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

Enantionterically pure (2R,4S)- and (2 R,4R)-2-[(S)-1, 2-dibenzy] oxyethyl]-4-[2-(diphenylmethoxy)ethyl]-1-[(S)-1-phenylethyl]piperidines eis-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 C-4 of the piperidine ring. These transformations led to 1, 2,4-trisubstituted piperidines with two new stereogenic centres with excellent stereo se lectivity. (c) 2007 Elsevier Ltd. All rights reserved.