Cyclic beta-amino acid derivatives: synthesis via lithium amide promoted tandem asymmetric conjugate addition-cyclisation reactions

Org Biomol Chem. 2005 Apr 7;3(7):1284-301. doi: 10.1039/b500223k. Epub 2005 Mar 2.

Abstract

The product distribution upon conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to dimethyl-(E,E)-nona-2,7-dienedioate can be controlled to give either the cyclic 1,2-anti-1,6-anti-beta-amino ester (derived from conjugate addition and intramolecular enolate cyclisation) or the acyclic bis-beta-amino ester derivative (derived from double conjugate addition) in high de. The introduction of a protected nitrogen functionality into the diester skeleton facilitates, after conjugate addition and intramolecular enolate cyclisation, the asymmetric construction of piperidines in high de; variation in the N-protecting group indicates that the highest stereoselectivity is observed with alpha-branched N-substituents. Tandem conjugate addition-aldol reactions can also be achieved stereoselectively, with lithium amide conjugate addition to epsilon- and zeta-oxo-alpha,beta-unsaturated esters giving the corresponding five and six membered cyclic beta-amino esters in high de. N-deprotection by hydrogenolysis of the products arising from these reactions furnishes a range of polyfunctionalised transpentacin and transhexacin derivatives in high de and ee.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Amino Acids, Cyclic / chemical synthesis*
  • Amino Acids, Cyclic / chemistry
  • Cyclization
  • Lithium / chemistry*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Optical Rotation
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Spectrophotometry, Infrared

Substances

  • Amides
  • Amino Acids, Cyclic
  • Piperidines
  • Lithium