A concise, stereoselective and scalable synthesis of optically pure (3R,4R)-1-benzyl- and (3R,4R)-1-Boc-3-methyl-4-aminopiperidines

An efficient, scalable and stereoselective synthesis of optically pure (3R,4R)-1-benzyl- and (3R,4R)-1-Boc-3-methyl-4-aminopiperidines has been developed starting from commercially available N-benzyl-3-methyl-4-piperidone. The synthesis employed chiral resolution of N-benzyl-3-methyl-4-piperidone, cis-selective reduction of a keto group, and subsequent Mitsunobu inversion of the resulting hydroxy group to install an amine with the desired trans-stereochemistry as the key steps. The method described herein demonstrated a competent route to the title compounds in a cost-effective, and scalable manner. [Display omitted] •We have reported an efficient, scalable and stereoselective synthesis of optically pure (3R,4R)-1-benzyl- and (3R,4R)-1-Boc-3-methyl-4-aminopiperidines starting from commercially available N-benzyl-3-methyl-4-piperidone.•The synthesis employed substrate-induced diastereoselective reduction of a keto group on chirally resolved (R)-3-methyl-4-piperidone followed by Mitsunobu inversion of the hydroxy group to install amine group with the desired trans-stereochemistry on adjacent carbon atoms.•The method described herein is operationally simple and demonstrated on 50-100 g scale at each step with good to excellent isolated yields.•We strongly believe the contribution of these studies warrants its publication in “Tetrahedron” as it offers convenient synthesis of pharmaceutically important “trans-3-methyl-4-aminopiperidine” core that are required in larger amounts to help address the needs of society, such as in drug discovery.