Enantiopure Alcohols Research Articles

ChemInform Abstract: Ruthenium‐Catalyzed Oxidative Kinetic Resolution of Unactivated and Activated Secondary Alcohols with Air as the Hydrogen Acceptor at Room Temperature.

Enantiopure alcohols are versatile building blocks for asymmetric synthesis and the kinetic resolution (KR) of racemic alcohols is a reliable method for preparing them. Although many KR methods have been developed, oxidative kinetic resolution (OKR), in which dioxygen is used as the hydrogen acceptor, is the most atom-efficient. Dioxygen is ubiquitous in air, which is abundant and safe to handle. Therefore, OKR with air has been intensively investigated and the OKR of benzylic alcohols was recently achieved by using an Ir catalyst without any adjuvant. However, the OKR of unactivated alcohols remains a challenge. An [(aqua)Ru(salen)] catalyzed OKR with air as the hydrogen acceptor was developed, in which the aqua ligand is exchanged with alcohol and the Ru complex undergoes single electron transfer to dioxygen and subsequent alcohol oxidation. This OKR can be applied without any adjuvant to activated and unactivated alcohols with good to high enantioselectivity. The unique influence of substrate inhibition on the enantioselectivity of the OKR is also described.

A solar light-driven, eco-friendly protocol for highly enantioselective synthesis of chiral alcohols via photocatalytic/biocatalytic cascades

The judicious utilization of solar light for the asymmetric synthesis of optically active compounds by imitating natural photosynthesis introduces a new concept that harnesses this renewable energy in vitro for ultimate transformation into chiral chemical bonds. Herein, we present a comprehensive description of such a biomimetic endeavor towards the design and construction of an asymmetric artificial photosynthesis system that comprises an efficient method of nicotinamide cofactor (NADPH) regeneration under visible light employing a graphene-based light harvesting photocatalyst and its subsequent utilization in an enzyme-catalyzed asymmetric reduction of prochiral ketones to expediently furnish the corresponding chiral secondary alcohols. A detailed optimization study revealed a major dependency of the reaction outcome on the amount of cofactor, photocatalyst and enzyme used, as well as the mode of their addition. A series of structurally diverse ketones bearing an array of (hetero)aryl/alkyl substituents proved to be highly suitable to our photocatalytic–biocatalytic cascade approach, providing (R/S)-1-(hetero)aryl/alkylethanols in excellent enantioselectivities (ee ∼ 95–>99.9%) under mild and environmentally benign conditions. To the best of our knowledge, the synthesis of these enantiopure alcohols employing a visible-light-driven nicotinamide cofactor regeneration strategy has been reported for the first time. Such enantioenriched alcohols act as versatile chiral building blocks for the synthesis of compounds having industrial and pharmaceutical relevance. In addition, this solar-to-chiral chemicals prototype appears advantageous from ecological and economical perspectives. We describe mechanistic pathways to demonstrate how the present catalytic synthesis protocol functions through perfect orchestration between visible-light-driven photocatalysis and biocatalysis to be successively applied in inducing asymmetry in an achiral molecule for the ultimate goal of solar energy utilization in the synthesis of valuable chiral fine chemicals. This work highlights the potential advantages of a bioinspired system to the pertinence of solar energy in asymmetric transformations leading to enantioenriched alcohol precursors, and thus opens up a new field of research that might emerge as an important breakthrough with promising implications towards generating a sustainable and non-fossil/non-nuclear energy future.

Stereoselectivity in Asymmetric Catalysis: The Case of Ruthenium-Catalyzed Ketone Hydrogenation.

The ruthenium-catalyzed asymmetric hydrogenation of simple ketones to generate enantiopure alcohols is an important process widely used in the fine chemical, pharmaceutical, fragrance, and flavor industries. Chiral diphosphine-RuCl2-1,2-diamine complexes are effective catalysts for the reaction giving high chemo- and enantioselectivity. However, no diphosphine-RuCl2-1,2-diamine complex has yet been discovered that is universal for all kinds of ketone substrates, and the ligands must be carefully chosen for each substrate. The procedure of finding the best ligands for a specific substrate can be facilitated by using virtual screening as a complement to the traditional experimental screening of catalyst libraries. We have generated a transition state force field (TSFF) for the ruthenium-catalyzed asymmetric hydrogenation of simple ketones using an improved Q2MM method. The developed TSFF can predict the enantioselectivity for 13 catalytic systems taken from the literature, with a mean unsigned error of 2.7 kJ/mol.

Engineering of P450pyr Hydroxylase for the Highly Regio‐ and Enantioselective Subterminal Hydroxylation of Alkanes

Terminal-selective cytochrome P450pyr has been successfully engineered through directed evolution for the subterminal hydroxylation of alkanes with excellent regio- and enantioselectivity. A sensitive colorimetric high-throughput screening (HTS) assay was developed for the measurement of both the regioselectivity and the enantioselectivity of a hydroxylation reaction. By using the HTS assay and iterative saturation mutagenesis, sextuple-mutant P450pyrSM1 was created for the hydroxylation of n-octane (1) to give (S)-2-octanol (2) with 98 % ee and >99 % subterminal selectivity. The engineered P450 is the first enzyme for this type of highly selective alkane hydroxylation, being useful for the C-H activation and functionalization of alkanes and the preparation of enantiopure alcohols. Molecular modeling provided structure-based understanding of the fully altered regioselectivity and the excellent enantioselectivity. Another sextuple-mutant P450pyrSM2 catalyzed the hydroxylation of propylbenzene (3) to afford (S)-1-phenyl-2-propanol (4) with 95 % ee and 98 % subterminal selectivity.

Engineering of P450pyr Hydroxylase for the Highly Regio‐ and Enantioselective Subterminal Hydroxylation of Alkanes

AbstractTerminal‐selective cytochrome P450pyr has been successfully engineered through directed evolution for the subterminal hydroxylation of alkanes with excellent regio‐ and enantioselectivity. A sensitive colorimetric high‐throughput screening (HTS) assay was developed for the measurement of both the regioselectivity and the enantioselectivity of a hydroxylation reaction. By using the HTS assay and iterative saturation mutagenesis, sextuple‐mutant P450pyrSM1 was created for the hydroxylation of n‐octane (1) to give (S)‐2‐octanol (2) with 98 % ee and >99 % subterminal selectivity. The engineered P450 is the first enzyme for this type of highly selective alkane hydroxylation, being useful for the CH activation and functionalization of alkanes and the preparation of enantiopure alcohols. Molecular modeling provided structure‐based understanding of the fully altered regioselectivity and the excellent enantioselectivity. Another sextuple‐mutant P450pyrSM2 catalyzed the hydroxylation of propylbenzene (3) to afford (S)‐1‐phenyl‐2‐propanol (4) with 95 % ee and 98 % subterminal selectivity.

Ruthenium‐Catalyzed Oxidative Kinetic Resolution of Unactivated and Activated Secondary Alcohols with Air as the Hydrogen Acceptor at Room Temperature

Enantiopure alcohols are versatile building blocks for asymmetric synthesis and the kinetic resolution (KR) of racemic alcohols is a reliable method for preparing them. Although many KR methods have been developed, oxidative kinetic resolution (OKR), in which dioxygen is used as the hydrogen acceptor, is the most atom-efficient. Dioxygen is ubiquitous in air, which is abundant and safe to handle. Therefore, OKR with air has been intensively investigated and the OKR of benzylic alcohols was recently achieved by using an Ir catalyst without any adjuvant. However, the OKR of unactivated alcohols remains a challenge. An [(aqua)Ru(salen)] catalyzed OKR with air as the hydrogen acceptor was developed, in which the aqua ligand is exchanged with alcohol and the Ru complex undergoes single electron transfer to dioxygen and subsequent alcohol oxidation. This OKR can be applied without any adjuvant to activated and unactivated alcohols with good to high enantioselectivity. The unique influence of substrate inhibition on the enantioselectivity of the OKR is also described.

Enantiopure dihalocyclopropyl alcohols and esters by lipase catalyzed kinetic resolution

Four halogenated cyclopropane derivatives with a side chain containing a primary (1 and 2) or secondary (3 and 4) alcohol moiety were subject to kinetic resolution catalyzed by lipases. Two of them containing secondary alcohol groups gave excellent results with Candida antarctica lipase B with E-values around 1000. Two enantiopure alcohols and two enantiopure butanoates are described: (1S,1′S)-1-(2′,2′-dichloro-3′,3′-dimethylcyclopropyl) ethanol (3), the corresponding (1R,1′R)-butanoate (3b) and (1S,1′S)-1-(1′-methyl-2′,2′-dibromocyclopropyl) ethanol (4) and the corresponding (1R,1′R)-butanoate (4b).

One-Pot Synthesis of Enantiopure 3,4-Dihydroisocoumarins through Dynamic Reductive Kinetic Resolution Processes

A straightforward chemoenzymatic synthesis of enantiopure 4-alkyl-3-methyl-3,4-dihydroisocoumarins through a ketoreductase-catalyzed one-pot dynamic reductive kinetic resolution is reported. E. coli/ADH-A cells have shown outstanding diastereo- and enantioselectivity toward the bioreduction of a series of racemic ketones, with the use of anion exchange resins or triethylamine being compatible in the same aqueous reaction medium. The so-obtained enantiopure alcohols were subsequently cyclized in acid media affording the corresponding lactones in good to excellent conversions (72-96%) and excellent selectivities (dr ≥99:1 and ee >99%).

Using water-miscible ionic liquids to improve the biocatalytic anti-Prelog asymmetric reduction of prochiral ketones with whole cells of Acetobacter sp. CCTCC M209061

The utilization of hydrophilic ionic liquids to improve the synthesis of enantiopure alcohols was successfully performed, via the anti-Prelog asymmetric reduction of ketones with whole cells of Acetobacter sp. CCTCC M209061 newly isolated from Chinese kefir. The best results were obtained with C2OHMIM·NO3, which showed good biocompatibility and also increased moderately cell membrane permeability, thus improving the reaction efficiency. Additionally, the optimal C2OHMIM·NO3 content, buffer pH, reaction temperature and substrate concentration for 4-(trimethylsilyl)-3-butyn-2-one reduction to (R)-4-(trimethylsilyl)-3-butyn-2-ol were 10.0% (v/v), 5.0, 30 °C and 12 mM, respectively. Under the optimized conditions, the initial reaction rate, the maximum yield and the product e.e. were 14.0 μmol/min·gcell, 91%, and >99%, respectively, which were much better than the results reported previously. The efficient whole-cell biocatalytic process proved to be feasible on a 400-mL preparative scale, and the immobilized cells still retained above 88.0% of their original activity after successive re-use for 10 batches, showing the good operational stability in the presence of C2OHMIM·NO3. Furthermore, the established biocatalytic system with Acetobacter sp. CCTCC M209061 and C2OHMIM·NO3 was shown to be highly effective for the anti-Prelog asymmetric reduction of other aryl ketones to the corresponding (R)-alcohols.

Syntheses of Enantiopure Aliphatic Secondary Alcohols and Acetates by Bioresolution with Lipase B from Candida antarctica

The lipase B from Candida antarctica (Novozym 435®, CALB) efficiently catalyzed the kinetic resolution of some aliphatic secondary alcohols: (±)-4-methylpentan-2-ol (1), (±)-5-methylhexan-2-ol (3), (±)-octan-2-ol (4), (±)-heptan-3-ol (5) and (±)-oct-1-en-3-ol (6). The lipase showed excellent enantioselectivities in the transesterifications of racemic aliphatic secondary alcohols producing the enantiopure alcohols (>99% ee) and acetates (>99% ee) with good yields. Kinetic resolution of rac-alcohols was successfully achieved with CALB lipase using simple conditions, vinyl acetate as acylating agent, and hexane as non-polar solvent.

Asymmetric Chemoenzymatic Synthesis of Ramatroban Using Lipases and Oxidoreductases

A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.

Enantiopure 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines via chemoenzymatic asymmetric transformations

A new divergent and asymmetric synthetic route has been developed for the production of enantiomerically pure isocoumarin and isoquinoline derivatives. Stereoselective formation of 2-(2-hydroxypropyl)benzonitriles has been identified as the key step. Rhizomucor miehei lipase has displayed from moderate to excellent selectivities in the acetylation of its (R)-enantiomers, while ADH-A from Rhodococcus ruber catalyzed the bioreduction of the corresponding ketones with excellent activities and stereopreferences. Enantiopure alcohols obtained in this manner have been used for the straightforward synthesis of a series of 3-methyl-3,4-dihydroisocoumarins and 3-methyl-1,2,3,4-tetrahydroisoquinolines with good overall yields.

Asymmetric preparation of antifungal 1-(4′-chlorophenyl)-1-cyclopropyl methanol and 1-(4′-chlorophenyl)-2-phenylethanol. Study of the detoxification mechanism by Botrytis cinerea

► The antifungal compound ( R )-1-(4′-chlorophenyl)-2-phenylethanol was prepared by means of treatment with ( R )-methyl oxazaborolidine, with >99% ee and 98% yield, and by lipase-mediated acetylation, with 99% ee . ► The antifungal compound ( S )-1-(4′-chlorophenyl)-2-phenylethanol was prepared by means of treatment with ( S )-methyl oxazaborolidine, with >99% ee and 98% yield, and by baker's yeast fermentation, with 97% ee . ► The antifungal compound ( R )-1-(4′-chlorophenyl)-1-cyclopropylmethanol was prepared by means of lipase-mediated hydrolysis, with 98% ee and 85.5% yield. ► The antifungal compound ( S )-1-(4′-chlorophenyl)-1-cyclopropylmethanol was prepared by means of baker's yeast fermentation, with 96% ee and 12% conversion. ► Biotransformation of 1-(4′-chlorophenyl)-1-cyclopropylmethanol by the phytopathogen Botrytis cinerea shows the detoxification pathways by the fungus. Chiral alcohols are important as bioactive compounds or as precursors to such molecules. On the basis of the different antifungal properties of the enantiopure alcohol derivatives of 4′-chlorophenyl cyclopropyl ketone and benzyl 4′-chlorophenyl ketone, their enantioselective synthesis by chemical and biocatalytic methods was studied. The detoxification pathways by the phytopathogen fungus Botrytis cinerea are reported.

Structure-enantioselectivity effects in 3,4-dihydropyrimido[2,1-b]benzothiazole-based isothioureas as enantioselective acylation catalysts

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ~50% conversion). Low catalyst loadings (0.10-0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

Biocatalytic reduction of prochiral aromatic ketones to optically pure alcohols by a coupled enzyme system for cofactor regeneration

A simple, highly efficient, and economical biphasic cell-free system was developed for biocatalytic reduction of prochiral aromatic ketones to furnish enantiopure alcohols. This system is characterized by using endogenous enzymes of the cell-free extract to form enzyme-coupled NADPH recycling system. Besides, it offered much higher productivity than whole cells and greatly simplified the preparation process of biocatalysts in comparison with isolated enzymes. Various prochiral aromatic ketones, especially α-substituted acetophenone derivatives, were reduced to chiral alcohols with excellent enantiomeric excess (ee) and moderate to good yield by this cell-free system.

Carbonyl reductase SCRII from Candida parapsilosis catalyzes anti-Prelog reaction to (S)-1-phenyl-1,2-ethanediol with absolute stereochemical selectivity

An (S)-specific carbonyl reductase (SCRII) was purified to homogeneity from Candida parapsilosis by following an anti-Prelog reducing activity of 2-hydroxyacetophenone. Peptide mass fingerprinting analysis shows SCRII belongs to short-chain dehydrogenase/reductase family. Its coding gene was cloned and overexpressed in Escherichia coli. The recombinant SCRII displays the similar enzymatic characterization and catalytic properties to SCR. It catalyzes the enantioselective reduction of 2-hydroxyacetophenone to (S)-1-phenyl-1,2-ethanediol with excellent optical purity of 100% in higher yield than SCR. Based on the sequence-structure alignment, several single-point mutations inside or adjacent to the substrate-binding loop or active site were designed. With respect to recombinant native SCRII, the A220 and E228 mutations almost lost enantioselectivity towards 2-hydroxyacetophenone reduction. The catalytic efficiencies (kcat/Km) for the A220 or E228 variants are <7% that of the unmutated enzyme. This work provides an excellent catalyst for enantiopure alcohol preparation and the lethal mutations of A220 and E228 suggest their importance in substrate-binding and/or catalysis.

Asymmetric addition of chiral methylmagnesium alkoxides to benzaldehyde

The ability of chiral methylmagnesium alkoxides derived from enantiopure alcohols to effect asymmetric addition to benzaldehyde has been investigated. The addition to benzaldehyde of chiral methylmagnesium alkoxides prepared from (–)-borneol, (+)-menthol or (+)-Nmethylpseudoephedrine afforded virtually racemic 1-phenylethanol. Equilibration of a more complex species, generated upon addition of one molar equiv of MeMgBr to various molar quantities of the dilithio salt of (+)-pseudoephedrine before addition of benzaldehyde had a dramatic effect on both the reactivity of the reagent and the enantioselectivity of the addition.

Convergent Synthesis of Both Enantiomers of 4‐Hydroxypent‐2‐ynoic Acid Diphenylamide for a Thrombin Receptor Antagonist Sch 530348 and Himbacine Analogues

AbstractSch 530348 and many himbacine analogues were prepared by using 4‐hydroxypent‐2‐ynoic acid diphenylamide as the only chiral material. We developed deracemization methods to prepare both enantiomers of this propargyl alcohol. These methods involved a resolution followed by inversion. The objective for the resolution step was to obtain the desired enantiomer as an ester, and undesired enantiomer as an alcohol. With (R)‐selective lipase, this was achieved by transesterifcation for (R)‐alcohol, and ester hydrolysis for (S)‐alcohol. The undesired enantiomer was inverted through the corresponding tosylate to yield the desired enantiomer as the ester. Deprotection of the ester gave enantiopure alcohol as the product. These methods not only overcame the 50% yield limit in resolution, but also eliminated the need to remove the undesired enantiomer.

Synthesis and reductive desulfurization of chiral non-racemic benzothienoindolizines. An efficient approach to a novel bioactive tylophorine alkaloid analogue and 6-phenylindolizidine

Enantiopure di- and tetrahydro[1]benzothieno[3,2- f]indolizines 3, 4, 9 and the benzothieno analogue 5 of the bioactive alkaloid tylophorine 10 were synthesized easily from the readily available benzo[ b]thiophene-3-carboxaldehyde 1 and ( S)-glutamic acid 2 in good overall yields. Applying a diastereoselective reductive desulfurization of benzo[ b]thiophene 3, 4 and 5 were readily converted into the enantiopure alcohols 11a–d, alcohols 11c,d and the target 6( R)-phenyl-8a( R)-indolizidine 6 (7 steps, 14%). During these reduction studies, the results obtained including the stereoinduction of the reaction are also discussed.

Burkholderia cenocepacia: a new biocatalyst for efficient bioreduction of ezetimibe intermediate

Ezetimibe is a selective acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor used in hypercholesterolemia. Synthesis of ezetimibe requires enantiopure 3-[5-(4-fluorophenyl)-5(S)-hydroxypentanoyl]-4(S)-4-phenyl-1,3-oxazolidin-2-one (FOP alcohol) as a crucial intermediate which is produced by reduction of the corresponding prochiral ketone (FOP dione). A new biocatalyst from acclimatized soil was screened for bioreduction of the above prochiral ketone. The microorganism was identified by 16S mRNA sequencing, as Burkholderia cenocepacia. Various physicochemical conditions were optimized to increase cellmass and enzyme activity. The overall increase in cellmass concentration and enzyme activity was 2.06 and 1.85-fold, respectively. Various reaction conditions, for example pH, temperature, agitation, and cellmass concentration, were optimized for maximum product yield (chiral alcohol) with excellent enantioselectivity. Best reduction was achieved in phosphate buffer (50 mM, pH 8.0) at 40 degrees C (200 rpm) and the yield of enantiopure alcohol from the corresponding prochiral ketone was 54%. This biocatalyst was also used for the reduction of various other prochiral ketones.