Resolution Of Racemic Secondary Alcohols Research Articles

Synergistic Palladium/Chiral Phosphoric Acid-Catalyzed Kinetic Resolution via Stereoselective Intramolecular Substitution of Unactivated Allylic Alcohols.

This paper reports the kinetic resolution of racemic secondary alcohols (O-nucleophiles) via stereoselective intramolecular allylic substitution. The reaction was enabled by synergistic palladium and chiral phosphoric acid catalysis and produced chiral cis-1,3-disubstituted 1,3-dihydroisobenzofurans with a selective factor of up to 60.9 and a diastereomeric ratio of up to 7.8:1. Asymmetric synthesis of a compound with antihistaminic activity was demonstrated as the application of this methodology.

Continuous‐Flow Dynamic Kinetic Resolution of Racemic Alcohols by Lipase–Oxovanadium Cocatalysis

A continuous‐flow dynamic kinetic resolution of racemic secondary alcohols was carried out using a single column reactor packed with a mixture of immobilized lipase and an immobilized oxovanadium species, VMPS4. As a result, optically pure esters were produced in 88–92 % yields. Problems encountered in this study were overcome by using fillers that efficiently maintained the initial distribution of the catalysts in the reactor and by using a packing method in which the mixing ratio of the two catalysts was varied in a stepwise fashion. The flow process led to an increased turnover number of each catalyst compared to those of batch reactions.

CALB Immobilized onto Magnetic Nanoparticles for Efficient Kinetic Resolution of Racemic Secondary Alcohols: Long-Term Stability and Reusability.

In this study, an immobilization strategy for magnetic cross-linking enzyme aggregates of lipase B from Candida antarctica (CALB) was developed and investigated. Magnetic particles were prepared by conventional co-precipitation. The magnetic nanoparticles were modified with 3-aminopropyltriethoxysilane (APTES) to obtain surface amino-functionalized magnetic nanoparticles (APTES–Fe3O4) as immobilization materials. Glutaraldehyde was used as a crosslinker to covalently bind CALB to APTES–Fe3O4. The optimal conditions of immobilization of lipase and resolution of racemic 1-phenylethanol were investigated. Under optimal conditions, esters could be obtained with conversion of 50%, enantiomeric excess of product (eep) > 99%, enantiomeric excess of substrate (ees) > 99%, and enantiomeric ratio (E) > 1000. The magnetic CALB CLEAs were successfully used for enzymatic kinetic resolution of fifteen secondary alcohols. Compared with Novozym 435, the magnetic CALB CLEAs exhibited a better enantioselectivity for most substrates. The conversion was still greater than 49% after the magnetic CALB CLEAs had been reused 10 times in a 48 h reaction cycle; both ees and eep were close to 99%. Furthermore, there was little decrease in catalytic activity and enantioselectivity after being stored at −20 °C for 90 days.

Asymmetric aerobic oxidation of secondary alcohols catalyzed by poly(N-vinyl-2-pyrrolidone)-stabilized gold clusters modified with cyclodextrin derivatives.

Surface modification of poly(N-vinyl-2-pyrrolidone)-stabilized gold clusters (1.8 ± 0.6 nm) with aminated cyclodextrins induced aerobic oxidative kinetic resolution of racemic secondary alcohols (krel = 1.2).

Enhancement of activity and reusability of lipase immobilized on magnetic mesoporous silica for the resolution of racemic secondary alcohols

Magnetic mesoporous silica (MMS) composites with an average mesopore size (~2.98 nm), large surface area (404–442 m2/g), and high saturated magnetization (17.7–33.5 emu/g) were successfully prepared by hydrothermal crystallization in the presence of monodisperse Fe3O4 microspheres. The as‐synthesized composites served as supports for lipase from Burkholderia cepacia (BCL) immobilization in isooctane via interfacial activation and were then employed as biocatalysts for the transesterification resolution of racemic aromatic secondary alcohols to synthesize chiral intermediates. The catalytic performance of the immobilized BCL (BCL/MMS) was notably improved compared to that of the non‐immobilized BCL, with the total conversion and enantiomeric excess reaching 50 and 99% of the maximum theoretical values, respectively. Furthermore, the magnetic BCL/MMS possessing the same textural properties and enzyme loading exhibited decreasing catalytic capability as their saturated magnetization value increased. Moreover, BCL/MMS could also be readily recycled from the reaction system by applying an external magnetic field so as to facilitate its reuse up to five cycles with retaining up to 90% of the initial activity. Its high activity, easy recovery, and excellent operational stability make the BCL/MMS a potential green catalyst for the synthesis of optically active intermediates.

Design and Assembly of a Chiral Metallosalen-Based Octahedral Coordination Cage for Supramolecular Asymmetric Catalysis.

Supramolecular containers featuring both high catalytic activity and high enantioselectivity represent a design challenge of practical importance. Herein, it is demonstrated that a chiral octahedral coordination cage can be constructed by using twelve enantiopure Mn(salen)-derived dicarboxylic acids as linear linkers and six Zn4 -p-tert-butylsulfonylcalix[4]arene clusters as tetravalent four-connected vertices. The porous cage features a large hydrophobic cavity (≈3944 Å3 ) decorated with catalytically active metallosalen species and is shown to be an efficient and recyclable asymmetric catalyst for the oxidative kinetic resolution of racemic secondary alcohols and the epoxidation of olefins with up to >99 % enantiomeric excess. The cage architecture not only prevents intermolecular deactivation and stabilizes the Mn(salen) catalysts but also encapsulates substrates and concentrates reactants in the cavity, resulting in enhanced reactivity and enantioselectivity relative to the free metallosalen catalyst.

Design and Assembly of a Chiral Metallosalen‐Based Octahedral Coordination Cage for Supramolecular Asymmetric Catalysis

AbstractSupramolecular containers featuring both high catalytic activity and high enantioselectivity represent a design challenge of practical importance. Herein, it is demonstrated that a chiral octahedral coordination cage can be constructed by using twelve enantiopure Mn(salen)‐derived dicarboxylic acids as linear linkers and six Zn4‐p‐tert‐butylsulfonylcalix[4]arene clusters as tetravalent four‐connected vertices. The porous cage features a large hydrophobic cavity (≈3944 Å3) decorated with catalytically active metallosalen species and is shown to be an efficient and recyclable asymmetric catalyst for the oxidative kinetic resolution of racemic secondary alcohols and the epoxidation of olefins with up to >99 % enantiomeric excess. The cage architecture not only prevents intermolecular deactivation and stabilizes the Mn(salen) catalysts but also encapsulates substrates and concentrates reactants in the cavity, resulting in enhanced reactivity and enantioselectivity relative to the free metallosalen catalyst.

Asymmetric Substitution Reactions Catalyzed by a Chiral Phosphoric Acid

Nucleophilic substitution reactions on the sp2- or sp3-hybridized carbon, including formal substitution such as addition-elimination sequence, are one of the fundamental transformations in organic synthesis. Compared with the addition reactions, development of catalytic enantioselective substitution reactions is still rare. This account summarizes our recent efforts to solve the problems by using chiral phosphoric acid catalysts. The first topic is the catalytic kinetic resolution of racemic secondary alcohols by an addition-elimination type acylation reaction. The desymmetrization of σ-symmetrical acid anhydrides is also described. The second topic is the enantioselective intramolecular SN2' reaction. We made clear that the choice of the leaving group is quite important. The last topic is the catalytic kinetic resolution of racemic β-aminoalcohols by nucleophilic benzylation reaction. Chiral phosphoric acid works as a nucleophilic catalyst to form the corresponding phosphonate in situ as a chiral electrophilic intermediate.

Advances in asymmetric oxidative kinetic resolution of racemic secondary alcohols catalyzed by chiral Mn(III) salen complexes.

Enantiomerically pure secondary alcohols are essential compounds in organic synthesis and are used as chiral auxiliaries and synthetic intermediates in the pharmaceutical, agrochemical, and fine chemical industries. One of the attractive and practical approaches to achieving optically pure secondary alcohols is oxidative kinetic resolution of racemic secondary alcohols using chiral Mn(III) salen complexes. In the last decade, several chiral Mn(III) salen complexes have been reported with excellent enantioselectivity and activity in the homogeneous and heterogeneous catalysis of the oxidative kinetic resolution of racemic secondary alcohols. This review article is an overview of the literature on the recent development of chiral Mn(III) salen complexes for oxidative kinetic resolution of racemic secondary alcohols. The catalytic activity of monomeric, dimeric, macrocyclic, polymeric, and silica/resin supported chiral Mn(III) salen complexes is discussed in detail.

Lipase immobilized in ordered mesoporous silica: A powerful biocatalyst for ultrafast kinetic resolution of racemic secondary alcohols

Although Burkholderia cepacia lipase (BCL) has been proved to be a potential catalyst for chiral resolution, it is rarely applied in industry because of the low catalysis activity and poor stability of the free form. In this article, BCL was immobilized on the phenyl-modified ordered mesoporous silica (Ph-OMMs) to obtain a novel immobilized lipase. Benefits from the bottle-neck mesoporous structure, high loading of BCL could be completed within only 15 min. When BCL@Ph-OMMs was used as a catalyst for the resolution of 1-phenylethanol, up to 50% conversion with more than 99% ees was obtained within only 25 min, which is about 65-folds faster than that of the free lipase. Stabilized BCL@Ph-OMMs was successfully used for the ultrafast resolution of six secondary alcohols by selectivity transesterification, which reached high conversion (50%) and high enantioselectivity (≥99%) within 20–180 min. The activity of BCL@Ph-OMMs was kept relatively constant in 50 consecutive cycles, which is the best result among the reported immobilized lipases. The study suggests that BCL@Ph-OMMs is an attractive catalyst in industrial applications.

Bioimprinted lipases in PVA nanofibers as efficient immobilized biocatalysts

Immobilization of lipases from Pseudomonas fluorescens (Lipase AK), Burkholderia (Pseudomonas) cepacia (Lipase PS) and lipase B from Pseudozyma (Candida) antarctica (CaLB) was investigated by entrapment in electrospun poly(vinyl alcohol) (PVA) nanofibers. The activity and selectivity of the lipases entrapped in PVA nanofibers were characterized in kinetic resolution of racemic secondary alcohols using acylation in organic media. Potential bioimprinting effect of eight substrate-mimicking additives [polyethylene glycols (PEGs), non-ionic detergents (NIDs) and various organosilanes] was tested with the fiber-entrapped lipases. The nanofibrous lipase biocatalyst entrapped in the presence of the additives were also characterized by rheology, differential scanning calorimetry and scanning electron microscopy. In addition to the known lipase-bioimprinting agents (PEGs, NIDs), phenyl- and octyltriethoxysilane also enhanced substantially the biocatalytic properties of lipases in their electrospun PVA fiber-entrapped forms. The reasons of bioimprinting effect of several additives were rationalized by docking studies in the open and closed form of CaLB.

ChemInform Abstract: Diethyl Tartrate Linked Chiral Macrocyclic Manganese(III)‐Salen Complex for Enantioselective Epoxidation of Olefins and Oxidative Kinetic Resolution of Racemic Secondary Alcohols.

AbstractThe catalyst can be recovered and reused up to four times with no loss in performance.

Kinetic resolution of racemic amino alcohols through intermolecular acetalization catalyzed by a chiral Brønsted acid.

The kinetic resolution of racemic secondary alcohols is a fundamental method for obtaining enantiomerically enriched alcohols. Compared to esterification, which is a well-established method for this purpose, kinetic resolution through enantioselective intermolecular acetalization has not been reported to date despite the fact that the formation of acetals is widely adopted to protect hydroxy groups. By taking advantage of the thermodynamics of acetalization by the addition of alcohols to enol ethers, a highly efficient kinetic resolution of racemic amino alcohols was achieved for the first time and in a practical manner using a chiral phosphoric acid catalyst.

Oxidative Kinetic Resolution of Secondary Alcohols with Salen–Mn(III)/NBS/NaClO System

The oxidative kinetic resolution of racemic secondary alcohols was efficiently catalyzed by a chiral Mn(III)–salen complex using sodium hypochlorite (NaClO) as an oxidant in the presence of 8 mol% N-bromosuccinimide (NBS) in a dichloromethylene-water mixture solvent at room temperature. Excellent ee’s (up to 99 %) of chiral secondary alcohols were achieved in most cases. Chiral Mn(III)–salen complex catalyzed oxidative kinetic resolution (OKR) of secondary alcohols has been achieved with sodium hypochlorite as an oxidant in the presence of a catalytic amount of N-bromosuccinimide. This novel protocol is very efficient for the OKR of a variety of secondary alcohols.

Cover Picture: Diethyl Tartrate Linked Chiral Macrocyclic Manganese(III)-Salen Complex for Enantioselective Epoxidation of Olefins and Oxidative Kinetic Resolution of Racemic Secondary Alcohols (ChemPlusChem 10/2014)

Cover Picture: Diethyl Tartrate Linked Chiral Macrocyclic Manganese(III)-Salen Complex for Enantioselective Epoxidation of Olefins and Oxidative Kinetic Resolution of Racemic Secondary Alcohols (ChemPlusChem 10/2014)

Diethyl Tartrate Linked Chiral Macrocyclic Manganese(III)–Salen Complex for Enantioselective Epoxidation of Olefins and Oxidative Kinetic Resolution of Racemic Secondary Alcohols

AbstractInvited for this month’s cover is the group of Dr. Sayed H. R. Abdi from Central Salt and Marine Chemicals Research Institute (CSMCRI), India. The cover picture shows a single metal complex that can catalyse the asymmetric epoxidation of non‐functionalised olefins as well as oxidative kinetic resolution of racemic alcohols, which is carried out with great ease. Read the full text of the article at 10.1002/cplu.201402131

Diethyl Tartrate Linked Chiral Macrocyclic Manganese(III)–Salen Complex for Enantioselective Epoxidation of Olefins and Oxidative Kinetic Resolution of Racemic Secondary Alcohols

AbstractA diethyl tartrate linked chiral macrocyclic manganese(III)–salen (salen=N,N′‐ethylenebis(salicylimine)) complex has been used for the enantioselective epoxidation of nonfunctionalized alkenes, namely, indene and chromenes, as well as oxidative kinetic resolution of racemic alcohols. For the epoxidation reaction, a 2.5 mol % catalyst loading in the presence of pyridine N‐oxide as an axial ligand and urea–H2O2 adduct as an oxidant gave respective epoxides in high yield (>97 %) and enantiomeric excess (ee, up to 92 %). The same catalyst at a loading of 1.5 mol % has provided enantioenriched (ee up to 97 %) secondary alcohols through oxidative kinetic resolution of racemic alcohols. The catalyst can be recovered and reused up to four times with no loss in performance.

Laboratory Evolution of Enantiocomplementary Candida antarctica Lipase B Mutants with Broad Substrate Scope

Candida antarctica lipase B (CALB) is a robust and easily expressed enzyme used widely in academic and industrial laboratories with many different kinds of applications. In fine chemicals production, examples include acylating kinetic resolution of racemic secondary alcohols and amines as well as desymmetrization of prochiral diols (or the reverse hydrolytic reactions). However, in the case of hydrolytic kinetic resolution of esters or esterifying kinetic resolution of acids in which chirality resides in the carboxylic acid part of the substrate, rate and stereoselectivity are generally poor. In the present study, directed evolution based on iterative saturation mutagenesis was applied to solve the latter problem. Mutants with highly improved activity and enantioselectivity relative to wild-type CALB were evolved for the hydrolytic kinetic resolution of p-nitrophenyl 2-phenylpropanoate, with the selectivity factor increasing from E = 1.2 (S) to E = 72 (S) or reverting to E = 42 (R) on an optional basis. Surprisingly, point mutations both in the acyl and alcohol pockets of CALB proved to be necessary. Some of the evolved CALB mutants are also efficient biocatalysts in the kinetic resolution of other chiral esters without performing new mutagenesis experiments. Another noteworthy result concerns the finding that enantiocomplementary CALB mutants for α-substituted carboxylic acid esters also show stereocomplementarity in the hydrolytic kinetic resolution of esters derived from chiral secondary alcohols. Insight into the source of stereoselectivity was gained by molecular dynamics simulations and docking experiments.

ChemInform Abstract: Oxidative Kinetic Resolution of Racemic Secondary Alcohols in Water with Chiral PNNP/Ir Catalyst.

Using water as solvent, the oxidative kinetic resolution of a wide range of racemic secondary alcohols with a chiral PNNP/Ir catalyst was investigated. The catalytic reaction proceeded smoothly with excellent enantioselectivity (up to 97% ee) under mild conditions, providing an environmentally benign process to achieve optically active alcohols.

Exploiting the enzymatic machinery of Arthrobacter atrocyaneus for oxidative kinetic resolution of secondary alcohols

Abstract We evaluated Arthrobacter atrocyaneus (R1AF57) as producer of oxidoreductases for oxidative kinetic resolution of racemic secondary alcohols via oxidation reaction. This bacterium was isolated from Amazon soil samples using medium enriched with ( RS )-1-(4-methylphenyl)ethanol as a carbon source. The kinetic resolution of several secondary alcohols through enantioselective oxidation mediated by resting cells and growing cells of A. atrocyaneus was efficiently achieved for the most alcohols. In general, it was possible to obtain only the ( S )-enantiomer from ( RS )-1-arylethanols.