Improved synthesis of (2S,5S)-5-tert-butylproline

(2S,5S)-N-Boc-5-tert-butylproline (1) was synthesized by an improved procedure featuring the conversion of (2S)-1-tert-butyldimethylsiloxy-2-N-(PhF)amino-5-oxo-6,6-dimethylheptane (16) into its corresponding imino alcohol followed by directed hydride delivery to reduce the imine functionality with a 95:5 diastereoselectivity. Ketone 16 was obtained from methyl 2-N-(PhF)amino-5-oxo-6,6-dimethylheptanoate (13), a previously reported precursor for the synthesis of (2S,5R)-5-tert-butylproline, by reduction to its corresponding diol, selective protection of the primary alcohol and oxidation of the secondary alcohol. This route provided (2S,5S)-N-Boc-5-tert-butylproline (1) of >96% enantiomeric purity suitable for peptide chemistry in 39% overall yield from ketone 13.