Prostaglandins three-component coupling synthesis

Suzuki, M. Morita, Y. Koyano, H. Koga, M. Noyori, R. Three-Component Coupling Synthesis of Prostaglandins. A Simplified, General Procedure, Tetrahedron 1990,46,4809. 

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). 

Suzuki, M. et al.. Three-component coupling synthesis of prostaglandins. A simphfied, general procedure, Tetrahedron, 46, 4809, 1990. 

In 1988, Noyori and coworkers disclosed a convergent three-component coupling synthesis of prostaglandin (113) [88], The whole prostaglandin framework was... 

Scheme 9.20 The three-component coupling synthesis of prostaglandins.

Scheme 5. Larock s palladium-promoted, three-component coupling strategy for prostaglandin synthesis.

A short synthesis of prostaglandin derivatives via a three component coupling reaction is reported, in which the enolates are trapped with nitroalkenes. The nitro group is removed via... 

Treating benzaldehyde with diethylzinc in the presence of 2 mol% (—)-DAIB gives (5)-alcohol in 98% ee (Scheme 2-43). When compound 112 is treated in the same manner, compound 113, a chiral building block in the three-component coupling prostaglandin synthesis, is also obtained with high ee (Scheme 2-43). 

Scheme 18.40 Synthesis of the allenic prostaglandin 123 by three-component coupling [121].

Overview The utility of combinatorial chemistry within drug discovery is ultimately linked to the ability to rapidly construct complex molecules on polymer supports. With this in mind, a polymer-supported approach to the prostaglandin core was seen as an important benchmark in the progress of this chemistry. First a two-step liquid-phase version of Noyori s (5) three-component coupling strategy was realized. It allowed the successful synthesis of PGE2 methyl ester la (6) and PGF2 (7) lb (Fig. 1). 

Dragoli, D.R. et al.. Parallel synthesis of prostaglandin El analogues, J. Comb. Chem., 1, 534, 1999. Johnson, C.R. and Braun, M.P., A two-step, three-component synthesis of PGEl utihzation of a-iodoenones in Pd(0)-catalyzed cross-couplings of organoboranes,/. Am. Chem. Soc., 115,11014,1993. 

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