An efficient synthesis of cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of pipecolic acid from cyclic enaminones

Abstract

An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH₄. In the last step, the cleavage of N-Cbz group under hydrogenolysis followed by the hydrolysis of the phosphonate or phosphinate functionalities, led to the target cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic acids, respectively.

Keywords: Cis-4-hydroxyphosphopipecolic acids; Cyclic enaminones; Cyclic α-aminophosphinic acids; Cyclic α-aminophosphonic acids; Diastereoselective reduction.