General route to 2,4,5-trisubstituted piperidines from enantiopure beta-amino esters. Total synthesis of pseudodistomin B triacetate and pseudodistomin F.
The Michael addition reaction of enantiopure beta-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 degrees 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.
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State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China. madw@pub.sioc.ac.cn
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D000470:Alkaloids / Q000138:chemical synthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D010880:Piperidines / Q000138:chemical synthesis*; D013237:Stereoisomerism; D014561:Urochordata / Q000737:chemistry*
D000470:Alkaloids; D000970:Antineoplastic Agents; D010880:Piperidines; C415192:pseudodistomin B triacetate; C109387:pseudodistomin F