Asymmetric Michael Addition of Malonates to Enones Catalyzed by a Primary β-Amino Acid and Its Lithium Salt

Abstract

Highly enantioselective Michael addition of malonates to enones was achieved using a mixed catalyst consisting of a primary β-amino acid, O-TBDPS (S)-β-homoserine, and its lithium salt. Various cyclic and acyclic enones were converted into 1,5-ketoesters in high yields (up to 92%) with high enantioselectivity (up to 97% ee) under mild reaction conditions. Details of synthesis of the catalyst, optimization of the reaction conditions for the Michael addition reaction, and a plausible reaction mechanism are described.

Asymmetric Michael Addition of β‐Ketoesters to Enones Catalyzed by the Lithium Salt of a Primary β‐Amino Acid

“…Because of the presence of the acidic proton in the b-ketoester moiety, Michael adduct 4 aa was obtained as a 1:1 mixture of diastereomers, (2R)-and (2S)-3-oxo-2-[(R)-3-oxocyclohexyl]-3-phenylpropanoic acid ethyl ester, each with the same ee value. As was the case in our previous work of the Michael addition reaction of malonates to enones, [5] a mixed solvent system that consisted of an highly polar aprotic solvent and a haloalkane gave better results in terms of chemical and optical yields than did a simple solvent system ( Table 1, entries [13][14][15][16][17][18][19][20]. By carefully adjusting the solvent systems that consisted of DMSO or DMF with either CH 2 Cl 2 or CHCl 3 , we found that a 3:2 mixture of DMSO/CH 2 Cl 2 was the appropriate mixed solvent for further investigations (Table 1, entry 19).…”

“…Without any additives, this reaction afforded 4 aa in 82 % yield with 85 % ee (Table 2, entry 1). In our previous study of the Michael addition of malonates to enones, the addition of a catalytic amount of acid greatly improved the yield of the Michael adduct, [5] whereas the addition of a base would en-hance the generation of the enolate of 2 a. Although the addition of a catalytic amount of acid or base did not greatly affect the yield and enantioselectivity of 4 aa, the addition of water improved both of these results ( Table 2, entries 2-6).…”

“…We then screened for the catalyst of this Michael addition reaction (Table 3). Because a mixed catalyst that consisted of the lithium salt of the amino acid (i.e., 1 a) and its original amino acid 1 b was more effective than using these catalysts individually in the Michael addition of malonates to enones, [5,10] we examined different ratios of the mixed catalyst 1 a/1 b in the reaction of 2 a to 3 a (Table 3, entries 1-5). Although mixed catalysts 1 a/1 b provided better enantioselectivity than that from using amino acid catalyst 1 b, there was no significant difference between the results that were obtained by using amino acid salt catalyst 1 a and the mixed catalysts 1 a/1 b.…”

“…The employment of a-and g-amino acid salt analogues 1 c and 1 d resulted in lower enantioselectivity than that from using bamino acid salt catalyst 1 a (Table 3, entries 6-8). [5] Thus, bamino acid lithium salt 1 a was chosen as the catalyst to be employed in further investigations. Under the optimized reaction conditions, we investigated the scope of the substrates by using various b-ketoesters in the Michael addition with 3 a ( Table 4).…”

“…We recently reported that the lithium salt of a readily available primary b-amino acid, that is, the lithium salt of O-tert-butyldiphenylsilyl-(S)-b-homoserine (1 a), was an effective catalyst for the asymmetric Michael addition of malonates to enones to synthesize various enantioenriched 5ketoesters (Scheme 1). [5,6] A mechanistic study of this reaction revealed that the lithium carboxylate group and the silyloxy group of catalyst 1 a play important roles to achieve this high enantioselectivity. [7] In our continuous efforts to achieve high enantioselectivity by using catalyst 1 a, we found that synthetically useful 1,5-diketones such as 3-benzoylmethylated cyclic ketones were easily prepared in enantioenriched forms through the asymmetric Michael addition of benzoylacetates to cyclic enones, and a summary of our results have been reported.…”