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Synthesis

Asymmetric third ring is a charm for indole-annulated compounds

Chemists develop an enantioselective synthesis for constructing medium-sized rings on indole’s two-ring framework

by Stephen K. Ritter
May 9, 2016 | A version of this story appeared in Volume 94, Issue 19

Fused-ring systems are special structural features of many natural product and synthetic compounds, contributing to the bioactivity that makes them useful as pharmaceuticals and agrochemicals. Chemists have numerous methods for generating small rings with six or fewer members, such as Diels-Alder and other cycloaddition reactions. They also have ways of constructing large rings with 10 or more members, including macrolactonization and ring-closing metathesis. However, the direct synthesis of medium-sized rings, especially enantioselectively, has remained a challenge because of steric constraints. Lin Huang, Li-Xin Dai, and Shu-Li You of Shanghai Institute of Organic Chemistry have now discovered a pathway around this roadblock by developing an intramolecular cascade reaction for building asymmetric seven- to nine-membered rings onto indole frameworks (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b02678). As an example, the team found that a chiral iridium catalyst can drive dearomatization of an allylic carboline to form a bridged intermediate. A subsequent ring-opening retro-Mannich step followed by hydrolysis results in expanding the size of the piperidine ring (shown). The researchers anticipate that their method will facilitate synthesis of new indole-annulated compounds to join those already among the ranks of commercial products.

Reaction scheme shows selective synthesis of indole derivative with seven- to nine-membered pendant ring.

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