Synthetic Studies on Substituted Citrate Natural Products based on the Cinchona Alkaloid-Catalyzed Asymmetric Baylis-Hillman reaction

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We have previously developed a highly enantioselective asymmetric BaylisHillman reaction which allows us to construct a wide variety of (α-methylene-β-hydroxy)esters with highly optical purity (>90% ee). The reaction relies upon the combinatorial use of two important reagents, 1,1,1,3,3,3-hexafluoroisopropyl acrylate as an activated alkene and (3R, 8K,,9S)-10,11-dihydro-3,9-epoxy-6'-hydroxy-cinchonane as a chiral, nucleophilic amine catalyst. In this research program, we have established the synthetic utility of the reaction system in a practical sense, by demonstrating its applicability to the crucial step in total syntheses of biologically active natural products, including a potent immunosuppressant amino acid, (-)-mycestericin E, and a novel proteasome inhibitor epopromycin B. The reaction was found to be applicable to α-keto ester-type substrates to furnish the corresponding α-methylene-β-alkoxycatbonyl-β-hydroxy)esters in good chemical yield with modest enantioselectivity. These reaction products should serve as useful synthons for the preparation of a series of substituted citratetype compounds.