Chiral Diols Research Articles

The Rational Design and Atroposelective Synthesis of Axially Chiral C2‐Arylpyrrole‐Derived Amino Alcohols

AbstractAxially chiral biaryl diols have achieved great success in asymmetric catalysis. By contrast, axially chiral biaryl amino alcohols are far less developed. Herein, we have rationally designed a versatileC1‐symmetric biaryl amino alcohol scaffold 1‐(1‐amino‐pyrrol‐2‐yl)naphthalen‐2‐ol (NPNOL) on the basis of axially chiral C2‐arylpyrrole framework. For its enantioselective synthesis, the chiral phosphoric acid‐catalyzed asymmetric Attanasi reaction between 1,3‐dicarbonyl compounds and azoalkenes had been established. By using this practical method, a wide range of NPNOLs were readily prepared in high yields and excellent atroposelectivities (38 examples, up to 89 % yield and 99 %ee). DFT calculations were performed to reveal the reaction mechanism and the origins of the enantioselectivity. The easy transformations of NPNOL‐derived products into organocatalysts/ligands and their preliminary applications in asymmetric catalytic reactions demonstrated the promising utility of NPNOL.

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.

Enantioselective Conjugate Addition of Boronic Acids to α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Diols.

Herein, we report the enantioselective conjugate addition of organic boronic acids to α,β-unsaturated 2-acyl imidazoles using (R)-3,3'-I2-BINOL as the catalyst. The catalytic system shows high efficiency and tolerance to alkenylboronic acids and heteroarylboronic acids. The corresponding Michael addition products were obtained in moderate to excellent yields and with moderate to excellent enantioselectivities (up to 97% ee). A gram-scale reaction was also conducted, and the desired product was obtained in high yield with no erosion in enantioselectivity. Finally, the synthetic utility of the methodology was demonstrated by transforming the 2-acyl imidazole moiety to the corresponding aldehyde, carboxylic acid, ester, and amide derivatives.

Methods for Determination of Absolute Configurations of Chiral Diols by THENA Ester and NMR Shift Difference

AbstractDetermination of the absolute configuration of chiral secondary diols by chiral derivatizing agent (CDA) and NMR shift difference is of great challenge due to the complication from the interference of the aromatic anisotropic shielding effect of the two CDAs in close proximity. In this work, tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid (THENA) was introduced as an alternative CDA for diols to overcome such complexity. Since the deshielding effect of THENA is weaker than the shielding effect of other CDAs, THENA would allow the direct analysis of the chemical shift difference in determining the absolute configuration of the chiral diols. In addition, an analytical method based on Riguera’s model could also be used to confirm the assignment. With a good agreement between the assigned configuration based on both analytical models, the absolute configuration of the chiral diols could be assigned with reliability.

High-Yield Synthesis of Enantiopure 1,2-Amino Alcohols from l-Phenylalanine via Linear and Divergent Enzymatic Cascades.

Enantiomerically pure 1,2-amino alcohols are important compounds due to their biological activities and wide applications in chemical synthesis. In this work, we present two multienzyme pathways for the conversion of l-phenylalanine into either 2-phenylglycinol or phenylethanolamine in the enantiomerically pure form. Both pathways start with the two-pot sequential four-step conversion of l-phenylalanine into styrene via subsequent deamination, decarboxylation, enantioselective epoxidation, and enantioselective hydrolysis. For instance, after optimization, the multienzyme process could convert 507 mg of l-phenylalanine into (R)-1-phenyl-1,2-diol in an overall isolated yield of 75% and >99% ee. The opposite enantiomer, (S)-1-phenyl-1,2-diol, was also obtained in a 70% yield and 98–99% ee following the same approach. At this stage, two divergent routes were developed to convert the chiral diols into either 2-phenylglycinol or phenylethanolamine. The former route consisted of a one-pot concurrent interconnected two-step cascade in which the diol intermediate was oxidized to 2-hydroxy-acetophenone by an alcohol dehydrogenase and then aminated by a transaminase to give enantiomerically pure 2-phenylglycinol. Notably, the addition of an alanine dehydrogenase enabled the connection of the two steps and made the overall process redox-self-sufficient. Thus, (S)-phenylglycinol was isolated in an 81% yield and >99.4% ee starting from ca. 100 mg of the diol intermediate. The second route consisted of a one-pot concurrent two-step cascade in which the oxidative and reductive steps were not interconnected. In this case, the diol intermediate was oxidized to either (S)- or (R)-2-hydroxy-2-phenylacetaldehyde by an alcohol oxidase and then aminated by an amine dehydrogenase to give the enantiomerically pure phenylethanolamine. The addition of a formate dehydrogenase and sodium formate was required to provide the reducing equivalents for the reductive amination step. Thus, (R)-phenylethanolamine was isolated in a 92% yield and >99.9% ee starting from ca. 100 mg of the diol intermediate. In summary, l-phenylalanine was converted into enantiomerically pure 2-phenylglycinol and phenylethanolamine in overall yields of 61% and 69%, respectively. This work exemplifies how linear and divergent enzyme cascades can enable the synthesis of high-value chiral molecules such as amino alcohols from a renewable material such as l-phenylalanine with high atom economy and improved sustainability.

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.

Induction and rationalization of supramolecular chirality in a highly flexible Zn(II)porphyrin dimer: structural, spectroscopic and theoretical investigations.

A highly flexible pyrrole-bridged Zn(II)porphyrin dimer has been successfully utilized as an efficient host which enables an accurate determination of the absolute configuration directly for a large number of chiral amino alcohols and 1,2-diols. The addition of substrates resulted in the formation of 1 : 1 sandwich complexes which, after the addition of excess substrates, produced 1 : 2 host-guest complexes. In principle, the 1 : 2 host-guest complexes can be stabilized in three possible conformations, viz. exo-exo, exo-endo, and endo-endo based on how a substrate binds to the metal. The endo-endo conformation is stabilized by two strong interligand H-bonds [O-H⋯O(H)] between encapsulated diols which thereby interlock the stereochemistry. In the absence of such interligand H-bonding interactions, exo-endo binding is preferred as it is indeed observed for amino alcohols which show weaker CD couplets due to the free movement of substrates. The sandwich complexes with amino alcohols show a more intense CD couplet compared to the diols due to the stronger binding of the amine functionality (-NH2) towards a Zn-atom over an alcoholic moiety (-OH). The CD amplitude showed linear dependence with a binding constant for the 1 : 1 sandwich complex upon varying the substrates. Spectroscopic investigations, single crystal X-ray structure determination of four such host-guest complexes and DFT studies have enabled us to rationalize systematically the origin of optical activity unambiguously in the 1 : 1 and 1 : 2 host-guest complexes, which lead to an absolute stereochemical determination of a large number of chiral substrates. The larger vertical and horizontal flexibility of a diethyl pyrrole spacer induces stronger binding of the substrates to form the 1 : 1 complex with a much larger torsional angle along with intense CD couplets. In contrast, a rigid dibenzothiophene-bridged tweezer, due to its limited horizontal and vertical flexibility, facilitates 1 : 2 complexation more as compared to the highly flexible pyrrole-bridged host which results in stronger binding of the substrate with the intense CD couplet for the former.

NMR analysis of the enantiomeric purity of chiral diols by a new chiral boron agent.

A new boric agent with bridged structure, boric acid D, was first synthesized and used as an excellent chiral derivative agent for highly efficient enantiodiscrimination of various diols. The derivatization reaction is fast and complete, easy to operate and has high accuracy in measurement of ee values. The characteristic split NMR signals are well-distinguishable with a large chemical shift nonequivalence (up to 0.39 ppm).

Asymmetric total synthesis of (+)-(2R,4'R,8'R)-α-tocopherol enabled by enzymatic desymmetrization.

A new and highly stereoselective synthesis of chiral diol (S)-14, the common synthetic intermediate to (+)-(2R,4'R,8'R)-α-tocopherol (1), was accomplished in seven steps with 13.8% overall yield. This developed route featured a lipase-catalyzed desymmetric hydrolysis of prochiral diester 39a, which was prepared through a challenging Heck coupling, to chiral quaternary carbon-containing monoester (R)-37a of the correct configuration in 81% yield and 96.7% ee, to the best of our knowledge, leading to the most efficient enzymatic desymmetric synthesis of the chiral chroman skeleton of vitamin E members reported to date. Coupled with the modified preparation of the phytol-derived side chain, the chemoenzymatic total synthesis of 1 was completed in 15 longest linear steps with 3.1% overall yield.

Role of local intermolecular contacts in the physical properties of induced helical phases based on nematic disubstituted azobenzene

The mesomorphic, dielectric, orientational and rheological properties of the induced chiral nematic phase on the base of 4-butyl-4′-octanoyloxyazoxybenzene (C4-AB-OCOC7) doped with 1R(+)-1′,7′,7′-trimethylbicyclo[2.2.1]heptane[2′,3′-b]-2,3-dicyanopyrazine ((R + )CDCP) and (2R,3R)(−)2,3 butanediol (R-)BD were studied. The clearing temperatures and the pitch were measured, and the value of the helical twisting power were calculated. A strong influence of the dopants structure on the thermal stability of the spiral phase and the dielectric anisotropy was shown. An increase in the orientational order parameter LC upon doping with a chiral diol and the formation of its H-bond with the ester group of the terminal substituent were established by 1H NMR. Stable structures of dopant - LC solvates, their dipole moments, anisotropy of polarizability and formation energy have been established by DFT simulation. The determining influence of local dipole–dipole contacts and H-bonds on the structure and properties of solvates has been substantiated. The calculated data allowed to establish the reasons for the effect of dopants on the physical properties of the spiral phases. The effect of (2R, 3R) (-) 2,3 butanediol on the kinematic viscosity of two nematic solvents - C4-AB-OCOC7 and a binary mixture of alkoxycyanobiphenyls (CB-2) was investigated. The influence of the dopant was shown to be determined by the geometry of solvates formed due to local H-bonds with electron-donor moieties of nematic solvents.

Copper‐Catalyzed Si—H Bond Insertion Polymerization for Synthesis of Optically Active Polyesters Containing Silicon

Comprehensive SummaryThe synthesis and characterization of chiral polymers with diverse structure remain a long‐term challenging research topic. Herein, a copper‐catalyzed enantioselective insertion of carbene into Si—H bond was applied to polycondensation, giving a new type of optically active degradable polyesters containing Si—C bond in the main chain. The polymerization features mild condition, broad substrate scope, excellent yields and enantioselectivities. Chiral diols could be obtained via reduction of optically active polyesters. Thermogravimetric analysis indicated these chiral polyesters exhibit good thermal stability.

Access to chiral homoallylic vicinal diols from carbonyl allylation of aldehydes with allyl ethers via palladium-catalyzed allylic C-H borylation

Access to chiral homoallylic vicinal diols from carbonyl allylation of aldehydes with allyl ethers via palladium-catalyzed allylic C-H borylation

Synthesis of Silicon-Stereogenic Silanols Involving Iridium-Catalyzed Enantioselective C–H Silylation Leading to a New Ligand Scaffold

Despite a growing focus on the construction of highly enantioenriched silicon-stereogenic organosilicon compounds, the enantioselective synthesis of silicon-stereogenic silanols through asymmetric catalysis remains a considerable challenge. Herein, we realized enantioselective construction of silicon-stereogenic diarylsilanols via an Ir-catalyzed C–H silylation of diarylsilanols along with stereospecific substitution or Tamao–Fleming oxidation. This strategy gives rise to a class of chiral diol catalyst cores (PSiOLs). Transformation of PSiOLs led to the ligand possessing both Si and P-stereocenters, which is capable of inducing excellent enantioselectivity in the rhodium(I)-catalyzed conjugate 1,4-addition of aryl boronic acids to cyclohexenone.

Highly efficient synthesis of rosuvastatin intermediate using a carbonyl reductase–cofactor co‐immobilized biocatalyst in the non‐aqueous biosystem

AbstractBACKGROUNDNon‐aqueous biocatalytic system has exhibited advantages including outstanding substrate solubility, facilitation for product purification, suppression of unwanted water‐dependent side reactions and rare wastewater discharge. However, limited by enzyme stability, selectivity and cofactor recycling, there has been no successful attempt to use carbonyl reductases in non‐aqueous phase.RESULTSIn this study, a non‐aqueous catalytic system of carbonyl reductase was developed for the first time with a carbonyl reductase–cofactor co‐immobilized biocatalyst. Using n‐hexane as the reaction medium, the key chiral diol intermediate of the top‐selling hypolipidemic drug rosuvastatin, tert‐butyl (3R,5S)‐6‐chloro‐3,5‐dihydroxyhexanoate ((3R,5S)‐CDHH) was prepared in a continuous packed‐bed bioreactor, with a total yield of 95.51%, enantiomeric excess (e.e.) > 99.5% and diastereomeric excess (d.e.) > 99.5% in a 44‐batch reaction. The yield of per unit biocatalyst was 34.42 mg U−1, and the space–time yield was 91.01 g h−1 L−1.CONCLUSIONOur work corroborated the valuable potential of carbonyl reductases in non‐aqueous biosynthesis of chiral pharmaceuticals and fine chemicals. © 2021 Society of Chemical Industry (SCI).

Oxidation of threo‐9,10‐Dihydroxystearic Acid Mediated by Micrococcus luteus as a Key Step in the Conversion of Oleic Acid into Pelargonic and Azelaic Acids

AbstractA sequential one‐pot chemoenzymatic procedure for the conversion of diol 1, easily obtained from oleic acid, into pelargonic and azelaic acids is herein described. The oxidation of diol 1 into a mixture of the corresponding regioisomeric hydroxyketones was promoted by an alcohol dehydrogenase from Micrococcus luteus, selected after an extensive screening of commercial enzyme kits and strain collections. The stereochemistry of the oxidation process of chiral diol 1 was also investigated. The hydroxyketones obtained by the biocatalyzed oxidation were submitted to further oxidative cleavage by a mild treatment with aqueous NaClO in a biphasic mixture, affording pelargonic and azelaic acids in high yield (76 and 71 %, respectively) with no need of column chromatography.

Tailoring an aldo-keto reductase KmAKR for robust thermostability and catalytic efficiency by stepwise evolution and structure-guided consensus engineering

t-Butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-2) is an advanced chiral diol intermediate of the cholesterol-lowering drug atorvastatin. KmAKRM5 (W297H/Y296W/K29H/Y28A/T63M) constructed in our previous work, displayed good biocatalytic performance on (3R,5R)-2. In the present work, stepwise evolution was applied to further enhance the thermostability and activity of KmAKRM5. For thermostability enhancement, N109 and S196 located far from the active site were picked out by structure-guided consensus engineering, and mutated by site-directed mutagenesis (SDM). For catalytic efficiency improvement, the residues A30 and T302 adjacent to the substrate-binding pocket were subjected to site-saturation mutagenesis (SSM). As a result, the “best” mutant KmAKRM9 (W297H/Y296W/K29H/Y28A/T63M/A30P/T302S/N109K/S196C) was developed, of which T5015 and Tm were 5.0 °C and 8.2 °C higher than those of KmAKRM5. Moreover, compared to KmAKRM5, KmAKRM9 displayed a 1.9-fold (846 vs 2436 min) and 6.7-fold (126 vs 972 min) longer half-lives at 40 and 50 °C, respectively. Structural analysis suggested that beneficial mutations introduced additional hydrophobic interactions and hydrogen bonds, contributing rigidification of the flexible loops and the increase of internal forces, hence increasing the thermostability and activity. 5 g DCW (dry cell weight) L−1KmAKRM9 completely reduced 350 g L−1t-butyl 6-cyano-(5R)-hydroxy-3-oxo-hexanoate ((5R)-1), within 3.7 h at 40 °C, yielding optically pure (3R,5R)-2 (d.e.p > 99.5%) with a space-time yield (STY) of 1.82 kg L−1 d−1. Hence, KmAKRM9 is a robust biocatalyst for the synthesis of (3R,5R)-2.

Total Synthesis of (−)‐Lepadin F based on a Stereoselective Diels–Alder Reaction Controlled by a Ketolactone‐type Dienophile

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels-Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by SN 2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (-)-lepadin F is synthesized from ethyl l-lactate for the first time.

Asymmetric double-conjugate addition of alkenylboronic acids to dienones catalyzed by chiral diols

An efficient asymmetric double-conjugate addition of organic boronic acids to dienones catalyzed by chiral 3,3′-disubstituted-BINOLs or hydroxytetraphenylenes has been developed.

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.

High-throughput assay for determining enantiomeric excess of chiral diols, amino alcohols, and amines and for direct asymmetric reaction screening.

Determining enantiomeric excess (e.e.) in chiral compounds is key to development of chiral catalyst auxiliaries and chiral drugs. Here we describe a sensitive and robust fluorescence-based assay for determining e.e. in mixtures of enantiomers of 1,2- and 1,3-diols, chiral amines, amino alcohols, and amino-acid esters. The method is based on dynamic self-assembly of commercially available chiral amines, 2-formylphenylboronic acid, and chiral diols in acetonitrile to form fluorescent diastereomeric complexes. Each analyte enantiomer engenders a diastereomer with distinct fluorescence wavelength/intensity originating from enantiopure fluorescent ligands. In this assay, enantiomers of amines and amine derivatives assemble with diol-type ligands containing a binaphthol moiety (BINOL and VANOL), whereas diol enantiomers form complexes with the enantiopure amine-type fluorescent ligand tryptophanol. The differential fluorescence is utilized to determine the amount of each enantiomer in the mixture with an error of <1% e.e. This method enables high-throughput real-time evaluation of enantiomeric/diastereomeric excess (e.e./d.e.) and product yield of crude asymmetric reaction products. The procedure comprises high-throughput liquid dispensing of three components into 384-well plates and recording of fluorescence using an automated plate reader. The approach enables scaling up the screening of combinatorial libraries and, together with parallel synthesis, creates a robust platform for discovering chiral catalysts or auxiliaries for asymmetric transformations and chiral drug development. The procedure takes ~4-6 h and requires 10-20 ng of substrate per well. Our fluorescence-based assay offers distinct advantages over existing methods because it is not sensitive to the presence of common additives/impurities or unreacted/incompletely utilized reagents or catalysts.