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Synthesis and evaluation of a series of C3-substituted CBI analogues of CC-1065 and the duocarmycins

Academic Article
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Overview

related to degree

  • Garbaccio, Robert, Ph.D. in Chemistry, Scripps Research 1994 - 1999

authors

  • Boger, Dale
  • Brunette, S. R.
  • Garbaccio, Robert

publication date

  • July 2001

journal

  • Journal of Organic Chemistry  Journal

abstract

  • The synthesis and evaluation of a series of C3-substituted 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of the CC-1065 and duocarmycin alkylation subunits are detailed, including methyl and the full series of halogens. Introduction of the key substituent was accomplished through directed metalation of the seco-CBI core followed by reaction of the resultant aryllithium with an appropriate electrophile. C3-Bromo and iodo substituents were only effectively installed on the hindered aryllithium intermediate using a novel halogen source, 1-bromo- and 1-iodophenylacetylene, that should prove generally useful beyond the studies we describe. X-ray crystal structures of the series show substantial distortion in the vinylogous amide due to unfavorable steric interactions between the C3-substituent and the N(2)-carbamate. In the halogen series, the N2-C2a bond length and the torsional angle chi(1) smoothly increase with the increasing size of the C3 substituent indicative of decreasing vinylogous amide conjugation through the series (H > F > Cl > Br > I). Unlike N-Boc-CBI, this series of substituted CBI analogues proved remarkably reactive toward solvolysis even at pH 7, where the reaction is uncatalyzed and the reactivity order (I > Br > Cl > F > H) follows a trend consistent with the extent of vinylogous amide conjugation and stabilization. The implications of these observations on the source of catalysis for the DNA alkylation reaction of the natural products are discussed.

subject areas

  • Alkylation
  • Animals
  • Antibiotics, Antineoplastic
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Humans
  • Indoles
  • Leucomycins
  • Leukemia L1210
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Pyrroles
  • Pyrrolidinones
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Spectrophotometry, Ultraviolet
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Identity

International Standard Serial Number (ISSN)

  • 0022-3263

Digital Object Identifier (DOI)

  • 10.1021/jo010309g

PubMed ID

  • 11463270
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Additional Document Info

start page

  • 5163

end page

  • 5173

volume

  • 66

issue

  • 15

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