Highly Enantioselective Hydrogenation of Unsymmetrical Benzophenones via Iridium-f-phamidol Catalysis.

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.

Robust, scalable, and highly selective spirocyclic catalysts for industrial hydroformylation and isomerization-hydroformylation.

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).

Desymmetric Hydrogenation of meso-Dicarboxylic Acids.

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.

Challenging Task of Ni-Catalyzed Highly Regio-/Enantioselective Semihydrogenation of Racemic Tetrasubstituted Allenes via a Kinetic Resolution Process.

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.

Design and Synthesis of Diphosphine Ligands Based on the Chiral Biindolyl Scaffold and Their Application in Transition-Metal Catalysis.

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.

Rhodium-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3-Dipolar Nitrones.

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.

Development of a One-Step Synthesis of oxa-Spirocyclic Diphosphine Ligands Driven by Their Application in the Industrial Synthesis of Sacubitril.

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.

PPM Ir-f-phamidol-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones Followed by Stereoselective Cyclization for Construction of Chiral 2-Aryl-pyrrolidine Pharmacophores.

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.

Highly enantioselective synthesis of both tetrahydroquinoxalines and dihydroquinoxalinones via Rh-thiourea catalyzed asymmetric hydrogenation.

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 H2 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, 1H 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.

Chemoselective and Divergent Synthesis of Chlorohydrins and Oxaheterocycles via Ir-Catalyzed Asymmetric Hydrogenation.

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.

Cobalt-Catalyzed Enantioselective Hydrogenation of Diaryl Ketones with Ferrocene-Based Secondary Phosphine Oxide Ligands.

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.

A Tetradentate Ligand Enables Iron-Catalyzed Asymmetric Hydrogenation of Ketones in a CO- or Isocyanide-Free Fashion.

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.

Ru-Catalyzed Asymmetric Reductive Amination of Aryl-Trifluoromethyl Ketones for Synthesis of Primary α-(Trifluoromethyl)arylmethylamines.

The ruthenium-catalyzed asymmetric reductive amination of aryl-trifluoromethyl ketones affording high value primary α-(trifluoromethyl)arylmethylamines using cheap NH4OAc as the nitrogen source and H2 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.

A 13-million turnover-number anionic Ir-catalyst for a selective industrial route to chiral nicotine.

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.

Facile access to chiral γ-butyrolactones via rhodium-catalysed asymmetric hydrogenation of γ-butenolides and γ-hydroxybutenolides.

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.

Concise Synthesis of Chiral Tricyclic Lactams by Tandem Dynamic Kinetic Asymmetric Reductive Amination/Lactamization Using Ammonium Salts.

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.

Fast Isomerization Before Isomerization-Hydroformylation: Probing the Neglected Period with A Novel Microfluidic Device.

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.

Stereodivergent Synthesis of Enantioenriched 2-Pyrrolidones via Diastereoselective Hydrogenation of α,ß-Unsaturated γ-Lactams.

Synthesis of optically enriched racetam analogues was achieved via highly remote diastereocontrolled and enantiocontrolled Pd/C-catalyzed hydrogenation of α,ß-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.

Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2.

S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro) 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 3CLpro and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CLpro 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.