A novel synthetic method for chiral α,α-dialkylmalonate via phase-transfer catalytic alkylation and its application to total synthesis of (–)-horsfiline

Abstract

Malonates are one of the most fundamental starting material in organic synthesis for C-C bond formation. Notably, chiral α,α-dialkylmalonates have been quite popularly employed in the synthesis of biologically active natural products and pharmaceuticals for the following reasons: the quaternary carbon center of chiral α,α-dialkylmalonates is not racemized, and malonates can be easily modified through chemical conversion of the two esters. In spite of these advantages, chiral malonates can only be obtained by the desymmetrization of (±)-α,α-dialkylmalonates or (±)-α,α-dialkylmalonic acids through enzymatic resolution using the selective hydrolysis of malonates or the selective esterification of malonic acids, respectively. Although the construction of chiral quaternary carbon centers through the asymmetric α-alkylation of carbonyl systems and β-ketoester systems has been extensively studied, to date, the enantioselective direct α-alkylation of malonates has not been reported. Our research team investigated a novel enantioselective synthesis of α,α-dialkylmalonates via direct α-alkylation under phase-transfer catalytic condition. First, our research team attempted the α-benzylation of benzyl tert-butyl α-methylmalonate under typical phase-transfer catalytic conditions. This enantioselective phase-transfer catalytic benzylation was performed using representative chiral phase-transfer catalysts. Of them, (S,S)-3,4,5-trifluorophenyl-NAS bromide surprisingly afforded the α-benzylated product with 70% of enantioselectivity. Five additional alkyl tert-butyl α-mono-methylmalonates were tested in phase-transfer catalytic benzylation and the diphenylmethyl group gave the best enantioselectivity. This substrate was chosen for further investigation of phase-transfer catalytic alkylation with various alkyl halides, and it showed very high chemical yields (up to 99%) and stereoselectivities (up to 97% ee). Additionally, our research team expanded the substrate scope to α-mono-aryl and halo-malonates, and these substrates also showed high enantioselectivities. Notably, the direct, double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without the loss of enantioselectivity. The high enantioselectivities and the mild reaction conditions could make this method very useful for the synthesis of valuable chiral building blocks. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxyindole systems. The spirooxindole structure is frequently found in biologically active oxyindoles. Their unique spiro structures have challenged many synthetic chemists to develop an efficient synthetic method. Among the various spirooxindole alkaloids, (–)-horsfiline was first isolated in 1991 from the leaves of the Horsfieldia superba plant. Our research team attempted to apply our method to the synthesis of the chiral spirooxindole alkaloid (–)-horsfiline. A new and efficient synthetic method for the preparation of (–)-horsfiline via the enantioselective phase-transfer catalytic α-allylation of malonate has been developed. (–)-Horsfiline was synthesized in 9 steps (including an in situ step) from diphenylmethyl tert-butyl malonate, and enantioselective phase-transfer catalytic alkylation was the key step (32% overall yield, >99% ee). The high enantioselectivity and chemical yield make this approach a practical route for the large-scale synthesis of spirooxindole natural products, thus enabling the systematic investigation of their biological activities.