Asymmetric synthesis of the aminocyclitol pactamycin, a universal translocation inhibitor

J Am Chem Soc. 2013 Nov 27;135(47):17990-8. doi: 10.1021/ja409944u. Epub 2013 Nov 18.

Abstract

An asymmetric total synthesis of the aminocyclopentitol pactamycin is described. The title compound is delivered in 15 steps from 2,4-pentanedione. Critical to this approach was the exploitation of a complex symmetry-breaking reduction strategy to assemble the C1, C2, and C7 relative stereochemistry within the first four steps of the synthesis. Multiple iterations of this reduction strategy are described, and a thorough analysis of stereochemical outcomes is detailed. In the final case, an asymmetric Mannich reaction was developed to install a protected amine directly at the C2 position. Symmetry-breaking reduction of this material gave way to a remarkable series of stereochemical outcomes leading to the title compound without recourse to nonstrategic downstream manipulations. This synthesis is immediately accommodating to the preparation of structural analogs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibiotics, Antineoplastic / chemical synthesis*
  • Oxidation-Reduction
  • Pactamycin / chemical synthesis*
  • Pentanones / chemistry
  • Protein Synthesis Inhibitors / chemical synthesis*
  • Stereoisomerism

Substances

  • Antibiotics, Antineoplastic
  • Pentanones
  • Protein Synthesis Inhibitors
  • Pactamycin
  • acetylacetone