Synthesis of enantiopure 7-[3-azidopyl]indolizidin-2-one amino acid. A constrained mimic of the peptide backbone geometry and heteroatomic side-chain functionality of the ala-lys dipeptide

J Org Chem. 2001 Feb 23;66(4):1181-5. doi: 10.1021/jo001252l.

Abstract

Enantiopure N-(BOC)amino-7-[3-azidopropyl]indolizidin-2-one acid 1 has been synthesized by displacement of the methanesulfonate of its 7-hydroxypropyl counterpart 11 with sodium azide and subsequent ester hydrolysis. N-(BOC)Amino-7-[3-hydroxypropyl]indolizidin-2-one ester 11 was obtained from a sequence commencing with the alkylation of (2S,8S)-di-tert-butyl 5-oxo-2,8-di-[N-(PhF)amino]azelate 5 (PhF = 9-(9-phenylfluorenyl)). Stereoselective allylation of 5, regioselective olefin hydroboration, selective primary alcohol protection as a silyl ether, and oxidation of the secondary alcohol gave (2S,4R,8S)-di-tert-butyl 4-[3-tert-butyldimethylsiloxypropyl]-5-oxo-2,8-di-[N-(PhF)amino]azelate 9 as a pure diastereomer in 33% overall yield. Linear ketone 9 was then converted into the indolizidinone heterocycle by a route featuring reductive amination, lactam cyclization, and isolation by way of a silyl ether which provided the (6S,7R)-isomer of 11.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Dipeptides / chemistry*
  • Indolizines / chemistry*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry / methods
  • Molecular Mimicry*
  • Molecular Structure
  • Stereoisomerism

Substances

  • Amino Acids
  • Dipeptides
  • Indolizines