NADH model mediated reduction of C=N substrates: enantioselective synthesis of D- and L-phenylglycinates

Hydride transfer from N,N, 1,2,4-pentamethyl-1,4-dihydronicotinamide, 1, to methyl 2-methoxycarbonylimino-phenylacetate, 3, was accomplished in an optical yield 2 95 %. Efficient chirality transfer from reduced NADH models to prochiral carbonyl substrates has i.a. been achieved with pentamethylated 1,4-dihydronicotinamide 1. ’ In comparison with 1,4-dihydroquinoline analogues,’ NADH model 1 is extremely reactive but equally stereoselective. In contrast to most other NADH models used, its oxidized form 2 is provided with stable axial chirality. The high asymmetric induction observed in the reduction of C=O substrates was accounted for by the adoption of a short-lived ternary complex, in which the amide carbonyl dipole and the transferred hydrogen adopt a ryn-out-of-plane orientation as predicted previously by quantumchemical calculations.3 Chelation by Mg’+ may rationalize the appropriate positioning of the substrate in the ternary complex. lS4 With the aim of broadening the scope of the hydride transfer reactions with NADH model 1 and to further test the concept of syn-out-of-plane orientation, efforts were undertaken to achieve enantioselective reduction of C=N substrates. Herein we describe the NADH model l-mediated enantioselective conversion of methyl 2-methoxycarbonylimino-phenylacetate, 3, into methyl N-carbomethoxy-phenylglycinate, 4, and a cyclic process allowing the conversion of racemic phenylglycine derivatives into an enantiomer of choice. Hitherto, the reduction of benzyliminoacetophenone with a 4-methyl-3-hydroxymethyl-1,4dihydropyridine is the only example of an NADH model mediated enantioselective hydride transfer to C =N substrates.’ When compared with ketones or aldehydes, the intrinsic chemical reactivity of imines towards a nucleophilic species will be significantly lower but that of iminium derivatives much higher. Taking into account the requirement of activation of carbonyl substrates either by an electron-withdrawing group (e.g., a geminal CO,Me) or by a coordinating group at appropiate distance (e.g., an o-OH) for efficient, stereoselective hydride uptake, attention was focused initially on iminium substrates. However, all efforts to induce hydride transfer from NADH model 1 to the iminium compounds 5 and 6 failed, but instead addition of the enamine moiety of 1 to the iminium substrates occurred. This behaviour reflects the inability of the