Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.

Journal article

Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

Authors: Yu, M; Wang, C; Kyle, A; Jakubec, P; Dixon, D

• Publication status: Published
• Journal: Nature
• Volume: 479
• Issue: 7371
• Pages: 88-93
• Publication date: 2011-11-01
• DOI: 10.1038/nature10563
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: Biological Products; Stereoisomerism; Alkanes; Alkenes; Chemistry Techniques, Synthetic; Cyclization; Epothilones; Catalysis; Carbolines