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Asymmetric synthesis of a CBI-based cyclic N-acyl O-amino phenol duocarmycin prodrug

Academic Article
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Overview

authors

  • Uematsu, M.
  • Boger, Dale

publication date

  • October 2014

journal

  • Journal of Organic Chemistry  Journal

abstract

  • A short, asymmetric synthesis of a cyclic N-acyl O-amino phenol duocarmycin prodrug subject to reductive activation based on the simplified 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) DNA alkylation subunit is described. A key element of the approach entailed treatment of iodo-epoxide 7, prepared by N-alkylation of 6 with (S)-glycidal 3-nosylate, with EtMgBr at room temperature to directly provide the optically pure alcohol 8 in 78% yield (99% ee) derived from an effective metal-halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. Following O-debenzylation, introduction of a protected N-methylhydroxamic acid, direct trannannular spirocyclization, and subsequent stereoelectronically controlled acid-catalyzed cleavage of the resulting cyclopropane (HCl), further improvements in a unique intramolecular cyclization with N-O bond formation originally introduced for formation of the reductively labile prodrug functionality are detailed.

subject areas

  • Alkylation
  • Cyclization
  • Cyclopropanes
  • Indoles
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Phenol
  • Prodrugs
  • Pyrrolidinones
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Identity

PubMed Central ID

  • PMC4201355

International Standard Serial Number (ISSN)

  • 0022-3263

Digital Object Identifier (DOI)

  • 10.1021/jo501839x

PubMed ID

  • 25247380
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Additional Document Info

start page

  • 9699

end page

  • 9703

volume

  • 79

issue

  • 20

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