Haloalkane dehalogenases from five sources were heterologously expressed in Escherichia coli, isolated, and tested for their ability to achieve kinetic resolution of racemic α‐bromoamides, which are important intermediates used in the preparation of bioactive compounds. To explore the substrate scope, fourteen α‐bromoamides, with different Cα‐ and N‐substituents, were synthesized. Catalytic activity towards eight substrates was found, and for five of these compounds the conversion proceeded with a high enantioselectivity (E value >200). In all cases, the (R)‐α‐bromoamide is the preferred substrate. Conversions on a preparative scale with a catalytic amount of enzyme (enzyme:substrate ratio less 1:50 w/w) were all completed within 17–46 h and optically pure α‐bromoamides and α‐hydroxyamides were isolated with good yields (31–50%). Substrate docking followed by molecular dynamics simulations indicated that the high enantioselectivity results from differences in the percentage of the time in which the substrate enantiomers are bound favourably for catalysis. For the preferred (R)‐substrates, the angle between the attacking aspartate oxygen atom of the enzyme, the attacked carbon atom of the substrate, and the displaced halogen atom, is more often in the optimal range (>157°) for reactivity. This can explain the observed enantioselectivity of LinB dehalogenase in a kinetic resolution experiment. 相似文献
Both enantiomers of optically pure 4‐bromo‐3‐hydroxybutanoate, which is an important chiral building block in the syntheses of various biologically active compounds including statins, were synthesized from rac‐4‐bromomethyl‐β‐lactone through kinetic resolution. Candida antarctica lipase B (CAL‐B) enantioselectively catalyzes the ring opening of the β‐lactone with ethanol to yield ethyl (R)‐4‐bromo‐3‐hydroxybutanoate with high enantioselectivity (E>200). The unreacted (S)‐4‐bromomethyl‐β‐lactone was converted to ethyl (S)‐4‐bromo‐3‐hydroxybutanoate (>99% ee), which can be further transformed to ethyl (R)‐4‐cyano‐3‐hydroxybutanoate, through an acid‐catalyzed ring opening in ethanol. Molecular modeling revealed that the stereocenter of the fast‐reacting enantiomer, (R)‐bromomethyl‐β‐lactone, is ∼2 Å from the reacting carbonyl carbon. In addition, the slow‐reacting enantiomer, (S)‐4‐bromomethyl‐β‐lactone, encounters steric hindrance between the bromo substituent and the side chain of the Leu278 residue, while the fast‐reacting enantiomer does not have any steric clash. 相似文献
Alcalase® (Subtilisin A) was immobilized by simple hydrophobic adsorption onto various surface‐grafted macroporous silica gels resulting in easy‐to‐prepare and stable biocatalysts enabling the efficient kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemic N‐Boc‐phenylalanine ethyl thioester with benzylamine. The immobilized Alcalase biocatalysts, which retained their activity and selectivity when stored at 4 °C for more than a year, were tested in enzymatic aminolysis in batch and continuous‐flow KRs resulting in (S)‐N‐Boc‐phenylalanine benzylamide in high enantiomeric purity. In KR of the racemic thioester by Alcalase‐catalyzed aminolysis in a continuous‐flow reactor, the productivity (specific reaction rate, rflow) and enantiomeric ratio (E) were studied in the 0–100 °C range. The effect of the temperature on base‐catalyzed racemization of the non‐transformed (R)‐thioester in a continuous‐flow reactor was also investigated in the 0–150 °C range. The continuous‐mode DKR of the racemic thioester in a serial cascade system of six biocatalyst‐filled columns at 50 °C for KR and five grafted silica gel‐filled columns at 150 °C for racemization resulted in the formation of the (S)‐benzylamide in 79% conversion, 8.17 g L −1 h−1 volumetric productivity and 98% ee. This is the first example of a dynamic kinetic resolution of an amino acid derivative in continuous‐flow mode using an alternating cascade of packed‐bed enzyme reactors and racemization reactors kept at different temperatures.
The diastereo‐ and enantioselective bioreduction of (±)‐2‐hydroxy‐1‐tetralone ( 6 ) to the corresponding enantiopure (1S,2R)‐cis‐1,2‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene ( 1 ) (83 % isolated yield, >99 % ee), mediated by resting cells of the yeast Trichosporon cutaneum CCT 1903 through dynamic kinetic resolution is reported. Deracemization of (±)‐ 6 was observed in kinetic studies on the biotransformation of the enantiomers (R)‐ 6 and (S)‐ 6 . 相似文献
A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl2[(S)‐SDP][(R,R)‐DPEN]} [(Sa,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved. 相似文献
Reaction of the complexes (SM,RC)‐[(η5‐C5Me5)M{(R)‐Prophos}(H2O)](SbF6)2 (M=Rh, Ir) with α,β‐unsaturated aldehydes diastereoselectively gave complexes (SM,RC)‐[(η5‐C5Me5)M{(R)‐Prophos}(enal)](SbF6)2 which have been fully characterized, including an X‐ray molecular structure determination of the complex (SRh,RC)‐[(η5‐C5Me5)Rh{(R)‐Prophos}(trans‐2‐methyl‐2‐pentenal)](SbF6)2. These enal complexes efficiently catalyze the enantioselective 1,3‐dipolar cycloaddition of the nitrones N‐benzylideneaniline N‐oxide and 3,4‐dihydroisoquinoline N‐oxide to the corresponding enals. Reactions occur with excellent regioselectivity, perfect endo selectivity and with enantiomeric excesses up to 94 %. The absolute configuration of the adduct 5‐methyl‐2,3‐diphenylisoxazolidine‐4‐carboxaldehyde was determined through its (R)‐(−)‐α‐methylbenzylamine derivative. 相似文献
The asymmetric 1,4‐addition of phenylboronic acid to cyclohexenone were performed by using a low amount of rhodium/(R)‐(6,6′‐dimethoxybiphenyl‐2,2′‐diyl)bis[bis(3,4,5‐trifluorophenyl)phosphine] (MeO‐F12‐BIPHEP) catalyst. Because the catalyst shows thermal resistance at 100 °C, up to 0.00025 mol% Rh catalyst showed good catalytic activity. The highest turnover frequency (TOF) and turnover number (TON) observed were 53,000 h−1 and 320,000, respectively. The enantioselectivities of the products were maintained at a high level of 98% ee in these reactions. The Eyring plots gave the following kinetic parameters (ΔΔH≠=−4.0±0.1 kcal mol−1 and ΔΔS≠=−1.3±0.3 cal mol−1 K−1), indicating that the entropy contribution is relatively small. Both the result and consideration of the transition state in the insertion step at the B3LYP/6‐31G(d) [LANL2DZ for rhodium] levels indicated that the less σ‐donating electron‐poor (R)‐MeO‐F12‐BIPHEP could be creating a rigid chiral environment around the rhodium catalyst even at high temperature. 相似文献
Efficient and practical syntheses of enantiomerically pure (R)‐(5‐amino‐2,3‐dihydro‐1H‐inden‐2‐yl)‐carbamic acid methyl ester ( 1 ) by three different routes via the resolution of different aminoindan intermediates are described. 相似文献
Various approaches to the preparation of enantiomerically pure (2R,2′R)‐(+)‐threo‐methylphenidate hydrochloride ( 1 ) are reviewed. These approaches include synthesis using enantiomerically pure precursors obtained by resolution, classical and enzyme‐based resolution approaches, enantioselective synthesis approaches, and approaches based on enantioselective synthesis of (2S,2′R)‐erythro‐methylphenidate followed by epimerization at the 2‐position. 1 Introduction 2 Methods for the Enhancement of Enantiomeric Purity of 1 3 Approaches Using Enantiomerically Pure Precursors Obtained by Resolution 4 Classical Resolution Approaches 4.1 Resolution of Amide and Acid Derivatives 4.2 Resolution of (±)‐threo‐Methylphenidate 5 Enzyme‐Based Resolution Approaches 6 Enantioselective Synthesis Approaches 7 Approaches Based on Enantioselective Synthesis of (2S,2′R)‐erythro‐Methylphenidate and Epimerization 8 Conclusions 相似文献
An efficient catalytic asymmetric hydrogenation of racemic α‐arylcyclohexanones with an ethylene ketal group at the 5‐position of the cyclohexane ring via dynamic kinetic resolution has been developed, giving chiral α‐arylcyclohexanols with two contiguous stereocenters with up to 99% ee and >99:1 cis/trans‐selectivity. Using this highly efficient asymmetric hydrogenation reaction as a key step, (−)‐α‐lycorane was synthesized in 19.6% overall yield over 13 steps from commercially available starting material. 相似文献
The hydrolytic kinetic resolution of five glycidaldehyde acetal derivatives was examined using the recombinant Aspergillus niger epoxide hydrolase as biocatalyst. This could successfully be performed, at room temperature, using solely demineralised water as solvent and following a two‐phase methodology allowing us to operate at a global substrate concentration as high as 200 g/L in the reactor. The observed E values were shown to be modest to excellent, depending on the structure of the acetal moiety, indicating that it is possible to achieve this resolution very efficiently just by choosing the right substituents. Both the unreacted (R)‐epoxide and the formed (S)‐diol could thus be obtained in good to excellent ee (ee>99 % for the epoxide). For the best substrates, the reaction could be performed within a few hours by using a biocatalyst over substrate molecular ratio of about 9 to 10×10−4 mol %. The turnover frequency (TOF) as well as the total turnover number (TON) of the enzyme proved to be excellent as compared to chemical catalysts – reaching respectively values in the order of 6×102 mol sub/mol enz/min and 6×104 mol sub/mol enz. The space‐time yield of the best (two‐phase) reactor could thus reach a value as high as 56 g/L/hour. As a demonstration experiment, a 50‐g scale resolution of glycidaldehyde 2,2‐dimethyltrimethylene acetal was performed. 相似文献
(R)‐4‐Hydroxymethyl‐2‐phenyl‐2‐oxazoline (R)‐ 1 ) was prepared from (L)‐serine. The respective tosylate ((S)‐ 2 ) was converted into sulfides (S)‐ 4 and (S)‐ 5 , and sulfone (S)‐ 6 , useful starting materials for the elaboration of additional chiral centers. A previously reported [ α]D25 value for (R)‐ 4 is corrected. 相似文献