Catalytic Enantioselective Electrophilic Aminations of Acyclic α-Alkyl β-Carbonyl Nucleophiles

Abstract

Highly enantioselective aminations of acyclic α-alkyl β-keto thioesters and trifluoroethyl α-methyl α-cyanoacetate (12) with as low as 0.05 mol% of a bifunctional cinchona alkaloid catalyst were established. This ability to afford high enantioselectivity for the amination of α-alkyl β-carbonyl compounds renders the 6′-OH cinchona alkaloid-catalyzed amination applicable for the enantio­selective synthesis of acyclic chiral compounds bearing N-substituted quaternary stereocenters. The synthetic application of this reaction is illustrated in a concise asymmetric synthesis of α-methylserine, a key intermediate previously utilized in the total synthesis of a small molecule immunomodulator, conagenin.

bifunctional catalysis - asymmetric organocatalysis - cinchona alkaloids - chiral amines - quaternary stereocenters

References and Notes

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<A NAME="RY01609ST-11">11</A>

Experimental procedure for the asymmetric amination of 3 (or 10) with 4a catalyzed by QD-1: To a solution of 3 or 10 (0.22 mmol, 1.1 equiv) and QD-1 in toluene (2.0 mL) at the indicated temperature under stirring, a solution of 4a in toluene (0.50 M, 0.40 mL, 0.20 mmol) was added dropwise in 5-10 min. The resulting reaction mixture was stirred until the color of the solution turned from yellow to colorless (or at the indicated time), and the amination product was isolated by flash chromatography.

<A NAME="RY01609ST-12">12</A>

Experimental procedure for the asymmetric amination of 3 (or 10) with 4a catalyzed by Q-1: A suspension of Q-1 in toluene (2.0 mL) was subjected to ultrasound until no chunky solid was visible (˜15 min). The resulting mixture was heated at 110 ˚C until a clear solution was formed (10-15 min). While it was still hot, the solution was allowed to pass a cotton plug to remove any trace amount of insoluble residue and then cooled to room temperature. Then 3 (or 10) (0.22 mmol, 1.1 equiv) was added. This mixture was stirred at the indicated temperature and a solution of 4a (0.50 M, 0.40 mL, 0.20 mmol) in toluene was added dropwise in 5-10 min. The stirring was continued until the color of the solution turned from yellow to colorless (or at the indicated time) and the amination product was isolated by flash chromatography separation.