Practical Synthesis of a Peptide Deformylase (PDF) Inhibitor

Abstract

A practical chromatography-free synthesis of an N-formylated hydroxylamine peptide deformylase inhibitor LCD320 is described. A diastereoselective Michael reaction of (4S)-3-[2-(cyclobutylmethyl)-1-oxo-2-propenyl]-4-(phenylmethyl)-2-oxazolidinone with O-benzyl hydroxylamine was used to establish the key stereogenic center. We found that traces of residual Li+ from a previous step had a great impact on the diastereoselectivity of this reaction. A very efficient amidation coupling reaction of proline derivative (2S,4R)-4-fluoro-1,2-pyrrolidinedicarboxylic acid 1,1-dimethylethyl ester with weakly nucleophilic 3-pyridazinamine using methanesulfonyl chloride in the presence of 1-methylimidazole in DMF was also developed that proceeded without racemization.