Stereodivergent Synthesis of the Four Stereoisomers of Diethyl 4-Hydroxyphosphopipecolate from Ethyl (R)-4-Cyano-3-hydroxybutanoate

Abstract

The stereodivergent synthesis of all four stereoisomers of diethyl 4-hydroxyphosphopipecolate from the commercial chiral building block ethyl (R)-4-cyano-3-hydroxybutanoate is described. Key steps in the synthesis of the target compounds involve the triethyl phosphite nucleophilic addition to chiral N-acyliminium ion easily obtained from (R)-4-hydroxypiperidin-2-one, giving diethyl (2R,4R)- and (2S,4R)-4-hydroxyphosphopipecolate diastereoisomers, easily separable by column chromatography followed by the 4-hydroxy epimerization through a sequential oxidation and highly diastereoselective reduction strategy, affording the diethyl (2R,4S)- and (2S,4S)-4-hydroxyphosphopipecolate, respectively, consistent with our recently found results. All synthesized compounds were thoroughly characterized.

Key words

stereodivergent synthesis - N-acyliminium ion - heterocyclic α-aminophosphonates - 4-hydroxyphosphopipecolates - diastereoselective reduction

Publication History

Received: 03 May 2024

Accepted after revision: 17 May 2024

Accepted Manuscript online:
17 May 2024

Article published online:
06 June 2024

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