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

Abstract

Many biologically active macrocycles contain a C–C double bond through which various other derivatives are prepared; the stereochemical identity of the alkene or the resulting moieties can be critical to the beneficial properties of such molecules. Catalytic ring-closing metathesis (RCM) is a widely employed method for the synthesis of large unsaturated rings;1,2 however, cyclizations often proceed without control of alkene stereochemistry.2 Such shortcoming is particularly costly with complex molecules when cyclization is performed after a long sequence of transformations.2 Here, we outline a reliable, practical and general approach for efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% Z selectivity due to control induced by a tungsten-based alkylidene. Utility is demonstrated by stereoselective preparation of anti-cancer epothilone C [Ref. 3–5] and anti-microbial nakadomarin A [Ref. 6], previously reported syntheses of which have been marred by late-stage non-selective RCM.7–15 The tungsten alkylidene can be manipulated in air, promoting reactions carried out in a fume hood to deliver products in useful yields and high Z selectivity. 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 concentration (0.1 molar).