Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines

An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (±)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively.     

New oligomeric catalyst for the hydrolytic kinetic resolution of terminal epoxides under solvent-free conditions

The solvent-free hydrolytic kinetic resolution of terminal epoxides catalyzed by a new oligomeric (salen)Co complex 2 is described. Extremely low loadings of catalyst were used to provide all epoxides examined in good yields and >99% ee under ambient conditions within 24 h.     

Mechanistic investigation leads to a synthetic improvement in the hydrolytic kinetic resolution of terminal epoxides

The mechanism of the hydrolytic kinetic resolution (HKR) of terminal epoxides was investigated by kinetic analysis using reaction calorimetry. The chiral (salen)Co-X complex (X = OAc, OTs, Cl) undergoes irreversible conversion to (salen)Co-OH during the course of the HKR and thus serves as both precatalyst and cocatalyst in a cooperative bimetallic catalytic mechanism. This insight led to the identification of more active catalysts for the HKR of synthetically useful terminal epoxides.     

Chiral nanoporous metal-metallosalen frameworks for hydrolytic kinetic resolution of epoxides

Chiral nanoporous metal-organic frameworks are constructed by using dicarboxyl-functionalized chiral Ni(salen) and Co(salen) ligands. The Co(salen)-based framework is shown to be an efficient and recyclable heterogeneous catalyst for hydrolytic kinetic resolution (HKR) of racemic epoxides with up to 99.5% ee. The MOF structure brings Co(salen) units into a highly dense arrangement and close proximity that enhances bimetallic cooperative interactions, leading to improved catalytic activity and enantioselectivity in HKR compared with its homogeneous analogues, especially at low catalyst/substrate ratios.     

High Fluorine Content Bis(fluoro‐Ponytailed) Bipyridine Palladium Complexes as Catalyst for Mizoroki‐Heck Reactions under Fluorous Biphasic Catalysis Conditions

Two highly fluorinated bipyridine derivatives, (4,4′‐bis(R_fCH₂OCH₂)‐2,2′‐bpy) {R_f = n‐C₁₀F₂₁ ( 1a ), n‐C₁₀F₂₃ ( 1b )}, have been synthesized starting from 4,4′‐bis(BrCH₂)‐2,2′‐bpy and the corresponding fluorinated alkoxides. The fluorine contents of ligands 1a‐b are 62.3% and 63.3%, respectively, both being white solids, virtually insoluble in CH₂Cl₂ or DMF and highly fluorophilic with a partition ratio between DMF and n‐C₈F₁₈ less than 1:1000. The reaction of ligands 1a‐b with [Pd(CH₃CN)₂Cl₂] results in novel Pd complexes [PdCl₂(4,4′‐bis‐(R_fCH₂OCH₂)‐2,2′‐bpy)] where R_f = n‐C₁₀F₂₁ ( 2a ), n‐C₁₀F₂₃ ( 2b ), respectively. The Pd complexes 2a‐b are pale yellow solids, soluble only in fluorinated solvents. The Pd complexes 2a‐b have been satisfactorily tested for Mizoroki‐Heck arylation under fluorous biphasic catalysis conditions in that the Pd complexes 2a‐b are easily recovered and maintain good catalytic activity after 8 consecutive cycles (> 90% yield). The TGA studies indicate that the Pd complexes 2a‐b are thermally stable up to 300 °C.     

Mechanistic basis for high reactivity of (salen)Co-OTs in the hydrolytic kinetic resolution of terminal epoxides

The (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides is a bimetallic process with a rate controlled by partitioning between a nucleophilic (salen)Co-OH catalyst and a Lewis acidic (salen)Co-X catalyst. The commonly used (salen)Co-OAc and (salen)Co-Cl precatalysts undergo complete and irreversible counterion addition to epoxide during the course of the epoxide hydrolysis reaction, resulting in quantitative formation of weakly Lewis acidic (salen)Co-OH and severely diminished reaction rates in the late stages of HKR reactions. In contrast, (salen)Co-OTs maintains high reactivity over the entire course of HKR reactions. We describe here an investigation of catalyst partitioning with different (salen)Co-X precatalysts and demonstrate that counterion addition to epoxide is reversible in the case of the (salen)Co-OTs. This reversible counterion addition results in stable partitioning between nucleophilic and Lewis acidic catalyst species, allowing highly efficient catalysis throughout the course of the HKR reaction.     

Shell cross-linked micelle-based nanoreactors for the substrate-selective hydrolytic kinetic resolution of epoxides

Shell cross-linked micelles (SCMs) containing Co(III)-salen cores were prepared from amphiphilic poly(2-oxazoline) triblock copolymers. The catalytic activity of these nanoreactors for the hydrolytic kinetic resolution of various terminal epoxides was investigated. The SCM catalysts showed high catalytic efficiency and, more significantly, substrate selectivity based on the hydrophobic nature of the epoxide. Moreover, because of the nanoscale particle size and the high stability, the catalyst could be recovered easily by ultrafiltration and reused with high activity for eight cycles.     

Fluorous phase transfer catalysts: From onium salts to crown ethers

Fluorous quaternary ammonium and phosphonium salts, as well as fluorous macrocyclic ligands, such as crown and aza-crown ethers, have been gradually emerging as viable alternatives to classical phase transfer catalysts. The major results thus far obtained in this burgeoning field will be the focus of this review.     

Selective introduction of a fluorine atom into carbohydrates and a nucleoside by ring-opening fluorination reaction of epoxides

Ring-opening fluorination reactions of epoxides using tetrabutylammonium bifluoride (TBABF)-KHF₂, or Et₃N-3HF under microwave irradiation were applied for the introduction of a fluorine atom into the carbohydrate molecules. When TBABF-KHF₂ was used as the fluorination reagent, a fluorine atom was introduced regioselectively and various functional groups can tolerate the conditions. When Et₃N-3HF was used under microwave irradiation, the reaction time could be remarkably shortened compared with the conventional oil-bath heating.     

Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols

The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.     

Mesoporous aluminosilicate promoted alcoholysis of epoxides

Mesoporous aluminosilicates efficiently catalyze the ring-opening of epoxides with a range of alcohols to give the corresponding β-alkoxyalcohols in high yields under extremely mild conditions and in short reaction times.     

The influence of solvent choice,acid activation and surfactant addition on the hydrolytic kinetic resolution (HKR) of terminal epoxides

The recently developed hydrolytic kinetic resolution (HKR) of epoxides catalysed by the Co-Jacobsen catalyst, is one of the most useful methods to obtain enantiomerically pure epoxides and/or diols. Several parameters can significantly influence the homogeneous reaction. Several factors including the used solvent, the activation of the catalyst and the use of surfactants, are investigated.     

Chiral cobalt salen complexes containing Lewis acid: A highly reactive and enantioselective catalyst for the hydrolytic kinetic resolution of terminal epoxides

A type of chiral salen complexes bearing Lewis acid, including FeCl₃, AlCl₃, ZnCl₂, and SnCl₄ has been synthesized. The prepared complexes proved to be reactive and enantioselective in the hydrolytic kinetic resolution of terminal epoxides. The catalysts could be recovered and reused several times with simple treatment after reaction, without loss of activity and enantioselectivity. (salen)Co(II) and Lewis acid in mol ratios of 1: 1, 1: 2, and 1: 3 showed the same activity, enatioselectivity, and stability. The characterization of the complexes in-situ generated by the reaction of (salen)Co(II) and Lewis acid in mol ratios of 1: 1, 1: 2, and 1: 3 in CH₂Cl₂ was performed by UV-Vis, which showed an identical spectrum and did not display any change along with the time prolonged. Thus, the present catalysts can be applicable for large scale processes for HKR reaction of racemic epoxides.     

Recent advances on nonenzymatic catalytic kinetic resolution of diols

As one of the most efficient and straight-forward strategies for obtaining optically pure compounds, catalytic kinetic resolution has been widely used in laboratory and industry. Although nonenzymatic catalytic kinetic resolution of secondary alcohol has been well developed, it still remains a formidable challenge for kinetic resolution of diols which play a significant role in natural products synthesis. The purpose of this digest is to present the recent progress on nonenzymatic catalytic kinetic resolution of representative diols.     

An efficient catalyst for ring opening of epoxides with phenol and thiophenol under solvent-free conditions

An efficient and rapid procedure for ring opening reaction of various epoxides with phenol and thiophenol derivatives was developed. The procedure can be obtained at room temperature under solvent-free condition in presence of (C₄H₁₂N₂)₂[BiCl₆]Cl·H₂O (1 mol %). This catalyst can be reused several times without significant loss of activity.     

Chiral Co(III)(salen)-catalysed hydrolytic kinetic resolution of racemic epoxides in ionic liquids

In the chiral Co(III)(salen)-catalysed HKR of racemic epoxides, in the presence of ionic liquids, Co(II)(salen) complex is oxidised without acetic acid to catalytically active Co(III)(salen) complex during reaction and, moreover, this oxidation state is stabilised against reduction to Co(II) complex which enables the reuse of the recovered catalyst for consecutive reactions without extra reoxidation.     

Commercialization of the hydrolytic kinetic resolution of racemic epoxides: toward the economical large-scale production of enantiopure epichlorohydrin

The hydrolytic kinetic resolution of racemic terminal epoxides utilizing chiral (salen)Co(III) catalysts provides practical access to enantiopure epoxides and diols. However, general issues surrounding catalyst activation combined with the specific problem of racemization of epichlorohydrin served to make the large-scale production of (R)- or (S)-epichlorohydrin difficult and uneconomical. A process for the large-scale production and isolation of active (salen)Co(III)OAc catalyst and a method of catalyst reduction after reaction using ascorbic acid have been developed to overcome these issues.