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An efficient rhodium-catalyzed asymmetric transfer hydrogenation of β-cyano α-ketoesters via dynamic kinetic resolution has been developed. Despite the challenge posed by multiple functional groups, the reaction proceeded smoothly under mild conditions, generating versatile synthons with two adjacent stereocenters in high yields with excellent enantio- and diastereoselectivities. Furthermore, the power of this strategy is highlighted by the scale-up reaction and the follow-up synthesis of cytoxazone and paclitaxel intermediates.

A novel synthetic route was developed for the construction of chiral cis -vicinal halohydrins derivatives through Ir/f-phamidol-catalysed asymmetric hydrogenation of corresponding α-halogenated ketones with high yields (up to 99% yield), excellent diastereoselectivities (>20 : 1 dr), enantioselectivities (up to 99% ee), and high substrate catalyst ratio (S/C = 1000).

Catalytic asymmetric synthesis of polysubstituted chiral cyclopropane presents a significant challenge in organic synthesis due to the difficulty in enantioselective control. Here we report a rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes affording chiral quaternary cyclopropanes. Importantly, the easy made sterically bulky ligand L1 can effectively suppress hydrogenation and decomposition reactions and give quaternary cyclopropanes with high regio- and enantioselectivities for both aryl and alkyl functionalized substrates. Control experiments and computational studies reveal the sterically hindered well-defined chiral pocket instead of the substrates bearing electron-withdrawing diester groups is important for controlling the enantioselectivity and regioselectivity. Scale-up reaction and follow-up diverse transformations are also presented. Density Functional theory (DFT) computations suggest that the regio- and enantio-selectivities originate from the cyclopropene insertion to the Rh-H bond. The high regioselectivity is found to benefit from the presence of more efficient noncovalent interactions (NCIs) manifesting in the form of C-H···Cl, C-H···N, and l.p(Cl)···π contacts., (© 2024. The Author(s).)

A sequence of f -phamidol-based tetradentate phosphine ligands have been developed and successfully used in iridium-catalyzed enantioselective hydrogenation of benzophenones to deliver chiral benzhydrols in almost quantitative yields and with excellent enantioselectivities (up to >99% yield and up to >99% ee). Moreover, the catalytic system shows a broad substrate scope and functional group tolerance. The synthetic utilities of this methodology have been showcased by gram-scale experiments and the formal synthesis of levocetirizine.

Hydroformylation (HF) or isomerization-hydroformylation (ISO-HF) represents the most direct and practical route for producing aldehydes on an industrial scale. To resolve the issues of low activity, low linear/branched ( l/b ) ratio, and low stability in HF and ISO-HF, we herein reported a class of spirocyclic diphosphites. Notably, the ligand termed O -SDPhite afforded excellent catalytic activity and regioselectivity for the HF of various olefins. Excellent l/b ratio and an unprecedented turnover number of up to 17,620,000 were achieved. O -SDPhite was also found to be effective in the regioselective ISO-HF of the industrially related cheap and abundant C4 Raffinates to n -valeraldehyde produced on a multimillion-ton scale. The reaction with O -SDPhite, superior to that of benchmark Biphephos, was continuously operated for 41 days and afforded an average 38.6 l/b ratio (31 days and 14.7 l/b ratio for Biphephos).

Efficient transformation of platform chemicals into key intermediates has been increasingly important for the pharmaceutical industry. The development of the catalytic reduction of abundant carboxylic acids with molecular hydrogen has been of both practical and theoretical value. We herein report the homogeneous hydrogenation of dicarboxylic acids with the strategy of desymmetrization. Using a rhodium/bisphosphine catalyst, one carboxyl group of meso -diacids was selectively reduced to yield chiral lactones with satisfactory enantioselectivity. This method provides a straightforward approach to produce chiral lactone intermediates for the manufacture of biotin, telaprevir, and other antivirus drugs. Both experimental and computational investigations were carried out, revealing a novel neighboring group coordination mechanism in the catalytic cycle.

Herein we have developed a highly practical and efficient one-step coupling protocol for the synthesis of chiral spiro diphosphine ligands, especially for the oxa -spiro diphosphine ligands O -SDP, which showed excellent reactivity and diastereoselectivity in the asymmetric hydrogenation of a key intermediate of Sacubitril. It should be noted that the one-step coupling protocol could be operated on a kilogram scale, and the resulting ruthenium catalyst of O -SDP could hydrogenate the key intermediate of Sacubitril on an industrial scale.

Owing to their distinctive 1,3-dipolar structure, the catalytic asymmetric hydrogenation of nitrones to hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol and susceptibility to N-O bond cleavage. In this study, the asymmetric hydrogenation and transfer hydrogenation of nitrones were accomplished with a tethered TsDPEN-derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine), the reaction proceeds via a novel 7-membered cyclic transition state, producing chiral hydroxylamines with up to 99 % yield and >99 % ee. The practical viability of this methodology was underscored by gram-scale catalytic reactions and subsequent transformations. Furthermore, mechanistic investigations and DFT calculations were also conducted to elucidate the origin of enantioselectivity., (© 2024 Wiley‐VCH GmbH.)

The first earth-abundant transition metal Ni-catalyzed highly regio- and enantioselective semihydrogenation of racemic tetrasubstituted allenes via a kinetic resolution process as a challenging task was well established. This protocol furnishes expedient access to a diversity of structurally important enantioenriched tetrasubstituted allenes and chiral allylic molecules with high regio-, enantio-, and Z / E -selectivity. Remarkably, this semihydrogenation proceeded with one carbon-carbon double bond of allenes, which was regioselective complementary to the Rh-catalyzed asymmetric version. Deuterium labeling experiments and density functional theory (DFT) calculations were carried out to reveal the reasonable reaction mechanism and explain the regio-/stereoselectivity.

An extremely concise, scalable, and stereoselective synthesis of a privileged chiral skeleton based on 2,2'-biindolyl and commercially available chiral building blocks has been developed. This novel skeleton allows for easy access to a range of bisphosphine ligands (decagram scale, up to 58% total yield, only three steps). The synthetic method is characterized by an efficient central-to-axial chirality transfer strategy. In particular, the superior performance of the ligands has been demonstrated in diverse reactions, including several asymmetric hydrogenations, asymmetric conjugate reductions, and cycloisomerization reactions, indicating a great potential for the application of the newly developed chiral backbones in further modifications and exploration of novel chiral ligands and catalysts.

Transition metal catalysts with a million turnovers and excellent selectivity are rarely reported but are crucial for the industrial manufacture of optical pure pharmaceuticals, natural products, and fine chemicals. In this paper, we report an unprecedented aninoic Ir-f-phamidol catalyst for asymmetric hydrogenation of γ-amino ketones followed by stereoselective cyclization for construction of valuable chiral 2-aryl-pyrrolidine pharmacophores. The Ir-f-phamidol catalyst showed up to 1,000,000 TON and >99% ee, as well as excellent tolerance of substrates and protecting groups, providing various chiral amino alcohol intermediates. Upon optimization of the conditions, the stereoselective cyclization reaction was highly smooth and efficient (quantitative conversions, 92 to >99% ee). Finally, this solution was applied in the preparation of high-value chiral entities containing such chiral 2-aryl-pyrrolidine pharmacophores.

We herein reported the design and synthesis of a ferrocene-based tetradentate ligand that is featured with modular synthesis and rigid skeleton. Its iron(II) complex facilitates asymmetric direct hydrogenation of ketones without the participation of extra strong-field ligand such as CO and isocyanide. Hydride donor lithium aluminum hydride (LAH) converted non-reactive Fe(II) species to reactive Fe(II) hydride species. With this catalyst, various chiral alcohols including the intermediate for montelukast could be prepared with satisfactory yields and enantioinduction., (© 2023 Wiley-VCH GmbH.)

Chlorohydrins and oxaheterocycles are synthetically valuable building blocks for diverse natural products and therapeutic substances. A highly efficient Ir/ f -phamidol-catalyzed asymmetric hydrogenation of ω-chloroketones was successfully developed, and various chlorohydrins and oxaheterocycles were obtained divergently with excellent yields and enantioselectivities (up to >99% yield and >99% ee). Synthetic utilities of this divergent transformation were demonstrated by gram-scale synthesis of key intermediates of several enantiomerically enriched drugs via this catalytic methodology.

A new class of cobalt catalytic system for asymmetric hydrogenation of ketones was herein reported, involving the development of novel ferrocene-based secondary phosphine oxide ligands. An unusual P-O bidentate coordination pattern with cobalt was confirmed by an X-ray diffraction study. The bichelating tetrahedral cobalt(II) complexes afforded high reactivities (up to 99% yield) and good to excellent enantioselectivities (up to 92% ee) in the AH of various ortho -substituted diaryl ketones. In addition, the diferrocenyl cobalt complex was characterized with intriguing UV-vis absorption and electrochemical properties.

The ruthenium-catalyzed asymmetric reductive amination of aryl-trifluoromethyl ketones affording high value primary α-(trifluoromethyl)arylmethylamines using cheap NH 4 OAc as the nitrogen source and H 2 as the reductant is reported. This user-friendly and simple catalytic method tolerates various aromatic functions with electron-withdrawing or -donating substituents at the para- or meta-positions and as well challenging heteroaromatic functions, yielding primary α-(trifluoromethyl)arylmethylamines with excellent chemoselectivities, enantioselectivities, and useful yields (80-97% ee, 51-92% isolated yields). Finally, scalable and concise synthesis of key drug intermediates using this methodology is presented.

Chiral tetrahydroquinoxalines and dihydroquinoxalinones represent the core structure of many bioactive molecules. Herein, a simple and efficient Rh-thiourea-catalyzed asymmetric hydrogenation for enantiopure tetrahydroquinoxalines and dihydroquinoxalinones was developed under 1 MPa H 2 pressure at room temperature. The reaction was magnified to the gram scale furnishing the desired products with undamaged yield and enantioselectivity. Application of this methodology was also conducted successfully under continuous flow conditions. In addition, 1 H NMR experiments revealed that the introduction of a strong Brønsted acid, HCl, not only activated the substrate but also established anion binding between the substrate and the ligand. More importantly, the chloride ion facilitated heterolytic cleavage of dihydrogen to regenerate the active dihydride species and HCl, which was computed to be the rate-determining step. Further deuterium labeling experiments and density functional theory (DFT) calculations demonstrated that this reaction underwent a plausible outer-sphere mechanism in this new catalytic transformation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

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., (© 2023. The Author(s).)

The atom- and step-efficient synthesis of chiral fused tricyclic lactams from readily available ketoesters using cheap ammonium salts as the nitrogen source is reported. This ruthenium-catalyzed system operates through an efficient tandem dynamic kinetic asymmetric reductive amination (ARA)/lactamization and produces chiral fused tricyclic lactams in high yields with excellent diastereo- and enantioselectivity (up to >99 % ee, >20 : 1 dr and 98 % yield). The robust method was also applied to the concise synthesis of key intermediates in the synthesis of rivastigmine analogues and chiral N-heterocyclic carbene catalysts., (© 2023 Wiley-VCH GmbH.)

By combining the concept of flash chemistry and radial synthesis, a novel microreactor (Flashstop reactor) was designed to study isomerization process of hydroformylation by a Rh/tetraphosphite catalyst in a time scale of seconds. It was found that in the initial 313 seconds, 60-99 % of 1-octene was isomerized to 2- and 3-octenes before the formation of aldehydes. Within this period, two different types of isomerization reactions were observed. It was proposed that a monohydride complex without CO ligand accounts for the ultrafast isomerization in the initial 30 seconds. The isomerization rate with such monohydride species was calculated much faster than that with the well-known H(CO)Rh(P-P) species. Both experimental and DFT computational studies were carried out to support this assumption. Fast transformations early on in catalytic cycles have been rarely studied due to the lack of proper tools. We believe that the Flashstop reactor is a powerful tool for analysis of kinetics in gas-liquid biphasic reactions within a time scale of seconds to minutes., (© 2023 Wiley-VCH GmbH.)

S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CL pro ) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CL pro and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CL pro with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The highly efficient Rh/ZhaoPhos-catalysed asymmetric hydrogenation of γ-butenolides and γ-hydroxybutenolides was successfully developed. This protocol provides an efficient and practical approach to the synthesis of various chiral γ-butyrolactones, which are synthetically valuable building blocks of diverse natural products and therapeutic substances, with excellent results (up to >99% conversion and 99% ee). Further follow-up transformations have been revealed to accomplish creative and efficient synthetic routes for several enantiomerically enriched drugs via this catalytic methodology., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Synthesis of optically enriched racetam analogues was achieved via highly remote diastereocontrolled and enantiocontrolled Pd/C-catalyzed hydrogenation of α,β -unsaturated γ-lactams. Various mono- and disubstituted 2-pyrrolidones were obtained in excellent yields and stereoselectivities, and a concise and large-scale synthesis of brivaracetam was developed from inexpensive l-2-aminobutyric acid. Surprisingly, stereodivergent hydrogenation was observed by modifying remote functionalized stereocenters and additives, which would provide alternative stereochemical options of chiral racetams synthesis.

Coronaviruses (CoVs) infect a broad range of hosts, including humans and various animals, with a tendency to cross the species barrier, causing severe harm to human society and fostering the need for effective anti-coronaviral drugs. GS-441524 is a broad-spectrum antiviral nucleoside with potent anti-CoVs activities. However, its application is limited by poor oral bioavailability. Herein, we designed and synthesized several conjugates via covalently binding NSAIDs to 5'-OH of GS-441524 through ester bonds. The ibuprofen conjugate, ATV041, exhibited potent in vitro anti-coronaviral efficacy against four zoonotic coronaviruses in the alpha- and beta-genera. Oral-dosed ATV041 resulted in favorable bioavailability and rapid tissue distribution of GS-441524 and ibuprofen. In MHV-A59 infected mice, ATV041 dose-dependently decreased viral RNA replication and significantly reduced the proinflammatory cytokines in the liver and the lung at 3 dpi. As a result, the MHV-A59-induced lung and liver inflammatory injury was significantly alleviated. Taken together, this work provides a novel drug conjugate strategy to improve oral PK and offers a potent anti-coronaviral lead compound for further studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Arene hydrogenation is the most straightforward method to prepare carbo- and heterocycles. However, the high resonance energy prevents aromatic substrates from hydrogenation. Herein the homogeneous, nucleophilic hydrogenation of less electron-rich arenes and heteroarenes is reported. The Co(P 4 N 2 )H species that has been demonstrated to be a strong hydride donor could deliver a hydride ion to the cyano (hetero)arene substrates. Deuterium labeling experiments supported a Michael-type reaction pathway. Theoretical analyses have been conducted to investigate the hydricity of the catalytically active CoH species and the electrophilicity of the arene substrates. An outlook for the synthesis of more challenging substituted benzenes was proposed based on the in silico modification of the CoH species., (© 2022 Wiley-VCH GmbH.)

Chiral succinimide moieties are ubiquitous in biologically active natural products and pharmaceuticals. Until today, despite the great interest, little success has been made for stereodivergent synthesis of chiral succinimides. Here, we report a general and efficient method for accessing 3,4-disubstituted succinimides through a dynamic kinetic resolution strategy based on asymmetric transfer hydrogenation. The Rh catalyst system exhibit high activities, enantioselectivities, and diastereoselectivities (up to 2000 TON, up to >99% ee, and up to >99:1 dr). Products with syn- and anti-configuration are obtained separately by control of the reaction conditions. For the N-unprotected substrates, both the enol and the imide group can be reduced by control of reaction time and catalyst loading. In addition, the detailed reaction pathway and origin of stereoselectivity are elucidated by control experiments and theoretical calculations. This study offers a straightforward and stereodivergent approach to the valuable enantioenriched succinimides (all 4 stereoisomers) from cheap chemical feedstocks in a single reaction step., (© 2022. The Author(s).)

Converting cheap and abundant internal alkenes to value-added linear aldehydes is of great importance but not an addressed issue. In this paper, an integration of a Milstein-type Ru-PNN catalyst and our Rh-Tribi/Tetrabi catalyst was first demonstrated in highly improved isomerization linear selective hydroformylation of 2-, 3-, and 4-alkenes, yielding excellent linear selectivities and activities (linear selectivity improvements of 2.2-58%, up to 94.2-98.6%, and turnover numbers improvements of 61-335 TON, up to 385-851) compared to the Ru-PNN/Rh-Bisbi system.

Cephalotaxine-type alkaloids (CTAs), represented by homoharringtonine (HHT, 1), display potent efficacy against different types of leukemia cells. In this study, a method for hydrogenation of β-substituted itaconic acid monoesters with chiral Ru[DTBM-SegPhos](OAc) 2 was developed. This metal-catalyzed asymmetric hydrogenation enabled the convenient semisynthesis of novel cephalotaxine derivatives with chiral 2'-substituted-succinic acid 4-mono-methyl esters as side chains. The preliminary structure-activity relationship (SAR) of the compounds' antineoplastic activities was studied. Eventually, we discovered compound 10b with potent antineoplastic activities against leukemia and broadly anticancer activities against a panel of cancer cells. Our study provided a highly enantioselective process enabling the semisynthesis of cephalotaxine derivatives, which are interesting for further study on a scientific basis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Masson SAS.)

Chiral β-heteroaryl amino alcohols are key fragments of many bioactive compounds and antibiotics, and the development of efficient synthetic methods for these compounds is of great value. The highly enantioselective hydrogenation of α- N -heteroaryl ketones was realized with a ruthenium-diphosphine-diamine catalyst, providing the corresponding chiral β-heteroaryl amino alcohols with up to 99% yield and up to >99% ee. The synthetic utilities of the current reaction were demonstrated by gram-scale synthesis of key intermediates of Sertaconazole and Cenobamate.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, 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.

The first rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of cyclopropyl-functionalized trisubstituted alkenes affording useful chiral cyclopropyl entities is reported. Compared to generally used diphosphine ligands for asymmetric catalysis, the modified hybrid phosphorus ligand, named (R,S)-DTBM-Yanphos, can convert a series of readily available cyclopropyl-functionalized trisubstituted alkenes into high-value chiral cyclopropyl-functionalized aldehydes with high selectivities (81-98 % ee). Gram-scale reactions (TON up to 1500) and follow-up transformations to the corresponding alcohol, acid, esters and nitrile are also presented. Finally, a possible hydroformylation mechanism involving ring-open-hydroformylation pathways is proposed based on control and deuteroformylation reactions., (© 2022 Wiley-VCH GmbH.)

Owing to the biological significance and great synthetic value of chiral lactones and their derivatives, increasing attention has been paid to developing effective synthetic methods for chiral lactones. We herein report an efficient asymmetric hydrogenation of benzo-fused ketoesters, γ-ketoesters and biaryl-bridged ketoesters catalyzed by chiral iridium complexes bearing ferrocene-based chiral ligands, furnishing a series of chiral lactones in superb yields and excellent enantioselectivities (up to 99% yields and up to 99% ee).

An unprecedented highly enantioselective Ru-catalyzed direct asymmetric reductive amination of α-keto amides with ammonium salts has been disclosed, efficiently offering valuable enantioenriched N-unprotected unnatural α-amino acid derivatives bearing a broad range of aryl or alkyl α-substituents. This protocol features easily accessible substrates, good functional-group tolerance and excellent enantiocontrol, making it a good complementary approach to the known methods. Moreover, this method is also applicable to the preparation of N-unprotected unnatural α-amino acid derivatives containing an additional stereogenic center at the β-position through a dynamic kinetic resolution (DKR) process. Convenient transformations of the obtained products into chiral N-unprotected unnatural α-amino acids, drug intermediates, peptides, and organocatalysts/ligands further showcase the utility of this method., (© 2022 Wiley-VCH GmbH.)

A phosphine-catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N-tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine-mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine-catalyzed organic transformations., (© 2022 Wiley-VCH GmbH.)

Due to the linear coordination nature of gold(I) catalysts, achieving high enantiocontrol in asymmetric gold catalysis is a great challenge. To improve the enantiocontrol of gold catalysis, an ion-pairing strategy was therefore proposed. A series of bifunctional P,N ligands based on chiral spirocyclic and biaryl scaffolds were synthesized and applied in the gold(I)-catalyzed desymmetric lactonization of alkynylmalonic acids. A wide range of chiral lactones containing an α-position quaternary stereocenter were synthesized with high yields, excellent regioselectivity and enantioselectivity under mild reaction conditions. The synthetic utilities of the current reaction were demonstrated by gram-scale synthesis and transformations of chiral lactones. The origin of enantioselectivity and the role of the alcohol additive were elucidated via control experiments and DFT calculations., (© 2022 Wiley-VCH GmbH.)

The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,β-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C[double bond, length as m-dash]C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

A new series of C 2 -symmetrical chiral ferrocene-based diphosphino-ethane ligands termed as f-DPE were developed. Assisted by the ion pairing interaction with the ligand, a wide scope of 2-substituted acrylic acids was hydrogenated to obtain chiral propanoic acids with high yields and enantioselectivities. The well-known anti-inflammatory drugs ibuprofen, naproxen, and flurbiprofen could be synthesized efficiently. In addition, the synthetic utilities of the current method were demonstrated by gram-scale experiments.

We herein report a convenient method to convert olefins to organic iodides and amines using an Ir/ZhaoPhos catalyst, molecular hydrogen, and an electrophilic iodine(I) reagent. High yields and regioselectivities were obtained under mild conditions. In addition, basic workup with potassium carbonate leads to C-N products. Control experiments and DFT calculations tentatively excluded the pathway involving the in situ formation of HI. Instead, a catalytic cycle involving the hydrogenation of the haliranium ion intermediate was proposed.

A novel synthetic route was developed for the construction of a chiral cis -hexahydro-γ-carboline derivative through Ir/ZhaoPhos-catalyzed asymmetric hydrogenation of corresponding tetrahydro-γ-carboline with high yields (up to 99% yield), excellent diastereoselectivities (up to >99 : 1 dr) and enantioselectivities (up to 99% ee), and high substrate-to-catalyst ratios (up to 5000).

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

The transition-metal-catalyzed asymmetric cycloisomerization of 1,7-enynes is regarded as a formidable challenge due to the poor ability of 1,7-enynes to serve as bidentate ligands to metal. In this Letter, a highly enantioselective rhodium(I)-catalyzed Alder-ene-type cycloisomerization of 1,7-enynes is disclosed, offering an efficient method for the synthesis of a wide range of fused six-membered cyclic compounds. Furthermore, a high turnover frequency experiment and deuterium-labeling experiment were performed to give insight into this transformation.

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.

A general and highly efficient method for asymmetric sequential hydrogenation of α,β-unsaturated ketones has been developed by using an iridium/f-Ampha complex as the catalyst, furnishing corresponding chiral alcohols with two contiguous stereocenters in high yields with excellent diastereo- and enantioselectivities (up to 99% yield, >20 : 1 dr and >99% ee). Control experiments indicated that the C[double bond, length as m-dash]C and C[double bond, length as m-dash]O bonds of the enones were hydrogenated sequentially, and the final stereoselectivities were determined by the dynamic kinetic resolution of ketones. Moreover, DFT calculations revealed that an outer sphere pathway was involved in both reduction of C[double bond, length as m-dash]C and C[double bond, length as m-dash]O bonds of enones. The synthetic utility of this method was demonstrated by a gram-scale reaction with very low catalyst loading (S/C = 20 000) and a concise synthetic route to key chiral intermediates of the antiasthmatic drug CP-199,330., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We report an efficient and straightforward method to synthesize enantio-enriched N -unprotected α-amino acetals via ruthenium-catalyzed direct asymmetric reductive amination. The α-amino acetal products are versatile and valuable platform molecules that can be converted to the corresponding α-amino acids, amino alcohols, and other derivatives by convenient transformations.

Owing to the biological significance and great synthetic value of 1,4-diarylbutane-1,4-diols and their derivatives, increasingly considerable attention has been paid to developing effective synthetic methods for chiral 1,4-diarylbutane-1,4-diols. We herein report an efficient asymmetric hydrogenation of 1,4-diaryldiketones catalyzed by a chiral iridium complex bearing f -amphox as ligand, furnishing a series of 1,4-diarylbutane-1,4-diols in excellent yields (up to >99%) with exceptional enantioselectivities (up to >99.9% ee) and diastereoselectivities (up to >100 : 1 dr).

A series of half-sandwich Ir(III) complexes 1-6 bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex 1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes 3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.

Chiral bridged [2,2,1] bicyclic lactones are privileged structural units in pharmaceutics and bioactive nature products. However, the synthetic methods for these compounds are rare. Here we report an efficient method for enantioselective construction of bridged [2,2,1] bicyclic lactones bearing a quaternary stereocenter via Rh-catalyzed asymmetric hydroformylation/intramolecular cyclization/pyridium chlorochromate (PCC) oxidation. By employing a hybrid phosphine-phosphite chiral ligand, a series of cyclopent-3-en-1-ols are transformed into corresponding γ-hydroxyl aldehydes with specific syn-selectivity. Then, hemiacetals form in situ and oxidation with PCC in one-pot affords bridged [2,2,1] bicyclic lactones in high yields and excellent enantiomeric excess. Replacing the hydroxyl group by an ester group, cyclopentanecarbaldehydes with a chiral all-carbon quaternary stereocenter in the γ-position can be generated efficiently., (© 2021. The Author(s).)

We report an asymmetric 1,2-reduction of cyclic α,β-unsaturated ketones to access various enantiomerically enriched cyclic allylic alcohols under mild conditions, catalyzed by in situ generated copper hydride ligated with ( R )-DTBM-C 3 *-TunePhos. α-Brominated cycloalkenones were reduced with excellent enantioselectivities of up to 98% ee, while substrates that were without α-substituents were reduced chemoselectively, with moderate enantioselectivities.