Prostaglandin asymmetric synthesis

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 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. 

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%. 

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. 

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.

Despite the excellent results obtained from 3, only one additional paper has been reported concerning its use in asymmetric synthesis. It describes the reaction of (R)-3 with 5-benzyloxymethyl-l,3-cyclopentadiene to afford almost exclusively one adduct, which was transformed into the sulfoxide (Ss)-6 by reaction with NaOH [21]. Bicyclic compound 6 was converted into enantiomerically pure norbornenone 7, a key intermediate in Corey s syntheses of prostaglandins (Scheme 4). 

The products of this highly efficient asymmetric synthesis are important intermediates in natural product chemistry, e.g., the total synthesis of steroids and prostaglandins. 

An extremely efficient synthesis of lactone [41] is provided (33,34) by asymmetric synthesis (Fig. 10). Alkylation of the anion of cyclopentadiene with methyl bromoacetate gave the unstable diene [59], Immediate asymmetric hydroboiation with (+)-di-3-pinanylborane gave, after oxidative workup, the hydroxy ester [60] in about 95% e.e. Lactonization involved conversion to mesylate [61] and saponification. The crystalline lactone [41] was readily brought to an enantiomerically pure state. This route is apparently the basis for commercial quantities of compound [41], the Corey lactone, and other prostaglandin intermediates offered by the Hungarian firm Chinoin. 

The preparation of a chiral pharmaceutical in enantiomerically homogeneous form is dearly a viable proposition. The tools—resolution, asymmetric synthesis, and the chiral carbon pool—are available. As exemplified by the prostaglandins, the manner in which these tools are used is limited only by the imagination and inventiveness of the chemist. 

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 ... 

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

Asymmetric Synthesis of Prostaglandins 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]. 

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