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The coumarin core is present as a characteristic structural motif in a large number of natural products and biologically active molecules. 1 Particularly, many of these naturally occurring 4-hydroxycoumarin and their synthetic analogues are important precursors for the synthesis of natural products and pharmaceuticals. 2 Enantioselective organocatalytic conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. 3 Although a number of reactions of α,β-unsaturated ketones as Michael acceptors have been reported, 3,4 the corresponding β,γ-unsaturated αketo esters have received relatively little attention as Michael acceptors. Recently, several groups have reported the asymmetric Michael addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters catalyzed by Cu(II)-bisoxazoline, N,N'-dioxide-Ni(II) complexes, thiourea catalysts. 5 Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin analogues is still a challenge. In the framework of our research program for the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 6 we recently reported asymmetric Michael addition reaction of active methylenes and methines using chiral catalysts. 7 Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters promoted by binaphthyl-modified thiourea organocatalyst. We initially investigated a reaction system with 4-hydroxycoumarin (1) with (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) in the presence of 10 mol % bifunctional organocatalysts (Fig. 1) at room temperature. As shown in Table 1, Takemoto’s catalyst I and quinine-derived thiourea catalyst II effectively promoted the reaction with moderate enantioselectivities (entry 1-2). While both of binaphthyl-modified (thio)urea catalysts III-IV and squaramide organocatalysts V-VI bearing both central and axial chiralities gave high enantioselectivities (entries 3-6). The best result has been obtained with binaphthyl-modified thiourea catalyst III. We studied the effect of the ester group of (E)-4-phenylbut-3-en2-one 2 using catalyst III in CH2Cl2 (entries 3 and 7). When employing synthetically attractive, methyl ester of (E)-2oxo-4-phenylbut-3-enoate (2b), the corresponding Michael adduct 3b was obtained with high enantioselectivity of 93% ee (entry 7). Among the solvents probed, the best results

Organocatalytic Asymmetric Michael Addition of 4-Hydroxycoumarin to β,γ-Unsaturated α-Keto Esters