Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis

• Published in: Journal of organic chemistry Vol. 84; no. 8; pp. 4680 - 4694
• Main Authors: Arrington, Kenneth, Barcan, Gregg A, Calandra, Nicholas A, Erickson, Greg A, Li, Ling, Liu, Li, Nilson, Mark G, Strambeanu, Iulia I, VanGelder, Kelsey F, Woodard, John L, Xie, Shiping, Allen, C. Liana, Kowalski, John A, Leitch, David C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.04.2019; Amer Chemical Soc
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Borates - chemical synthesis; Borates - chemistry; Borates - pharmacology; Boronic Acids - chemical synthesis; Boronic Acids - chemistry; Boronic Acids - pharmacology; Catalysis; Chemistry; Chemistry, Organic; Molecular Structure; Palladium - chemistry; Physical Sciences; Science & Technology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; REAGENTS; CROSS-COUPLING REACTION; MECHANISM; CONVERSION; POLYMERASE INHIBITOR; ARYL HALIDES; ARYLATION; COMPLEXES; C-H BORYLATION; DISCOVERY
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.8b02269

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan–Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu­(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.