A Convenient Method for Preparation of α-Imino Carboxylic Acid Derivatives and Application to the Asymmetric Synthesis of Unnatural α-Amino Acid Derivative

Abstract

We describe herein a manganese(IV) oxide-mediated oxidation of N-p-methoxyphenyl (PMP)-protected glycine derivatives for the synthesis of α-imino carboxylic acid derivatives. Using this methodology, utilization of unstable glyoxic acid derivatives was avoided. Furthermore, using this methodology we synthesized novel α-imino carboxylic acid derivatives such as α-imino phenyl ester, perfluoroalkyl etsers, imides, and thioester. The asymmetric Mannich reaction of those novel imine derivatives with 1,3-dicarbonyl compound is also described, and the novel α-imino imide gave improved chemical yield and stereoselectivity compared with those obtained by the use of the conventional α-imino ester-type substrate. Key words α-imino carboxylic acid derivative; heterogeneous oxidant; asymmetric organocatalysis; thiourea; unnatural α-amino acid Unnatural α-amino acids are often seen in varieties of biologically active compounds, 1-4) including pharmaceutics, and have been used as indispensable chiral building blocks for the synthesis of such active compounds. 5,6) Additionally, increasing utilities of unnatural amino acids as a key structural element have also been shown in fields of chemical biology and asymmetric transformation. 7-11) These contexts evoke much interest of synthetic chemists in asymmetric synthesis of the structural unit. 12,13) Enabling easy access to diverse α-amino acids only by changing nucleophiles employed, Mannich-type reaction of α-imino ester has been widely utilized for the asymmetric synthesis. 14-20) Generally, condensation of glyoxa-lates and primary amines affords α-imino esters as the requisite substrate for Mannich-type reaction (Chart 1a); however, the glyoxalates are unstable, and suffer easy hydrolysis or po-lymerization at room temperature. Additionally, high susceptibility of the resulting α-imino ester to silica gel has forced us to directly use the imino esters for the Mannich reaction without purification, thereby leading to difficulty in maintaining the reaction outcome. In this context, cross-dehydrogena-tive coupling (CDC) has been investigated for the synthesis of α-functionalized amino acids 21-23) (Chart 1b). The CDC protocol features oxidative preparation of α-imino ester from glycinates with the use of the oxidants such as 2,3-dichlo-ro-5,6-dicyanobenzoquinone (DDQ), CuOAc, Ru(bpy) 3 Cl 2 / light (or N-oxyl radical), or Cu(I)/molecular oxygen, followed by in situ Mannich reaction. Although the CDC protocol is free from the use of unstable glyoxalates, the in situ Mannich reaction has to be performed in the presence of the employed oxidant due to difficulty in achieving complete separation of the imino ester and oxidant, by which the use of the CDC remains within application to the coupling of oxidant-tolerant functional units. Here, we envisioned that the heterogeneous oxidation system enabling facile removal of insoluble oxidants by filtration allowed the imino ester to be readily obtained and subsequently subjected to Mannich reaction under oxidant-free conditions (Chart 1c). Among a wide variety of oxidants, manganese(IV) oxide is potential choice of heterogeneous oxidant. 24,25) The mild oxidative potential and easily separable nature allow manganese(IV) oxide to be favorably utilized in the oxidative transformation at the near final step of complex molecules such as natural products. Although manganese(IV) oxide-mediated conversion of aliphatic amines to the corresponding imines mainly consisting of N-heteroaromatization of cyclic amines has been reported, 26,27) application to the synthesis of α-imino ester remains to be reported. 28) Being potentially applied to N-protected glycine derivatives possessing replacement of the ester function with other carboxylic acid equivalents such as amide or imide, the envisioned oxidative protocol could expand its substrate scope to barely accessible molecules by addition-dehydration sequence for the imine formation. Such amides or imides could provide an additional site for formation of an intermediary complex (substrate-catalyst -nucleophile) involved in the following asymmetric Man-nich reaction.