Prochiral Substrates Research Articles

Enantioselective Desymmetrization of 1,3‐Dicarbonyl Compounds through Transition‐Metal‐Catalyzed Intramolecular Cyclization Reactions

AbstractThe development of reliable approaches to construct enantioenriched cyclic ketones bearing multiple stereocenters has attracted intense interest in synthetic chemistry, yet remains a challenging research area due to the difficulties in efficiently controlling the reaction enantioselectivity and diastereoselectivity. Desymmetrization of C2‐symmetric prochiral substrates has witnessed a practical and accessible strategy for creating more than one stereocenters in a single operation. In recent years, enantioselective desymmetrization of 1,3‐dicarbonyl compounds has been developed via transition‐metal‐catalyzed transformations for facile assembly of optically active cyclic ketones bearing congested stereocenters with diverse functionality. In this review, we would like to describe intramolecular enantioselective desymmetrization reactions of 1,3‐dicarbonyl derivatives, including C2‐functional group tethered 1,3‐diketones and 1,3‐diesters. This review is organized according to types of tethered groups, which aims to highlight the recent advances and briefly discuss about future perspectives in this domain.

Kinetic Resolution as a General Approach to Enantioenrichment in Prebiotic Chemistry.

ConspectusThe origin of the single chirality of the chemical building blocks of life remains an intriguing topic of research, even after decades of experimental and theoretical work proposing processes that may break symmetry and induce chiral amplification, a term that may be defined as the enhancement of enantiomeric excess starting from prochiral substrates or from a racemic mixture or a small imbalance between enantiomers. Studies aimed at understanding prebiotically plausible pathways to these molecules have often neglected the issue of chirality, with a focus on the stereochemical direction of these reactions generally being pursued after reaction discovery. Our work has explored how the stereochemical outcome for the synthesis of amino acids and sugars might be guided to rationalize the origin of biological homochirality. The mechanistic interconnection between enantioenrichment in these two groups of molecules provides insights concerning the handedness extant in modern biology. In five separate examples involving the synthesis of life's building blocks, including sugars, RNA precursors, amino acids, and peptides, kinetic resolution emerges as a key protocol for enantioenrichment from racemic molecules directed by chiral source molecules. Several of these examples involve means not only for chiral amplification but also symmetry breaking and chirality transfer across a range of racemic monomer molecules. Several important implications emerge from these studies: one, kinetic resolution of the primordial chiral sugar, glyceraldehyde, plays a key role in a number of different prebiotically plausible reactions; two, the emergence of homochirality in sugars and amino acids is inherently intertwined, with clear synergy between the biological hand of each molecule class; three, the origin story for the homochirality of enzymes and modern metabolism points toward kinetic resolution of racemic amino acids in networks that later evolved to include sophisticated and complete catalytic and co-catalytic cycles; four, a preference for heterochiral ligation forming product molecules that cannot lead to biologically competent polymers can in fact be a driving force for a route to homochiral polymer chains; and five, enantioenrichment in complex mixtures need not be addressed one compound at a time, because kinetic resolution induces symmetry breaking and chirality transfer that may lead to general protocols rather than specific cases tailored to each individual molecule. Such chirality transfer mechanisms perhaps presage strategies utilized in modern biology.Our latest work extends the study of monomer enantioenrichment to the ligation of these molecules into the extended homochiral chains leading to the complex polymers of modern biology. A central theme in all of these reactions is the key role that kinetic resolution of a racemic mixture of amino acids or sugars plays in enabling enantioenrichment under prebiotically plausible conditions. This work has uncovered important trends in symmetry breaking, chirality transfer, and chiral amplification. Kinetic resolution of racemic mixtures emerges as a general solution for chiral amplification in prebiotic chemistry, leading to the single chirality of complex biological molecules and genetic polymers.

Multifunction magnetic chiral MOF composite: A novel post-synthetic super catalyst for enhancing the asymmetric CO2 fixation

Here in, a novel neutral Chiral Metal−Organic Framework (CMOF) composite, Cu(II)-l-proline/TCT/APTES/Fe3O4/MIL-101(Fe) (Cu(II)-HPro/TCT/APTES/Fe3O4/MIL-101(Fe)), has been derived from the chiral Cu(II)-l-proline complex (Cu(II)-HPro) attached to TCT/APTES/Fe3O4 and MIL-101(Fe). Achiral MIL-101(Fe) was chiralized by the incorporation of chiral Cu(II)-HPro complex anchored to TCT/APTES/Fe3O4 using ultrasonic-assisted electrostatic self-assembly technique (postsynthetic modification). The resulted super catalyst has chiral species acting as Lewis base sites, together with two active metal sites (Fe and Cu) acting as Lewis acid centers leading to multifunctionality. Due to chiral auxiliary Lewis bases and Lewis acids, the catalytic activity of the Cu(II)-HPro/TCT/APTES/Fe3O4/MIL-101(Fe) composite was evaluated in asymmetric catalysis of prochiral substrates. This asymmetric super catalyst has proved to be highly active in CO2 fixation reaction at ambient pressure, low-temperature, solvent-free medium with high conversion and enantioselectivity. Based on the results, enantiomeric excess (ee) [97 % (S)], carbonate selectivity (>99 %), and conversion (>99 %) all demonstrate the superior performance of the investigated catalytic system. Furthermore, the magnetic characteristic, together with excellent structure stability, leads to high recyclability for 7 runs without a significant reduction of catalytic activity. The outcomes showed that chiralization of MIL-101(Fe) could occur through a simple and green approach, which may be a practical way to create chiral multifunctionalized metal−organic frameworks (MOFs).

Cordyceps fungus-mediated enantioselective synthesis of chiral alcohol and enhanced biocatalytic efficiency in cyclodextrin/surfactant-buffer system

Asymmetric synthesis of chiral alcohols by biocatalysts holds promising prospect. In this study, a medicinal Cordyceps fungus, namely Tolypocladium inflatum, was adopted as a novel biocatalyst for the synthesis of chiral alcohols. Among the assessed prochiral ketone substrates, T. inflatum exhibited the best catalytic activity towards 1-(4-bromophenyl)−2,2,2-trifluoroethanone (BPFO), yielding a valuable pharmaceutical intermediate (S)−1-(4-bromophenyl)−2,2,2-trifluoroethanol ((S)-BPFL) with >99.9 % enantiomeric excesses (ee). For more efficient biosynthesis of (S)-BPFL, cyclodextrins or surfactants were introduced to the reaction system as additives to strengthen this bioprocess. Among which methyl β-cyclodextrin (MCD) improved cell membrane permeability and alleviated product inhibition, while Triton X-100 enhanced BPFO solubility. Furthermore, synergistic promotion for BPFO bioreduction by MCD and Triton X-100 was observed. Under the optimal reaction conditions, 50 mM BPFO was converted into (S)-BPFL with 89.1 % yield and >99.9 % ee in 12 h, showing 16-fold increase of space-time yield in the developed MCD/Triton X-100-buffer system compared to neat buffer solution. This study illustrated the potential of the enantioselective preparation of chiral alcohols mediated by Cordyceps fungus. Additionally, the biocatalytic efficiency was significantly improved in the constructed synergistic reaction system, and the underlying mechanism was also explored.

Reducing the vicissitudes of heterologous prochiral substrate catalysis by alcohol dehydrogenases through machine learning algorithms

Alcohol dehydrogenases (ADHs) are popular catalysts for synthesizing chiral synthons a vital step for active pharmaceutical intermediate (API) production. They are grouped into three superfamilies namely, medium-chain (MDRs), short-chain dehydrogenase/reductases (SDRs), and iron-containing alcohol dehydrogenases. The former two are used extensively for producing various chiral synthons. Many studies screen multiple enzymes or engineer a specific enzyme for catalyzing a substrate of interest. These processes are resource-intensive and intricate. The current study attempts to decipher the ability to match different ADHs with their ideal substrates using machine learning algorithms. We explore the catalysis of 284 antibacterial ketone intermediates, against MDRs and SDRs to demonstrate a unique pattern of activity. To facilitate machine learning we curated a dataset comprising 33 features, encompassing 4 descriptors for each compound. Subsequently, an ensemble of machine learning techniques viz. Partial Least Squares (PLS) regression, k-Nearest Neighbors (kNN) regression, and Support Vector Machine (SVM) regression, was harnessed. Moreover, the assimilation of Principal Component Analysis (PCA) augmented precision and accuracy, thereby refining and demarcating diverse compound classes. As such, this classification is useful for discerning substrates amenable to diverse alcohol dehydrogenases, thereby mitigating the reliance on high-throughput screening or engineering in identifying the optimal enzyme for specific substrate.

Pd-catalyzed asymmetric carbonyl alkynylation: Synthesis of axial chiral ynones

Ynones are important skeletons in bioactive molecules and valuable building blocks for organic synthesis, thus great efforts have been devoted to their preparation. While, introducing prochiral substrates to construct ynones bearing a chiral framework is unrealized to date. Herein, we reported the first example of Pd/SOP-catalyzed asymmetric carbonylative alkynylation via a non-classical carbonylative Sonogashira-type approach (acyl-Pd(II) species generated from nucleophiles). By using cyclic diaryliodonium salts as prochiral substrates, various axial chiral ynones with good functional group tolerance (39 examples), satisfied yields (71%-96%) and excellent enantioselectivities (generally 94%-99% ee) were produced. Synthesis of bioactive compounds, scale-up experiment and useful transformations were also conducted to demonstrate the utility of this process.

Biocatalytic characterization of an alcohol dehydrogenase variant deduced from Lactobacillus kefir in asymmetric hydrogen transfer

Hydrogen transfer biocatalysts to prepare optically pure alcohols are in need, especially when it comes to sterically demanding ketones, whereof the bioreduced products are either essential precursors of pharmaceutically relevant compounds or constitute APIs themselves. In this study, we report on the biocatalytic potential of an anti-Prelog (R)-specific Lactobacillus kefir ADH variant (Lk-ADH-E145F-F147L-Y190C, named Lk-ADH Prince) employed as E. coli/ADH whole-cell biocatalyst and its characterization for stereoselective reduction of prochiral carbonyl substrates. Key enzymatic reaction parameters, including the reaction medium, evaluation of cofactor-dependency, organic co-solvent tolerance, and substrate loading, were determined employing the drug pentoxifylline as a model prochiral ketone. Furthermore, to tap the substrate scope of Lk-ADH Prince in hydrogen transfer reactions, a broad range of 34 carbonylic derivatives was screened. Our data demonstrate that E. coli/Lk-ADH Prince exhibits activity toward a variety of structurally different ketones, furnishing optically active alcohol products at the high conversion of 65–99.9% and in moderate-to-high isolated yields (38–91%) with excellent anti-Prelog (R)-stereoselectivity (up to >99% ee) at substrate concentrations up to 100 mM.

StereoPHIP: Stereoselective Parahydrogen-Induced Polarization.

Parahydrogen-induced polarization (PHIP) followed by polarization transfer to 13 C is a rapidly developing technique for the generation of 13 C-hyperpolarized substrates. Chirality plays an essential role in living systems and differential metabolism of enantiomeric pairs of metabolic substrates is well documented. Inspired by asymmetric hydrogenation, here we report stereoPHIP, which involves the addition of parahydrogen to a prochiral substrate with a chiral catalyst followed by polarization transfer to 13 C spins. We demonstrate that parahydrogen could be rapidly added to the prochiral precursor to both enantiomers of lactic acid (D and L), with both the (R,R) and (S,S) enantiomers of a chiral rhodium(I) catalyst to afford highly 13 C-hyperpolarized (over 20 %) L- and D-lactate ester derivatives, respectively, with excellent stereoselectivity. We also show that the hyperpolarized 1 H signal decays obtained with the (R,R) and (S,S) catalysts were markedly different. StereoPHIP expands the scope of conventional PHIP to the production of 13 C hyperpolarized chiral substrates with high stereoselectivity.

StereoPHIP: Stereoselective Parahydrogen‐Induced Polarization

AbstractParahydrogen‐induced polarization (PHIP) followed by polarization transfer to 13C is a rapidly developing technique for the generation of 13C‐hyperpolarized substrates. Chirality plays an essential role in living systems and differential metabolism of enantiomeric pairs of metabolic substrates is well documented. Inspired by asymmetric hydrogenation, here we report stereoPHIP, which involves the addition of parahydrogen to a prochiral substrate with a chiral catalyst followed by polarization transfer to 13C spins. We demonstrate that parahydrogen could be rapidly added to the prochiral precursor to both enantiomers of lactic acid (D and L), with both the (R,R) and (S,S) enantiomers of a chiral rhodium(I) catalyst to afford highly 13C‐hyperpolarized (over 20 %) L‐ and D‐lactate ester derivatives, respectively, with excellent stereoselectivity. We also show that the hyperpolarized 1H signal decays obtained with the (R,R) and (S,S) catalysts were markedly different. StereoPHIP expands the scope of conventional PHIP to the production of 13C hyperpolarized chiral substrates with high stereoselectivity.

Interrogating the Crucial Interactions at Play in the Chiral Cation-Directed Enantioselective Borylation of Arenes.

Rendering a common ligand scaffold anionic and then pairing it with a chiral cation represents an alternative strategy for developing enantioselective versions of challenging transformations, as has been recently demonstrated in the enantioselective borylation of arenes using a quinine-derived chiral cation. A significant barrier to the further generalization of this approach is the lack of understanding of the specific interactions involved between the cation, ligand, and substrate, given the complexity of the system. We have embarked on a detailed computational study probing the mechanism, the key noncovalent interactions involved, and potential origin of selectivity for the desymmetrizing borylation of two distinct classes of substrate. We describe a deconstructive, stepwise approach to tackling this complex challenge, which involves building up a detailed understanding of the pairwise components of the nominally three component system before combining together into the full 263-atom reactive complex. This approach has revealed substantial differences in the noncovalent interactions occurring at the stereodetermining transition state for C-H oxidative addition to iridium for the two substrate classes. Each substrate engages in a unique mixture of diverse interactions, a testament to the rich and privileged structure of the cinchona alkaloid-derived chiral cations. Throughout the study, experimental support is provided, and this culminates in the discovery that prochiral phosphine oxide substrates, lacking hydrogen bond donor functionality, can also give very encouraging levels of enantioselectivity, potentially through direct interactions with the chiral cation. We envisage that the findings in this study will spur further developments in using chiral cations as controllers in asymmetric transition-metal catalysis.

Application of alkane-diyl based chiral phosphine-aminophosphine (P-NP) and thioether-aminophosphine (S-NP) ligands in Rh-catalyzed asymmetric hydrogenation

Rhodium(I)-complexes of five new alkane-diyl based phosphine-aminophosphine (P,NP) type chiral ligands (Ph2PCH(CH3)(CH2)nCH(CH3)N(R1)PR22 (n = 0-2, R1 = Me, Et, iPr, R2 = Ph, Cy)) and a thioether-aminophosphine type compound ((S,S)-PhSCH(CH3)(CH2)CH(CH3)N(iPr)PPh2) have been synthesized. The investigation of the coordination chemistry of structurally analogous systems by NMR and IR spectroscopy and in one case by X-ray crystallography enabled the comparison of the effect of (i) the ligand backbone length, (ii) the N-substituent, (iii) the type of the coordinating functionality and (iv) the P-substituent in aminophosphine moiety on the stereo-electronic properties of the complexes. The novel Rh-compounds were tested in the asymmetric hydrogenation of a broad range of prochiral substrates including dimethyl itaconate, dehydroaminoacid derivatives and α,β-unsaturated enol ester phosphonates. Catalysts modified by the pentane-2,4-diyl based phosphine-aminophosphine ligands provided superior catalytic performance compared to the analogous butane- and hexane-diyl based systems and thioether containing compound. Most importantly, by the proper choice of the N-substituent outstanding enantioselectivities could be obtained in the asymmetric hydrogenation of acetamidocinnamic acid derivatives (up to 98% ee) and enol ester phosphonates (up to 97% ee).

Catalytic Asymmetric Conjugate Reduction.

Enantioselective reduction reactions are privileged transformations for the construction of trisubstituted stereogenic centers. While these include established synthetic strategies, such as asymmetric hydrogenation, methods based on the enantioselective addition of hydridic reagents to electrophilic prochiral substrates have also gained importance. In this context, the asymmetric conjugate reduction (ACR) of α,β-unsaturated compounds has become a convenient approach for the synthesis of chiral compounds with trisubstituted stereocenters in α-, β-, or γ-position to electron-withdrawing functional groups. Because such activating groups are diverse and amenable of further derivatizations, ACRs provide a general and powerful synthetic entry towards a variety of valuable chiral building blocks. This Review provides a comprehensive collection of catalytic ACR methods involving transition-metal, organic, and enzymatic catalysis since its first versions dating back to the late 1970s.

Catalytic Asymmetric Conjugate Reduction

AbstractEnantioselective reduction reactions are privileged transformations for the construction of trisubstituted stereogenic centers. While these include established synthetic strategies, such as asymmetric hydrogenation, methods based on the enantioselective addition of hydridic reagents to electrophilic prochiral substrates have also gained importance. In this context, the asymmetric conjugate reduction (ACR) of α,β‐unsaturated compounds has become a convenient approach for the synthesis of chiral compounds with trisubstituted stereocenters in α‐, β‐, or γ‐position to electron‐withdrawing functional groups. Because such activating groups are diverse and amenable of further derivatizations, ACRs provide a general and powerful synthetic entry towards a variety of valuable chiral building blocks. This Review provides a comprehensive collection of catalytic ACR methods involving transition‐metal, organic, and enzymatic catalysis since its first versions dating back to the late 1970s.

Sulfoxide-Directed or 3d-Metal Catalyzed C–H Activation and Hypervalent Iodines as Tools for Atroposelective Synthesis

ConspectusThe expanding applications of atropisomeric compounds combined with the growing diversity of such chiral molecules translate into an urgent need for innovative synthetic strategies allowing their rapid, efficient, and sustainable synthesis. Recently, the C-H activation approach has provided new opportunities for synthesizing axially chiral compounds. The two complementary approaches allowing implementation of the C-H activation methodology toward the synthesis of the chiral molecules imply either ortho-functionalization of the preexisting prochiral or atropo-unstable biaryl substrates or direct C-H arylation of sterically encumbered aromatics. The first approach required the preinstallation of a directing group on a biaryl precursor, which drastically limits the diversity of thus generated products. To tackle this important synthetic limitation, we have envisioned using a chiral sulfoxide as both directing group and chiral auxiliary. Indeed, in addition to efficiently coordinating the Pd-catalyst thus allowing chiral induction, the sulfoxide moiety can be easily removed, via the sulfoxide/lithium exchange, after the C-H activation step, thus guaranteeing an almost unlimited postdiversification of the atropisomeric products. The efficiency and generality of this concept could be illustrated by developing atropo-diastereoselective oxidative Heck reaction, direct acetoxylation, and iodination, as well as direct arylation. Besides, the synthetic utility of this methodology was demonstrated by designing an expedient synthesis of a direct steganone precursor. This unique transformation also allowed us to build up unprecedented triaryl scaffolds with two perfectly controlled chiral axes, original chiral skeletons for new ligand design. While considering the atroposelective direct arylations, the clear antagonism between the harsh reaction conditions frequently required for the coupling of two sterically hindered compounds and the atropo-stability of the new product, resulted in the scarcity of such transformations. To solve this fundamental challenge, we have focused on the application of a low-valent cobalt catalyst, prompted to catalyze C-H activation of indoles at the C2 position under extremely mild reaction conditions (room temperature). Accordingly, atroposelective C2-arylation of indoles could be achieved using an original carbene ligand and delivering the uncommon atropoisomerically pure indoles in excellent yields and enantioselectivities. Detailed combined experimental and theoretical mechanistic studies shed light on the mechanism of this transformation, providing strong evidence regarding the origin of the enantioselectivity. Finally, the antagonism between steric hindrance required to guarantee the atropo-stability of a molecule and harsh reaction conditions required to couple two partners is a strong limitation not only for the development of atroposelective C-H arylation reaction but also for the development of direct synthesis of the C-N axially chiral compounds. Despite the long history and incredible advances achieved in Ullmann-Goldberg and Buchwald-Hartwig couplings, atroposelective versions of such transformations have remained unprecedented until recently. Our idea to tackle this challenging issue consisted in using hypervalent iodines as highly reactive coupling partners, thus allowing the desired N-arylations to occur at room temperature. This hypothesis could be validated by reporting first atropo-diastereoselective Cu-catalyzed N-arylation, using sulfoxide λ3-iodanes as the coupling partners. Subsequently, the enantioselective version of this atroposelective N-arylation was successfully established by using a chiral Cu-complex bearing a BOX ligand. In conclusion, we report herein designing tailored-made solutions to provide new synthetic strategies to construct the atropisomeric molecules, including biaryls and C-N axially chiral molecules.

Rhodium‐Catalyzed Dynamic Kinetic Asymmetric Hydrosilylation to Access Silicon‐Stereogenic Center

AbstractStrategies on the construction of enantiomerically pure silicon‐stereogenic silanes generally relies on desymmetrization of prochiral and symmetric substrates. However, dynamic kinetic asymmetric transformations of organosilicon compounds have remained underdeveloped and unforeseen owing to a lack of an effective method for deracemization of the static silicon stereocenters. Here we report the first Rh‐catalyzed dynamic kinetic asymmetric intramolecular hydrosilylation (DyKAH) with “silicon‐centered” racemic hydrosilanes that enables the facile preparation of silicon‐stereogenic benzosiloles in good yields and excellent enantioselectivities. The special rhodium catalyst controlled by non‐diastereopure‐type mixed phosphine‐phosphoramidite ligand with axial chirality and multiple stereocenters can induce enantioselectivity efficiently in this novel DyKAH reaction. Density functional theory (DFT) calculations suggest that the amide moiety in chiral ligand plays important role in facilitating the SN2 substitution of chloride ion to realize the chiral inversion of silicon center.

Rhodium-Catalyzed Dynamic Kinetic Asymmetric Hydrosilylation to Access Silicon-Stereogenic Center.

Strategies on the construction of enantiomerically pure silicon-stereogenic silanes generally relies on desymmetrization of prochiral and symmetric substrates. However, dynamic kinetic asymmetric transformations of organosilicon compounds have remained underdeveloped and unforeseen owing to a lack of an effective method for deracemization of the static silicon stereocenters. Here we report the first Rh-catalyzed dynamic kinetic asymmetric intramolecular hydrosilylation (DyKAH) with "silicon-centered" racemic hydrosilanes that enables the facile preparation of silicon-stereogenic benzosiloles in good yields and excellent enantioselectivities. The special rhodium catalyst controlled by non-diastereopure-type mixed phosphine-phosphoramidite ligand with axial chirality and multiple stereocenters can induce enantioselectivity efficiently in this novel DyKAH reaction. Density functional theory (DFT) calculations suggest that the amide moiety in chiral ligand plays important role in facilitating the SN 2 substitution of chloride ion to realize the chiral inversion of silicon center.

Intracellular Assembly of Interacting Enzymes Yields Highly-Active Nanoparticles for Flow Biocatalysis.

All-enzyme hydrogel (AEH) particles with a hydrodynamic diameter of up to 120 nm were produced intracellularly with an Escherichia coli-based in vivo system. The inCell-AEH nanoparticles were generated from polycistronic vectors enabling simultaneous expression of two interacting enzymes, the Lactobacillus brevis alcohol dehydrogenase (ADH) and the Bacillus subtilis glucose-1-dehydrogenase (GDH), fused with a SpyCatcher or SpyTag, respectively. Formation of inCell-AEH was analyzed by dynamic light scattering and atomic force microscopy. Using the stereoselective two-step reduction of a prochiral diketone substrate, we show that the inCell-AEH approach can be advantageously used in whole-cell flow biocatalysis, by which flow reactors could be operated for >4 days under constant substrate perfusion. More importantly, the inCell-AEH concept enables the recovery of efficient catalyst materials for stable flow bioreactors in a simple and economical one-step procedure from crude bacterial lysates. We believe that our method will contribute to further optimization of sustainable biocatalytic processes.

Recent Advances in Asymmetric Transformations of Unactivated Alkanes and Cycloalkanes through Direct C—H Functionalization

Comprehensive SummaryThe direct conversion of unactivated alkanes and cycloalkanes into structurally diverse molecules through aliphatic C—H functionalization is a useful process, which has attracted intense interest from academia and industry. Methods to control chemo‐ and site‐selectivity, combined with asymmetric catalysis, provide appealing access to high value‐added enantiomer‐enriched compounds but are far less developed. This review focuses on recent progress in (i) asymmetric reactions of alkanes or cycloalkanes with prochiral substrates which generate a stereocenter adjacent to the cleaved C(sp3)–H bond, and (ii) C(sp3)–H enantiodiscriminatory reactions creating a new stereogenic center on the carbon of a cleaved C(sp3)–H bond. Elegant strategies are discussed, including (a) metal carbene‐induced C—H insertions by chiral rhodium catalysts, (b) metal‐oxo‐mediated C—H oxidation by biomimetic manganese catalysts, (c) enzyme catalysis by cytochromes P450 variants, and (d) dual catalysis by a photocatalyst and a chiral Lewis acid (CLA) or a chiral phosphoric acid (CPA). These catalytic systems can not only precisely recognize primary, secondary and tertiary C—H bonds at specific positions in alkanes and cycloalkanes, but also support a high level of stereoselectivity in the reactions. It is expected that the advances will stimulate further progress in asymmetric catalysis, synthetic methodology, pharmaceutical development and industrial processes.

Development of a new chemo-enzymatic catalytic route for synthesis of (S)− 2-chlorophenylglycine

(S)-2-chlorophenylglycine ((S)-CPG) is a key chiral intermediate for the synthesis of clopidogrel. Herein, a novel, efficient and environmentally friendly chemo-enzymatic route for the preparation of optically pure (S)-CPG was developed. A straightforward chemical synthesis of the corresponding prochiral keto acid substrate (2-chlorophenyl)glyoxylic acid (CPGA) was developed with 91.7% yield, which was enantioselectively aminated by leucine dehydrogenase (LeuDH) to (S)-CPG. Moreover, protein engineering of LeuDH was performed via directed evolution and semi-rational design. A beneficial variant EsLeuDH-F362L with enlarged substrate-binding pocket and increased hydrogen bond between K77 and substrate CPGA was constructed, which exhibited 2.1-fold enhanced specific activity but decreased thermal stability. Coupled with a glucose dehydrogenase from Bacillus megaterium (BmGDH) for NADH regeneration, EsLeuDH-F362L completely converted up to 0.5 M CPGA to (S)-CPG in 8 h at 40 °C.

Substrate selectivity and kinetic studies of (S)-specific alcohol dehydrogenase purified from Candida parapsilosis ATCC 7330

Biocatalytic reduction catalysed by alcohol dehydrogenases is a valuable tool for asymmetric synthesis of chiral alcohols. This study reports the broad substrate specificity of NADH dependent (S) - specific alcohol dehydrogenase (S-ADH) purified from Candida parapsilosis ATCC 7330. The substrates for this enzyme include aliphatic and aromatic ketones, cyclic and diketones, aldehydes, ketoesters, primary and secondary alcohols. The kinetic studies of different substrates indicate that ketones and secondary alcohols are the most preferred substrates of S-ADH with highest catalytic efficiencies reported for reduction of acetone (4153 s−1mM−1) and oxidation of 2-propanol (1358 s−1mM−1). The double reciprocal plots obtained for varied concentrations of acetophenone (0.2–16 mM) at a fixed concentration of NADH (0.05, 0.1 and 0.2 mM) and with varied concentrations of NADH (0.01–0.2 mM) at a fixed concentration of acetophenone (1, 4, 8 and 16 mM) showed intersecting lines indicating sequential kinetic mechanism. S-ADH follows Prelog's stereopreference in reducing prochiral carbonyl substrates to yield (S)-alcohols with >99% enantiomeric excess using a simple coupled substrate approach for cofactor recycling.