Racemic Alcohols Research Articles

Synthesis, resolution, and absolute configuration determination of a vicinal amino alcohol with axial chirality. Application to the synthesis of new box and pybox ligands.

New racemic vicinal amino alcohol derivatives with 4‐benzylidenecyclohexane skeleton and axial chirality have been prepared. A preparatively easy and efficient protocol for resolution of the N‐benzoylamino alcohol is described. Using a 250 × 20 mm (L × ID) Chiralpak® IA column, and the appropriate mixture of n‐hexane/ethanol/chloroform as eluent, both enantiomers of N‐benzoylamino alcohol 3 are obtained with >99% enantiomeric excess (ee) by successive injections of a solution of the racemic sample in chloroform. The obtained axially chiral vicinal amino alcohol is used to synthesize structurally novel bisoxazoline ligands in high yields.

Asymmetric Ruthenium-Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives.

The asymmetric hydroalkylation of racemic allylic alcohols has been developed for the synthesis of chiral amino acid derivatives with two remote chiral centers by borrowing hydrogen catalysis. The stereoselectivities are controlled by a single chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and an interesting diastereoselectivity amplification process of the product. The method could be used for the synthesis of several types of biologically important molecules, including stereodivergent synthesis of chiral pyrrolidine derivatives.

Asymmetric Ruthenium‐Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives

AbstractThe asymmetric hydroalkylation of racemic allylic alcohols has been developed for the synthesis of chiral amino acid derivatives with two remote chiral centers by borrowing hydrogen catalysis. The stereoselectivities are controlled by a single chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and an interesting diastereoselectivity amplification process of the product. The method could be used for the synthesis of several types of biologically important molecules, including stereodivergent synthesis of chiral pyrrolidine derivatives.

Kinetic Resolution of Tertiary Alcohols by Chiral Organotin-Catalyzed O-Acylation.

A novel highly enantioselective method for the kinetic resolution of racemic tertiary alcohols has been achieved through chiral organotin-catalyzed intermolecular acylation of the hydroxyl group. This process has demonstrated a broad substrate scope (both alkyl- and aryl-substituted tertiary alcohols) with high enantioselectivity under mild reaction conditions, affording the corresponding products and the recovered tertiary alcohols with high enantioselectivities, with s factors up to >200.

Stereo-Divergent Enzyme Cascades to Convert Racemic 4-Phenyl-2-Butanol into either (S)- or (R)-Corresponding Chiral Amine.

The synthesis of enantiopure chiral amines from racemic alcohols is a key transformation in the chemical industry, e. g., in the production of active pharmaceutical ingredients (APIs). However, this reaction remains challenging. In this work, we propose a one‐pot enzymatic cascade for the direct conversion of a racemic alcohol into either (S)‐ or (R)‐enantiomers of the corresponding amine, with in‐situ cofactor recycling. This enzymatic cascade consists of two enantio‐complementary alcohol dehydrogenases, both NADH and NADPH oxidase for in‐situ recycling of NAD(P)+ cofactors, and either (S)‐ or (R)‐enantioselective transaminase. This cell‐free biocatalytic system has been successfully applied to the conversion of racemic 4‐phenyl‐2‐butanol into the high value (S)‐ or (R)‐enantiomers of the amine reaching good (73 % (S)) and excellent (>99 % (R)) enantioselectivities.

An Engineered Cholesterol Oxidase Catalyses Enantioselective Oxidation of Non-steroidal Secondary Alcohols.

The enantioselective oxidation of 2° alcohols to ketones is an important reaction in synthetic chemistry, especially if it can be achieved using O2‐driven alcohol oxidases under mild reaction conditions. However to date, oxidation of secondary alcohols using alcohol oxidases has focused on activated benzylic or allylic substrates, with unactivated secondary alcohols showing poor activity. Here we show that cholesterol oxidase (EC 1.1.3.6) could be engineered for activity towards a range of aliphatic, cyclic, acyclic, allylic and benzylic secondary alcohols. Additionally, since the variants demonstrated high (S)‐selectivity, deracemisation reactions were performed in the presence of ammonia borane to obtain enantiopure (R)‐alcohols.

Enantiocontrol over Acyclic Quaternary Stereocenters by Acylative Organocatalyzed Kinetic Resolution

AbstractIn the present paper, we described the efficient enantioselective kinetic resolution (KR) of racemic diastereocontrolled secondary alcohols bearing a quaternary stereocenter using a commercially available chiral isothiourea organocatalyst. This methodology is a general KR leading to the enantiocontrol of acyclic quaternary stereocenter with high levels of stereoselectivity (s up to 185) on a large scope. The hydroxyl function can easily serve as a traceless group by oxidation or reduction process.

Biocatalytic deracemization of racemic naphthyl alcohols by using a novel yeast isolate Rhodotorula kratochvilovae (MTCC 13029)

Enantiopure alcohols are key intermediates for the synthesis of a plethora of pharmaceuticals, agrochemicals and fine chemicals. Present study reports the deracemization of racemic naphthyl ethanols into their enantiopure S-forms by CHF-15P (Rhodotorula kratochvilovae, MTCC 13029) whole cells, isolated from the high altitude of the Himalayan mountain range. Initially, the biocatalyst was able to deracemize rac-1-(6-methoxy-2-naphthyl)ethanol to S-1-(6-methoxy-2-naphthyl)ethanol with 86.3% yield and 82.6% eeS. The studies on the effect of physicochemical parameters showed 92.3% yield with eeS>99% of product in a medium containing 2 mM substrate concentration and 2% glucose at 30 °C temperature, pH 7.0 (0.2 M sodium phosphate buffer), with 100 mg/mL cell concentration. In addition, the deracemization of rac-1-(6-methyl-2-naphthyl)ethanol and rac-1-(2-naphthyl)ethanol was achieved within 12 h at 30 °C with 96.4 and 98.8% of yield (98.2% and >99% eeS), respectively. The process of deracemization occurs via the formation of a ketone intermediate. The appearance of ketone has been demonstrated by high performance liquid chromatography (HPLC) and confocal laser scanning microscopy. However, rac-1-(1-naphthyl)ethanol and rac-1-(4-fluoro-1-naphthyl)ethanol were not deracemized under the same condition. In gram scale preparation, 92.8% yield with eeS>99% was obtained.

Iridium‐Catalyzed Enantioselective and Chemodivergent Allenylic Alkylation of Vinyl Azides for the Synthesis of α‐Allenylic Amides and Ketones**

AbstractThe first enantioselective synthesis of α‐allenylic amides and ketones through allenylic alkylation of vinyl azides is reported. In these chemodivergent reactions, cooperatively catalyzed by a IrI/(phosphoramidite,olefin) complex and Sc(OTf)3, vinyl azides act as the surrogate for both amide enolates and ketone enolates. The desiccant (molecular sieves) plays a crucial role in controlling the chemodivergency of this enantioconvergent and regioselective reaction: Under otherwise identical reaction conditions, the presence of the desiccant led to α‐allenylic amides, while its absence resulted in α‐allenylic ketones. Utilizing racemic allenylic alcohols as the alkylating agent, the overall process represents a dynamic kinetic asymmetric transformation (DyKAT), where both the products are formed with the same absolute configuration. To the best of our knowledge, this is the first example of the use of vinyl azide as the ketone enolate surrogate in an enantioselective transformation.

Iridium-Catalyzed Enantioselective and Chemodivergent Allenylic Alkylation of Vinyl Azides for the Synthesis of α-Allenylic Amides and Ketones.

The first enantioselective synthesis of α-allenylic amides and ketones through allenylic alkylation of vinyl azides is reported. In these chemodivergent reactions, cooperatively catalyzed by a IrI /(phosphoramidite,olefin) complex and Sc(OTf)3 , vinyl azides act as the surrogate for both amide enolates and ketone enolates. The desiccant (molecular sieves) plays a crucial role in controlling the chemodivergency of this enantioconvergent and regioselective reaction: Under otherwise identical reaction conditions, the presence of the desiccant led to α-allenylic amides, while its absence resulted in α-allenylic ketones. Utilizing racemic allenylic alcohols as the alkylating agent, the overall process represents a dynamic kinetic asymmetric transformation (DyKAT), where both the products are formed with the same absolute configuration. To the best of our knowledge, this is the first example of the use of vinyl azide as the ketone enolate surrogate in an enantioselective transformation.

Recent Advances in Catalytic Nonenzymatic Kinetic Resolution of Tertiary Alcohols

AbstractThe kinetic resolution (KR) of racemates is one of the most widely used approaches to access enantiomerically pure compounds. Over the past two decades, catalytic nonenzymatic KR has gained popularity in the field of asymmetric synthesis due to the rapid development of chiral catalysts and ligands in asymmetric catalysis. Chiral tertiary alcohols are prevalent in a variety of natural products, pharmaceuticals, and biologically active chiral compounds. The catalytic nonenzymatic KR of racemic tertiary alcohols is a straightforward strategy to access enantioenriched tertiary alcohols. This short review describes recent advances in catalytic nonenzymatic KR of tertiary alcohols, including organocatalysis and metal catalysis.1 Introduction2 Organocatalysis2.1 Peptide Catalyst2.2 Chiral Phosphoric Acid Catalyst2.3 Chiral Lewis Base Catalyst2.4 Chiral Quaternary Ammonium Salt Catalyst3 Metal Catalysis3.1 Mixed La-Li Heterobimetallic Catalyst3.2 Rh Catalyst3.3 Hf Catalyst3.4 Pd Catalyst3.5 Cu Catalyst3.6 Ag Catalyst4 Conclusion and Outlook

Asymmetric Hydrogenation of Racemic Allylic Alcohols via an Isomerization–Dynamic Kinetic Resolution Cascade

Prochiral racemic allylic alcohols are converted to enantioenriched chiral alcohols bearing adjacent stereocenters catalyzed by a diamine diphosphine Ru complex in the presence of tBuOK. The protocol features a broad substrate scope (56 examples) and high diastereo- and enantioselectivities (up to >99:1 dr, >99% ee) and could be applied to the synthesis of enantioenriched chromane and indane compounds. Mechanistic studies suggest that the reaction proceeds via tBuOK-promoted allylic alcohol isomerization followed by Ru-catalyzed hydrogenative dynamic kinetic resolution.

Kinetic resolution of racemic tertiary allylic alcohols through SN2′ reaction using a chiral bisphosphoric acid/silver(i) salt co-catalyst system

A highly efficient kinetic resolution (KR) of racemic tertiary allylic alcohols was achieved through an intramolecular allylic substitution reaction using a co-catalyst system composed of chiral bisphosphoric acid and silver carbonate. This reaction afforded enantioenriched diene monoepoxides along with the recovery of tertiary allylic alcohols in a highly enantioselective manner, realizing an extremely high s-factor in most cases. The present method provides a new access to enantioenriched tertiary allylic alcohols, multifunctional compounds that are applicable for further synthetic manipulations.

A biomimetic metal–organic framework with cuboid inner cavities for enantioselective separation

A biomimetic metal–organic framework with cuboid inner cavities and multiple recognition sites was constructed from a phenylalanine-derived ligand. It can enantioselectively separate various racemic alcohols, diols and epoxides with ee up to 99.5%.

A Novel Approach for the Synthesis of (<i>R</i>) and (<i>S</i>)-Nicotine

Nicotine is an alkaloid mainly found in leaves of tobacco and is used therapeutically for patients seeking relief from tobacco dependence in the form of products such as gums, patches, lozenges etc. In these products, majorly nicotine derived from tobacco is used which is inherently contaminated with undesirable nicotine related substances as impurities at low levels and is difficult to remove. Hence, use of synthetic nicotine is considered as an option which will be devoid of such impurities. In this work, a short and efficient synthesis of (R) and (S) nicotine was achieved by leveraging a key esterification between racemic homoallylic alcohol intermediate (2) and (S)-Ibuprofen (3) to produce diastereomers (5a) and (5b) which were easily separable under standard column chromatography conditions. Use of (S)-Ibuprofen (3) as a chiral resolving agent constitutes a novel approach which was not reported earlier. A subsequent hydrolysis of the diastereomers furnished the homoallylic alcohol intermediates (S)-6a and (R)-6a with high enantiopurity, which was effectively translated to the corresponding (R)-nicotine and (S)-nicotine respectively.

Chiral phosphoric acid-catalyzed regio- and enantioselective reactions of functionalized propargylic alcohols

Chiral phosphoric acid has been utilized for covalent activation of propargylic alcohols to act as pre-catalyst. With this activation mode, a range of highly regio- and enantioenriched heterocyclic products could be generated efficiently from racemic propargylic alcohols.

Organocatalytic enantioselective SN1-type dehydrative nucleophilic substitution: access to bis(indolyl)methanes bearing quaternary carbon stereocenters.

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution. A broad range of 3,3′-, 3,2′- and 3,1′-BIMs were obtained under mild conditions with excellent efficiency and enantioselectivity (80 examples, up to 98% yield and >99 : 1 er). By utilizing racemic 3-indolyl tertiary alcohols as precursors of alkyl electrophiles and indoles as C–H nucleophiles, this organocatalytic strategy avoids pre-activation of substrates and produces water as the only by-product. Mechanistic studies suggest a formal SN1-type pathway enabled by chiral phosphoric acid catalysis. The practicability of the obtained enantioenriched BIMs was further demonstrated by versatile transformation and high antimicrobial activities (3al, MIC: 1 μg mL−1).

Deracemization of racemic alcohols combining photooxidation and biocatalytic reduction.

We described a cascade reaction for deracemization of racemic alcohols combining photooxidation and enzymatic reduction under mild conditions without the isolation of intermediate ketones. Using different ketoreductases, a variety of racemic alcohols can be successfully converted into (R)- or (S)-enantiomers in high yields (up to 95%) and stereoselectivity (up to 99%).

Construction of a chiral zinc-camphorate framework for enantioselective separation.

A chiral metal-organic framework (CMOF) with open chiral channels and multiple recognition sites is constructed from camphoric acid and a dipyridyl ligand. It can act as an efficient chiral solid adsorbent, capable of separating a variety of racemic alcohols and epoxides with excellent enantioselectivities.

Cross-Linked Enzyme-Adhered Nanoparticles (CLEANs) for Continuous-Flow Bioproduction.

Nanostructured but micro-sized biocatalysts were created by bottom-up technology using multi-functionalized silica nanoparticles (NPs) as nano-sized building blocks to form cross-linked enzyme-adhered nanoparticles (CLEANs) as robust micro-sized particles with beneficial internal structure and good mechanical properties. Systematic surface modification of NPs with a grafting mixture consisting of organosilanes with reactive (aminopropyl) and inert (e. g., vinyl, propyl, phenyl, or octyl) functions resulted in functional NPs enabling cross-linking agents, such as glutardialdehyde or bisepoxides (glycerol diglycidyl ether, neopentylglycol diglycidyl ether, and poly(propylene glycol) diglycidyl ether), to bind and cross-link enzymes covalently and to form macroporous microparticles. These CLEANs were able to diminish several weaknesses of traditional cross-linked enzyme aggregates as biocatalysts, such as poor mechanical resistance, difficult recovery, and storage, strengthening their use for packed-bed enzyme reactors. Lipase B from Candida antarctica (CaLB) was selected as model enzyme for development of robust CLEANs, which were successfully tested for various industrially relevant applications including a kinetic resolution of a racemic alcohol and the production of various natural fragrance compounds under continuous-flow conditions.