General Route to 2,4,5-Trisubstituted Piperidines from Enantiopure β-Amino Esters. Total Synthesis of Pseudodistomin B Triacetate and Pseudodistomin F

Abstract

The Michael addition reaction of enantiopure β-amino esters with methyl acrylate followed by Dieckmann condensation and enol silylation affords the enol ethers 6, which are hydrogenated with catalysis by Raney-Ni at 80 atm and 80 °C to provide 2,4,5-trisubstituted piperidines with high diastereoselectivity. In this case Ni−H attacks the C−C double bond from the direction of the 2-alkyl group to provide the products in which 2,4,5-trisubstrited groups are all cis to each other. While hydrogenation of enol ether 13 without a N-Boc protecting group gives the product 15 in which the 4-hydroxy group and 5-ester moiety are trans to the 2-alkyl group. By using the diastereoselective hydrogenation products 9d and 9e as key intermediates, pseudodistomin B triacetate and pseudodistomin F are synthesized. The key steps for these transformations include Curtius rearrangement and Julia olefination.