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

Chemical Science
Tristin E RosePatrick G Harran

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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Citations

Feb 14, 2019·Natural Product Reports·Kuan Zheng, Ran Hong
Sep 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ishika SahaPatrick G Harran
Jan 25, 2018·Chemistry : a European Journal·Sherif J Kaldas, Andrei K Yudin
Jun 4, 2019·Chemical Reviews·Ivan V SmolyarValentine G Nenajdenko

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Methods Mentioned

BETA
NMR
amidation

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