Chiral Products Research Articles

An Engineered Imine Reductase for Highly Diastereo‐ and Enantioselective Synthesis of β‐Branched Amines with Contiguous Stereocenters

Abstractβ‐Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo‐ and enantioselective biocatalytic approach for preparing a broad range of β‐branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution‐asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild‐type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9 % ee, >99 : 1 dr, and >99 % conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74 % yield, >99.9 % ee, and 98 : 2 dr at a challenging substrate loading of 110 g L−1. Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution‐asymmetric reductive amination reaction system.

Rh(I)/Sulfoxide-Imine-Olefin Complex Catalyzed Enantioselective Allylic Alkylation of 2-Fluoromalonate: Synthesis of Chiral α-Fluorolactone Bearing Vicinal Stereogenic Centers.

Highly enantioselective Rh-catalyzed allylic substitution of the racemic branched allylic substrates with 2-fluoromalonate was realized enabled by a novel chiral sulfoxide-imine-olefin ligand under mild reaction conditions. The utilization of CuSO4 is beneficial for improving the enantioselectivity. Notably, the chiral fluoro-containing allyl products can be employed in a selective cyclic esterification to form chiral α-fluorolactone bearing vicinal stereogenic centers.

Engineering Neuroglobin for Synthesis of Chiral Organoborons via Carbene B-H Insertion.

Organoborons have recently received much attention, while a biocatalytic platform for the synthesis of chiral organoborons is limited only to Rma cytochrome c. In this study, we exploited the other heme protein, neuroglobin (Ngb), and engineered a quadruple mutant, A15C/H64G/V68F/F28M Ngb, by redesigning the heme active site using the structural information on A15C Ngb and molecular docking studies. The enzyme was shown to be efficient in catalyzing carbene transfer B-H insertion reactions between pyridine/quinoline boranes and benzyl 2-diazopropanoates and their derivatives (29 examples). The designed cavity in the heme distal site favors the binding of large volume substrates such as those containing a quinoline, naphthyl, or biphenyl group. As further determined by the X-ray crystallography of 6c, the chiral products are in the R-configuration, with up to 98:2 e.r. Furthermore, both the whole cell and cell lysate containing the enzyme are reactive toward the B-H insertion reactions. This study presents a convenient biocatalytic platform that may be generally applicable for the synthesis of functional chiral organoborons.

A Dual Role for the N-Perfluorobutanesulfinamide Auxiliary in an Asymmetric Decarboxylative Mannich Reaction.

Herein, we demonstrate that the enhanced electrophilicity of N-perfluorobutanesulfinamide auxiliary-derived imines enables a highly selective decarboxylative Mannich reaction under mild conditions. The molecular sieves-mediated transformation tolerates a broad substrate scope and produces chiral β-amino thioesters in high yield. Additionally, we demonstrate that the N-perfluoroalkyl sulfinyl group can function as a phase tag for fluorous purification, thus enabling the rapid isolation of the chiral amine products by solid-phase extraction. The synthetic utility of this method is illustrated by the synthesis of sitagliptin, ruspolinone, and the natural product negamycin.

Chemodivergent Parallel Kinetic Resolution of Paracyclophanes: Enantiomer Fishing with Different Substrates

AbstractAn unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N‐heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio‐ and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.

Chemodivergent Parallel Kinetic Resolution of Paracyclophanes: Enantiomer Fishing with Different Substrates.

An unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N-heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio- and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.

Catalyst Control over S(IV)-stereogenicity via Carbene-derived Sulfinyl Azolium Intermediates.

Stereoselective synthesis utilizing small-molecule catalysts, particularly N-heterocyclic carbene (NHC), has facilitated swift access to enantioenriched molecules through diverse activation modes and NHC-bound reactive intermediates. While carbonyl derivatives, imines, and "activated" alkenes have been extensively investigated, the exploration of heteroatom-centered analogues of NHC-bound intermediates has long been neglected, despite the significant potential for novel chemical transformations they offer once recognized. Herein, we disclose a carbene-catalyzed new activation mode by generating unique sulfinyl azolium intermediates from carbene nucleophilic addition to in situ-generated mixed sulfinic anhydride intermediates. Combined experimental and computational mechanistic investigations pinpoint the chiral NHC-catalyzed formation of sulfinyl azolium intermediate as the enantio-determining step. The novel "S"-based carbene reactive intermediate imparts high efficiency for the catalytic construction of sulfur-stereogenic compounds, giving rise to sulfinate esters with high yields and enantioselectivities under mild conditions. Notably, distinct from most of the NHC-catalyzed enantioselective transformations focusing on the "C" central chiral products, our study realizes a unique carbene-catalyst control over chiral "S" stereocenters via direct asymmetric S-O bond formation for the first time. Furthermore, these sulfinyl-containing products could serve as versatile synthetic platforms for enantioenriched S-stereogenic functional molecules and exhibit remarkable antibacterial activities against rice plant pathogens, which is valuable for the development of novel agrochemical agents.

Synthesis of axially chiral biaryls via Pd(II)-catalyzed direct C(sp2)−H olefination

Herein, a protocol for the construction of axially chiral biaryls via Pd-catalyzed direct C–H olefination of 1-arylisoquinoline N-oxides through kinetic resolution have been uncovered. The atroposelective C–H olefination of 1-arylisoquinoline N-oxides is achieved with alkenes such as acrylates, styrenes, phenylvinyl sulfone, acrylonitrile, and maleimides. The commercially available, cost-effective, and bench-stable chiral mono-protected amino acid is successfully utilized as the chiral ligand to achieve atroposelective products via kinetic resolution. The high conformational stability of the axially chiral products observed from the DFT calculations, shows their excellent stability. A plausible mechanism has been proposed based on the preliminary mechanistic studies, which was further evidenced by the DFT calculations.

Catalytic Enantioselective Propargylation of Pyrazolones by Amide-Based Phase-Transfer Catalysts.

In this paper, we developed a highly enantioselective alkylation of 4-substituted pyrazolones catalyzed by phase-transfer catalysis. Cheap halohydrocarbons were employed as electrophilic alkylationg agents, and propargyl, allyl, and benzyl products with all-carbon quaternary stereocenters were afforded with excellent enantioselectivities and good yields. We found that the unique structures of the catalyst (hydrogen bond donors of the C-9 hydroxyl group and amide group, the triphenyl at the NH-position) were important for good enantioselectivity. Furthermore, chiral propargyl products could be easily connected to azide molecules by click cycloaddition, which offers unique opportunities to obtain structurally diverse chiral pyrazolones.

Chiral Bioelectrocatalytic Oxidations Driven By Electrocatalytic Oxygen Reduction and Horseradish Peroxidase or Cytochrome P450

Biocatalysis, the use of enzymes for synthesis, has emerged as a powerful tool for synthesis of chiral molecules in pharmaceutical and fine chemical industries. Natural enzymes offer inherent stereoselectivity, making them attractive catalysts for this purpose. Peroxidases and cytochrome P450s enzymes utilize an iron-heme cofactor to perform a diverse array of chemical transformations including CH2 hydroxylation, epoxidations, and sulfur-oxidations. Here, we report chiral biocatalytic oxidations in microemulsion media driven by horseradish peroxidase (HRP) coupled with a synthetic Cu2+-polymer electrocatalyst to convert O2 to H2O2. This tandem system uses crosslinked layer-by-layer (LBL) films of polyelectrolytes with Cu2+- poly(2-hydroxy-3-dipicolylamino) propyl methacrylate (Py-PGMADPA) to drive O2 reduction. Peroxide in turn activates HRP crosslinked in LbL films on magnetic beads (MB) to biocatalytically oxidize styrene, ethylbenzene, and methyl phenylacetate to chiral products. R-stereoisomers of these reactants were selectively formed with a high enantiomeric excess of > 80%. Conductive microemulsion reaction media are used to provide solubility to the non-polar reactants and water to hydrate the enzymes to function. The enzyme films show high thermal stability and high chiral selectivity up to 90 °C. A second synthetic goal was to compare chiral products of reactions catalyzed by cyt P450’s natural catalytic pathway mimicked by electrocatalysis versus via electrochemical generation of H2O2. We immobilized baculosome-P450s in LBL films with polystyrene sulfonate for the natural catalytic pathway, and for peroxide activation crosslinked P450 LbL on magnetic beads. These synthetic hybrid approaches open new doors to designing biocatalytic syntheses using an electrochemical driving force. Keywords: Biocatalysis, organic syntheses, cytochrome P450, horseradish peroxidase, regioselective and stereoselective oxidation

An Engineered Imine Reductase for Highly Diastereo- and Enantioselective Synthesis of β-Branched Amines with Contiguous Stereocenters.

β-Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo- and enantioselective biocatalytic approach for preparing a broad range of β-branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution-asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild-type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9% ee, >99:1 dr, and >99% conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74% yield, >99.9% ee, and 98:2 dr at a challenging substrate loading of 110 g L-1. Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution-asymmetric reductive amination reaction system.

Enantioselective Rh‐Catalyzed Hydroboration of Dialkyl Ketone‐Derived Silyl Enol Ethers

AbstractA Rh‐catalyzed asymmetric hydroboration of dialkyl ketone‐derived silyl enol ethers with HBpin has been developed using a commercially available catalyst and ligand ([RhCl (cod)]2 and MeO‐BIBOP). A variety of silyl enol ethers undergo this asymmetric transformation, providing the corresponding products with high enantioselectivity (up to 97 : 3 % er). In addition, the utility of this protocol is demonstrated by the versatile transformation of chiral borylether products to a range of valuable derivatives.

Stereoconvergent and Enantioselective Synthesis of Z-Homoallylic Alcohols via Nickel-Catalyzed Reductive Coupling of Z/E-1,3-Dienes with Aldehydes.

Stereoconvergent reactions enable the transformation of mixed stereoisomers into well-defined, chiral products─a crucial strategy for handling Z/E-mixed olefins, which are common but challenging substrates in organic synthesis. Herein, we report a stereoconvergent and highly enantioselective method for synthesizing Z-homoallylic alcohols via the nickel-catalyzed reductive coupling of Z/E-mixed 1,3-dienes with aldehydes. This process is enabled by an N-heterocyclic carbene ligand characterized by C2-symmetric backbone chirality and bulky 2,6-diisopropyl N-aryl substituents. Our method achieves excellent stereocontrol over both enantioselectivity and Z-selectivity in a single step, producing chiral Z-homoallylic alcohols that are valuable in natural products and pharmaceuticals.

Phosphazene-Catalyzed Cascade Esterification/Stereoselective Aza-Michael Addition of Chiral β-Trifluoromethyl-α,β-unsaturated N-Acylated Oxazolidin-2-ones

AbstractUpon treatment of chiral β-trifluoromethyl-α,β-unsaturated N-acylated oxazolidin-2-ones with a range of alcohols using phosphazene base as a catalyst, the unexpected cascade esterification/stereoselective aza-Michael addition was observed. The reactions proceeded with high diastereoselectivities (up to >99:1) to give a series of enantioenriched aza-Michael addition products in good to high yields. The structure and stereochemistry of the representative aza-Michael adduct were confirmed by X-ray crystal structure analysis. The plausible mechanism was proposed on the basis of the experimental results.The synthetic transformations of chiral aza-Michael addition products were also demonstrated highlighting the synthetic application of the present work.

Unusual Cascade Reactions of 8-Acetoxy-6-hydroxymethyllimonene with Salicylic Aldehydes: Diverse Oxygen Heterocycles from Common Precursors.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

Rhodium-Catalyzed Enantioselective Intramolecular Hydroalkoxylation of Allenes and Application in the Total Synthesis of (R,R,R)-α-Tocopherol.

We report herein of a novel, enantioselective and rhodium- catalyzed cyclisation of allenyl alcohols towards chiral α-vinylic, cyclic ethers employing a rhodium/(R,R)-Me-ferrocelane catalyst. The corresponding chiral cyclic products were obtained in general high yields and enantioselectivities. The synthetic value of our obtained products was further exemplified by transformations of the allylic ether function. Furthermore, applying our newly developed method in our previously reported route towards the total synthesis of (R,R,R)-α-tocopherol, we accomplished a significantly improved 2nd generation synthesis of the chromane building providing a total number of 13 steps and an overall total yield of 27 %.

Thermally Stable P-Chiral Supramolecular Phosphines, their Self-Assembly and Implication in Rh-Catalyzed Asymmetric Hydrogenation.

P-chiral supramolecular phosphine ligands are crucial for asymmetric transformations, but their synthesis is tedious. We report a one-step synthesis of thermally stable P-chiral supramolecular phosphines and their performance in the asymmetric hydrogenation of functionalized alkenes. A rational designing and synthesis of (R, R)-QuinoxP* ligated palladium complex (Pd-2) in excellent yield is reported. This Pd-2 catalyzed a direct P-C coupling of 2,3-dihydro-1-H-phosphindole (A1)/1,2,3,4-tetrahydrophosphindoline (A2) with 1-(3-iodophenyl)urea (B1)/2-iodo /6-hydroxy pyridine (B2) and,produced corresponding ligands L1-L3. The P-C coupling between A1 and B2 produced 6-(2,3-dihydro-1H-phosphindol-1-yl)pyridine-2(1H)-one (L2) with an excellent enantiomeric excess of up to 99 %. L2 was found to be remarkably stable even at 150 °C and did not oxidize/hydrolyze for at least 24 hours in open air. Such thermal stability and an impediment to oxidation are unprecedented. L2 self-assembled and produced L2-C1 (Pt), L2-C2(Pd), and L2-C3(Rh) assemblies. The utility of the self-assembled P-chiral ligand was demonstrated in the Rh-catalyzed asymmetric hydrogenation (AH) of functionalized olefins. The L2-C3 catalyzed AH of functionalized alkenes and delivered chiral products with excellent enantioselectivity of >99 %. A small library of 16 substrates was subjected to AH using L2-C3 to produce chiral compounds with excellent conversion and ee.

Catalytic Enantioselective Synthesis of Axially Chiral Diaryl Ethers Via Asymmetric Povarov Reaction Enabled Desymmetrization.

Axially chiral diaryl ethers represent a distinct class of atropisomers, characterized by a unique dual C─O axes system, which have been found in a variety of natural products, pharmaceuticals, and ligands. However, the catalytic enantioselective synthesis of these atropoisomers poses significant challenges, due to the difficulty in controlling both chiral C─O axes, and their more flexible conformations. Herein, an efficient protocol for catalytic enantioselective synthesis of axially chiral diaryl ethers is presented using organocatalyzed asymmetric Povarov reaction-enabled desymmetrization, followed by aromatizations. This method yields a wide range of novel quinoline-based diaryl ether atropoisomers in good yields and high enantioselectivities. Notably, various aromatization protocols are developed, resulting in a diverse set of polysubstituted quinoline-containing diaryl ether atropisomers. Thermal racemization studies suggested excellent configurational stabilities for these novel diaryl ether atropisomers (with racemization barriers up to 38.1kcalmol-1). Moreover, this research demonstrates for the first time that diaryl ether atropisomers lacking the bulky t-Bu group can still maintain a stable configuration, challenging the prior knowledge in the field. The fruitful derivatizations of the functional group-rich chiral products further underscore the value of this method.

2.2]Benzoindenophane-Based Chiral Indenyl Ligands: Design, Synthesis, and Applications in Asymmetric C-H Activation.

Development of chiral indenyl ligands for asymmetric C-H activation is a longstanding challenge, and extremely few successes have been achieved. In this paper, we describe a class of readily accessible, facilely tunable and user-friendly chiral indenyl ligands featuring a [2.2]benzoindenophane skeleton via a divergent synthesis strategy. The corresponding chiral indenyl rhodium catalysts were successfully applied in the asymmetric C-H activation reaction of O-Boc hydroxybenzamide with alkenes to give various chiral dihydroisoquinolone products (up to 97 % yield, up to 98 % ee). Moreover, the asymmetric C-H activation reaction of carboxylic acids with alkynes was also successfully accomplished, providing a range of axially chiral isocoumarins (up to 99 % yield, up to 94 % ee). Notably, this represents the first example of enantioselective transition metal catalyzed C(sp2)-H activation/oxidative coupling of benzoic acids with internal alkynes to construct isocoumarins. Given many attractive features of this class of indenyl ligands, such as convenient synthesis, high tunability and exclusive face-selectivity of coordination, its applications in more catalytic asymmetric C-H activation and in other asymmetric catalysis are foreseen.

2.2]Benzoindenophane‐Based Chiral Indenyl Ligands: Design, Synthesis, and Applications in Asymmetric C−H Activation

AbstractDevelopment of chiral indenyl ligands for asymmetric C−H activation is a longstanding challenge, and extremely few successes have been achieved. In this paper, we describe a class of readily accessible, facilely tunable and user‐friendly chiral indenyl ligands featuring a [2.2]benzoindenophane skeleton via a divergent synthesis strategy. The corresponding chiral indenyl rhodium catalysts were successfully applied in the asymmetric C−H activation reaction of O‐Boc hydroxybenzamide with alkenes to give various chiral dihydroisoquinolone products (up to 97 % yield, up to 98 % ee). Moreover, the asymmetric C−H activation reaction of carboxylic acids with alkynes was also successfully accomplished, providing a range of axially chiral isocoumarins (up to 99 % yield, up to 94 % ee). Notably, this represents the first example of enantioselective transition metal catalyzed C(sp2)−H activation/oxidative coupling of benzoic acids with internal alkynes to construct isocoumarins. Given many attractive features of this class of indenyl ligands, such as convenient synthesis, high tunability and exclusive face‐selectivity of coordination, its applications in more catalytic asymmetric C−H activation and in other asymmetric catalysis are foreseen.