Chiral Vicinal Diols Research Articles

Asymmetric permanganate dihydroxylation of enoates: substrate scope, mechanistic insights and application in bicalutamide synthesis

Chiral cinchoninium catalysed permanganate dihydroxylation of enoates with different substitution types, including challenging tetrasubstituted ones, provides good yields of chiral vicinal diols in up to 98% ee.

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review.

Sharpless asymmetric dihydroxylation is an important reaction in the enantioselective synthesis of chiral vicinal diols that involves the treatment of alkene with osmium tetroxide along with optically active quinine ligand. Sharpless introduced this methodology after considering the importance of enantioselectivity in the total synthesis of medicinally important compounds. Vicinal diols, produced as a result of this reaction, act as intermediates in the synthesis of different naturally occurring compounds. Hence, Sharpless asymmetric dihydroxylation plays an important role in synthetic organic chemistry due to its undeniable contribution to the synthesis of biologically active organic compounds. This review emphasizes the significance of Sharpless asymmetric dihydroxylation in the total synthesis of various natural products, published since 2020.

Characterization of four diol dehydrogenases for enantioselective synthesis of chiral vicinal diols

Enantiopure vicinal diols are important building blocks used in the synthesis of fine chemicals and pharmaceutical compounds. Diol dehydrogenase (DDH) mediated stereoselective oxidation of racemic vicinal is an efficient way to prepare enantiopure vicinal diols. In this study, four new bacterial DDHs (AnDDH from Anoxybacillus sp. P3H1B, HcDDH from Hazenella coriacea, GzDDH from Geobacillus zalihae and LwDDH from Leptotrichia wadei ) were mined from the GenBank database and expressed in E. coli T7. The four DDHs were purified and biochemically characterized for oxidation activity toward ( R )-1-phenyl-1,2-ethanediol, with the optimal reaction condition of pH9.0 (AnDDH), 10.0 (HcDDH) and 11.0 (GzDDH and LwDDH) and the temperatures at 40 °C (AnDDH), 50 °C (HcDDH) and 60 °C (GzDDH and LwDDH), respectively. The four enzymes were stable at the pH from 7.0 to 9.0 and below 40 °C. Kinetic parameters of four DDHs showed that the HcDDH from Hazenella coriacea had high activity toward a broad range of vicinal diols. A series of racemic vicinal diols were successfully resolved by recombinant E. coli (HcDDH-NOX) resting cells co-expression of an NADH oxidase (NOX), affording ( S )-diols and (1 S , 2 S )- trans -diols in ≥99% ee. The synthetic potential of HcDDH was proved by E. coli (HcDDH-NOX) via kinetic resolution of racemic trans -1,2-indandiol on a 100 ml scale reaction, ( S , S )- trans -1,2-indandiol was prepared in 46.7% yield and >99% ee. In addition, asymmetric reduction of four α-hydroxy ketones (10–300 mmol·L −1 ) by E. coli (HcDDH-GDH) resting cells resulted in >99% ee and 69–98% yields of ( R )-vicinal diols. The current research expands the toolbox of DDHs to synthesize chiral vicinal diols and demonstrated that the mined HcDDH is a potential enzyme in the synthesis of a broad range of chiral vicinal diols.

Gram-Scale Synthesis of (R)-P-Chlorophenyl-1,2-Ethanediol at High Concentration by a Pair of Epoxide Hydrolases.

(R)-p-chlorophenyl-1,2-ethanediol (pCPED) is an important intermediate for the synthesis of (R)-eliprodil that is widely applied in the treatment of ischemic stroke. To prepare (R)-pCPED with high enantiomeric excess (ee p) and yield via the enantioconvergent hydrolysis of racemic styrene oxide (rac-pCSO) at high concentration, the bi-enzymatic catalysis was designed and investigated by a pair of epoxide hydrolases, a mutant (PvEH1Z4X4-59) of Phaseolus vulgaris EH1 and a mutant (RpEHF361V) of Rhodotorula paludigena RpEH. Firstly, the maximum allowable concentration of rac-pCSO was confirmed. Subsequently, the addition mode and the weight ratio of two Escherichia coli cells were optimized. Finally, under the optimized reaction conditions—the cell weight ratio 20:1 of E. coli/pveh1z4x4-59 to E. coli/rpeh F361V, a simultaneous addition mode, and reaction temperature at 25°C—300 mM rac-pCSO in the 100 ml 4% (v/v) Tween-20/phosphate buffer system (100 mM, pH 7.0) was completely hydrolyzed within 5 h, affording (R)-pCPED with 87.8% ee p, 93.4% yield, and 8.63 g/L/h space–time yield (STY). This work would be an efficient technical strategy for the preparation of chiral vicinal diols at industrial scale.

Mutation of an atypical oxirane oxyanion hole improves regioselectivity of the α/β-fold epoxide hydrolase Alp1U

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.

Manipulating the regioselectivity of a Solanum lycopersicum epoxide hydrolase for the enantioconvergent synthesis of enantiopure alkane- and alkene-1,2-diols

This work engineered a superior double-site mutant SlEH1W106T/F189L used for the enantioconvergent biosynthesis of (R)-1b–6b with high eep values.

Multigram scale, chiron-based synthesis of sacubitril

Based on a chiron approach, sacubitril, a neprilysin inhibitor and API of Entresto, was synthesized in 7 steps with an overall yield of 40%. Two chiral centers of sacubitril are easily obtained from the starting material, one inherited and another inverted. Noteworthy steps are an efficient and mild preparation of epoxide from chiral vicinal diol using C4F9SO2F/DBU, and a one-flask preparation of succinic amide from azide. All the reactions are performed on multigram scales.

Critical control by scaffold flexibility achieved in diastereodifferentiating photocyclodimerization of 2-anthracenecarboxylate

By progressively increasing the flexibility of chiral vicinal diol scaffold (from rigid cyclic tetrasaccharide to flexible 2,3-butanediol via glucose and trans-1,2-cyclohexandiol) in the diastereodifferentiating photocyclodimerization to head-to-head (HH) dimers of 2-anthracenecarboxylate on the scaffold, the anti/syn preference was dramatically inverted from 42:1 to 1:12, while the enantiomeric excess of the chiral anti-HH dimer was consistently kept high at >99% due to the excited-state dynamics that strongly disfavors the si–si enantiotopic face attack against the antipodal re–re face attack, exclusively affording the (P)-enantiomer.

Enantioselective trans-Dihydroxylation of Aryl Olefins by Cascade Biocatalysis with Recombinant Escherichia coli Coexpressing Monooxygenase and Epoxide Hydrolase

Cascade biocatalysis via intracellular epoxidation and hydrolysis was developed as a green and efficient method for enantioselective dihydroxylation of aryl olefins to prepare chiral vicinal diols in high ee and high yield. Escherichia coli (SSP1) coexpressing styrene monooxygenase (SMO) and epoxide hydrolase SpEH was developed as a simple and efficient biocatalyst for S-enantioselective dihydroxylation of terminal aryl olefins 1a–15a to give (S)-vicinal diols 1c–15c in high ee (97.5–98.6% for 10 diols; 92.2–93.9% for 3 diols) and high yield (91–99% for 6 diols; 86–88% for 2 diols; 67% for 3 diols). Combining SMO and epoxide hydrolase StEH showing complementary regioselectivity to SpEH as a biocatalyst for the cascade biocatalysis gave rise to R-enantioselective dihydroxylation of aryl olefins, being the first example of this kind of reversing the overall enantioselectivity of cascade biocatalysis. E. coli (SST1) coexpressing SMO and StEH was also engineered as a green and efficient biocatalyst for R-dihy...

A Green Approach towards the Synthesis of Enantio Pure Diols Using Horse Radish Peroxidase Enzyme Immobilized on Magnetic Nanoparticles

Enantiopure epoxides and their corresponding chiral vicinal diols serve as valuable intermediates in the synthesis of biologically active pharma and agro-compounds and also value added fine chemicals. Biocatalysts are well known for their selective hydrolysis of racemic epoxides to give optically pure chiral diols. This study highlights an efficient process of synthesis of chiral vicinal diols in good yields and enantioselectiviy using horse radish peroxidase enzyme immobilized on the amine functionalized magnetic nano particles (Fe3O4 nanoparticles) as enzyme carriers. It also facilitates separation of MNP-immobilized enzymes by applying external magnetic field. The immobilization of magnetic nano particles was confirmed by transmission electron microscope (TEM) and scanning electron microscope (SEM). The MNP-immobilized peroxidase enzyme improved stability of the enzyme and has shown broader substrate specificity in enantioselective hydrolysis of racemic epoxides, under mild and environmentally friendly conditions. The methodology MNP-immobilized enzyme developed in the synthesis of chiral diols has a potential for use in large-scale applications.

A two-step biocatalytic cascade in micro-aqueous medium: using whole cells to obtain high concentrations of a vicinal diol

Two-step biocatalytic cascade yields chiral vicinal diols with excellent stereoselectivity and space-time-yields up to 330 g L−1 d−1 under micro-aqueous reaction conditions.

A general approach using spiroborate reversible cross-linked Au nanoparticles for visual high-throughput screening of chiral vicinal diols

Since enantiopure vicinal diols are important intermediates for the synthesis of numerous pharmaceutical and industrial products, enantioseparation of chiral vicinal diols has received much attention. Here we report a stepwise protocol for creating high-throughput screening (HTS) assays for concentration and enantiomeric excess (ee) of vicinal diols applied to asymmetric dihydroxylation (AD) reactions by using spiroborate reversible cross-linked Au nanoparticles (AuNPs). The enantioselective assays have been demonstrated by NMR spectroscopy and successfully used to rapidly analyze the AD reactions of trans-stilbene with different reaction time and chiral ligands. The first and second steps involve the decoration of a small library of chiral AuNPs with saccharides that possess chiral cis-vicinal diol sites, and verification of the borate-directed assembly and disassembly of the chiral AuNPs. The third step concerns discovery of the optimal chiral AuNPs for a given analyte. The fourth step involves the evaluation of the accuracy and HTS performance of the method. The errors resulting from the analysis of true unknowns are remarkably low, within 2.7% for ee and 0.05 mM for total concentration. The method developed for hydrobenzoin has been applied to analyze the real AD reactions of trans-stilbene. Since the enantioseparation is based on enantioselective ligand exchange (eLE) principle and the reversibility of boron chemistry, this proof of concept approach can be easily adapted to other kinds of asymmetric reactions by using relevant optical nanoprobes.

Asymmetric Synthesis of (S)-metoprolol via Sharpless Asymmetric Dihydroxylation Induced by A Recoverable Polymer Ligand QN-AQNOPEG- OMe

The catalytic asymmetric dihydroxylation (AD) discovered by Sharpless, a Nobel Prize winner in 2001, has rapidly become an invaluable synthetic tool in the possibility of converting prochiral olefins to chiral vicinal diols. After our long-running investigation of optimized methodology for the production of stereo-defined diols based on the AD reaction, an efficient and environmentally friendly approach for the synthesis of (S)-metoprolol via AD reaction was reported. The synthetic route proceeded in four-step reactions of nucleophilic substitution, AD reaction, cyclization, and nucleophilic ring opening. The key step, AD reaction, proceeded effectively in homogeneous catalysis by using a soluble polymer chiral ligand QN-AQN-OPEG-OMe, which can be easily separated from the reaction system and reused at least four times while maintaining its high catalytic activity and enantioselectivity. This protocol has been demonstrated to produce kilogram quantities of (S)-metoprolol on scale. Keywords: Asymmetric dihydroxylation, asymmetric synthesis, polymer ligand, recoverable, (S)-metoprolol, biocatalysis, migraine, headaches, anxiety, beta-blocker

Asymmetric reduction of α-hydroxy aromatic ketones to chiral aryl vicinal diols using carrot enzymes system

Abstract Asymmetric reduction of α-hydroxy aromatic ketones was carried out by using carrot enzymes system, yielding corresponding chiral vicinal diols with special functional groups. The optimum reaction conditions were obtained after investigation of various influencing factors. Chiral aryl vicinal diols were produced with good yields and excellent enantiomeric excesses under appropriate conditions. Meanwhile, the steric factors and electronic effects of the substituents on the aromatic ring were shown to have an interesting influence on both yield and enantioselectivity.

Synthesis of β,γ-disubstituted-γ-lactones through a Johnson–Claisen rearrangement: a short route to xylobovide, nor-canadensolide, canadensolide, sporothriolide and santolinolide

The Johnson–Claisen rearrangement of allyl alcohols with chiral vicinal diol functionality was employed to access chiral β,γ-disubstituted-γ-lactones in high enantio- and diastereoselectivity. These were efficiently converted into nor-canadensolide, the advanced γ-(lactone–lactol) intermediate for xylobovide, canadensolide and sporothriolide and the lactone moiety of the santolinolides.

Pattern-Based Recognition for the Rapid Determination of Identity, Concentration, and Enantiomeric Excess of Subtly Different Threo Diols

A pattern-based recognition approach for the rapid determination of the identity, concentration, and enantiomeric excess of chiral vicinal diols, specifically threo diols, has been developed. A diverse enantioselective sensor array was generated using three chiral boronic acid receptors and three pH indicators. The optical response produced by the sensor array was analyzed by two pattern-recognition algorithms: principal component analysis and artificial neural networks. Principal component analysis demonstrated good chemoselective and enantioselective separation of the analytes, and an artificial neural network was used to accurately determine the concentrations and enantiomeric excesses of five unknown samples with an average absolute error of +/-0.08 mM in concentration and 3.6% in enantiomeric excess. The speed of the analysis was enhanced by using a 96-well plate format, portending applications in high-throughput screening for asymmetric-catalyst discovery. X-ray crystallography and (11)B NMR spectroscopy was utilized to study the enantioselective nature of the boronic acid host 2.

A diethyltartrate-based synthesis of both (−)- and (+)-arundic acid

A diethyltartrate-based synthesis of both enantiomers of the acute ischemic stroke therapeutic agent, arundic acid is presented. Separable diastereomers were obtained through the Johnson–Claisen rearrangement of the chiral vicinal diol based on the diethyltartrate skeleton and were converted separately into the two enantiomers of arundic acid.

Chiral vicinal diols as platforms for separable diastereomers in Johnson–Claisen rearrangement: a new short route to (−)-nor-canadensolide, (−)-canadensolide and (−)-sporothriolide

The chiral vicinal diols prepared by asymmetric dihydroxylation in high enantioselectivities provide an excellent platform for separable diastereomers in the Johnson–Claisen rearrangement. The separated syn-diastereomers were converted into the advanced γ-(lactone-lactol) intermediates (in six steps, 26–27% overall yields) for the synthesis of (−)-nor-canadensolide, (−)-canadensolide and (−)-sporothriolide.

Improved enantioselective conversion of styrene epoxides and meso-epoxides through epoxide hydrolases with a mutated nucleophile-flanking residue

In epoxide hydrolase from Agrobacterium radiobacter (EchA), phenylalanine 108 flanks the nucleophilic aspartate and forms part of the substrate-binding pocket. The influence of mutations at this position on the activity and enantioselectivity of the enzyme was investigated. Screening for improved enantioselectivity towards para-nitrophenyl glycidyl ether (pNPGE) using spectrophotometric progress curve analysis yielded five different mutants with 3- to 7-fold improved enantioselectivity. The increase in enantioselectivity was in most cases the result of an enhanced catalytic efficiency toward the preferred enantiomer. Several mutations at position F108 resulted in a higher activity toward cis-disubstituted meso-epoxides, which were converted to a single product enantiomer. Mutant F108C converted cis-2,3-epoxybutane to (2 R,3 R)-2,3-butanediol of >99% ee with a 7-fold improved activity, and mutant F108A hydrolyzed cyclohexene oxide to (1 R,2 R)-1,2-cyclohexanediol of >99% ee with a more than 150-fold higher activity than wild-type enzyme. It is concluded that single amino acid substitutions in the active site of epoxide hydrolase can result in enzyme variants with catalytic properties that are suitable for preparative scale production of ( S)-epoxides and chiral vicinal diols in high yield and with excellent ee.

Synthesis of chiral vicinal diols and analysis of them by capillary zone electrophoresis

This paper describes an improved access to 1,4-bis (9-O-quininyl) phthalazine [(QN)(2)PHAL], a very useful chiral ligand for catalytic asymmetric dihydroxylation (AD), by using CaH(2) as acid-binding reagent in a high yield under mild conditions. The application of (QN)(2)PHAL to the AD reactions of eight olefins exhibited excellent enantioselectivity and activity with corresponding chiral vicinal diols. Furthermore, a capillary zone electrophoresis method was developed to separate the aforementioned chiral vicinal diols by using of neutral beta-cyclodextrin (beta-CD) as chiral selector and borate as running buffer. High resolution was achieved under the optimal conditions of beta-CD 2.2% (w/v), pH 10, 200 mM borate buffer at 15 kV, and 20 degrees C within 15 min. The relative standard deviations of the corrected peak areas and migration time were less than 3.9% and 1.3%, respectively. In addition, the developed method was successfully applied to the determination of the purity and the enantiomeric excesses value (%ee) of the AD reaction products.