,' 85 ( 11), 84(100), 83(30), 5 5(24). High resolution calculated f o r C-^H^O^: 212.1412. Pound: 212.1408. -73-Cis-4,5-epoxy-2(E)-decen-1-ol (81 ). Ethyl cis-4,5-epoxy-2(E)-decenoate ( 80, 1.59 g, 7.5 mM) was dissolved in 150 ml dry tetrahydrofuran. The solution was cooled to -20°C (CCl^ and dry ice) and to this — - solution was added 15.8 ml of 20$ DIBAH in hexane over a period of 15 min. The solution was l e f t at -20°C for 1 hr. and then 5 ml of aqueous saturated ammonium chloride was added. The mixture was stirred at room temperature for 1 hr. To the solution was then added MgSO^  and Celite; the entire mixture was f i l t e r e d and the organic solvent removed under reduced pressure yielding 1.64 g of crude product 81. This crude product (.111 g) was purified "by TLC (CCl^:Et 20 = 4:2) and the band at Rf .75 and .25 were removed and eluted with ethyl ether yielding 0.031 g of starting material and 0.052 g of the desired alcohol 81, respectively. The overall yield based upon recovery of starting material is 83$. IR: 3700 & 3500 (-0H), 960 (C=C). NMR: 6.11 (d t, J=15 & 5, 1H), 5.61 (d d t, J=15, 8 & 1, 1H), 4.25 (d d, J=5 & 1, 1H), 3.45 (d d, J=8 & 4, 1H), 3.01 (d,t, J=4 & 6, 1H), 2.2 (m, 1H), 1.1-1.7 (m, 8H), 0.7-1.1 (t, J=6, 3H). Mass Specturm: 170(4),. 169(13), 168(7), 152(9), 149(38), 139(27), 123(8), 109(10), 99(40), 98(34), 94(11), 93(13), 91(12), 84(19), 83(63), 82(23), 81(65), 80(14), 79(37), 78(12), 77(25), 71(56), 70(100), 69(58), 67(58). High Resolution calculated for C^H^O^ 170.1307 Pound: 170.1311. -74-Cis-4,5-epoxy-2(E)-decen-1-yl mesylate ( 4 2 ) . A 0 .273 g (1.6 mM) sample of cis -4,5-epoxy -2(E)-deeen-1-ol (81) was dissolved in 15 ml dry tetrahydrofuran. This solution was cooled to 0°C, and 0.33 ml (2 .4 mM) of — t r i e t h y l a m i n e and 0.14 ml (1.8 mM) of methanesulfonyl chloride were added. After 5 min. the solution turned cloudy and the mixture was stirred at 0°C for 2 hr. The reaction mixture was diluted with ethyl ether and washed with brine. The organic layer was dried and the solvent removed under reduced pressure yielding 0.344 g (87$) of mesylate 42. IR: 1360 & 1180 ( - S 0 3 - ) , 970 & 905 (C=C). NMR: 5.8-6.1 (m, 2H), 4 .68 (d, J=5, 2H), 3.38 (d d, J=4 &2, 1H), 2.98 (s & m, 4H) , 2 . 2 - 2 . 7 (m, 8H) , 0 .8 -1 .1 (m, 3H). Cyclic ester 36. A 0 .507 g ( 3 . 0 0 mM) sample of the purrolidine enamine"^ of methyl acetoacetate was dissolved in 100 ml dry tetrahydro-furan. The solution was cooled to -60°C and to this solution was added 4 .8 ml of a 1.6 M n-butyllithium in hexane. This solution was l e f t at -60°C for 30 min. and then at room temperature for 1 hr. The solution was then cooled back to -60°C at which time O.78O g (3.14 mM) of cis -4,5-epoxy -2(E)-decen-1-yl mesylate (42) was added. ,The solution was l e f t at -60°C for 30 min. and then at 0°C for 12 hrs. The mixture was ~ again cooled to -60°C and a solution of 1.08 ml diisopropyl-amine and 4 .8 ml of 1.6 M n-butyllithium was added. This solution was l e f t at -60°C for 30 min and at room temperature for 12 hr. To this solution was added a mixture of 10 ml of water, 10 ml acetic acid and 1 g sodium acetate. This mixture was l e f t to s t i r for 4 hr. and the resulting solution was neutralized with aqueous saturated NaHCO-^ . The ether layer was washed with brine and dried. The organic solvent was removed under reduced pressure. The sample was purified by TLC (EtOAc;CH2C12 = 9:1) and the band at Rf .5 was removed and eluted with ethyl ether yielding 0.16 g (20$) of purified product 36. IR: 3700 (-0H), 1760 (cyclopentanone), 1730 (COOMe), 910 (C=C). NMR: 5.5-5.7 (m, 2H), 4.0-4.2 (bs, 1H), 3.7 (s, 3H), 2.7-3.6 (m, 2H), 1.8-2.7 (m, 5H), 0.7-1.8 (m, 11H). Mass Spectrum: 268(3), 250(8), 197(18), 180(10), 168(16), 167(26), 166(13), 165(100), 163(10), 155(12), 154(31), 153(10), 151(10), 148(17), 142(12), 141(67), 139(26), 138(13), 137(69), 136(47), 135(32), 127(14), 123(38), 122(10), 121(11), 120(11), 119(10), 116(13), 110(10), 109(62), 107(18), 99(59), 97(15), 96(20), 95(22), 93(10), 91(12), 83(17), 81(20), 79(22), 77(11), 71(27), 69(10), 67(16), 57(18), 55(40), 53(19). High resolution calculated for C^H^O^: 268.1674 Pound: 268.1685 -76-Cyclic ester 88. A 0.591 g (3.5 mM) of the pyrrolidine enamine of 34 methyl acetoacetate was dissolved in 130 ml dry tetrahydro-furan. The solution was cooled to -60°C and to this solution was added 5.6 ml of 1.6 M n-butyllithium in hexane. This was l e f t at -60°C for 30 min.' and then at room temperature for 1 hr. The solution was cooled hack to -60°C at which time 0.930 g (3.75 mM) of trans-4,5-epoxy-2(E)-decen-1-yl mesylate (67) was added. The solution was l e f t at -60°C for 30 min. and then at 0°C for 12 hrs. The mixture was again cooled to -60°C and a solution of 1.3ml of diisopropylamine and 5.6 ml of 1.6 M n-butyllithium was added. This solution was l e f t at -60UC for 30 min. and then at room temperature for 12 hr. To this solution was added a mixture of 10 ml of water, 10 ml acetic acid and 1 g sodium acetate. This was l e f t to s t i r for 4 hr. and the resulting solution was neutralized with aqueous saturated NaHCO-^ . the ether layer was washed with brine and dried. The organic solvent was removed under reduced pressure. The crude product was purified by TLC (EtOAciCR^Clg = 9:1) and the band at Rf .5 was removed and eluted with ethyl ether yielding 0.130 g (16$) of product 88. IR: 3700 (-0H), 1760 (cyclopentanone), 1730 (COOMe), 910 (C=C). NMR: 5.5-5.7 (m, 2H), 4.0-4.2 (bs, 1H), 3.7 (s, 3H), 2.7-3.6 (m, 2H), 1.8-2.7 (m, 5H), 0.7-1.8 (m, 11H). -77-Mass Spectrum: 268(1.5), 250(5), 237(6), 197(13), 180(8), 167(15), 166(11), 165(100), 163(7), 154(20), 148(13), 141(42), 138(10), 137(55), 136(25), 135(21), 123(26), 116(10), 109(36), 99(33), 95(11), 91(11), 79(17), 71(16). -78-BIBLIOGRAPHY 1. (a) J. P. Mead and A. J. Pluco, "The Unsaturated and Polyunsaturated Fatty Acids in Health & Disease" Thomas, Springfield I l l i n o i s , 1976, Chapter 4. (h) J. C. Colbert, "prostaglandins; Isolation and Synthesis", Noyes Data Corp., New Jersey, 1973. (c) S. M. M. Karim (ed.), "Prostaglandins and Reproduction", University Park Press, Baltimore, 1975. (d) R. H. Kahn and W. E. M. Lands (ed.), "Prostaglandins and Cyclic AMP: Biological Actions and Cl i n i c a l Applications", Academic Press, New York, 1975. (e) K. Nakanishi, T. Goto, S. Ito, S. Natori and S. Nazoe (ed.), "Natural Products Chemistry", Academic Press, New York, 1975. 2. U. 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