Efficient stereoselective synthesis of enantiopure cis- and trans-1,2,4-trisubstituted piperidines

Enantiomerically pure (2R,4S)- and (2R,4R)-2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenylmethoxy)ethyl]-1-[(S)-1-phenylethyl]piperidines cis-1 and trans-1 have been synthesised from N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine in six steps in 31% and 18% overall yields, respectively. The efficiency of the synthetic strategy developed for the synthesis of these compounds relies on: (a) the totally diastereoselective tandem Mannich–Michael reaction between Danishefsky’s diene and the starting glyceraldimine, (b) the high yielding Wadsworth–Emmons reaction of the 4-piperidone intermediate and (c) the diastereodivergent reduction of the exocyclic C–C double bond at C₄ of the piperidine ring. These transformations led to 1,2,4-trisubstituted piperidines with two new stereogenic centres with excellent stereoselectivity.