Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams

A new strategy for catalytic enantioselective C-acylation to generate α-quaternary-substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzonitriles, and aryl halides produces β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos-type ligand and addition of LiBr enable the construction of quaternary stereocenters on α-substituted lactams to form β-keto lactams in up to 94% ee

Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams

A new strategy for catalytic enantioselective C-acylation to generate α-quaternary-substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzonitriles, and aryl halides produces β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos-type ligand and addition of LiBr enable the construction of quaternary stereocenters on α-substituted lactams to form β-keto lactams in up to 94% ee

Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective β-Lactone Formation by N-Heterocyclic Carbene Catalysis

This study describes the combined experimental and computational elucidation of the mechanism and origins of stereoselectivities in the NHC-catalyzed dynamic kinetic resolution (DKR) of α-substituted-β-ketoesters. Density functional theory computations reveal that the NHC-catalyzed DKR proceeds by two mechanisms, depending on the stereochemistry around the forming bond: 1) a concerted, asynchronous formal (2+2) aldol-lactonization process, or 2) a stepwise spiro-lactonization mechanism where the alkoxide is trapped by the NHC-catalyst. These mechanisms contrast significantly from mechanisms found and postulated in other related transformations. Conjugative stabilization of the electrophile and non-classical hydrogen bonds are key in controlling the stereoselectivity. This reaction constitutes an interesting class of DKRs in which the catalyst is responsible for the kinetic resolution to selectively and irreversibly capture an enantiomer of a substrate undergoing rapid racemization with the help of an exogenous base

Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective β-Lactone Formation by N-Heterocyclic Carbene Catalysis

This study describes the combined experimental and computational elucidation of the mechanism and origins of stereoselectivities in the NHC-catalyzed dynamic kinetic resolution (DKR) of α-substituted-β-ketoesters. Density functional theory computations reveal that the NHC-catalyzed DKR proceeds by two mechanisms, depending on the stereochemistry around the forming bond: 1) a concerted, asynchronous formal (2+2) aldol-lactonization process, or 2) a stepwise spiro-lactonization mechanism where the alkoxide is trapped by the NHC-catalyst. These mechanisms contrast significantly from mechanisms found and postulated in other related transformations. Conjugative stabilization of the electrophile and non-classical hydrogen bonds are key in controlling the stereoselectivity. This reaction constitutes an interesting class of DKRs in which the catalyst is responsible for the kinetic resolution to selectively and irreversibly capture an enantiomer of a substrate undergoing rapid racemization with the help of an exogenous base

Transition Metal Catalyzed Synthesis of Aryl Sulfides

The presence of aryl sulfides in biologically active compounds has resulted in the development of new methods to form carbon-sulfur bonds. The synthesis of aryl sulfides via metal catalysis has significantly increased in recent years. Historically, thiolates and sulfides have been thought to plague catalyst activity in the presence of transition metals. Indeed, strong coordination of thiolates and thioethers to transition metals can often hinder catalytic activity; however, various catalysts are able to withstand catalyst deactivation and form aryl carbon-sulfur bonds in high-yielding transformations. This review discusses the metal-catalyzed arylation of thiols and the use of disulfides as metal-thiolate precursors for the formation of C-S bonds

Room Temperature Catalyst System for the Hydroarylation of Olefins

A simple protocol for the hydroarylation of olefins to yield diarylmethine products is described. A Friedel–Crafts-type synthetic strategy allows direct access to biorelevant products in high atom efficiency. A combination of substoichiometric amounts of TMSCl and ZnBr₂ promotes a rapid hydroarylation process at ambient temperature. The method is high yielding and is amenable to scale-up protocols

Ni-Catalyzed Enantioselective <i>C</i>‑Acylation of α‑Substituted Lactams

A new strategy for catalytic enantio­selective <i>C</i>-acylation to generate α-quaternary-substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzo­nitriles, and aryl halides produces β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos-type ligand and addition of LiBr enable the construction of quaternary stereo­centers on α-substituted lactams to form β-keto lactams in up to 94% ee

Metal Ion Complexes of <i>N,N</i>′‑Bis(2-Pyridylmethyl)-<i>trans</i>-1,2-Diaminocyclohexane-<i>N,N</i>′‑Diacetic Acid, H₂bpcd: Cis/Trans Isomerization Equilibria

The synthesis of <i>N,N</i>′-bis­(2-pyridylmethyl)-<i>trans</i>-1,2-diaminocyclohexane-<i>N,N</i>′-diacetic acid (H₂bpcd) and its complexation of Ga­(III) and Co­(III) are reported. H₂bpcd and the metal–bpcd^2– complexes, isolated as hexafluorophosphate salts, were characterized by elemental analysis, X-ray crystallography, IR spectroscopy, and ¹H and ¹³C NMR spectroscopy. [Ga­(bpcd)]­PF₆, [Ga­(C₂₂H₂₆N₄O₄)]­PF₆, crystallized in the orthorhombic space group <i>Ibca</i>, with <i>a</i> = 13.8975(7) Å, <i>b</i> = 15.0872(7) Å, <i>c</i> = 22.2418(10) Å, and <i>Z</i> = 8. Ga is coordinated in a distorted octahedral geometry provided by a N₄O₂ donor atom set with <i>trans</i>-monodentate acetate groups and <i>cis</i>-2-pyridylmethyl N atoms, i.e., the <i>trans</i>-O,O isomer. The diamagnetic [Co­(bpcd)]­PF₆, [Co­(C₂₂H₂₆N₄O₄)]­PF₆, also crystallized from solution in the <i>Ibca</i> space group as the <i>trans</i>-O,O isomer. The ¹H and ¹³C assignments for H₂bpcd and metal–bpcd^2– complexes were made on the basis of 2D COSY and HSQC experiments, which were used to differentiate among three possible isomers, i.e., one cis (<i>C</i>₁ symmetry) and two trans (<i>C</i>₂ symmetry). NMR results indicate that the [Ga­(bpcd)]⁺, [Co­(bpcd)]⁺, and <i>cis</i>-O,O, <i>cis</i>-N_py,N_py-[Ga­(bppd)]⁺ cations, where bppd^2– stands for bis­(2-pyridylmethyl)-1,3-diaminopropane diacetate, are present in solution as isomers with the same symmetry as observed in the solid state. The crystallographic data and the dramatic shift that occurs in the position of the cis/trans isomerization equilibria for the [Ga­(bpad)]⁺ cations simply by increasing the number of bridging CH₂ groups in the ligand’s diamine backbone represent a unique opportunity to assess the accuracy of modern computational methods. The performance of several local density functionals using a pseudopotential-based SDD basis set was compared with the more rigorous HF and MP2 ab initio calculations. The SVWN5 and SV5LYP functionals provide significantly better Ga–O and Ga–N distances than the HF method or the nonlocal BLYP functional. However, to provide proper isomerization energies the pseudopotential-DFT calculations must be augmented by MP2 single-point energies and calculations of solvation free energies

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88–1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. US National Institutes of Health and Operation Warp Spee