Fluorous biphasic hydrolytic kinetic resolution of terminal epoxides

Although application of light-fluorous techniques facilitates the isolation of reaction products from the hydrolytic kinetic resolution (HKR) of terminal epoxides catalysed by cobalt complexes of salen ligands, the extension of the original fluorous biphasic approach to this reaction is far from being a trivial exercise. The nature of the counter anion has a dramatic effect on the catalytic activity of heavily fluorinated chiral (salen) cobalt(III) complexes. Excellent enantioselectivities are obtained in the fluorous biphasic HKR of 1,2-hexene oxide when fluorinated anions are introduced (e.e.s up to 99% both for the diol and the epoxide), with C₈F₁₇COO^- affording reaction rates even higher than those observed with non-fluorous systems.     

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.     

Novel catalytic kinetic resolution of racemic epoxides to allylic alcohols

[formula: see text] The kinetic resolution of racemic epoxides via catalytic enantioselective rearrangement to allylic alcohols was investigated. Using the Li-salt of (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo [2.2.1] heptane 1 as catalyst allowed both epoxides and allylic alcohols to be obtained in an enantioenriched form.     

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.     

Dynamic kinetic resolution of racemic beta-haloalcohols: direct access to enantioenriched epoxides

The direct chemo-enzymatic DKR of racemic beta-haloalcohols is reported, yielding the corresponding optically active epoxides in a single step. The mutant haloalcohol dehalogenase HheC Cys153Ser Trp249Phe is used for the asymmetric ring closure, whereas racemization of the remaining enantiomer of the haloalcohol is achieved using the new iridacycle 3, one of the most effective racemization catalysts to date for beta-haloalcohols.     

Formation of enantiopure 5-substituted oxazolidinones through enzyme-catalysed kinetic resolution of epoxides

Halohydrin dehalogenase from Agrobacterium radiobacter catalyzed the enantioselective ring opening of terminal epoxides with cyanate as a nucleophile, yielding 5-substituted oxazolidinones in high yields and with high enantiopurity (69-98% ee). This is the first example of the biocatalytic conversion of a range of epoxides to the corresponding oxazolidinones.     

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.     

Self-assembly approach toward chiral bimetallic catalysts: bis-urea-functionalized (salen)cobalt complexes for the hydrolytic kinetic resolution of epoxides

A series of novel bis-urea-functionalized (salen)Co complexes has been developed. The complexes were designed to form self-assembled structures in solution through intermolecular urea-urea hydrogen-bonding interactions. These bis-urea (salen)Co catalysts resulted in rate acceleration (up to 13 times) in the hydrolytic kinetic resolution (HKR) of rac-epichlorohydrin in THF by facilitating cooperative activation, compared to the monomeric catalyst. In addition, one of the bis-urea (salen)Co(III) catalyst efficiently resolves various terminal epoxides even under solvent-free conditions by requiring much shorter reaction time at low catalyst loading (0.03-0.05 mol %). A series of kinetic/mechanistic studies demonstrated that the self-association of two (salen)Co units through urea-urea hydrogen bonds was responsible for the observed rate acceleration. The self-assembly study with the bis-urea (salen)Co by FTIR spectroscopy and with the corresponding (salen)Ni complex by (1)H NMR spectroscopy showed that intermolecular hydrogen-bonding interactions exist between the bis-urea scaffolds in THF. This result demonstrates that self-assembly approach by using non-covalent interactions can be an alternative and useful strategy toward the efficient HKR catalysis.     

High kinetic resolution in the addition of a racemic allenylzinc onto enantiopure N-tert-butanesulfinimines: concise synthesis of enantiopure trans-2-ethynylaziridines

Enantiopure trans-ethynyl N-tert-butanesulfinylaziridines (R(S))-6 were prepared in good to excellent yields by the condensation of the racemic allenylzinc species 1 derived from 3-chloro-1-trimethylsilylpropyne onto the corresponding enantiopure N-tert-butanesulfinimines (R(S))-5. The absolute stereochemistry of enantiopure N-tert-butanesulfinylaziridines (R(S))-6 was shown to be (R(S),2R,3R) and results from a chelate-type transition state in which the zinc atom of allenylzinc 1 is coordinated by both the nitogen and the oxygen atoms of the imine. Further removal of the N-tert-butanesulfinyl auxiliary of alkyl 3-substituted and 3,3-disubstituted ethynyl N-tert-butanesulfinylaziridines (R(S))-6 could be achieved by treatment with HCl in MeOH affording the corresponding deprotected aziridines (2R,3R)-9 and (2R)-9 respectively as enantiomerically pure compounds.     

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.     

Importance of counterion reactivity on the deactivation of Co-salen catalysts in the hydrolytic kinetic resolution of epichlorohydrin

Possible modes of deactivation of Jacobsen's Co-salen catalyst during the hydrolytic kinetic resolution (HKR) of epichlorohydrin were explored by UV-vis spectroscopy, X-ray absorption spectroscopy, and electrospray ionization mass spectrometry, combined with recycling studies. Although an active Co(III)-salen catalyst deactivated substantially after multiple cycles without regeneration, the catalyst maintained its +3 oxidation state throughout the runs. Thus, deactivation of Co-salen during HKR was not the result of Co reduction. The mass spectrum of a deactivated material showed that catalyst dimerization does not account for the loss of activity. Results from various catalyst pretreatment tests, as well as from catalysts containing various counterions (acetate, tosylate, chloride, iodide) indicated that the rate of addition of the Co-salen counterions to epoxide forming Co-OH during the reaction correlated with deactivation. The extent of counterion addition to epoxide was influenced by the exposure time and the nucleophilicity of the counterion. An oligo(cyclooctene)-supported Co-OAc salen catalyst, which was 25 times more active than the standard Co-salen catalyst, was recycled multiple times with negligible deactivation.     

Direct catalytic synthesis of enantiopure 5-substituted oxazolidinones from racemic terminal epoxides

A venerable scaffold for asymmetric synthesis and drug development, chiral 5-substituted oxazolidinones are obtained in almost enantiomerically pure form (up to 99.9% ee) starting from racemic terminal epoxides. The salient features of this process include the very simple and convenient experimental protocol and the employment of a readily accessible catalyst and inexpensive, easily handled starting materials. An enantioconvergent approach for the total conversion of racemic epoxide into a single stereoisomeric oxazolidinone is also described.     

Poly(styrene)-supported co-salen complexes as efficient recyclable catalysts for the hydrolytic kinetic resolution of epichlorohydrin

Here we describe an unprecedented synthetic approach to poly(styrene)-supported chiral salen ligands by the free radical polymerization of an unsymmetrical styryl-substituted salen monomer (H2salen = bis(salicylidene)ethylenediamine). The new method allows for the attachment of salen moieties to the polymer main chain in a flexible, pendant fashion, avoiding grafting reactions that often introduce ill-defined species on the polymers. Moreover, the loading of the salen is controlled by the copolymerization of the styryl-substituted salen monomer with styrene in different ratios. The polymeric salen ligands are metallated with cobalt(II) acetate to afford the corresponding supported Co-salen complexes, which are used in the hydrolytic kinetic resolution of racemic epichlorohydrin, exhibiting high reactivity and enantioselectivity. Remarkably, the copolymer-supported Co-salen complexes showed a better catalytic performance (>99 % ee, 54 % conversion, one hour) in comparison to the homopolymeric analogues and the small molecule Co-salen complex. The soluble poly(styrene)-supported catalysts were recovered by precipitation after the catalytic reactions and were recycled three times to afford almost identical enantiomeric excesses as the first run, with slightly reduced reaction rates.     

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.     

Kinetic resolution of racemic epoxides using a chiral diamine catalyst

The kinetic resolution of a variety of racemic epoxides has been performed using a chiral bicyclic diamine ligand. Using 5 mol % of catalyst very high selectivity could be achieved; both epoxide and the corresponding allylic alcohol could be obtained in up to 99% ee.     

Synthesis of enantiopure chloroalcohols by enzymatic kinetic resolution

3-Alkenyl and heteroaryl chloroalcohols have been obtained in excellent enantiomeric excess (>99%) by enzymatic kinetic resolution using the haloalcohol dehalogenase HheC. Yields were close to the theoretical maximum for all substrates employed. Furthermore, the applicability of this methodology on multigram scale has been established.     

Ring-expanding olefin metathesis: a route to highly active unsymmetrical macrocyclic oligomeric co-salen catalysts for the hydrolytic kinetic resolution of epoxides

In the presence of the third generation Grubbs catalyst, the ring-expanding olefin metathesis of a monocyclooct-4-en-1-yl functionalized salen ligand and the corresponding Co(II)(salen) complex at low monomer concentrations results in the exclusive formation of macrocyclic oligomeric structures with the salen moieties being attached in an unsymmetrical, flexible, pendent manner. The TOF-MALDI mass spectrometry reveals that the resulting macrocyclic oligomers consist predominantly of dimeric to tetrameric species, with detectable traces of higher homologues up to a decamer. Upon activation under aerobic and acidic conditions, these Co(salen) macrocycles exhibit extremely high reactivities and selectivities in the hydrolytic kinetic resolution (HKR) of a variety of racemic terminal epoxides under neat conditions with very low catalyst loadings. The excellent catalytic properties can be explained in terms of the new catalyst's appealing structural features, namely, the flexible oligomer backbone, the unsymmetrical pendent immobilization motif of the catalytic sites, and the high local concentration of Co(salen) species resulting from the macrocyclic framework. This ring-expanding olefin metathesis is suggested to be a simple way to prepare tethered metal complexes that are endowed with key features--(i) a high local concentration of metal complexes and (ii) a flexible, single point of attachment to the support--that facilitate rapid and efficient catalysis when a bimetallic transition state is required.     

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.