Lipase-mediated enantioselective acylation of alcohols with functionalized vinyl esters: acyl donor tolerance and applications

Enzymatic acylation is commonly used for the kinetic resolution of alcohols and amines. The simple acyl group introduced during the enzymatic reaction is usually removed or replaced by another group. Retention of more complex acyl moieties as part of the target structures would be a more efficient strategy. We have studied the enantioselective acylation of a model alcohol substrate, 1-phenylethanol, with vinyl esters bearing various functionality on the acyl moieties in the presence of three lipases (Candida antarctica, Candida rugosa and Burkholderia cepacia) frequently used in organic synthesis. C. antarctica lipase is the most versatile lipase for this type of biotransformations. We applied this strategy to the synthesis of a protein kinase C ligand and a natural product, phoracantholide.     

In-depth study on aminolysis of poly(?-caprolactone): Back to the fundamentals

The aminolysis can effectively introduce primary amine (?NH₂) groups onto polyester materials, enabling a variety of subsequent surface biofunctionalization reactions. However, less attention has been paid to the basic knowledge of aminolysis reaction in terms of reaction kinetics and its influences on materials properties. In this study, taking the widely used poly(?-caprolactone) (PCL) as a typical example, the influences of diamines and solvent property on the surface ?NH₂ density are firstly assessed by using X-ray photoelectron spectroscopy (XPS) and colorimetric analysis. Results show that smaller diamine molecules and nonpolar alcohols could accelerate the reaction. The reaction kinetics with 1,6-hexanediamine is further investigated as a function of temperature, reaction time, and diamine concentration. During the initial stage, the reaction shows a 1^st order kinetics with the diamine concentration and has an activation energy of 54.5 kJ/mol. Ionization state of the ?NH₂ groups on the PCL surface is determined, revealing that the pKa of ?NH₃ ⁺ (<5) is much lower than that of the corresponding diamine molecules in solution. After aminolysis, surface hydrophilicity of PCL membrane is significantly enhanced, while surface elastic modulus and average molecular weight are decreased to some extent, and others such as weight, surface morphology and bulk mechanical strength are not apparently changed. The introduced ?NH₂ groups are found to be largely lost at 37 °C, but can be mostly maintained at low temperature.     

Removal of the acyl donor residue allows the use of simple alkyl esters as acyl donors for the dynamic kinetic resolution of secondary alcohols

The dynamic kinetic resolution of secondary alcohols using a lipase and a ruthenium catalyst as developed by Bäckvall required some improvements to make it suitable for its use in an industrial process. The use of p-chlorophenyl acetate as acyl donor is not desirable in view of the toxicity of the side product. We herein report that simple alkyl esters can be used as acyl donors if the alcohol or ketone residue formed during the enzymatic acylation is continuously removed during the reaction. The addition of a ketone speeds up the racemisation process and allowed us to reduce the amounts of enzyme and ruthenium catalyst. The scope of this method was explored and a suitable range of acyl donors found. Various benzylic and aliphatic alcohols were reacted using isopropyl butyrate or methyl phenylacetate as acyl donor and in most cases the ester was isolated in >95% yield and 99% ee. Furthermore, it was demonstrated that the alcohol by-products of the enzymatic resolution could be used as the hydrogen source in the asymmetric reductive transesterification of ketones.     

Synthesis of Polyanionic Cellulose Carbamates by Homogeneous Aminolysis in an Ionic Liquid/DMF Medium

Polyanionic cellulose carbamates were synthesized by rapid and efficient homogeneous aminolysis of cellulose carbonate half-esters in an ionic liquid/DMF medium. Cellulose bis-2,3-O-(3,5-dimethylphenyl carbamate), as a model compound, reacted with different chloroformates to cellulose carbonates. These intermediates were subjected to aminolysis, for which both the reactivity of different chloroformates towards C6-OH and the reactivity/suitability of the respective carbonate half-ester in the aminolysis were comprehensively studied. Phenyl chloroformate and 4-chlorophenyl chloroformate readily reacted with C6-OH of the model cellulose derivative, while 4-nitrophenyl chloroformate did not. The intermediate 4-chlorophenyl carbonate derivative with the highest DS (1.05) was then used to evaluate different aminolysis pathways, applying three different amines (propargyl amine, β-alanine, and taurine) as reactants. The latter two zwitterionic compounds are only sparingly soluble in pure DMF as the typical reaction medium for aminolysis; therefore, several alternative procedures were suggested, carefully evaluated, and critically compared. Solubility problems with β-alanine and taurine were overcome by the binary solvent system DMF/[EMIM]OAc (1:1, v/v), which was shown to be a promising medium for rapid and efficient homogeneous aminolysis and for the preparation of the corresponding cellulose carbamate derivatives or other compounds that are not accessible by conventional isocyanate chemistry. The zwitterionic cellulose carbamate derivatives presented in this work could be promising chiral cation exchangers for HPLC enantiomer separations.     

Synthesis of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide mimetics

The synthesis of a new class of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide mimetics is described. The protocol employs a reaction between an N-protected amino acyl fluoride and an amino acid-derived amidoxime. All the three commonly employed urethanes have been used in this protocol for N-protection. The course of the reaction was found to be high yielding and all new compounds were well characterized by NMR and mass spectroscopy. The O-acyl amidoxime intermediate has also been isolated as a stable solid.     

β-Keto ester aminolysis of pheophorbide a methyl ester: a facile route for asymmetric chlorin ring substitution

A chemoselective aminolysis of the β-keto ester of pheophorbide a methyl ester is demonstrated opening a facile access to an asymmetric amide functionalization of a chlorin ring using a range of aromatic and aliphatic, primary and secondary amine nucleophiles. Aminolysis of pheophorbide a methyl ester with trans-1,2-diaminocyclohexane is shown to give a symmetric open face chlorin dimer.     

Addition of thiol-ended polystyrene to acrylates

Polystyrene containing end thiol groups has been prepared via the aminolysis or alcoholysis of its trithioester under conditions established previously for the model reaction of bis(1-phenylethyl) trithiocarbonate. The aminolysis of polystyrene with M _n = 8.2 × 10³ by n-hexylamine at 100°C in toluene led to the formation of a polymer with M _n = 4 × 10³ and a polydispersity coefficient of 1.13. The unimodal molecular-mass distribution of the polymer and its narrow polydispersity that is nearly equal to the initial polydispersity suggest that all trithiocarbonate groups of the starting polystyrene are involved in hydrolysis. The addition of 1-phenylethylthiol and thiol-ended polystyrene to methyl acrylate and methyl methacrylate via the Michael hydrolysis has been studied, and it has been demonstrated that the addition proceeds quantitatively at room temperature. The addition may be directly implemented with the use of dithioesters in the presence of the catalytic amount of a base; therefore, the stage of thiol synthesis can be eliminated. For the quantitative addition to acrylates, the preliminary hydrolysis of the polymer is however preferable.     

4,5-Dihydro-5-thioxo-]H-tetrazoie-l-alkanoic and alkanesulfonic acids and their amide derivatives

Homologous 4,5-dihydro-5-thioxo-1H-tetrazole-l-alkanoic and alkanesulfonic acids were prepared by reaction of sodium azide with methyl (carboxyalkyl)- and (sulfoalkyl) carbamodithioates, respectively. 4,5-Dihydro-5-thioxo-1H-tetrazole-i-alkanamides were derived from the corresponding alkanoic acids by aminolysis of their acid chlorides or imidazolides. Analogous alkane-sulfonamides were synthesized by the reaction of methyl [[[(1,1-dimethylethyl) amino]sulfonyl]-alkyljcarbamodithioates with sodium azide followed by removal of the 1,1-dimethylethyl group with trifluoroacetic acid.     

Chemistry of naphthazarin derivatives. Transetherification selectivity of naphthazarin methoxy derivatives

Transetherification of naphthazarin methoxy derivatives in basic conditions occurs only with primary monohydric alcohols. 1,3-Butanediol due to the assistance of the hydroxy group at the C¹ atom gives rise to a mixture of transetherification products at the primary and secondary hydroxy groups in a ratio 3: 1. The reaction with methyl α-D-glucopyranoside affords predominantly methyl 6-O-(5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-α-D-glucopyranoside, previously unknown water-soluble naphthoquinone-carbohydrate conjugate.     

Preparation of amidated derivatives of monocarboxy cellulose

Amidated derivatives of monocarboxy cellulose (MCC), the product of cellulose oxidation, containing carboxyl groups only at C-6 position, were prepared and characterised. Two-step way of amidation was based on the esterification of C-6 carboxyls in MCC by reaction with methanol at 60 °C for 72 h and further amino-de-alkoxylation (aminolysis) of the obtained methyl ester with n-alkylamines, hydrazine and hydroxylamine in the N,N-dimethylformamide medium. Purity and substitution degree of the products were monitored by vibration spectroscopic methods (FTIR and FT Raman) and organic elemental analysis. Analytical methods confirmed the preparation of highly or moderately substituted N-alkylamides, hydrazide and hydroxamic acid of MCC.     

Studies on Cu(I)-catalyzed synthesis of simple 3-substituted 1,2-allenes and optically active 2-substituted secondary 2,3-allenols

The sequential treatment of terminal alkynes or propargylic alcohols with n-BuLi and MOMCl afforded the corresponding propargylic methyl ethers, which would react with primary alkyl Grignard reagents under the catalysis of CuBr to afford 3-substituted 1,2-allenes or 2-substituted secondary 2,3-allenols, respectively. The reaction may be applied to the synthesis of optically active 2-substituted secondary 2,3-allenols with up to >99% ee without any protection to the free hydroxyl group in the starting 4-hydroxy-2-alkynyl methyl ethers.     

Surface modification of polymer-based microfluidic devices

We report the chemical modification of poly(methyl methacrylate) (PMMA), and poly(carbonate) (PC) surfaces for applications in microfluidic systems. For PMMA, a reaction of the surface methyl ester groups with a monoanion of α,ω-diaminoalkanes (aminolysis reaction) to yield amine-terminated PMMA surfaces will be described. Furthermore, it was found that the amine functionalities were tethered to the PMMA backbone through an alkane bridge to amide bonds formed during the aminolysis of the surface ester functionalities. The electro-osmotic flow (EOF) in aminated-PMMA microchannels was reversed when compared to that in unmodified channels. Finally, the availability of the surface amine groups was further demonstrated by their reaction with n-octadecane-1-isocyanate to form PMMA surfaces terminated with well ordered and highly crystalline octadecane chains, appropriate for performing reverse-phase separations. Examples of reverse-phase separations of ion-paired double-stranded DNAs in electric fields (capillary electrochromatography (CEC)) will be demonstrated using a PMMA-based fluidic chip. For PC, sulfonation of the surface with SO₃ will be described; this sulfonation makes the surface very hydrophilic. EOF studies of the sulfonated-PC surfaces indicated changes in the pH-dependent profile when compared to unmodified PC.     

Efficient Swern oxidation and Corey–Kim oxidation with ion-supported methyl sulfoxides and methyl sulfides

The Swern oxidation of various benzylic and allylic alcohols, primary alcohols, and secondary alcohols with two ion-supported methyl sulfoxides A-1 (C₆) and B-1 (C₁₀), and oxalyl chloride in the presence of triethylamine in dichloromethane, followed by simple diethyl ether extraction of the reaction mixture, gave the corresponding aldehydes and ketones, respectively, in good yields with high purity. Similarly, the Corey–Kim oxidation of various benzylic and allylic alcohols, primary alcohols, and secondary alcohols with two ion-supported methyl sulfides A-2 (C₆) and B-2 (C₁₀), and N-chlorosuccinimide in the presence of triethylamine in dichloromethane, followed by simple diethyl ether extraction of the reaction mixture, furnished the corresponding aldehydes and ketones, respectively, in good yields with high purity. Both reactions did not produce any unpleasant odor at all. In the Swern oxidation, ion-supported methyl sulfides were recovered in high yields and could be re-oxidized to produce ion-supported methyl sulfoxides A-1 (C₆) and B-1 (C₁₀), for reuse in the same oxidation. In the Corey–Kim oxidation, ion-supported methyl sulfides A-2 (C₆) and B-2 (C₁₀) were recovered in high yields and could be also reused for the same oxidation.     

Grafting of Polymers onto a Crosslinked Polymer Carrying Carboxyl Groups as a Model Compound for Carbon Black

Abstract

A cation-exchange resin (a crosslinked polymer carrying carboxyl groups) was used as a model compound for carbon black, and the grafting of several polymers to the resin was investigated. Reaction of acyl chloride groups that had been placed on the ion-exchange resin with polymers having hydroxyl or amino groups, such as polypropylene glycol, polyethylene glycol, polybutadiene glycol, polyvinyl alcohol, silicone diol, silicone diamine, and polyethyleneimine, resulted in grafting to the ion-exchange resin. In further experiments, primary amino groups were placed on the cation-exchange resin by reaction of acyl chloride groups with ethylenediamine. It was found that ring-opening polymerization of γmethyl L-glutamate N-carboxyanhydride is initiated by the amino groups on the resin, and polypeptide was grafted from the cation-exchange resin. Therefore, the reactivity of carboxyl groups on the resin was found to be similar to that on carbon black. However, carboxyl groups on the resin failed to initiate the cationic polymerization of vinyl monomers, in contrast to those on carbon black. This suggested that the acidity of carboxyl groups on carbon black is greater than on the cation-exchange resin.     

Kinetics of the reactions of tert-butanol with C2-C5 alcohols on sulfo cation exchangers

The kinetics of etherification of tert-butanol with aliphatic alcohols on gel KU-2×8 and macroporous KU-23 sulfo cation exchangers was studied. The first order of reaction with respect to tert-butanol and the -CSO₃H groups of a catalyst was established. The activation energy of the process observed on KU-2×8 was 60–95 kJ/mol. It was shown that the etherification of tert-butanol on KU-2×8 occurred in a surface layer. The reactivity of primary alcohols introduced into the reaction with tert-butanol increased with their molecular weights (C₂–C₅). The rate of reaction with secondary alcohols was lower than that with primary alcohols.     

Aminolysis of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-(nitroamino)pyrimidin-4(3<Emphasis Type="Italic">H</Emphasis>)-one

The aminolysis of 6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methyl-2-(nitroamino)pyrimidin-4(3H)-one with various amines in butan-1-ol and under solvent-free conditions is successful when the amino group in the reagent is sterically unshielded and the reaction medium is characterized by a high dielectric permittivity. Reactions of the title compound with sterically shielded amines are accompanied by alcoholysis where the amine acts as a base catalyst.     

Organocatalytic desymmetrization of cyclic meso-anhydrides through enantioselective alcoholysis with functionalized primary nitroallylic alcohols

The direct organocatalytic desymmetrization of cyclic meso-anhydrides was achieved by alcoholysis with nitroallylic alcohols. The reaction between primary nitroallylic alcohols and cyclic meso-anhydrides catalyzed by cinchonidine derived thiourea organocatalyst II (10 mol %) proceeded smoothly. The corresponding hemiesters were obtained in high chemical yields with high to excellent levels of stereoselectivity (up to 90% yield and 99% ee). On the other hand, the reversal of enantioselectivity was observed when an amino cinchonidine derivative (III) was used as the organocatalyst under the similar reaction conditions. This demonstrated an example of activation of the nucelophilic component in the desymmetrization of cyclic meso-anhydrides.     

New functional chiral P-based ligands and application in ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral β-amino alcohols were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium catalytic systems generated from [Ru(arene)(μ-Cl)Cl]₂ complexes and chiral phosphinite ligands based on amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(η⁶-benzene)ruthenium(II)] acts an excellent catalyst in the reduction of α-naphthyl methyl ketone, giving the corresponding alcohol with up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation is characterized by low reversibility under these conditions.     

A general approach toward the synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines

An expedient synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines was developed by treating 8-amino-4-[N-(4-aminophenyl)-N-(methyl)amino]pyrazolo[1,5-a]-1,3,5-triazine with various acyl chlorides following by the displacement of the so-formed N-(methyl)-N-[4-(acylamido)phenyl]amino leaving group with various amines. Applications to high-throughput synthesis are suggested.     

Peptide bond formation by aminolysin-A catalysis: a simple approach to enzymatic synthesis of diverse short oligopeptides and biologically active puromycins

A new S9 family aminopeptidase derived from the actinobacterial thermophile Acidothermus cellulolyticus was cloned and engineered into a transaminopeptidase by site-directed mutagenesis of catalytic Ser(491) into Cys. The engineered biocatalyst, designated aminolysin-A, can catalyze the formation of peptide bonds to give linear homo-oligopeptides, hetero-dipeptides, and cyclic dipeptides using cost-effective substrates in a one-pot reaction. Aminolysin-A can recognize several C-terminal-modified amino acids, including the l- and d-forms, as acyl donors as well as free amines, including amino acids and puromycin aminonucleoside, as acyl acceptors. The absence of amino acid esters prevents the formation of peptides; therefore, the reaction mechanism involves aminolysis and not a reverse reaction of hydrolysis. The aminolysin system will be a beneficial tool for the preparation of structurally diverse peptide mimetics by a simple approach.