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

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.

SUBMITTER: Rose TE

PROVIDER: S-EPMC6014094 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Rose Tristin E TE Curtin Brice H BH Lawson Kenneth V KV Simon Adam A Houk K N KN Harran Patrick G PG

Chemical science 20160309 7

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 <i>endo</i>-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 comp ...[more]

PMID: 30155060

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