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

Abstract

There are a large number of chemical transformations in which alkenes act as the reactants and/or products of the reaction. Perhaps the most widely utilized approach to synthesis of unsaturated large rings is catalytic ring-closing metathesis (RCM), but this reaction often proceeds with little control over alkene. Amir Hoveyda and colleagues have developed a method for highly efficient and stereoselective synthesis of macrocyclic alkenes by catalytic RCM. It involves catalytic Z-isomer-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and allylic amides, used previously only in E-isomer-selective processes. The effectiveness of the method is demonstrated by the stereoselective synthesis of anticancer agents epothilone C and nakadomarin A. 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 rings1,2; however, cyclizations often proceed without control of alkene stereochemistry2. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations2. 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 RCM7,8,9,10,11,12. 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.