Catalytic enantioselective synthesis of prostaglandin E(1) methyl ester using a tandem 1,4-addition-aldol reaction to a cyclopenten-3,5-dione monoacetal.

Abstract

Conjugate addition reactions are among the most important carbon-carbon bond formation reactions in organic synthesis, and considerable progress has been made in the development of asymmetric Michael additions and 1,4-additions of organometallic reagents. Recently, highly enantioselective copper-catalyzed conjugate addition reactions of diorganozinc reagents to enones have been reported. Among the various chiral ligands introduced for this purpose phosphoramidite 4, developed in our laboratories, shows nearly complete stereocontrol in the reaction of (functionalized) dialkylzinc (R2Zn) reagents with six-, sevenand eightmembered cycloalkenones. On the basis of this methodology, catalytic routes are now available to enantiomerically pure products, embedding cyclohexane and larger rings in their structure. In contrast, the catalytic enantioselective 1,4-addition to 2-cyclopentenone is a major challenge, particularly because chiral cyclopentane structures are ubiquitous in natural products. Employing TADDOL-based phosphoramidite ligands we obtained up to 62% ee when the Et2Zn addition to 2-cyclopentenone was run in the presence of molecular sieves. Furthermore, with using chiral bidentate phosphoramidite ligands, the enantioselectivity improved to 83%. Chan reached 89% ee using a diphosphite ligand, whereas Pfaltz enhanced the enantioselectivity in this addition to 94%. Recently Hoveyda reported ee values up to 97% using a chiral peptide-based phosphine ligand in the 1,4addition of diethylzinc to 2-cyclopentenone. Although these catalysts give excellent enantioselectivities, the isolated yields for the 3-substituted cyclopentanones are often moderate. Possible reasons are the lower reactivity of 2-cyclopentenone in comparison with other cyclic enones, the side-reactions of the resulting zinc enolate with the starting material and the high volatility of the 1,4-addition product. Performing the reaction in the presence of an aldehyde increases the yield considerably.