Divergent and programmable skeletal remodeling of complex macrocycles with a small method set

• 成果类型: Article
• 署名作者: Nikbakht, Ali; Li, Xinghan; Wan, Jing; Qin, Can; Hoveyda, Amir H.
• 署名单位: Universites de Strasbourg Etablissements Associes; Centre National de la Recherche Scientifique (CNRS); Universite de Strasbourg; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Boston College
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aee3540
• 发表日期: 2026-05-21
• 页码: eaee3540
• 关键词: RING-CLOSING METATHESIS; 1ST TOTAL-SYNTHESIS; stereoselective-synthesis; OLEFIN METATHESIS; cross-metathesis; natural-products; PHORBOXAZOLE-A; EPOTHILONE; DISCOVERY; efficient

摘要

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.