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On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan.

  • Author(s): Rose, Tristin E
  • Curtin, Brice H
  • Lawson, Kenneth V
  • Simon, Adam
  • Houk, KN
  • Harran, Patrick G
  • et al.
Abstract

A Friedel-Crafts alkylation is described that efficiently transforms tryptophan-containing peptides into macrocycles of varying ring connectivity. Factors are surveyed that influence the distribution of regioisomers, with a focus on indole C3-alkylations leading to bridged endo-pyrroloindolines. We probe the stability and stereochemistry of these pyrroloindolines, study their rearrangement to C2-linked indolic macrocycles, and demonstrate a scalable, stereoselective synthesis of this compound class. Placing the macrocyclization in sequence with further template-initiated annulation leads to extraordinary polycyclic products and further demonstrates the potential for this chemistry to drive novel peptidomimetic lead discovery programs.

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