Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular sp2–sp3 Suzuki–Miyaura Coupling and Ring Closing Metathesis

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp2–sp3 Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.