Biomimetic Asymmetric Reduction Based on the Regenerable Coenzyme NAD(P)H Models.

ConspectusIn nature, the coenzyme NAD(P)H is utilized for the transfer of hydrogen and electrons in biocatalytic reduction, which involves the process of recycling, coenzyme usage, and reduction. Inspired by the biological system, a series of nonregenerable achiral and chiral NAD(P)H models were synthesized and employed. However, this approach faced intractable limitations, such as the need for an equivalent amount of mimics, accompanied by the production of byproducts, which resulted in poor atom economy and difficult separation of products. Therefore, the development of new and efficient methodologies for synthesis, regeneration, and application of the NAD(P)H models in organic synthesis is greatly desired.To tackle these challenges, the regenerable achiral and chiral coenzyme NAD(P)H models were designed and synthesized based on the principles of biocatalytic reduction and applied them in biomimetic asymmetric reduction (BMAR) reactions. This Account summarizes our endeavors in rational design, synthesis, regeneration, and application of the NAD(P)H models. First, we will introduce the design and synthesis of regenerable and achiral coenzyme NAD(P)H models (dihydrophenanthridine and dihydropyrroloquinoxaline), which were successfully applied to BMAR of imines and heteroaromatics using homogeneous ruthenium complex as a regeneration catalyst, chiral phosphoric acid as a transfer catalyst, and hydrogen as the terminal reductant. Regenerable and achiral NAD(P)H models require the addition of chiral catalysts or chiral ligands for stereoselective control during the BMAR process. However, the screening of the chiral transfer catalysts is tedious. Narrow substrate scope further limited their application in organic synthesis. Therefore, we designed and synthesized regenerable and chiral NAD(P)H models (CYNAM and FENAM) with planar chirality, which were successfully applied in asymmetric reduction of imines and heteroaromatics using commercially available achiral Brønsted acids, Lewis acids, or organocatalysts as transfer catalysts and a homogeneous ruthenium complex as a regeneration catalyst. Notably, the original factor of enantioselective control is from the chiral NAD(P)H models. In addition, this strategy could also realize the asymmetric reduction of a myriad of electron-deficient tetrasubstituted alkenes, which are challenging substrates in transition metal catalyzed asymmetric hydrogenation. This methodology provides an efficient strategy for the synthesis of chiral building blocks and bioactive molecules. Finally, the detailed mechanism of BMAR, based on the regenerable NAD(P)H models, was elaborated through a combination of experiments and density functional theory calculations. In summary, we believe that the results presented in this Account hold significant implications beyond our work and have the potential for further applications in the field of biomimetic asymmetric catalysis and synthetic methodology.

The Proton of Alcohols as Hydrogen Source in Diboron-Mediated Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Cyclic N-Sulfonyl Imines.

The proton of alcohols as the sole hydrogen source in diboron-mediated nickel-catalyzed asymmetric transfer hydrogenation of cyclic N-sulfonyl imines has been developed, providing the chiral cyclic sulfamidates in excellent enantioselectivities. The mechanistic investigations suggested that the proton of alcohols could be activated by tetrahydroxydiboron to form active nickel hydride species.

Dearomatization of [2.2]Paracyclophane-Derived N-Sulfonylimines through Cyclopropanation with Sulfur Ylides.

An unprecedented dearomatization of [2.2]paracyclophane-derived cyclic N-sulfonylimines was conducted through cyclopropanation with sulfur ylides, giving a series of dearomative cyclopropanes with good yields. DFT calculations suggested that the dearomatization was attributed to the relatively weak aromaticity of [2.2]paracyclophane derivatives that resulted from the effect of the unique [2.2]paracyclophane skeleton and the electron-withdrawing N-sulfonyl group. Some downstream elaborations of the products were demonstrated.

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor.

The chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine is the key core skeleton of potent Bruton's tyrosine kinase (BTK) inhibitor Zanubrutinib, and the catalyst-controlled asymmetric hydrogenation of planar multinuclear pyrimidine heteroarenes with multiple N atoms could provide an efficient route toward its synthesis. Owing to the strong aromaticity and poisoning effect toward chiral transition metal catalyst, asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines with multiple nitrogen atoms is still a challenge for synthesizing the chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine. Herein, an efficient iridium-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines has been developed using substrate activation strategy, with up to 99% ee. The decagram scale synthesis further demonstrated the potential and promise of this procedure in the synthesis of Zanubrutinib. In addition, a mechanistic study indicated that the hydrogenation starts with 1,2-hydrogenation.

Synthesis of Tridentate PNO Ligands with Planar Chirality and Application in Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones.

A series of [2,2]paracyclophane-based tridentate PNO ligands with planar chirality were designed and synthesized. The easily prepared chiral tridentate PNO ligands were successfully applied to the iridium-catalyzed asymmetric hydrogenation of simple ketones, giving chiral alcohols with high efficiency and excellent enantioselectivities (up to 99% yield and >99% ee). Control experiments revealed the indispensability of both N-H and O-H in the ligands.

Palladium-catalyzed stereoselective construction of chiral allenes bearing nonadjacent axial and two central chirality.

It is challenging to enantioselectively construct molecules bearing multiple nonadjacent stereocenters, in contrast to those bearing a single stereocenter or adjacent stereocenters. Herein, we report an enantio- and diastereoselective synthesis of substituted chiral allenes with nonadjacent axial and two central chiral centers through a combination of retro-oxa-Michael addition and palladium-catalyzed asymmetric allenylic alkylation. This methodology exhibits good functional-group compatibility, and the corresponding allenylic alkylated compounds, including flavonoid frameworks, are obtained with good yields and diastereoselectivities and excellent enantioselectivities (all >95% ee). Furthermore, the scalability of the current synthetic protocol was proven by performing a gram-scale reaction.

Brønsted acid-catalyzed C6 functionalization of 2,3-disubstituted indoles for construction of cyano-substituted all-carbon quaternary centers.

We report a Brønsted acid-catalyzed C6 functionalization of 2,3-disubstituted indoles with 2,2-diarylacetonitriles for efficient construction of cyano-substituted all-carbon quaternary centers with excellent yields. The synthetic utility was demonstrated by the conversion of the cyano-group which enables the divergent preparation of aldehydes, primary amines and amides. Control experiments suggested that this process involves C-H oxidation of 2,2-diarylacetonitriles to in situ generate δ,δ-disubstituted p-quinone methide intermediates. This protocol provides an efficient method for C6 functionalization of 2,3-disubstituted indoles to construct all-carbon quaternary centers.

Recent advances in transition-metal-catalyzed carbene insertion to C-H bonds.

C-H functionalization has been emerging as a powerful method to establish carbon-carbon and carbon-heteroatom bonds. Many efforts have been devoted to transition-metal-catalyzed direct transformations of C-H bonds. Metal carbenes generated in situ from transition-metal compounds and diazo or its equivalents are usually applied as the transient reactive intermediates to furnish a catalytic cycle for new C-C and C-X bond formation. Using this strategy compounds from unactivated simple alkanes to complex molecules can be further functionalized or transformed to multi-functionalized compounds. In this area, transition-metal-catalyzed carbene insertion to C-H bonds has been paid continuous attention. Diverse catalyst design strategies, synthetic methods, and potential applications have been developed. This critical review will summarize the advance in transition-metal-catalyzed carbene insertion to C-H bonds dated up to July 2021, by the categories of C-H bonds from aliphatic C(sp3)-H, aryl (aromatic) C(sp2)-H, heteroaryl (heteroaromatic) C(sp2)-H bonds, alkenyl C(sp2)-H, and alkynyl C(sp)-H, as well as asymmetric carbene insertion to C-H bonds, and more coverage will be given to the recent work. Due to the rapid development of the C-H functionalization area, future directions in this topic are also discussed. This review will give the authors an overview of carbene insertion chemistry in C-H functionalization with focus on the catalytic systems and synthetic applications in C-C bond formation.

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls.

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

Asymmetric Transfer Hydrogenation of 2,3-Disubstituted Flavanones through Dynamic Kinetic Resolution Enabled by Retro-Oxa-Michael Addition: Construction of Three Contiguous Stereogenic Centers.

A ruthenium-catalyzed asymmetric transfer hydrogenation of 2,3-disubstituted flavanones was developed for the construction of three contiguous stereocenters under basic conditions through a combination of dynamic kinetic resolution and retro-oxa-Michael addition, giving chiral flavanols with excellent enantioselectivities and diastereoselectivities. The reaction proceeded via a base-catalyzed retro-oxa-Michael addition to racemize two stereogenic centers simultaneously in concert with a highly enantioselective ketone transfer hydrogenation step. The asymmetric transfer hydrogenation could be achieved at gram scale without loss of the activity and enantioselectivity.

Palladium-Catalyzed Asymmetric Hydrogenation of Unprotected 3-Substituted Indoles.

A palladium-catalyzed asymmetric hydrogenation of unprotected 3-substituted indoles was developed, providing a series of 3-substituted indolines in excellent yields with ≤94.4:5.6 er. The large sterically hindered bisphosphine ligand played a crucial role in the enantioselective control. In addition, the gram-scale hydrogenation experiment and product derivatizations were performed successfully.

Copper-Catalyzed [4 + 1] Annulation of Enaminothiones with Indoline-Based Diazo Compounds.

A concise synthetic route to spiroindoline-fused S-heterocycles was developed through copper-catalyzed [4 + 1] annulation using enaminothiones as donor-acceptor synthons. Both 3-diazoindolin-2-imines and 3-diazooxindoles were amenable to work as effective C1 building blocks. The reaction proceeds via a copper-catalyzed cascade process involving the in situ generation of copper(I) carbene and C-S/C-C bond formation. This synthetic protocol features the use of readily available substrates, diverse substituent tolerance, and good to excellent yields.

Tunable Construction of Multisubstituted 1,3-Dienes and Allenes via a 1,4-Palladium Migration/Carbene Insertion Cascade.

Efficient palladium-catalyzed vinylic C-H alkenylation and allenylation of gem-disubstituted ethylenes with N-tosylhydrazones of aryl alkyl and diaryl ketones were achieved to access trisubstituted 1,3-dienes and tetrasubstituted allenes, respectively. An aryl to vinyl 1,4-palladium migration/carbene insertion/ß-hydride elimination sequence proceeded to switch the chemo- and regioselectivities to give structurally diverse products. Use of 2-FC6H4OH additive enables enhancement of the reaction efficiency through accelerating the key 1,4-palladium migration process.

Rhodium-Catalyzed Asymmetric Hydrogenation of All-Carbon Aromatic Rings.

Compared with heteroarenes, homogeneous asymmetric hydrogenation of all-carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine-catalyzed asymmetric hydrogenation of all-carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central-chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group. The key to success is the introduction of chiral diphosphine ligands with steric hindrance and strong electron-donating properties. The axially chiral monophosphine ligands could be obtained by simple conversion of the hydrogenation products bearing the phosphine atom.

Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic N-Sulfonylimines via Palladium-Catalyzed Addition of Arylboronic Acids.

A facile method for kinetic resolution of [2.2]paracyclophane-derived cyclic N-sulfonylimines based on palladium-catalyzed addition of arylboronic acids was developed, giving two kinds of planar chiral [2.2]paracyclophane derivatives in excellent diastereoselectivities and up to 99% of enantioselectivities with high selectivity factors (s up to 128).

Nickel-Catalyzed Asymmetric Hydrogenation for Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic N-Sulfonylimines.

Nickel-catalyzed asymmetric hydrogenation for kinetic resolution of [2.2]paracyclophane-derived cyclic N-sulfonylimines was successfully developed. High selectivity factors were observed in most cases (s up to 89), providing the recovered materials and hydrogenation products in good yields with high levels of enantiopurity. The recovered materials and hydrogenation products are useful synthetic intermediates for the synthesis of planar chiral [2.2]paracyclophane-based compounds.

Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of ß-Substituted α-Oxobutyrolactones.

A concise and effective ruthenium-catalyzed asymmetric transfer hydrogenation of ß-substituted α-oxobutyrolactones has been developed, delivering a series of cis-ß-substituted α-hydroxybutyrolactone derivatives with excellent yields, enantioselectivities, and diastereoselectivities. Two consecutive stereogenic centers were constructed in one step through dynamic kinetic resolution under basic conditions. The reaction could be conducted on a gram scale without loss of activity and enantioselectivity. The reductive products could be easily transformed into useful building blocks.

Chiral Phosphoric Acid-Catalyzed Pictet-Spengler Reactions for Synthesis of 5',11'-Dihydrospiro[indoline-3,6'-indolo[3,2-c]qui-nolin]-2-ones Containing Quaternary Stereocenters.

Chiral phosphoric acid-catalyzed Pictet-Spengler reactions of 2-(1H-indolyl)aniline derivatives and isatins by the condensation/cyclization process have been realized. A series of enantioenriched 5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-c]quinolin]-2-ones bearing quaternary stereogenic centers were obtained with excellent yields and up to >99% ee. This protocol was suitable for the Pictet-Spengler reactions of 2-(1-benzyl-5-methyl-1H-pyrrol-2-yl)aniline, and a variety of 1',5'-dihydro-spiro[indoline-3,4'-pyrrolo[3,2-c]quinolin]-2-ones could also be obtained in good yields and up to 88% ee.

Transition-metal mediated carbon-sulfur bond activation and transformations: an update.

Carbon-sulfur bond cross-coupling has become more and more attractive as an alternative protocol to establish carbon-carbon and carbon-heteroatom bonds. Diverse transformations through transition-metal-catalyzed C-S bond activation and cleavage have recently been developed. This review summarizes the advances in transition-metal-catalyzed cross-coupling via carbon-sulfur bond activation and cleavage since late 2012 as an update of the critical review on the same topic published in early 2013 (Chem. Soc. Rev., 2013, 42, 599-621), which is presented by the categories of organosulfur compounds, that is, thioesters, thioethers including heteroaryl, aryl, vinyl, alkyl, and alkynyl sulfides, ketene dithioacetals, sulfoxides including DMSO, sulfones, sulfonyl chlorides, sulfinates, thiocyanates, sulfonium salts, sulfonyl hydrazides, sulfonates, thiophene-based compounds, and C[double bond, length as m-dash]S functionality-bearing compounds such as thioureas, thioamides, and carbon disulfide, as well as the mechanistic insights. An overview of C-S bond cleavage reactions with stoichiometric transition-metal reagents is briefly given. Theoretical studies on the reactivity of carbon-sulfur bonds by DFT calculations are also discussed.

ZnCl2 -Catalyzed [4+1] Annulation of Alkylthio-Substituted Enaminones and Enaminothiones with Sulfur Ylides.

Concise construction of furan and thiophene units has played an important role in the synthesis of potentially bioactive compounds and functional materials. Herein, an efficient Lewis acid ZnCl2 catalyzed [4+1] annulation of alkylthio-substituted enaminones is reported, that is, α-oxo ketene N,S-acetals with sulfur ylides to afford 2-acyl-3-aminofuran derivatives. In a similar fashion, [4+1] annulation of the corresponding enaminothiones, that is, α-thioxo ketene N,S-acetals, with sulfur ylides efficiently proceeded to give multisubstituted 3-aminothiophenes. This method features wide substrate scopes as well as broad functional group tolerance, offering a concise route to highly functionalized furans and thiophenes.