title: Synthesis of bis-macrocyclic HCV protease inhibitor MK-6325 via intramolecular sp²-sp³ Suzuki-Miyaura coupling and ring closing metathesis.
abstract: 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 sp(2)-sp(3) 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.
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Scott
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Cheng-yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Michel
authors.initials: M
authors.lastname: Journet
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Belyk
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jaume
authors.initials: J
authors.lastname: Balsells
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Birgit
authors.initials: B
authors.lastname: Kosjek
authors.forename: Carl A
authors.initials: CA
authors.lastname: Baxter
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Stewart
authors.forename: Christopher
authors.initials: C
authors.lastname: Wise
authors.forename: Mahbub
authors.initials: M
authors.lastname: Alam
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Zhiguo Jake
authors.initials: ZJ
authors.lastname: Song
authors.affiliation: †Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Lushi
authors.initials: L
authors.lastname: Tan
mesh_terms: D002384:Catalysis; D016174:Hepacivirus / Q000187:drug effects; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C000600429:MK-6325; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases