Efficient and Selective Formation of Macrocyclic Disubstituted Z Alkenes by Ring-Closing Metathesis (RCM) Reactions Catalyzed by Mo- or W-Based Monoaryloxide Pyrrolide (MAP) Complexes: Applications to Total Syntheses of Epilachnene, Yuzu Lactone, Ambrettolide, Epothilone C, and Nakadomarin A

[摘要]：The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.27.5mol% of a Mo- or W-based monoaryloxide pyrrolide (MAP) complex at 22 degrees C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73% Z) epilachnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97% Z), and nakadomarin A (15-membered ring: up to 97% Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule.

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