Diastereoselective synthesis of novel 5-substituted morpholine-3-phosphonic acids: further exploitation of N-acyliminium intermediates

Abstract

The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids is reported. The principal feature of the synthesis is the introduction of a dimethyl phosphonate group into 5-substituted morpholin-3-ones. The procedure is based on the preparation of N-Boc-(S)-5-phenyl- and N-Boc-(S)-5-benzylmorpholin-3-one from l-phenylglycine and l-phenylalanine methyl esters, followed by the formation of the 3-methoxylated compounds and subsequent reaction with trimethyl phosphite in the presence of BF3·OEt2. Diastereoselectivity in the formation of cis-disubstituted products is in agreement with the nucleophilic addition to other methoxylated derivatives.