Enantioselective Conjugate Addition of 4-Hydroxycoumarin to Enones Catalyzed by Binaphthyl-Modified Primary Amine Organocatalyst

Abstract

The Michael addition reaction is widely recognized as one of the most general methods for formation of C-C bonds in organic synthesis, and the development of enantioselective catalytic conjugate addition reaction has been subject of intensive research. In addition to the great success catalyzed by metal complexes, the powerful and environmentally friendly organocatalyst-mediated asymmetric conjugate addition reaction has been explored intensively in recent years. Enantioselective organocatalytic conjugate addition reaction of β-ketoesters to α,β-unsaturated carbonyl compounds represents a direct and most appealing approach to chiral 1,5-dicarbonyl compounds that are versatile intermediates in organic synthesis. Particularly, the addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. Further investigation showed that (S)-warfarin had higher anticoagulant activity than the R enantiomer. As a result, achieving the optically pure R or S enantiomer of warfarin would be of great importance. Among the established strategies for the synthesis of chiral warfarin, chiral auxiliary strategy, hydrogenation, and hetero-Diels-Alder reaction have been intensively studied. Recently, several groups reported an enantioselective conjugate addition reaction of 4-hydroxycoumarin to enones, catalyzed by chiral secondary amines, primary amines, and bifunctional primaryamine thioureas. Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin is still a challenge. As part of the research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, we recently reported asymmetric conjugate addition reaction of active methylenes and methines. Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by binaphthyl-modified primary amine organocatalyst. Validation of the feasibility of the proposed Michael addition process started by evaluating a model reaction between 4-hydroxycoumarin (1) with (E)-4-phenylbut-3-en-2-one (2a) in the presence of 20 mol % bifunctional catalysts (Fig. 1) and 40 mol % of TFA as additive at room temperature. As shown in Table 1, 9-amino-9-deoxyepicinchonidine (I) effectively promoted the reaction with high enantioselectivity (entry 1). While chiral primary amine organocatalysts (IIIV) bearing both central and axial chiral elements gave moderate to high enantioselectivity (entries 2-4). The best result has been obtained with binaphthyl-modified 1,2diphenylethylenediamine catalyst (III). We examined our