Lipase-catalyzed kinetic resolution of tetronic acid derivatives bearing a chiral quaternary carbon: total synthesis of (S)-(−)-vertinolide

We have developed a chemoenzymatic synthesis of (S)-vertinolide 1 with a chiral quaternary carbon atom at C5. In the kinetic resolution of tetronic acid precursor 6, lipase PS-D furnished the recovered alcohol 6 with an (R)-stereochemistry in a ratio of 95% ee, whereas lipase AY gave (S)-alcohol 6 with 93% ee. Chemical transformations of (S)-alcohol 6 provided (S)-vertinolide 1 in 33% yield in five steps with no loss of enantiomeric excess.     

Enhanced selectivity in Novozym 435 catalyzed kinetic resolution of secondary alcohols and butanoates caused by the (R)-alcohols

In esterifications of secondary alcohols catalyzed by immobilized lipase B from Candida antarctica (Novozym 435) the E-values decreased during the reaction. Hydrolysis of the corresponding butanoates showed the opposite effect. When an enantiopure (R)-alcohol, related but different, was added to the transesterification reaction, the E-value was significantly enhanced.     

Kinetic resolution of poly(ethylene glycol)-supported carbonates by enzymatic hydrolysis

The enzyme-mediated enantioselective hydrolysis of poly(ethylene glycol) (PEG)-supported carbonates is disclosed. The water-soluble carbonates were prepared by immobilization of a racemic secondary alcohol (4-benzyloxy-2-butanol) onto low-molecular weight (av MW 550 and 750) monomethoxy PEG through a carbonate linker. For the screening of the hydrolytic enzymes, the substrate was enantioselectively hydrolyzed by commercially available lipase from porcine pancreas (PPL; Type II, Sigma) to afford the optically active compounds. In this system, the separation of the remaining (S)-substrate and the resulting (R)-alcohol was achieved by an extraction process without a laborious column chromatography. The (S)-carbonate was easily hydrolyzed with K₂CO₃ to afford the corresponding (S)-alcohol. Other MPEG-supported substrates were also hydrolyzed to afford the corresponding optically active alcohols.     

Cumin scented leaf essential oil of Cinnamomum chemungianum: compositions and their in vitro antioxidant, α-amylase, α-glucosidase and lipase inhibitory activities

As part of our work on prospecting of Cinnamomum of the Western Ghats, chemical compositions, antioxidant, α-amylase, α-glucosidase and lipase inhibitory activities of leaf essential oil (EO) of Cinnamomum chemungianum were evaluated. Chemical characterisation of the cumin scented leaf EO from five locations in the southern Western Ghats revealed that they were highly varied. EO from Kannikatti (CC²) exhibited good α-amylase inhibitory activity with IC₅₀ value of 5.97 μg/mL, whereas the EOs from Chemungi (CC¹) and Athirumala (CC⁵) showed better α-glucosidase inhibition with IC₅₀ of 56.65 and 62.12 μg/mL, respectively. The EOs from Chemungi, Kannikatti and Athirumala were found to inhibit lipase with IC₅₀ of 919.75, 923.17 and 838.46 μg/mL, respectively. The EO of C. chemungianum may be used in food products as it has cumin scent and mild inhibitory activities.     

Glycosylidene Carbenes. Part 19. Regioselective glycosidation of allyl 2-deoxy-2-phthalimido-D-allopyranosides

The regio- and stereoselectivity of the glycosidation of the partially protected mono-alcohols 3 and 7 , the diols 2 and 8 , and the triol 4 by the diazirine 1 have been investigated. Glycosidation of the α-D -diol 2 (Scheme 2) gave regioselectively the 1,3-linked disaccharides 11 and 12 (80%, α-D /β-D 9:1), whereas the analogous reaction with the βD -anomer 8 led to a mixture of the anomeric 1,3- and 1,4-linked disaccharides 13 (12.5%), 14 (16%), 15 (13%), and 16 (20.5%; Table 2). Protonation of the carbene by OH–C(4) of 2 is evidenced by the observation that the α-D -mono-alcohol 3 did not react with 1 under otherwise identical conditions, and that the β-D -alcohol 7 yielded predominantly the β-D -glucoside 18 (52%) besides 14% of 17 . Similarly as for the glycosidation of the diol 2 , the influence of the H-bond of HO? C(4) on the direction of approach of the carbene, the role of HO? C(4) in protonating the carbene, and the stereoelectronic control in the interception of the ensuring oxycarbenium cation are evidenced by the reaction of the triol 4 with 1 (Scheme 3), leading mostly to the α-D -configurated 1,3-linked disaccharide 19 (41%), besides its anomer 20 (16%), and some 4-substituted β-D -glucoside 21 (9%). No 1,6-linked disaccharides could be detected. In agreement with the observed reactivity, the ¹H-NMR and IR spectra reveal a strong H-bond between HO? C(3) and the phthalimido group in the α-D -, but not in the β-D -allosides. The different H-bonds in the anomeric phthalimides are in keeping with the results of molecular-mechanics calculations.     

New dihydrophenanthrenes from Dendrobium infundibulum

Two new dihydrophenanthrenes, dendroinfundin A (1) and dendroinfundin B (2) were isolated from the whole plant of Dendrobium infundibulum, together with 7 known compounds (3–9). The structures of the new compounds (1 and 2) were established on the basis of their spectroscopic data. All of the isolates were evaluated for their α-glucosidase and pancreatic lipase inhibitory activities. Batatasin III (5) and dendrosinen B (9) showed strong α-glucosidase inhibitory activity. Dendrosinen B (9) also exhibited appreciable pancreatic lipase inhibitory effect.     

Regiospecific Acetylation of Substituted α,α′‐Benzylidenedimethanols with Vinyl Acetate using Porcine Pancreas Lipase

Acetylation of substituted α,α′‐benzylidenedimethanols with 10 equivalents of vinyl acetate in the presence of 50 w/w% of porcine pancreas lipase (PPL) type II regiospecifically proceeded to afford only the corresponding E‐monoacetates in excellent yields without Z‐monoacetates, diacetate, or the starting materials.     

Norbornanes. Part 10. Solvolysis of the Stereoisomeric 6-Cyano-2-norbornyl p-Toluenesulfonates. A Correction

The solvolysis products of the stereoisomeric 6-cyano-2-norbornyl p-toluene sulfonates 1 - 4 (R ? CN) in dioxane/water 7 : 3 have been determined. In contrast to an earlier report the 6exo-cyano-2exo-norbornyl p-toluenesulfonate ( 1 ; R?CN) yields 30% of the 2endo-alcohol 9 (R?CN) beside the 2exo-alcohol 10 and the norbornenes 12 and 13. The results confirm that - I substituents at C(6) reduce 1,3-bridging in the intermediate norbornyl cation and hence its rate of rearrangement. The relatively high rate constants for some 6-fluoro- and 6-cyano-2exo norbornyl p-toluenesulfonates are ascribed to C, C-hyperconjugation assisted by the conjugative effects of the 6-fluoro and cyano substituents.     

Enzyme-mediated enantioselective hydrolysis of soluble polymer-supported carboxylates

The enzyme-mediated enantioselective hydrolysis of water-soluble polymer-supported carboxylates is disclosed. The representative monomethoxy poly(ethylene glycol) (MPEG, av MW 5000)-supported substrate was synthesized by immobilization of (±)-1-phenylethanol onto the modified MPEG (MPEG/NH₂) through an carboxylate linker with a succinate spacer. For the screening of the hydrolytic enzymes, the substrate was enantioselectively hydrolyzed by lipase from Candida antarctica (Novozym 435) in a mixed solvent (hexane/buffer=9/1) at 30 °C to afford the remaining (S)-substrate and the resulting (R)-alcohol (E value>200). The products were easily separated by a simple procedure without any laborious column chromatography. The substrate was hydrolyzed with NaOH in MeOH/H₂O to afford the corresponding (S)-alcohol. We also found that the structure of the spacer between the MPEG moiety and the carboxylate linker strongly affected both the reactivity and enantioselectivity, and the substrate bearing a glutarate spacer gave the best result. Our procedure was applicable for the preparation of several optically active alcohols.     

Resolution of a chiral alcohol through lipase-catalyzed transesterification of its mixed carbonate by poly(ethylene glycol) in organic media

A simple approach to the resolution of chiral alcohols through a lipase-catalyzed transesterification of one enantiomer of the corresponding trifluoroethyl carbonate by a low molecular weight poly(ethylene glycol), PEG, is described. The method was demonstrated through resolution of (RS)-sec-phenethyl alcohol. The alcohol was converted to its 2,2,2-trifluoroethyl carbonate, 2, and the (R)-enantiomer was selectively transesterified with PEG in warm diisopropyl ether using porcine pancreas lipase, PPL, as the catalyst. The two carbonate enantiomers were easily separated by cooling and filtering off the solid PEG having the (R)-alcohol covalently attached. Hydrolysis of the unchanged (S)-carbonate was achieved in dilute aqueous base, and the enantiomeric excess of the (S)-alcohol was found to be 80% by NMR in the presence of the chiral shift reagent Eu(hfc)₃. Methanolysis of the modified (R)-PEG carbonate yielded (R)-sec-phenethyl alcohol having enantiomeric excess=96% by NMR with Eu(hfc)₃.     

Chemoenzymatic Dynamic Kinetic Asymmetric Transformations of β-Hydroxyketones

Herein we report on the development and application of chemoenzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT) of α-substituted β-hydroxyketones (β-HKs), using Candida antartica lipase B (CALB) as transesterification catalyst and a ruthenium complex as epimerization catalyst. An operationally simple protocol allows for an efficient preparation of highly enantiomerically enriched α-substituted β-oxoacetates. The products were obtained in yields up to 95 % with good diastereomeric ratios.     

Living Carbocationic Polymerization. XLIX. Two-Stage Living Polymerization of Isobutylene to Di-tert-chlorine Telechelic Polyisobutylene

Abstract

A two-stage process was developed for the living polymerization of isobutylene (IB) employing di-tert-alcohol initiators in conjunction with BCl₃ coinitiator in the first or initiation stage, followed by TiCl₄ coinitiator in the second or propagation stage; the process was shown to yield high molecular weight (up to M ⁿ 20,000), narrow molecular weight distribution (MWD) M ^w/M ⁿ = 1.1–1.2) di-tert-chlorine telechelic polyisobutylenes (^tCl-PIB-Cl^t). The initiation stage involves the homogeneous solution living polymerization of IB induced by the di-tert-alcohol/BCl₃ combination in the presence of an electron donor such as N,N-dimethylacetamide in CH₃Cl solvent at ?80°C and proceeds up to M ⁿ < 5000; this is followed by the propagation stage in which TiCl₄ and the bulk of IB plus a sufficient amount of n-C₆H₁₄ are added to the charge to bring the solvent composition to CH₃Cl/n-C₆H₁₄ 60/40 v/v and the living polymerization is continued until high M ⁿ product is obtained. This two-stage process was developed because 1) it employs very inexpensive chemicals; 2) di-tert-alcohol/BCl₃ combinations initiate living IB polymerization in CH₃Cl but the product after reaching M ⁿ ≤ 5000 precipitates out of the CH₃Cl solution, and di-tert-alcohol/BCl₄ combinations do not initiate IB polymerization; and 3) di-tert-alcohol/BCl₃ systems do not initiate (or only very slowly) the living polymerization of IB in CH₃Cl/n-C₆H₁₄ mixtures, whereas similar TiCl₄-based systems do. The polymerization remains living during both stages although the propagating species and solvent polarity are profoundly altered. The livingness of the system has been analyzed by kinetic experiments and the structure of the ^tCl-PIB-Cl^t product by routine spectroscopic means.     

Lipase-catalyzed ring-opening polymerization of α-methyl-δ-valerolactone and α-methyl-ε-caprolactone

Lipase-catalyzed ring-opening polymerization of α-methyl-substituted medium-size lactones, α-methyl-δ-valerolactone and α-methyl-ε-caprolactone, were carried in bulk. Immobilized lipase derived from Candida antarctica is active in the polymerization of both monomers. The polymerization proceeds under mild reaction conditions to give the corresponding aliphatic polyester having a hydroxy group at one end and a carboxylic acid group at the other.     

The influence of microwave irradiation on lipase-catalyzed kinetic resolution of racemic secondary alcohols

The influence of microwave irradiation on the Novozyme 435^® (Candida antarctica lipase) catalyzed kinetic resolution of secondary alcohols with different functional groups was studied in comparison to the use of conventional heating at 60 °C. p-Chlorophenyl acetate was used as an acyl donor and toluene as the solvent. (±)-1-Phenyl-1-propanol 1, (±)-1-(4-bromophenyl)-propan-1-ol 3, (±)-1-phenylbut-3-en-1-ol 5 and (±)-3-bromo-2-(2-hydroxypropyl)-1,4-dimethoxynaphthalene 7 were successfully resolved into their (S)-alcohols and (R)-esters, respectively, in good enantiomeric excess. Resolution of (±)-ethyl-5-(4-methoxybenyloxy)-3-hydroxypentanoate 9 afforded its (R)-alcohol and (S)-ester using this method. In addition, microwave-assisted lipase transesterification of meso-symmetric diol 11 effected desymmetrization to ester 12 with high enantiomeric excess. In all cases studied, the conversion value for the microwave-assisted lipase kinetic resolution of secondary alcohols was higher than that obtained using conventional heating.     

Kinetics of craze initiation in polystyrene in N-alcohols

The kinetics of craze initiation has been investigated for unmodified and rubber-modified polystyrenes in n-alcohols. The dependence on time and temperature of the critical strain at which crazes could be detected visually was determined with a Bergen elliptical strain device. Sorption studies were also conducted at room temperature on films exposed to the saturated vapor of n-alcohol. The analysis of crazing data in terms of the Eyring model gave activation energies from 9.4 to 17.4 kcal/mole, increasing with increasing chain length of n-alcohol and increasing rubber content. The activation volume multiplied by a stress concentration factor decreased with increasing rubber content and was nearly independent of the chain length of the n-alcohol. The larger the diffusion coefficient, which we measured by sorption experiments, the smaller was the activation energy for craze initiation. The values of diffusion coefficients, estimated from the experimental data on craze initiation, were found to be comparable with those from the sorption experiments. It was concluded that the rate of craze initiation on exposure to liquids is controlled by the diffusion of the molecules of liquid into polymer.     

Transformation of racemic ethyl 3-hydroxybutanoate into the (R)-enantiomer exploiting lipase catalysis and inversion of configuration

Racemic ethyl 3-hydroxybutanoate rac-1 was transformed into ethyl (R)-acetoxybutanoate (ee = 92%) with 85–90% chemical yields using enantioselective acylation with isopropenyl acetate in the presence of Candida antarctica lipase B (CAL-B, Novozym 435) under solvent-free conditions, followed by mesylation of the unreacted (S)-alcohol in the reaction mixture and inversion of configuration with cesium acetate in DMF in one pot. When the (R)-acetoxybutanoate was subjected to alcoholysis with ethanol and CAL-B, enantiopure (R)-1 (ee >99%) was produced.     

Lipase catalyzed regio- and stereospecific hydrolysis: chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid

Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)-butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α-thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both (S)- and (R)-enantiomers of α-lipoic acid and their analogues.     

Efficient Differentiation of the Hydroxyl Groups of 3,4-O-Isopropylidene-D-Galactopyranosides by Lipase Catalyzed Esterification and De - Esterification

Abstract

The Pseudomonas sp. (LPS) promoted acyl transfer from vinyl acetate to selected 3,4-O-isopropylidene-D-galactopyranosides takes place in a completely selective manner giving in high yield the corresponding 6-O-acetates. The acetylation rate is strongly dependent on the type and the orientation of the aglycon, varying from a maximum of reactivity for the 1-deoxy derivative, 1,5-anhydro-3,4-O-isopropylidene-D-galactitol (1d), to a minimum for β configurated alkyl glycosides and showing a complete loss of reactivity for 3′,4′:2,3:5,6-tri-O-isopropylidenelactose dimethyl acetal (1e). The latter compound is, however, selectively 6′-O-esterified in good yield by lipase from Candida Antarctica and vinyl acetate. Also the course of the enzymatic hydrolysis of 2,6-di-O-acetyl-3,4-O-isopropylidene-D-galactopyranosides 2 is dependent on the type of the aglycon, both for the reaction rate and the selectivity. The 2-O-acetates 4 are selectively obtained in good yields with porcine pancreatic lipase (PPL) promoted hydrolysis in the case of β and α-methyl, and 1-deoxy derivatives (2a, 2b and 2d), while for β-benzyl (2c) and lactose (2e) analogues satisfactory results are obtained with lipase from Mucor miehei (IM20).

     

A new flavone glucoside together with known ellagitannins and flavones with anti-diabetic and anti-obesity activities from the flowers of pomegranate (Punica granatum)

A new flavone glucoside tricetin 4′-O-β-glucopyranoside (1) and four known ellagitannins and flavones tricetin (2), luteolin (3), ellagic acid (4), and granatin B (5) were isolated from the flowers of Punica granatum L. (Lythraceae). Their structures were established by 1D and 2D NMR as well as mass spectrometry analyses. Among all tested compounds, tricetin (2) exhibited the strongest α-glucosidase inhibitory activity that was comparable to the anti-diabetic drug acarbose. Comparative structure-function analysis of tri-, tetra-, and pentahydroxy flavones [apigenin, luteolin (3), and tricetin (2), respectively] suggested that a greater number of hydroxyl groups on the flavone molecule enhanced its suppression of α-glucosidase, α-amylase, and lipase activities.     

Lipase-mediated resolution of 3-hydroxy-4-trityloxybutanenitrile: synthesis of 2-amino alcohols,oxazolidinones and GABOB

Lipase-mediated kinetic resolution of 3-hydroxy-4-trityloxybutanenitrile gave the (S)-alcohol and (R)-acetate in good yields and high enantioselectivities. The resolution using Pseudomonas cepacia lipase (Burkholderia cepacia) immobilized on modified ceramic particles (PS-C) in diisopropyl ether gave the best results. The use of base additives in this transesterification drastically reduces the reaction time without effecting the yields or enantioselectivities. Resolved 3-hydroxy-4-trityloxybutanenitrile has been utilized for the synthesis of enantiomerically pure 5-tosyloxymethyl-1,3-oxazolidine-2-one, which is an important intermediate for the preparation of β-adrenergic blocking agents and oxazolidinone based antimicrobial agents. Enantiomerically pure (R)-3-hydroxy-4-trityloxybutanenitrile and (S)-5-tosyloxymethyl-1,3-oxazolidine-2-one have been utilized in the enantioconvergent synthesis of (R)-GABOB.