Asymmetric synthesis of prostaglandins

The method has been used for a short asymmetric synthesis of (-)-prostaglandin Ej methyl ester (PGEj) (2-58) starting from 2-47, 2-55 and 2-56 (Scheme 2.12) [17]. The domino reaction provided 2-57 in 60 % yield as mixture of two diastereomers in reasonable stereoselectivity (trans-threo trans-erythro ratio 83 17). Further transformations led to 2-58 in an overall yield of 7% and 94% ee in seven steps. 

Compound 78, or prostanoic acid, the simplest prostaglandin compound, contains an a-side chain and also an co-side chain. Asymmetric synthesis of prostaglandins must involve the assembly of these subunits, as well as the introduction of other functionalities. 

Asymmetric Synthesis of Prostaglandins with many Chiral Centres... 

Without question, the most significant advance in the use of sulfur-centered nucleophiles was made by Shibasaki, who discovered that 10 mol% of a novel gallium-lithium-bis(binaphthoxide) complex 5 could catalyze the addition of tert-butylthiol to various cyclic and acyclic meso-epoxides with excellent enantioselectiv-ities and in good yields (Scheme 7.11) [21], This work builds on Shibasaki s broader studies of heterobimetallic complexes, in which dual activation of both the electrophile and the nucleophile is invoked [22]. This method has been applied to an efficient asymmetric synthesis of the prostaglandin core through an oxidation/ elimination sequence (Scheme 7.12). 

The first catalytic 1,4-addition of diethylzinc to 2-cyclopentenone with over 90% ee was described by Pfaltz and Escher, who used phosphite 54 with biaryl groups at the 3,3 -positions of the BINOL backbone.46 Chan and co-workers achieved high enantioselectivity in the same reaction (up to 94% ee) by using chiral copper diphosphite catalyst (R,R,R)-41 48,48a 48d Hoveyda and co-workers used ligand 46 to realize excellent enantiocontrol (97% ee) in the 1,4-additions of 2-cyclopentenones,52 which may be used in the practical asymmetric synthesis of some substituted cyclopentanes (including prostaglandins). 

Compound 168 is a key intermediate for the synthesis of prostaglandin or prostacyclin compounds. Scheme 5-50 shows its preparation via a retro Diels-Alder reaction and subsequent treatment. Using enzyme-catalyzed acetylation, Liu et al.80 succeeded in the asymmetric synthesis of enantiomerically pure (+)/ (—)-156 and (—)-168 from the meso-Aio 164. When treated with vinyl acetate, meso-diol 164 can be selectively acetylated to give (+)-165 in the presence of Candida cyclindracea lipase (CCL). The yield for the reaction is 81%, and the enantiomeric excess of the product is 98.3%. 

The synthesis of prostaglandins (PGs) is another good example of a preparation in which asymmetric organic reactions play an important role. 

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

The Michael addition of (+)-(5 )-51 to the aj3-unsaturated ketone 217 constitutes a key step in the asymmetric synthesis of the optically active cyclopentanone 318, which is precursor of the 11-deoxy-prostaglandins (321). 

Scheme 2.1.4.31 Asymmetric synthesis of a prostaglandin building block.

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

FIG. 19. Asymmetric homogeneous hydrogenation of a ketone in the synthesis of prostaglandin Ej. ACMP = o-anisylcyclohexylmethylphosphine. 

An asymmetric, thermal [2 + 2] cycloaddition of ketemmmium salts derived from rrm -2.5-dimethylpyirolidme has been employed in the synthesis of prostaglandins. An intramolecular [2 + 2] cycloaddition affords a cis-fused bicyclic system which is then further transformed into a common prostaglandin intermediate (eq 12). 

The asymmetric total synthesis of prostaglandin Ei utilizing a two-component coupling process was achieved in the laboratory of B.W. Spur. The hydroxylated side-chain of the target was prepared via the catalytic asymmetric reduction of a y-iodo vinyl ketone with catecholborane in the presence of Corey s CBS catalyst. The reduction proceeded in 95% yield and >96% ee. The best results were obtained at low temperature and with the use of the B-n-butyl catalyst. The 6-methyl catalyst afforded lower enantiomeric excess and at higher temperatures the ee dropped due to competing non-catalyzed reduction. 

Nakazawa, M., Sakamoto, Y., Takahashi, T., Tomooka, K., Ishikawa, K., Nakai, T. A new approach to asymmetric synthesis of Stork s prostaglandin intermediate. Tetrahedron Lett. 1993, 34, 5923-5926. 

Since R-48 is also an important versatile synthon for prostaglandin synthesis, there has been interest in devising asymmetric methods for its preparation. Japanese workers 7 subjected a 1 1 mixture of cis and trans 44 to esterases from baker s yeast and were able to obtain the optically active (R,R)-45, (R,R)-46 and (S)-predominant 47. Thus a simultaneous kinetic resolution of the dlacetate (44) and asymmetric synthesis of the monoacetate (46) were effected by this hydrolysis. These were converted to prostaglandin synthons.6 ... 

Allyl epoxides are produced by the acclaimed Sharpless asymmetric epoxidation reaction [75], and are important intermediates and products. For example, an allyl epoxide is a vital part of the structure of amphidinolides, a series of unique macrolides isolated from dinoflagellates (Amphidinium sp.). Amphidinolide H (AmpH) is a potent cytotoxic 26-membered macrolide with potent cytotoxicity for several carcinoma cell lines [76]. An allyl epoxide is involved in the total synthesis of prostaglandin A2 with a cuprate reagent [77]. Allyl epoxides derived from Sharpless chemistry are a practical method for construction of polypropionate structures by Lewis acid-induced rearrangement [78,79]. Other allyl epoxides such as l,2-epoxy-3-methyl-3-butanol are useful organic intermediates for the production of a-hydroxyketones, which are used for the synthesis of various natural... 

Conjugate addition of the complete allylic alcohol fragment is possible with the mixed cuprate reagents 33 prepared by asymmetric reduction (chapter 26) of acetylenic ketones 29 to give the alcohols 30, protection as a silyl ether 31 and hydroboration-iodination. Lithiation and reaction with hexynyl copper (I) gives the mixed cuprate 33 from which the less stable anion is transferred selectively to an enone.3 This approach has been widely used in the synthesis of prostaglandins. 

Kinetic resolution on diastereoisomeric mixtures Comparison between enzymatic and classical resolution Asymmetric Synthesis of a Prostaglandin with many Chiral Centres... 

The first synthetically useful application reported used ( + )-8-phenylmenthyl acrylate (+)-(lf) as chiral dienophile for the asymmetric synthesis of the prostaglandin intermediate 129. 

Highly stereoselective arylation reactions were reported, as shown in Equation 5.46. With an optically active diamine ligand, a modest asymmetric induction was observed (Equation 5.47). An asymmetric synthesis of a synthetic prostaglandin AH 13 205 was accomplished using the diastereoselective cobalt-catalyzed cycliza-tion/arylation sequence as key step [55]. 

We illustrate an alternative strategy, namely asymmetric induction, by E. J. Corey s preparation of a key intermediate in his synthesis of prostaglandins. In asymmetric induction, the reactive functional group of an achiral molecule is placed in a chiral environment by reacting it with a chiral auxiliary. The strategy is that the chiral auxiliary then exerts control over the stereoselectivity of the desired reaction. The chiral auxiliary chosen by Corey was 8-phenylmenthol. This molecule has three chiral centers and can exist as a mixture of 2 = 8 possible stereoisomers. It was prepared in enantiomerically pure form from naturally occurring, enantiomeri-cally pure menthol. 

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