ArticleScience (New York, N.Y.)2026
Divergent and programmable skeletal remodeling of complex macrocycles with a small method set.
Article in Science (New York, N.Y.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The bioactivity of complex organic macrocycles can vary unpredictably with their three-dimensional structural contours. Here, we present a streamlined, programmable, and systematic strategy for skeletal remodeling of large organic rings. The central diversification platform (hub) is a readily available macrocyclic olefin or a diene. Six transformations, all but one catalytic, are needed: macrocyclic ring-opening/cross-metathesis for cleaving a ring to generate a diene, cross-metathesis and allylic substitution for one-unit chain homologation, alkene isomerization and ethenolysis for one-unit chain clipping, and macrocyclic ring-closing metathesis for reforming a ring. The methods are practical, mild, efficient, and amenable to iteration. Fourteen analogs of anticancer agent epothilone C (the primary model macrocycle) were accessed through a divergent network of reactions that correspond to an average of three steps per analog from the diene hub.
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