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Synfacts 2015; 11(6): 0571-0573
DOI: 10.1055/s-0034-1380762
DOI: 10.1055/s-0034-1380762
Synthesis of Natural Products and Potential Drugs
Synthesis of HCV Protease Inhibitor MK-6325
Li H, * Scott JP. * et al. Merck Research Laboratories, Rahway, USA and Merck Sharp & Dohme Research Laboratories, Hoddesdon, UK
Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular sp 2–sp 3 Suzuki–Miyaura Coupling and Ring Closing Metathesis.
Org. Lett. 2015;
17: 1533-1536
Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular sp 2–sp 3 Suzuki–Miyaura Coupling and Ring Closing Metathesis.
Org. Lett. 2015;
17: 1533-1536
Further Information
Publication History
Publication Date:
18 May 2015 (online)
Key words
MK-6325 - HCV NS3/4A protease inhibitors - ring-closing metathesis - Suzuki–Miyaura coupling - macrocyclization
Significance
MK-6325 is a potent HCV NS3/4A protease inhibitor. The construction of the daunting bis-macrocyclic structure was accomplished by a ring-closing metathesis (RCM) to forge the 15-membered macrocycle followed by an intramolecular Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle.
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Comment
The route depicted delivered multikilogram quantities of the MK-6325. Construction of fragment D was achieved using (1) a Novozyme 435 resolution with succinic anhydride and (2) an iridium-catalyzed hydroboration. CataCXium A (G) was superior to all other ligands evaluated for the Suzuki–Miyaura reaction.
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