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

Abstract

A convergent eight-stage synthesis of the boroncontaining 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 S N Ar 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 KPF 6 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 PCyPh 2 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 K 2 CO 3 /pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield. Article pubs.acs.org/joc

Understanding the Activation of Air-Stable Ir(COD)(Phen)Cl Precatalyst for C–H Borylation of Aromatics and Heteroaromatics

“…Pioneering reports by Hartwig/Ishiyama and Maleczka/Smith III in the early 2000s propelled the area of iridium-catalyzed borylation to be a viable alternative route to aryl and heteroaryl boronates via C–H borylation for a variety of highly desirable intermediates and products . While the earlier works of Maleczka/Smith III using phosphine based systems − have not gained popularity due to lower conversions, both groups eventually identified [Ir­(OMe)­(COD)] 2 as the preferred precatalyst in conjunction with either 4,4′-di- tert -butyl-2,2′-bipyridyl (dtbbpy) or 3,4,7,8-tetramethyl-1,10-phenanthroline (Me 4 Phen) as a ligand for improved activity. ,, [Ir­(OMe)­(COD)] 2 being employed due to the formation of the innocuous MeOBpin byproduct versus the use of [Ir­(Cl)­(COD)] 2 which generates ClBpin and subsequently reacting with the nitrogen/phosphine based ligands, thereby preventing ligand complexation with Ir. − Metal-catalyzed borylation technology has allowed for the total synthesis of various natural products such as (±)-thysanone, (+)-complanadine, and drug targets which would be cumbersome to prepare by classical methods. , Extensive use of the catalyst systems [Ir­(MeO)­(COD)] 2 /Me 4 Phen or dtbbpy led to the notion that this combination creates the most efficient Ir-based catalyst systems for C–H borylations with the broadest substrate scope. ,, Although high quality [Ir­(OMe)­(COD)] 2 was originally commercialized by our group on multigram quantities, multikilogram implementation had presented challenges due to shelf-life concerns and batch-to-batch variations, as documented by both academia and industry. − While our attempts to synthesize a stable [Ir­(OMe)­(COD)­(Phen)] were not successful, we focused our efforts toward identifying methodologies in accessing stable complexes from [Ir­(Cl)­(COD)] 2 . From scattered reports on the use of other electronically diverse diamine , and phosphine ligands for borylations, we saw this as a possible platform to create highly active and selective Ir precatalysts.…”

Process Development, Manufacture, and Understanding of the Atropisomerism and Polymorphism of Verinurad

“…This was attributed to potassium bromide coating the poorly organic soluble potassium acetate base, and potassium pivalate was identified as an alternative carboxylate base with improved organic solvent solubility capable of significantly increasing reaction rates. Interestingly, similar observations have also recently been reported by a number of groups suggesting a potentially broader substrate scope for the acceleration of such transformations. , …”

Advancement in Organic Synthesis Through High Throughput Experimentation

“…Leitch and coworkers utilized HTE capability for optimizing one of the synthetic steps in the development of GSK8175, [71] a target containing a benzofuran moiety. Challenges in this synthesis were the presence of a methoxymethyl ether (MOM) protecting group, potential formation of desbromo by‐products, and the complexity of the substrate that contained chloro and bromo substituents in the aryl halide analog.…”