Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that the parent nucleoside of remdesivir, GS-441524, possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5′-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5′-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.

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Developing catalysts with both useful enantioselectivities and million turnover numbers (TONs) for asymmetric hydrogenation of ketones is attractive for industrial production of high-value bioactive chiral entities but remains a challenging. Herein, we report an ultra-efficient anionic Ir-catalyst integrated with the concept of multidentate ligation for asymmetric hydrogenation of ketones. Biocatalysis-like efficacy of up to 99% ee (enantiomeric excess), 13,425,000 TON (turnover number) and 224 s−1 TOF (turnover frequency) were documented for benchmark acetophenone. Up to 1,000,000 TON and 99% ee were achieved for challenging pyridyl alkyl ketone where at most 10,000 TONs are previously reported. The anionic Ir-catalyst showed a novel preferred ONa/MH instead of NNa/MH bifunctional mechanism. A selective industrial route to enantiopure nicotine has been established using this anionic Ir-catalyst for the key asymmetric hydrogenation step at 500 kg batch scale, providing 40 tons scale of product.

Asymmetric hydrogenation of tetrasubstituted alkenes remains a formidable challenge in asymmetric catalysis. We report herein an unprecedented Rh-catalyzed enantioselective and diastereoselective hydrogenation of easily accessed α,β-disubstituted unsaturated lactams to afford synthetically valuable chiral lactams with 1,2-consecutive stereocenters. The reaction could be performed on the gram scale, and the products could be concisely transformed to enantiomerically pure trans-3,4-disubstituted piperidines, which are prevalent structural units in medicinal agents.

Due to their low reactivity, difficult enantiocontrol, and proneness to N–O bond cleavage, the catalytic asymmetric hydrogenation of oximes to hydroxylamines has remained a significant challenge. Herein, a Lewis and Brønsted acid cooperation strategy was established for the asymmetric hydrogenation of oximes, providing the corresponding hydroxylamines with up to 95% yield and up to 96% ee. Addition of Lewis and Brønsted acid was crucial to obtain high conversion and enantioselectivity. Mechanistic investigations indicates that the thiourea fragment of the ligand, Lewis acid (In­(OTf)3 or Zn­(OAc)2), as well as the Brønsted acid (l-CSA) played vital roles in the control of reactivity and enantioselectivity of the reaction. In addition, the synthetic elaboration of this transformation was demonstrated by gram scale experiment with retention of the yield and enantioselectivity.