Orange Light-Driven C(sp2)-C(sp3) Cross-Coupling via Spin-Forbidden Ir(III) Metallaphotoredox Catalysis.

We report the development and characterization of a library of Ir(III) photocatalysts capable of undergoing spin-forbidden excitation (SFE) under orange light irradiation (595 nm). These catalysts were successfully applied to the construction of synthetically valuable C(sp2)-C(sp3) bonds inaccessible with existing methods of low-energy light-driven dual nickel/photoredox catalysis, demonstrating the synthetic utility of this photocatalyst family. The photocatalysts are capable of accessing both oxidatively and reductively activated coupling partners, illustrated through deaminative arylation and potassium alkyl trifluoroborate cross-coupling reactions with aryl halides. We demonstrate diverse substrate scopes of both cross-coupling paradigms under mild conditions in the first example of low-energy light-driven C(sp2)-C(sp3) metallaphotoredox coupling.

Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

Applications of Bolm's Ligand in Enantioselective Synthesis.

One pathway for the preparation of enantiomerically pure compounds from prochiral substrates is the use of metal complex catalysis with chiral ligands. Compared to the other frequently used chiral ligands, chiral 2,2'-bipyridines have been underexploited, despite the data indicating that such ligands have considerable potential in synthetic chemistry. One of those is the so-called Bolm's ligand, a compound possessing chiral alcohol moieties in the side chains attached to the 2,2'-bipyridine scaffold. Various metal salts have been used in combination with Bolm's ligand as potent catalysts able to bring about enantioselective alkylations, allylations, conjugate additions, desymmetrization of meso-epoxides, aldol reactions, etc. This review aims to summarize Bolm's ligand applications in the area of enantioselective synthesis over the last three decades since its preparation.

Optimized methods for preparation of 6(I)-(ω-sulfanyl-alkylene-sulfanyl)-ß-cyclodextrin derivatives.

A general high-yielding method for the preparation of monosubstituted ß-cyclodextrin derivatives which have attached a thiol group in position 6 is described. The thiol group is attached through linkers of different lengths and repeating units (ethylene glycol or methylene). The target compounds were characterized by IR, MS and NMR spectra. A simple method for their complete conversion to the corresponding disulfides as well as a method for the reduction of the disulfides back to the thiols is presented. Both, thiols and disulfides are derivatives usable for well-defined covalent attachment of cyclodextrin to gold or polydopamine-coated solid surfaces.

Complete sets of monosubstituted γ-cyclodextrins as precursors for further synthesis.

Regioselective alkylation of γ-cyclodextrin with allyl or propargyl bromide, using optimized reaction conditions, followed by peracetylation of the remaining hydroxyl groups and separation of isomers resulted in the set of peracetylated 2(I)-O-, 3(I)-O- and 6(I)-O-alkylated cyclodextrins in up to 19% yields. Ozonolysis or oxidative cleavage of peracetylated allyl derivatives resulted in a complete set of peracetylated 2(I)-O-, 3(I)-O-, and 6(I)-O-formylmethyl or -carboxymethyl derivatives. All of these derivatives are useful precursors for further preparation of regioselectively monosubstituted derivatives of γ-cyclodextrin.