The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to expand. Papain-like protease (PLpro) is one of two SARS-CoV-2 proteases potentially targetable with antivirals. PLpro is an attractive target because it plays an essential role in cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex, and disruption of host responses. We report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the SARS-CoV-2 enzyme. We determined the high resolution structure of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors. This collection of structures details inhibitors recognition and interactions providing fundamental molecular and mechanistic insight into PLpro. All compounds inhibit the peptidase activity of PLpro in vitro, some block SARS-CoV-2 replication in cell culture assays. These findings will accelerate structure-based drug design efforts targeting PLpro to identify high-affinity inhibitors of clinical value.

The number of new cases world-wide for the COVID-19 disease is increasing dramatically, while efforts to contain Severe Acute Respiratory Syndrome Coronavirus 2 is producing varied results in different countries. There are three key SARS-CoV-2 enzymes potentially targetable with antivirals: papain-like protease (PLpro), main protease (Mpro), and RNA-dependent RNA polymerase. Of these, PLpro is an especially attractive target because it plays an essential role in several viral replication processes, including cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex (RTC), and disruption of host viral response machinery to facilitate viral proliferation and replication. Moreover, this enzyme is conserved across different coronaviruses and promising inhibitors have already been discovered for its SARS-CoV variant. Here we report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the enzyme from SARS-CoV-2 in both wild-type and mutant forms. These efforts include the first structures of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors, determined at 1.60–2.70 Angstroms. This collection of structures provides fundamental molecular and mechanistic insight to PLpro, and critically, illustrates details for inhibitors recognition and interactions. All presented compounds inhibit the peptidase activity of PLpro in vitro, and some molecules block SARS-CoV-2 replication in cell culture assays. These collated findings will accelerate further structure-based drug design efforts targeting PLpro, with the ultimate goal of identifying high-affinity inhibitors of clinical value for SARS-CoV-2.

Under mild conditions (room temperature, 80 psi of H2) Cp*Rh­(2-(2-pyridyl)­phenyl)H catalyzes the selective hydrogenation of the CC bond in α,β-unsaturated carbonyl compounds, including natural product precursors with bulky substituents in the β position and substrates possessing an array of additional functional groups. It also catalyzes the hydrogenation of many isolated double bonds. Mechanistic studies reveal that no radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to existing protocols for similar hydrogenation processes.

Even though there are dozens of biologically active 2‐substituted and 2,6‐disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich‐type additions to nitrones, one using β‐ketoacids under catalyst‐free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2‐substituted materials, as well as other ring variants, in the form of β‐N‐hydroxy‐aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8‐step total syntheses of the 2,6‐disubstituted piperidine alkaloids (−)‐lobeline and (−)‐sedinone.

A novel recyclable prolinamide-derived ionic-liquid-supported organocatalyst of asymmetric cross-aldol reactions in aqueous medium has been developed. In its presence, aromatic aldehydes react with cyclic or linear ketones to afford chiral aldol adducts in moderate to high yields and with ex-

Novel C-symmetric N,N'-bis-[(pyrrolidin-2-yl)methyl-squaramide] TFA salts bearing (R,R)- or (S,S)-1,2-di(pyridin-2-yl)ethane spacer groups were synthesized and applied, in combination with TEA, as efficient organocatalysts for asymmetric reactions between cyclohexanone derivatives and β-nitrostyrenes to afford the corresponding Michael adducts in high yields with good to excellent enantioselectivity. The catalytic procedure is readily scalable and recyclable over four times without a negative impact on the selectivity of the reaction. Some of the prepared compounds are valuable precursors to useful bioactive molecules.

Among defensive alkaloids isolated from ladybugs, the heterodimeric member chilocorine C possesses an alluring monomeric unit that combines quinolizidine and indolizidine substructures. Indeed, the overall stereochemical disposition of its ring fusions is distinct from those of related natural products. Herein we show that a carefully orchestrated sequence with several chemoselective transformations, including a designed cascade that accomplishes nine distinct chemical reactions in one-pot, can smoothly forge that domain and ultimately enable a 15-step, 11-pot enantiospecific synthesis of the natural product. Mechanistic studies, density functional theory calculations, and the delineation of several other unsuccessful approaches highlight its unique elements.

Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines,o nly al imited number of approaches exist for their synthesis.H erein is described two Mannich-type additions to nitrones,one using bketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas,w hichc an generate abroad arrayofs uch 2-substituted materials,a swell as other ring variants,i nt he form of b-N-hydroxy-aminoketones.B oth processes have broad scope,w ith the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods,a long with other critical steps,has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (À)-lobeline and (À)-sedinone. Scheme 1. Selected piperidine-containing natural products, precedent for enantioselective functionalizations to generate such heterocycles, and two unique approaches based on using nitrones.