A new strategy for the stereoselective synthesis of unnatural α-amino acids

A new method for the synthesis of racemic non-proteinogenic alpha-amino acids has been developed, which involves (i) hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to electron rich alkenes such as enol ethers, enamines and allylsilanes, (ii) NaCNBH3 reduction of the C=N bond in the oxazines thus generated, the stereochemistry of the products being controlled by epimerisation of the thermodynamically less stable isomer to the more stable one, (iii) protection of the N-H group as N-Boc and (iv) finally, N-O bond cleavage of both free and protected products to give proline or bis-homoserine derivatives, respectively. An example with concomitant reduction of the carboxylate group, resulting in the formation of the respective amino alcohol is reported. Applying this methodology to a homochiral enol ether, the protected parent D-proline was prepared in enantiomerically pure form, whereas the asymmetric synthesis of the respective bishomoserine was unsuccessful. (C) 2004 Elsevier Ltd. All rights reserved.