Kinetic Resolution Of Secondary Alcohols Research Articles

Bienzymatic Dynamic Kinetic Resolution of Secondary Alcohols by Esterification/Racemization in Water.

Dynamic kinetic resolution (DKR) is a key method used to prepare optically pure compounds in 100% theoretical yield starting from racemic substrates by combining the interconversion of substrate enantiomers with an enantioselective transformation. Various chemoenzymatic DKR approaches have been developed to deracemize secondary alcohols, typically requiring an organic solvent to facilitate enantioselective acylation, primarily catalyzed by lipases, alongside racemization mediated by an achiral, non-enzymatic catalyst. Achieving both steps in an aqueous solution remained elusive. Here, we report a DKR of racemic sec-alcohols in an aqueous solution requiring only two biocatalysts. The first key to success was to achieve fast racemization in a buffer employing a non-stereoselective variant of alcohol dehydrogenase (Lk-ADH-Prince) via a hydrogen-borrowing oxidation-reduction sequence. Engineered variants of the acyltransferase from Mycobacterium smegmatis (MsAcT) enabled enantioselective acyl transfer in water. Besides the appropriate choice of the enzymes, identifying a suitable acyl donor was a second key to the success. The DKR was successfully demonstrated using (R)-selective MsAcT variants for a broad range of racemic (hetero)benzylic alcohols using 2,2,2-trifluoroethyl acetate as the acyl donor, yielding (R)-acetates with up to >99% conv. and high-to-excellent optical purity (83-99.9% ee). The (S)-acetates were accessible using a stereocomplementary (S)-selective MsAcT variant.

Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols

Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols

Recyclable and Scalable Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols Using Rotating Bed Reactors for Catalyst Compartmentalization

Recyclable and Scalable Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols Using Rotating Bed Reactors for Catalyst Compartmentalization

Cover Feature: Kinetic Resolution of Secondary Alcohols Catalyzed at the Exterior of Chiral Coordinated Capsules (Chem. Eur. J. 11/2024)

Cover Feature: Kinetic Resolution of Secondary Alcohols Catalyzed at the Exterior of Chiral Coordinated Capsules (Chem. Eur. J. 11/2024)

Kinetic Resolution of Secondary Alcohols Catalyzed at the Exterior of Chiral Coordinated Capsules.

Confined spaces inside molecular hosts can function as reaction vessels. However, this concept significantly limits the scope of reactants. When the exterior of molecular hosts is used instead, we can ease the restriction because reactants are not necessary to be trapped inside molecular hosts, although studies along this line have not been reported. As a proof-of-concept of enantioselective reactions at the exterior of chiral molecular hosts, we utilized host-guest complexes of enantiomerically enriched Cu-coordinated capsules and guests possessing a catalytic center to realize the kinetic resolution of secondary alcohols. Under suitable reaction conditions, a selectivity factor of 2.6 was realized, demonstrating that the reactions occur at the exterior of the capsules. A series of experiments indicated that the substituents on the 2,2'-bipyridyl arms and the alkyl chains on the lower rim contributed to the enantioselectivity of the reactions.

Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols and Amines Employing Copper-Based Photocatalysis

A tandem photo- and biocatalytic dynamic kinetic resolution of secondary alcohols and amines was achieved employing a commercially available lipase, Candida antarctica lipase B (CALB), and a heteroleptic copper complex. The process is an example of using copper-based photocatalysis to promote hydrogen atom transfer (HAT) processes employing thiyl radicals. Screening of 48 complexes and 5 disulfides identified Cu(dtbbpy)(DPEPhos)BF4 and (Ph3SiS)2 as an optimal catalyst system to promote the HAT process. The catalytic system represents a general system for radical-mediated racemization applicable to both aliphatic and aromatic alcohols and amines (18 examples, 60 → 97% yield, 76 → 99% ee).

Development of Dynamically Chiral Helical Polymer Catalysts Based on Post-Polymerization Modification of Boronyl Pendants

Catalytic asymmetric synthesis is one of the most efficient methods for the preparation of chiral compounds with high optical purity. Although a variety of robust chiral scaffolds have been developed to achieve efficient chiral catalysts which show high catalytic activities and stereoselectivities, use of dynamic chiral scaffold is desired for the development of advanced chiral catalysts featuring stimuli-responsive properties such as chirality-switching and asymmetric amplification. We have developed chirality-switchable helical polymer ligands bearing monodentate phosphine pendants, which exhibit high enantioselectivities based on solvent-dependent dynamic screw-sense control of poly(quinoxaline-2,3-diyl)s (PQXs) having chiral side chains. However, the application has been limited to palladium-catalyzed asymmetric reactions. This article describes the development of helically chiral polymer catalysts based on post-polymerization modification of bornyl pendants (-B(OH)2) attached to the PQXs. Introduction of 2,2′-bipyridine pendants to chiral PQXs through Suzuki-Miyaura coupling at the boronyl pendants led to the development of chirality-switchable helical polymer ligands for copper-catalyzed asymmetric reactions. In addition, introduction of 4-aminopyridine pendants into the chiral PQXs provided chirality-switchable efficient asymmetric nucleophilic catalysts for kinetic resolution of secondary alcohols and asymmetric Steglich-type acyl rearrangements. Furthermore, by using the boronyl pendants as molecular recognition sites for screw-sense induction to achiral PQXs, a chiral-guest-responsive helical polymer ligand bearing monodentate phosphine pendants was developed for the palladium-catalyzed asymmetric reaction. Using an amino alcohol as a chiral additive, the screw-sense induction proceeded with asymmetric amplification, giving the corresponding product with higher optical purity than that of the chiral additive.

Immobilization of Pseudomonas fluorescens lipase on chitosan crosslinked with polyaldehyde starch for kinetic resolution of sec-alcohols

The lipase from Pseudomonas fluorescens was immobilized on chitosan beads, with polyaldehyde starch (PAS) and glutaraldehyde (GA) being compared as crosslinking agents. With PAS, the best values for activity retention (53%), immobilization efficiency (94%), and hydrolytic activity in organic medium (156 U g−1) were obtained with an aldehyde content on chitosan of 3.5 mmol mg−1. With GA, the best results were an activity retention of 33%, an immobilization efficiency of 100%, and a hydrolytic activity in organic medium of 100 U g−1. When used in the kinetic resolution of secondary alcohols, the lipase immobilized on chitosan crosslinked with PAS gave a conversion of 43% in 24 h for (RS)-1-phenylethanol, and 36% in 36 h for (RS)-1-phenylpropanol. In both cases, the enantiomeric excess of the product (eep) was higher than 99%. These are promising results that support further studies into the immobilization of lipases on modified carbohydrates for use in organic media.

Design, Synthesis, and Application of Chiral Bicyclic Imidazole Catalysts.

Asymmetric organocatalysis has been considered to be an efficient and reliable strategy for the stereoselective preparation of optically active chemicals. In particular, chiral tertiary amines as Lewis base organocatalysts bearing core structures including quinuclidine, dimethylaminopyridine (DMAP), N-methylimidazole (NMI), amidine, etc. have provided new and powerful tools for various chemical transformations. However, due to the limitations in structural complexity, synthetic difficulty, low catalytic efficiency, and high cost, the industrial application of such catalysts is still far from being widely adopted. Therefore, the development of new chiral tertiary amine catalysts with higher activity and selectivity is greatly desired.In order to address the contradiction between activity and selectivity caused by the ortho group, a bicyclic imidazole structure bearing a relatively large bond angle ∠θ was designed as the skeleton of our new catalysts. 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (abbreviated as TIP) are two of the utilized skeletons. In addition to obtaining satisfactory catalytic activity, excellent enantioselectivity would also be expected because the stereocontrol R group is neither far nor close to the catalytic active site (sp2-N atom) and is adjustable. Based on this skeleton, a family of chiral bicyclic imidazole catalysts were easily prepared and successfully applied in several enantioselective reactions for the synthesis of a variety of valuable chiral compounds.6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) is the predominantly utilized skeleton. First, HO-DPI, the key intermediate of the designed chiral bicyclic imidazole catalysts, could be efficiently synthesized from imidazole and acrolein, then separated by kinetic resolution or optical resolution. Second, Alkoxy-DPI, the alkyloxy-substituted chiral bicyclic imidazole catalysts, were synthesized by a one-step alkylation from HO-DPI. This type of catalyst has been successfully applied in asymmetric Steglich rearrangement (C-acylation rearrangement of O-acylated azlactones), asymmetric phosphorylation of lactams, and a sequential four-step acylation reaction. Third, Acyloxy-DPI, the acyloxy-substituted chiral bicyclic imidazole catalysts, were synthesized with a one-step acetylative kinetic resolution from racemic HO-DPI or acylation from enantiopure HO-DPI. The catalyst AcO-DPI has been successfully applied in enantioselective Black rearrangement and in direct enantioselective C-acylation of 3-substituted benzofuran-2(3H)-ones and 2-oxindoles. Fourth, Alkyl-DPI was synthesized via a two-step reaction from racemic HO-DPI and separated easily by resolution. The catalyst Cy-DPI has been successfully applied in dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective O-acylation. Cy-PDPI was synthesized through a Cu-catalyzed amidation from Cy-DPI and successfully applied in the kinetic resolution of secondary alcohols with good to excellent enantioselectivities. Finally, the carbamate type chiral bicyclic imidazole catalysts, Carbamate-DPI, were readily synthesized from HO-DPI, and the catalyst Ad-DPI bearing a bulky adamantyl group was successfully applied in the synthesis of the anti-COVID-19 drug remdesivir via asymmetric phosphorylation. Alongside our initial work, this Account also introduces four elegant studies by other groups concerning asymmetric phosphorylation utilizing chiral bicyclic imidazole catalysts.In summary, this Account focuses on the chiral bicyclic imidazole catalysts developed in our group and provides an overview on their design, synthesis, and application that will serve as inspiration for the exploration of new organocatalysts and related reactions.

Highly Efficient Kinetic Resolution of Aryl-Alkenyl Alcohols by Ru-Catalyzed Hydrogen Transfer.

No matter through asymmetric reduction of ketones or kinetic resolution of secondary alcohols, enantioselective synthesis of the corresponding secondary alcohols is challenging when the two groups attached to the prochiral or chiral centers are spatially or electronically similar. For examples, dialkyl (sp3 vs. sp3), diaryl (sp2 vs. sp2), and aryl-alkenyl (sp2 vs. sp2) alcohols are difficult to produce with high enantioselectivities. By exploiting our recently developed Ru-catalysts of minimal stereogenicity, we reported herein a highly efficient kinetic resolution of aryl-alkenyl alcohols through hydrogen transfer. This method enabled such versatile chiral building blocks for organic synthesis as allylic alcohols, to be readily accessed with excellent enantiomeric excesses at practically useful conversions.

PQXdpap: Helical Poly(quinoxaline-2,3-diyl)s Bearing 4-(Dipropylamino)pyridin-3-yl Pendants as Chirality-Switchable Nucleophilic Catalysts for the Kinetic Resolution of Secondary Alcohols.

Helically chiral poly(quinoxaline-2,3-diyl)s bearing 4-(dipropylamino)pyridin-3-yl pendants at the 5-position of the quinoxaline ring (PQXdpap) exhibited high catalytic activities and moderate to high selectivities (up to s = 87) in the acylative kinetic resolution of secondary alcohols. The solvent-dependent helical chirality switching of PQXdpap between pure toluene and a 1:1 mixture of toluene and 1,1,2-trichloroethane enabled the preparation of either compound of a pair of enantiomerically pure alcohols (>99% ee) from a single catalyst.

Acylative Dynamic Kinetic Resolution of Secondary Alcohols: Tandem Catalysis by HyperBTM and Bäckvall's Ruthenium Complex.

Non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols by enantioselective acylation using an isothiourea-derived HyperBTM catalyst and racemization of slowly reacting alcohol by Bäckvall's ruthenium complex is reported. The DKR approach features high enantioselectivities (up to 99:1), employs easy-to-handle crystalline 4-nitrophenyl isobutyrate as the acylating reagent, and proceeds at room temperature and under an ambient atmosphere. The stereoinduction model featuring cation-π system interactions between the acylated HyperBTM catalyst and π electrons of an alcohol aryl subunit has been elaborated by DFT calculations.

The Size-Accelerated Kinetic Resolution of Secondary Alcohols.

The factors responsible for the kinetic resolution of alcohols by chiral pyridine derivatives have been elucidated by measurements of relative rates for a set of substrates with systematically growing aromatic side chains using accurate competitive linear regression analysis. Increasing the side chain size from phenyl to pyrenyl results in a rate acceleration of more than 40 for the major enantiomer. Based on this observation a new catalyst with increased steric bulk has been designed that gives enantioselectivity values of up to s=250. Extensive conformational analysis of the relevant transition states indicates that alcohol attack to the more crowded side of the acyl‐catalyst intermediate is favoured due to stabilizing CH‐π‐stacking interactions. Experimental and theoretical results imply that enantioselectivity enhancements result from accelerating the transformation of the major enantiomer through attractive non‐covalent interactions (NCIs) rather than retarding the transformation of the minor isomer through repulsive steric forces.

Palladium Complexes Bearing Chiral bis(NHC) Chelating Ligands on a Spiro Scaffold: Synthesis, Characterization, and Their Application in the Oxidative Kinetic Resolution of Secondary Alcohols

A series of chiral bis-N-heterocyclic carbene ligands H2[(S)-1a–d]X2 (X = Br, I) on a spiro scaffold and their palladium complexes (S)-2a–d and (S)-3a,b were prepared and applied in the enantiosele...

Polymer compositions on kinetic resolution of secondary alcohols using polymer-supported silyl chlorides

Modulating the polarity of the polymer backbone affects the selectivity of asymmetric silylation.

Anodic Oxidation for the Stereoselective Synthesis of Heterocycles.

Stereodefined aliphatic heterocycles are one of the fundamental structural motifs observed in natural products and biologically active compounds. Various strategies for the synthesis of these building blocks based on transition metal catalysis, organocatalysis, and noncatalytic conditions have been developed. Although electrosynthesis has also been utilized for the functionalization of aliphatic heterocycles, stereoselective transformations under electrochemical conditions are still a challenging field in electroorganic chemistry. This Account consists of four main topics related to our recent efforts on the diastereo- and/or enantioselective synthesis of aliphatic heterocycles, especially N-heterocycles, using anodic oxidations as key steps. The first topic is the development of stereoselective synthetic methods for multisubstituted piperidines and pyrrolidines from anodically prepared α-methoxy cyclic amines. Our strategies were based primarily on N-acyliminium ion chemistry, and the key electrochemical transformations were diastereoselective anodic methoxylation, diastereoselective arylation, and anodic deallylative methoxylation. Furthermore, we found a unique property of the N-cyano protecting group that enabled the electrochemical α-methoxylation of α-substituted cyclic amines. The second topic of investigation is memory of chirality in electrochemical decarboxylative methoxylation. We observed that the electrochemical decarboxylative methoxylation of oxazolidine and thiazolidine derivatives with the appropriate N-protecting group occurred in a stereospecific manner even though the reaction proceeded through an sp2 planar carbon center. Our findings demonstrated the first example of memory of chirality in N-acyliminium ion chemistry. The third topic is the synthesis of chiral azabicyclo-N-oxyls and their application to chiral organocatalysis in the electrochemical oxidative kinetic resolution of secondary alcohols. The final topic is stereoselective transformations utilizing anodically generated halogen cations. We investigated the oxidative kinetic resolution of amino alcohol derivatives using anodically generated bromo cations. We also developed an intramolecular C-C bond formation of keto amides, a diastereoselective bromoiminolactonization of α-allyl malonamides, and an oxidative ring expansion reaction of allyl alcohols. It is noteworthy that most of the electrochemical reactions were performed in undivided cells under constant-current conditions, which avoided a complicated reaction setup and was beneficial for a large-scale reaction. In addition, we developed some enantioselective electrochemical transformations that are still challenges in electroorganic chemistry. We hope that our research will contribute to the further development of diastereo- and/or enantioselective transformations and the construction of valuable heterocyclic compounds using an electrochemical approach.

Base-Free Dynamic Kinetic Resolution of Secondary Alcohols with a Ruthenium-Lipase Couple.

We report the dynamic kinetic resolution (DKR) of various secondary alcohols by the combination of a ruthenium catalyst and an anionic surfactant-activated lipoprotein lipase. The DKR reactions performed under totally base-free conditions at room temperature provided the products of excellent enantiopurities (91-99% ee or greater) in high yields (92-99%). More importantly, the DKR of α-arylallyl alcohols was achieved for the first time with high yields (87-91%).

Bioinspired Manganese and Iron Complexes for Enantioselective Oxidation Reactions: Ligand Design, Catalytic Activity, and Beyond

The development of efficient methods for the enantioselective oxidation of organic molecules continues to be an important goal in organic synthesis; in particular, the use of earth-abundant metal catalysts and environmentally friendly oxidants in catalytic asymmetric oxidation reactions has attracted significant interest over the last several decades. In nature, metalloenzymes catalyze a wide range of oxidation reactions by activating dioxygen under mild conditions. Inspired by selective and efficient oxidation reactions catalyzed by metalloenzymes, researchers have developed a number of synthetic model compounds that mimic the functionality of metalloenzymes. Among the reported biomimetic model compounds, tetradentate aminopyridine (N4) ligands have emerged as appealing frameworks because of their easy synthesis and facile diversification, and their complexes with metals such as Fe and Mn have proven to be versatile and powerful catalysts for a variety of (enantioselective) oxidation reactions. In this Account, we describe our efforts on the design of chiral N4 ligands and the use of their manganese and iron complexes in asymmetric oxidation reactions with H2O2 as the terminal oxidant, aiming to show general strategies for asymmetric oxidation reactions that can guide the rational design of ligands and relevant metal catalysts. In studies of manganese catalysts, the aryl-substituted (R,R)-mcp [mcp = N,N'-dimethyl-N,N'-bis(pyridine-2-ylmethyl)cyclohexane-1,2-diamine] manganese complexes exhibited high enantioselectivity in the asymmetric epoxidation (AE) of various olefins with H2O2 while requiring stoichiometric acetic acid as an additive for the activation of H2O2. To address this issue, we established bulkier N4 ligands for this catalytic system in which a catalytic amount of sulfuric acid enables the manganese-complex-catalyzed AE with improved stereocontrol and efficiency. In addition, this system was found to be active for the oxidative kinetic resolution of secondary alcohols. Further exploration of the structure-reactivity relationships has shown that aminobenzimidazole N4 ligands derived from l-proline, in which the conventional pyridine donors are replaced by benzimidazoles, act as promising ligands. These novel C1-symmetric manganese catalysts showed dramatically improved activities with unprecedented turnover numbers in the AE reactions. Notably, this class of manganese complexes can catalyze the oxidation of the C-H bonds of spirocyclic hydrocarbons and spiroazacyclic compounds in a highly enantioselective manner, providing ready access to chiral spirocyclic β,β'-diketones and spirocyclic alcohols. Remarkably, iron catalysts with these chiral N4 ligands are effective for AE of olefins, enabling rare examples of highly enantioselective syntheses of epoxides by the iron catalysts. Finally, mechanistic studies provide valuable insights into the roles of the carboxylic acid and sulfuric acid in the catalytic oxidation reactions. Thus, the results described in this Account have demonstrated the importance of tunability and compatibility of the ligands for the development of efficient oxidation catalysts with earth-abundant transition metals and environmentally benign oxidants, and we hope that our study will pave the way for the discovery of efficient oxidation catalysis.

Controlled Exchange of Achiral Linkers with Chiral Linkers in Zr-Based UiO-68 Metal-Organic Framework.

The development of highly robust heterogeneous catalysts for broad asymmetric reactions has always been a subject of interest, but it remains a synthetic challenge. Here we demonstrated that highly stable metal-organic frameworks (MOFs) with potentially acid-labile chiral catalysts can be synthesized via postsynthetic exchange. Through a one- or two-step ligand exchange, a series of asymmetric metallosalen catalysts with the same or different metal centers are incorporated into a Zr-based UiO-68 MOF to form single- and mixed-M(salen) linker crystals, which cannot be accomplished by direct solvothermal synthesis. The resulting MOFs have been characterized by a variety of techniques including single-crystal X-ray diffraction,N2 sorption, CD, and SEM/TEM-EDS mapping. The single-M(salen) linker MOFs are active and efficient catalysts for asymmetric cyanosilylation of aldehydes, ring-opening of epoxides, oxidative kinetic resolution of secondary alcohols, and aminolysis of stilbene oxide, and the mixed-M(salen) linker variants are active for sequential asymmetric alkene epoxidation/epoxide ring-opening reactions. The chiral MOF catalysts are highly enantioselective and completely heterogeneous and recyclable, making them attractive catalysts for eco-friendly synthesis of fine chemicals. This work not only advances UiO-type MOFs as a new platform for heterogeneous asymmetric catalysis in a variety of syntheses but also provides an attractive strategy for designing robust and versatile heterogeneous catalysts.

Novel nanohybrid biocatalyst: application in the kinetic resolution of secondary alcohols

In this work, a nanohybrid material was developed and used for the first time to the kinetic resolution of secondary alcohols as rac-indanol, rac-1-phenylethanol (rac-1), rac-1-(3-bromophenyl)-1-ethanol (rac-2) and rac-1-(3-methylphenyl)-1-ethanol (rac-3). Chiral indanol is used as a precursor intermediate for the synthesis of enantiomeric drugs, such as (+)-Indatraline, Irindalone, Indinavir, (+)-Sertraline and Rasagiline mesylate. Chiral 1-phenylethanol is used as an ophthalmic preservative, a solvatochromic dye and an inhibitor of cholesterol absorption and as a mild floral fragrance. For this purpose, the ultrasound irradiation was used to couple APTES on the superparamagnetic nanoparticles surface. Then, the system was activated with glutaraldehyde and used as a support for immobilization of lipase from Pseudomonas fluorescens. Thermal stability analysis was performed in buffer and hexane, showing an excellent stability in buffer solution at 60 °C, holding 72% of the initial activity, even after 7 h. In hexane (40 °C), the immobilized enzyme retained 100% of activity with 693 min of half-life time at 50 °C. The high thermal stability is mainly related to the covalent bonding between enzymes and support. Immobilized lipase on magnetic support proved to be a robust biocatalyst in the kinetic resolution, leading to (S)-indanol with high selectivity (e.e. > 99%, E > 200) in 1.75 h at 50 °C, being reused five times without significant loss of the activity and selectivity. The kinetic resolution of rac-1, via acetylation reaction, catalyzed by lipase from Pseudomonas fluorescens immobilized on magnetic support, led to (R)-acetate with enantiomeric excess > 99% and to the remaining (S)-alcohol with enantiomeric excess of 94%, conversion of 49% and E > 200, after 48 h of reaction at 40 °C. Under the same reactions conditions, rac-2 and rac-3 were slightly less reactive, since the corresponding (R)-acetates were obtained with conversion values of 44%, but with high enantioselectivity (enantiomeric excesses > 99% and E values > 200). These results correspond to an important step in heterogeneous catalysis due to the ability to obtain important precursors for the synthesis of enantiomerically pure chiral drugs and other bioactive substances.