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Total synthesis of chloropeptin II (complestatin) and chloropeptin I

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Overview

related to degree

  • Garfunkle, Joie, Ph.D. in Chemistry, Scripps Research 2004 - 2009
  • Trzupek, John, Ph.D. in Chemistry, Scripps Research 2001 - 2006

authors

  • Garfunkle, Joie
  • Kimball, F. S.
  • Trzupek, John
  • Takizawa, S.
  • Shimamura, H.
  • Tomishima, M.
  • Boger, Dale

publication date

  • November 2009

journal

  • Journal of the American Chemical Society  Journal

abstract

  • The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (-SiEt(3)) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (-Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R:S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.

subject areas

  • Chlorophenols
  • Cyclization
  • Indoles
  • Macrocyclic Compounds
  • Peptides, Cyclic
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Identity

PubMed Central ID

  • PMC2783344

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja907193b

PubMed ID

  • 19839632
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Additional Document Info

start page

  • 16036

end page

  • 16038

volume

  • 131

issue

  • 44

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