- Bridging racemic lactate esters with stereoselective polylactic acid using commercial lipase catalysis
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A productive and enantioselective hydrolysis of racemic mixtures of lactate esters with commercial Candida rugosa lipase was performed. This step contributes to a novel envisioned route for stereoselective PLA production by combining recent chemocatalytic developments with this biocatalytic contribution, foreseeing two separate l- and d-lactate enantiomer streams. A study of the hydrolysis kinetics identified an unexpected rate determining step at the origin of an unprecedented ester reactivity order.
- Van Wouwe, Pieter,Dusselier, Michiel,Basic, Aurelie,Sels, Bert F.
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- Synthesis of (R)-lactic acid and (2R,5R)-2-tert-Butyl-5-methyl-1,3-dioxolan-4-one
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Abstract A convenient procedure for the synthesis of very expensive (R)-lactic acid from relatively inexpensive (R)-alanine is described. Its subsequent conversion into a chiral dioxolanone can be carried out by using an inexpensive pivalaldehyde-tert-butanol mixture.
- Aitken, R. Alan,Meehan, Anna,Power, Lynn A.
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- Structures, chemotaxonomic significance, cytotoxic and Na+,K+-ATPase inhibitory activities of new cardenolides from Asclepias curassavica
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Five new cardenolide lactates (1-5) and one new dioxane double linked cardenolide glycoside (17) along with 15 known compounds (6-16 and 18-21) were isolated from the ornamental milkweed Asclepias curassavica. Their structures were elucidated by extensive spectroscopic methods (IR, UV, MS, 1D- and 2D-NMR). The molecular structures and absolute configurations of 1-3 and 17 were further confirmed by single-crystal X-ray diffraction analysis. Simultaneous isolation of dioxane double linked cardenolide glycosides (17-21) and cardenolide lactates (1-5) provided unique chemotaxonomic markers for this genus. Compounds 1-21 were evaluated for the inhibitory activities against DU145 prostate cancer cells. The dioxane double linked cardenolide glycosides showed the most potent cytotoxic effect followed by normal cardenolides and cardenolide lactates, while the C21 steroids were non-cytotoxic. Enzymatic assay established a correlation between the cytotoxic effects in DU145 cancer cells and the Ki for the inhibition of Na+,K+-ATPase. Molecular docking analysis revealed relatively strong H-bond interactions between the bottom of the binding cavity and compounds 18 or 20, and explained why the dioxane double linked cardenolide glycosides possessed higher inhibitory potency on Na+,K+-ATPase than the cardenolide lactate. This journal is
- Zhang, Rong-Rong,Tian, Hai-Yan,Tan, Ya-Fang,Chung, Tse-Yu,Sun, Xiao-Hui,Xia, Xue,Ye, Wen-Cai,Middleton, David A.,Fedosova, Natalya,Esmann, Mikael,Tzen, Jason T. C.,Jiang, Ren-Wang
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- Enhancement of the catalytic activity of D-lactate dehydrogenase from Sporolactobacillus laevolacticus by site-directed mutagenesis
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Sporolactobacillus laevolacticus is a producer of D-lactic acid with high optical purity. The amino acid sequence of D-lactate dehydrogenase (D-LDH) from S. laevolacticus was compared with those of other lactate producers. To enhance the activity of D-LDH from S. laevolacticus, some amino acid residues close to the substrate binding site or the active center were replaced by site-directed mutagenesis. Ala234 of D-LDH from S. laevolacticus was found to be an important amino acid residue that positively affects catalytic activity. Site-saturation mutagenesis of the 234th residue was performed. The mutant D-LDH at the 234th residue from alanine to serine or glycine showed enhanced catalytic activity toward pyruvate. The kinetic analysis revealed that the kcat/Km of D-LDH_A234S and _A234G on pyruvate increased 1.9- and 1.2-fold, respectively. Furthermore, the double mutant D-LDH_T75L/A234S improved kcat/Km by 6.8-fold compared to that of wild-type D-LDH. These results showed the potential of the mutant D-LDH for microbial production of D-lactic acid by heterologous expression.
- Nakano, Kento,Sawada, Shoichi,Yamada, Ryosuke,Mimitsuka, Takashi,Ogino, Hiroyasu
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- Use of wastewater sludge as a raw material for production of L-lactic acid
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This study utilizes wastewater sludges to produce L-lactic acid, a precursor of biodegradable plastic. The high concentrations of cellulose contained in the sludge, derived from a paper manufacturing facility, have been found to be convertible to L-lactic acid at a rate as high as 6.91 g/L. To achieve such a high conversion rate, the sludge must be pretreated with cellulase. This pretreatment includes inoculation of the sludge with lactic acid bacteria, strain LA1, after the sludge has been subjected to enzymatic hydrolysis. This study utilizes wastewater sludges to produce L-lactic acid, a precursor of biodegradable plastic. The high concentrations of cellulose contained in the sludge, derived from a paper manufacturing facility, have been found to be convertible to L-lactic acid at a rate as high as 6.91 g/L. To achieve such a high conversion rate, the sludge must be pretreated with cellulase. This pretreatment includes inoculation of the sludge with lactic acid bacteria, strain LA1, after the sludge has been subjected to enzymatic hydrolysis.
- Nakasaki, Kiyohiko,Akakura, Naoki,Adachi, Tomohiko,Akiyama, Tetsuo
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- Reversible ketomethylene-based inhibitors of human neutrophil proteinase 3
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Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibitors are still in their infancy. We have designed ketomethylene-based inhibitors for PR3 that show low micromolar IC50 values. Their synthesis was made possible by amending a previously reported synthesis of ketomethylene dipeptide isosteres to allow for the preparation of derivatives suitable for solid phase peptide synthesis. The best inhibitor (Abz-VADnV[ψ](COCH2)ADYQ-EDDnp) was found to be selective for PR3 over HNE and to display a competitive and reversible inhibition mechanism. Molecular dynamics simulations show that the interactions between enzyme and ketomethylene-containing inhibitors are similar to those with the corresponding substrates. We also confirm that N- and C-terminal FRET groups are important for securing high inhibitory potency toward PR3.
- Budnjo, Adnan,Narawane, Shailesh,Grauffel, Cédric,Schillinger, Anne-Sophie,Fossen, Torgils,Reuter, Nathalie,Haug, Bengt Erik
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- Site-Specific, covalent immobilization of dehalogenase ST2570 catalyzed by formylglycine-generating enzymes and its application in batch and semi-continuous flow reactors
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Formylglycine-generating enzymes can selectively recognize and oxidize cysteine residues within the sulfatase sub motif at the terminus of proteins to form aldehyde-bearing formylglycine (FGly) residues, and are normally used in protein labeling. In this study, an aldehyde tag was introduced to proteins using formylglycine-generating enzymes encoded by a reconstructed set of the pET28a plasmid system for enzyme immobilization. The haloacid dehalogenase ST2570 from Sulfolobus tokodaii was used as a model enzyme. The C-terminal aldehyde-tagged ST2570 (ST2570CQ) exhibited significant enzymological properties, such as new free aldehyde groups, a high level of protein expression and improved enzyme activity. SBA-15 has widely been used as an immobilization support for its large surface and excellent thermal and chemical stability. It was functionalized with amino groups by aminopropyltriethoxysilane. The C-terminal aldehyde-tagged ST2570 was immobilized to SBA-15 by covalent binding. The site-specific immobilization of ST2570 avoided the chemical denaturation that occurs in general covalent immobilization and resulted in better fastening compared to physical adsorption. The site-specific immobilized ST2570 showed 3-fold higher thermal stability, 1.2-fold higher catalytic ability and improved operational stability than free ST2570. The site-specific immobilized ST2570 retained 60% of its original activity after seven cycles of batch operation, and it was superior to the ST2570 immobilized to SBA-15 by physical adsorption, which loses 40% of its original activity when used for the second time. It is remarkable that the site-specific immobilized ST2570 still retained 100% of its original activity after 10 cycles of reuse in the semi-continuous flow reactor. Overall, these results provide support for the industrial-scale production and application of site-specific, covalently immobilized ST2570.
- Jian, Hui,Wang, Yingwu,Bai, Yan,Li, Rong,Gao, Renjun
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- Affinity of a vancomycin polymer with bacterial surface models
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The affinity between a vancomycin polymer (3) and cell wall intermediate mimics of vancomycin resistant bacteria (VRE) was determined by use of surface plasmon resonance (SPR). The increased affinity of 3 over monomeric vancomycin derivatives 1 and 2 suggests the importance of tighter binding to VRE surfaces in the enhanced antibacterial activities of 3.
- Arimoto, Hirokazu,Oishi, Takehisa,Nishijima, Manabu,Kinumi, Tomoya
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- Development of a Novel Biocatalyst for the Resolution of rac-Pantolactone
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A novel L-pantolactone hydrolase, Lph, from Agrobacterium tumefaciens Lu681 was characterized, which stereospecifically hydrolyses L-pantolactone to L-pantoic acid yielding D-pantolactone with > 95% enantiomeric excess. The enzyme was found to be a 30 kDa-Zn2+-hydrolase with a Km for L-pantolactone of 7 mM and a Vmax of 30 U/mg. The corresponding lph gene was identified as an 807 bp ORF and cloned into E. coli. It was overexpressed under control of Ptac and Prha yielding enzyme activities of up to 600 U/g dry weight. Resolution of D,L-pantolactone in repeated batches with isolated Lph and enzyme recovery by membrane filtration gave D-pantolactone with 50% yield and 90-95% ee over 6 days. Covalent immobilization to EupergitC led to a stable biocatalyst easy to handle in a repeated batch production of D-pantolactone. Further improvements in the activity of Lph were achieved by directed evolution of the enzyme. Activities of mutants F62S, K197D and F100L were increased 2.3, 1.7, and 1.5 fold, respectively.
- Kesseler, Maria,Friedrich, Thomas,Hoeffken, Hans Wolfgang,Hauer, Bernhard
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- D-(-)-Lactic acid production from cellobiose and cellulose by Lactobacillus lactis mutant RM2-24
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Lactobacillus lactis mutant RM2-24 utilizes cellobiose efficiently, converting it into d-(-)-lactic acid. Cellobiose-degrading enzyme activities were determined for whole cells, cell extracts and disrupted cells. Aryl-β-glucosidase activity was detected in whole cells and disrupted cells, suggesting that these activities are confined to the cells. The mutant produced 80 g l-1 of lactic acid from 100 g l-1 of cellobiose with 1.66 g l-1 h-1 productivity. Production of d-lactic acid from different cellulose samples was also studied. The cellulose samples at high concentration (10%) were hydrolyzed by cellulase enzyme preparation (10 FPU g-1 cellulose) derived from Penicillium janthinellum mutant EU1 generated in our own laboratory. We obtained a maximum 72% hydrolysis, yielding glucose and cellobiose as the main end products. Lactic acid was produced from these cellulose samples by simultaneous saccharification and fermentation (SSF) in a media containing a cellulase enzyme preparation derived from Penicillium janthinellum mutant EU1 and cellobiose utilizing Lactobacillus lactis mutant RM2-24. A maximum lactic acid concentration of 73 g l-1 was produced from a concentration of 100 g l-1 of bagasse-derived cellulose, the highest productivity and yield being 1.52 g l-1 h-1 and 0.73 g g-1, respectively. Considering that bagasse is a waste material available in abundance, we propose to use this biomass to produce cellulose and then sugars, which can be fermented to valuable products such as ethanol and lactic acid.
- Singhvi, Mamta,Joshi, Dipti,Adsul, Mukund,Varma, Anjani,Gokhale, Digambar
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- Novel urushiols with human immunodeficiency virus type 1 reverse transcriptase inhibitory activity from the leaves of Rhus verniciflua
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Two novel urushiols, 1 and 2, and two known urushiols, 3 and 4, were isolated from the leaves of Rhus verniciflua and were examined for their human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitory activity. The novel urushiols were found to be 1,2-dihydroxyphenyl-3-[7(E),9(Z),11(Z)-pentadecatrienyl]-14-ol (1) and 1,2-dihydroxyphenyl-3-[8(Z),10(E),12(E)-pentadecatrienyl]-14-ol (2) by spectroscopic analyses. The absolute configuration at C-14 in 1 and 2 was determined to be a racemic mixture of (R) and (S) isomers by ozonolysis. Compound 2 (IC50: 12.6 μM) showed the highest HIV-1 RT inhibitory activity among the four urushiols, being 2.5-fold more potent than the positive control, adriamycin (IC50: 31.9 μM). Although the known urushiols were isolated from the sap and leaves of R. verniciflua, 1 was exclusively present in the leaves, and higher amounts of 2 were found in the leaves than in the sap. Present findings indicate that the leaves of R. verniciflua represent a new biological resource from which novel and known urushiols may be prepared, and the possible use of novel urushiols as bioactive products.
- Kadokura, Kazunari,Suruga, Kohei,Tomita, Tsuyoshi,Hiruma, Wataru,Yamada, Motoyuki,Kobayashi, Akio,Takatsuki, Akira,Nishio, Toshiyuki,Oku, Tadatake,Sekino, Yoshihiro
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- Asymmetric hydrolysis of 2-hydroxy-carboxylic esters using recombinant Escherichia coli
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Optically active 2-hydroxy-carboxylates are important compounds for their use as intermediates in the synthesis of pharmaceuticals and stereoblock polymers. Enterobacter sp. DS-S-75 and the recombinant Escherichia coli harbouring the 4-chloro-3-hydroxybutyrate (CHB) hydrolase gene from the strain DS-S-75 showed asymmetric hydrolytic activity towards 2-hydroxy-carboxylates, as well as towards CHB. It was discussed that the hydroxyl group in the substrate was particularly important for the asymmetric hydrolytic activity of the CHB hydrolase, and as such, it was re-designated to EnHCH (hydroxy-carboxylic ester hydrolase derived from Enterobacter sp.). Using the recombinant cell, both the reaction rate and the concentration of the substrates were significantly improved upon when compared to that of DS-S-75. Optically active 2-hydroxy-carboxylates could be synthesized on a practical basis for industrial production in this report.
- Nakagawa, Atsushi,Kato, Ko,Shinmyo, Atsuhiko,Suzuki, Toshio
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- Asymmetric Electroreduction of Ketone and Aldehyde Derivatives to the Corresponding Alcohols Using Alcohol Dehydrogenase as an Electrocatalyst
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Asymmetric electroreduction of ketone and aldehyde derivatives was examined for two electrochemical reduction systems using alcohol dehydrogenase (ADH) as an electrocatalyst. The reaction system A is concerned with reduction of substrates catalyzed by ADH coupled with regeneration of cofactors by another enzyme with assistance of methyl viologen as an electron mediator, and the reaction system B is concerned with the use of ADH as the sole enzyme which catalyzes both reduction of substrates and regeneration of cofactors. In the latter case, a redox couple of phenethyl alcohol/ acetophenone is used as an electron mediator to induce the reaction. The electrolysis using the system A allowed asymmetric reduction of acetophenone, propiophenone, phenoxy-2-propanone, pyruvic acid, and 2-phenylpropionaldehyde to the corresponding optically active alcohols with the enantiomer excesses (ee) close to 100% and the current efficiencies larger than 92%, and the turnover number of the cofactor higher than 50 was obtained for electrochemical reduction of phenoxy-2- propanone for 30 h. The reaction system B gave 100% ee for reduction of propiophenone, phenoxy- 2-propanone, and pyruvic acid. However, the amount of products obtained was very small for reduction of benzoylformic acid, and a low enantiomer excess was obtained for reduction of phenylpropionaldehyde. Discussion is made focusing on what substrates are suitable for asymmetric reduction induced by the reaction system B.
- Yuan, Ruo,Watanabe, Shozo,Kuwabata, Susumu,Yoneyama, Hiroshi
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- Au/Pt/TiO2 catalysts prepared by redox method for the chemoselective 1,2-propanediol oxidation to lactic acid and an NMR spectroscopy approach for analyzing the product mixture
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1,2-propanediol obtained from the waste glycerol is the most prominent substrate to produce lactic acid (LA) through the sustainable green catalytic oxidative route. We showed that bimetallic Au/Pt/TiO2 catalysts that could be easily prepared by the redox reaction with preadsorbed hydrogen possessed a high activity in the formation of lactic acid from 1,2-propanediol through selective primary hydroxyl group oxidation by an oxygen-air mixture or an air. The most efficient catalyst with the highest TON value was the sample with the lowest Au content. Even the addition of 0.025 wt.% of gold to the 1%Pt/TiO2 catalyst by the redox method resulted in the enhanced 1,2-propanediol conversion up to 96% with the 91% selectivity to LA. The high oxidation activity of the Au/Pt/TiO2 catalysts was ascribed to the strong interaction between the two metals in Au/Pt bimetallic particles and between the bimetallic particles and the support, which was proved by X-ray photoelectron spectroscopy (XPS) analysis, Fourier transform infrared spectroscopy of adsorbed CO (DRIFTS) technique, and temperature programmed reduction method (TPR-H2). The reaction products were identified and analyzed with the use of 1D and 2D nuclear magnetic resonance spectroscopy (NMR) methods, which also allowed suggesting a plausible up-to-date scheme of 1,2-propanediol catalytic oxidation.
- Redina, Elena,Greish, Alexander,Novikov, Roman,Strelkova, Anastasiya,Kirichenko, Olga,Tkachenko, Olga,Kapustin, Gennady,Sinev, Ilya,Kustov, Leonid
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- Chiral synthesis of furanosesquiterpene, (+)-ipomeamarone
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(+)-Ipomeamarone, a furanosesquiterpene isolated from mold-damaged sweet potato (Ipomea batatas) as one of the phytoalexins, was synthesized starting from (S)-lactic acid as the chiral source using Seebach's chiral self-reproduction method.
- Matsuo, Keizo,Arase, Takahiko,Ishida, Shigetoshi,Sakaguchi, Yusuke
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- Enzyme-Catalyzed Organic Synthesis: NAD(P)H Cofactor Regeneration by Using Glucose 6-Phosphate and the Glucose-6-Phosphate Dehydrogenase from Leuconostoc mesenteroides
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Glucose 6-phosphate dehydrogenase (from Leuconostoc mesenteroides) and glucose 6-phosphate comprise a useful system for regeneration of reduced nicotinamide cofactors for use in enzyme-catalyzed organic sysnthesis.This enzyme is approximately equally active in reduction of NAD and NADP.It is commercially available, inexpensive, stable, and easily immobilized.Glucose 6-phosphate can be prepared in quantity by hexokinase-catalysed phosphorylation of glucose by ATP (coupled with ATP regeneration) or by other methods.The operation in this regeneration system is illustrated by syntheses of enantiomerically enriched D-lactic acid (0.4 mol, enantiomeric excess 95percent) and (S)-benzyl-α-d1 alcohol (0.4 mol, enantiomeric excess 95percent) and by synthesis of treo-DS(+)-isocitric acid (0.17 mol).Factors influencing the stability of NAD(P)(H) in solution have been explored.
- Wong, Chi-Huey,Whitesides, George M.
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- From lignocellulosic biomass to lactic- and glycolic-acid oligomers: A gram-scale microwave-assisted protocol
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The conversion of lignocellulosic biomass into platform chemicals is the key step in the valorization of agricultural waste. Of the biomass-derived platform chemicals currently produced, lactic acid plays a particularly pivotal role in modern biorefineries as it is a versatile commodity chemical and building block for the synthesis of biodegradable polymers. Microwave-assisted processes that furnish lactic acid avoid harsh depolymerization conditions while cutting down reaction time and energy consumption. We herein report a flash catalytic conversion (2 min) of lignocellulosic biomass into lactic and glycolic acids under microwave irradiation. The batch procedure was successfully adapted to a microwave-assisted flow process (35 mL min-1), with the aim of designing a scalable process with higher productivity. The C2 and C4 units recovered from the depolymerization were directly used as the starting material for a solvent and catalyst-free microwave-assisted polycondensation that afforded oligomers in good yields.
- Carnaroglio, Diego,Tabasso, Silvia,Kwasek, Beata,Bogdal, Dariusz,Gaudino, Emanuela Calcio,Cravotto, Giancarlo
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- Creation of bioorthogonal redox systems depending on nicotinamide flucytosine dinucleotide
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Many enzymes catalyzing biological redox chemistry depend on the omnipresent cofactor, nicotinamide adenine dinucleotide (NAD). NAD is also involved in various nonredox processes. It remains challenging to disconnect one particular NAD-dependent reaction from all others. Here we present a bioorthogonal system that catalyzes the oxidative decarboxylation of l-malate with a dedicated abiotic cofactor, nicotinamide flucytosine dinucleotide (NFCD). By screening the multisite saturated mutagenesis libraries of the NAD-dependent malic enzyme (ME), we identified the mutant ME-L310R/Q401C, which showed excellent activity with NFCD, yet marginal activity with NAD. We found that another synthetic cofactor, nicotinamide cytosine dinucleotide (NCD), also displayed similar activity with the ME mutants. Inspired by these observations, we mutated d-lactate dehydrogenase (DLDH) and malate dehydrogenase (MDH) to DLDH-V152R and MDH-L6R, respectively, and both mutants showed fully active with NFCD. When coupled with DLDH-V152R, ME-L310R/Q401C required only a catalytic amount of NFCD to convert l-malate. Our results opened the window to engineer bioorthogonal redox systems for a wide variety of applications in systems biology and synthetic biology.
- Ji, Debin,Wang, Lei,Hou, Shuhua,Liu, Wujun,Wang, Jinxia,Wang, Qian,Zhao, Zongbao K.
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- Lipase-catalyzed oligomerization and hydrolysis of alkyl lactates: Direct evidence in the catalysis mechanism that enantioselection is governed by a deacylation step
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Lipase-catalyzed oligomerization of alkyl d-and l-lactate monomers (RDLa and RLLa, respectively) was studied for the first time. It has been found that the oligomerization occurs enantioselectively only for d-lactates to give oligomers up to heptamers of lactic acid (LA) in good to high yields by using primary C1 to C8 alkyl groups and sec-butyl group for d-lactate monomers. No reaction happened for all l-lactates in similar conditions. Lipase-catalyzed hydrolysis of alkyl d-and l-lactates was also examined, revealing that the hydrolysis took place for both d-and l-lactates, although l-lactates proceeded a couple of times slower. The hydrolysis results clearly demonstrate that the lipase catalysis mechanism involves an acyl-enzyme intermediate (EM) formation via the acylation step from both d-and l-lactates as a rate-determining step, and the subsequent deacylation step, a nucleophilic attack of water to the EM, takes place to produce free LA. On the other hand, in the oligomerization of d-lactates, the deacylation step, in which a sec-alcohol group of the monomer or of the propagating chain-end attacks to the EM, is only allowed for the sec-d-alcohol group to give a one-LA-unit-elongated oligomer. l-Lactates form the EM; however, the subsequent deacylation reaction with both the sec-l-and sec-d-alcohol groups does not take place, failing in the oligomerization to occur. These results provide with the first direct evidence in the lipase catalysis that the enantioselection is governed by the deacylation step. In the co-oligomerization between l-and d-lactates, the l-isomer retarded the reaction rate of the d-isomer, which was found due to the function of the former as a competitive inhibitor in the acylation step toward the latter.
- Ohara, Hitomi,Onogi, Akihisa,Yamamoto, Masafumi,Kobayashi, Shiro
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- Promoting effect of solvent on Cu/CoO catalyst for selective glycerol oxidation under alkaline conditions
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Cu/CoO catalysts were employed for the selective oxidation of glycerol in the aqueous phase under basic conditions. The effect of the solvent on the catalytic performance was investigated and the impact on the catalyst was thoroughly elucidated. Detailed characterization of the catalysts by HR-TEM, XRD, and XPS analysis before and after the reaction revealed that the addition of co-solvents (ethanol, n-propanol, or tert-butanol) drastically altered the catalyst properties. In particular, the amount of the catalytically active CoO(OH) phase generated during the reaction depends on the co-solvent used. Generally, the co-solvent has a beneficial effect on the catalytic activity and improves the glycerol conversion by a factor of up to 1.8, which could be linearly correlated to the ET(30) solvent polarity.
- Dodekatos, Georgios,Ternieden, Jan,Schünemann, Stefan,Weidenthaler, Claudia,Tüysüz, Harun
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- Highly Efficient Deracemization of Racemic 2-Hydroxy Acids in a Three-Enzyme Co-Expression System Using a Novel Ketoacid Reductase
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Enantiopure 2-hydroxy acids (2-HAs) are important intermediates for the synthesis of pharmaceuticals and fine chemicals. Deracemization of racemic 2-HAs into the corresponding single enantiomers represents an economical and highly efficient approach for synthesizing chiral 2-HAs in industry. In this work, a novel ketoacid reductase from Leuconostoc lactis (LlKAR) with higher activity and substrate tolerance towards aromatic α-ketoacids was discovered by genome mining, and then its enzymatic properties were characterized. Accordingly, an engineered Escherichia coli (HADH-LlKAR-GDH) co-expressing 2-hydroxyacid dehydrogenase, LlKAR, and glucose dehydrogenase was constructed for efficient deracemization of racemic 2-HAs. Most of the racemic 2-HAs were deracemized to their (R)-isomers at high yields and enantiomeric purity. In the case of racemic 2-chloromandelic acid, as much as 300 mM of substrate was completely transformed into the optically pure (R)-2-chloromandelic acid (> 99% enantiomeric excess) with a high productivity of 83.8 g L?1 day?1 without addition of exogenous cofactor, which make this novel whole-cell biocatalyst more promising and competitive in practical application.
- Xue, Ya-Ping,Wang, Chuang,Wang, Di-Chen,Liu, Zhi-Qiang,Zheng, Yu-Guo
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- Chiron approach towards optically pure γ-valerolactone from alanine
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A concise synthesis of both enantiomers of γ-valerolactone has been developed from commercially available Alanine. The key steps in the synthesis of these γ-Lactones are DIBAL-H reduction of ester (9) followed by in situ Wittig reaction with EtO2CCH = PPh3 ylide (13) (Z/E = 1: 3.5) and one pot lactonization triggered by deprotection of O-TBS ether (14).
- Datrika, Rajender,Kallam, Srinivasa Reddy,Katta, Rambabu,Siddaiah, Vidavalur,Pratap
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- Efficient bioconversion of crude glycerol from biodiesel to optically pure d-lactate by metabolically engineered Escherichia coli
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Biodiesel has attracted considerable attention as one of the best choices among alternative and renewable fuels. Large quantities of crude glycerol are produced as a main co-product with increasing biodiesel production. Currently, the problem of waste glycerol utilization needs to be crucially addressed, not only for environmental protection but also for the economy of the biodiesel industry. In this paper, the use of crude glycerol for the production of d-lactate by engineered Escherichia coli was investigated. Engineered E. coli B0013-070 with a homolactic pathway for d-lactate synthesis by elimination of byproduct pathways (ethanol, succinate, formate and acetate) could convert 20 g L-1 of crude glycerol to 13.6 g L-1 of d-lactate with a yield of 0.67 g g-1 glycerol. Overexpression of d-lactate dehydrogenase by a low-copy vector in E. coli B0013-070 resulted in the increased production and yield of d-lactate, in which 14.5 g L-1 of d-lactate was produced with a yield of 0.72 g g-1 glycerol from crude glycerol. The effect of temperature on d-lactate fermentation by the engineered strain E. coli B0013-070-pTHldhA was also investigated, and 34 °C and 40 °C were found to be the optimal temperatures for cell growth and lactate production, respectively. The engineered strain B0013-070-pTHldhA produced 100.3 g L-1 of d-lactate with 99.97% optical purity from 531.5 g of crude glycerol with an overall productivity of 2.78 g L-1 h-1 and a yield of 75.4 g per 100 g glycerol (0.77 mol mol-1) using two phase fermentation combined with a temperature shifting strategy in a 7 L bioreactor. In summary, this paper shows that crude glycerol could be directly converted to d-lactate without any prior purification.
- Chen, Xian-Zhong,Tian, Kang-Ming,Niu, Dan-Dan,Shen, Wei,Algasan, Govender,Singh, Suren,Wang, Zheng-Xiang
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- Linfuranones B and C, Furanone-Containing Polyketides from a Plant-Associated Sphaerimonospora mesophila
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Two new furanone-containing polyketides, linfuranones B and C, were isolated from a plant-associated actinomycete of the genus Sphaerimonospora. Their structures were determined by NMR and MS spectroscopic analyses, and the absolute configurations were established by anisotropic methods and chemical degradation approaches. In silico analysis of biosynthetic genes suggested that linfuranone B is generated from linfuranone C by oxidative cleavage of the polyketide chain. Linfuranones B and C induced preadipocyte differentiation into matured adipocytes at 20-40 μM without showing cytotoxicity.
- Akiyama, Hirofumi,Indananda, Chantra,Thamchaipenet, Arinthip,Motojima, Atsuko,Oikawa, Tsutomu,Komaki, Hisayuki,Hosoyama, Akira,Kimura, Akane,Oku, Naoya,Igarashi, Yasuhiro
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- Enantioselective oxidation of racemic 1,2-propanediol to D-(-)-lactic acid by Gluconobacter oxydans
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Gluconobacter oxydans DSM 2003 was firstly used in the production of (R)-2-hydroxy-propionic acid through microbial oxidation of racemic 1,2-propanediol. The biotransformation was processed with high enantiomeric excess (99%) and near theoretical yield (4
- Su, Wu,Chang, Zhiyuan,Gao, Keliang,Wei, Dongzhi
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- Coenzyme B12-dependent glycerol dehydratase deficiency in Klebsiella pneumoniae
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The physiology and fermentation properties of coenzyme B12-dependent glycerol dehydratase deficient mutant Klebsiella pneumoniae B1.9131 were investigated. Compared with that of wild type strain, glycerol dehydratase activity decreased by 80 %. Activities of dha regulon coded two enzymes are influenced by inactivation of GDHt. 1,3-Propanediol oxidoreductase activity decreased by 62 % while glycerol dehydrogenase activity increased by 36 %. Fed-batch fermentation showed that more of the metabolic flux of glycerol was directed to lactate and ethanol in the mutant. Instead, lactate other than 1,3-propanediol was the main product and its final concentration increased from 41 to 76 g L-1 with mutant isolate. The concentration of 1,3-propanediol decreased from 91 to 40 g L-1. The results demonstrate that GDHt is not indispensable in glycerol metabolism but is crucial for the efficient synthesis of 1,3-propanediol.
- Zheng, Zong-Ming,Wang, Ti-Peng,Xu, Yun-Zhen,Liu, De-Hua
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- Asymmetric Synthesis of Optically Active 3-Cyclohexene-1-carboxylic Acid Utilizing Lactic Ester as a Chiral Auxiliary in the Diastereoselective Diels–Alder Reaction
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The optically active 3-cyclohexene-1-carboxylic acid was synthesized through a TiCl4-catalyzed diastereoselective Diels–Alder reaction utilizing lactic acid ester as a chiral auxiliary, which can be removed by washing with H2O. The (S)- and (R)-isomers were both derived from easily available ethyl l-lactate.
- Fujita, Ryunosuke,Hayashi, Wakana,Kubota, Shunichi,Nishi, Tatsuya,Nishiyama, Akira,Ochiai, Hidenori,Sasagawa, Miwa
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supporting information
(2022/02/09)
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- Nicotinamide adenine dinucleotide analog, and synthesis method and application thereof
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The invention discloses a nicotinamide adenine dinucleotide (NAD) analogue, and a synthesis method and an application thereof. The structural formula of the NAD analogue is shown in the description; and in the formula, a carboxyl group is used as 1-position carbon, the spatial configuration of the chiral center of the 2-position carbon atom of the analog is S, the substituent R is a C1-C5 alkyl group or an alkyl group formed by substituting H in the C1-C5 alkyl group with one of -OH, -COOH, -CONH2, -SCH3 and other six groups shown in the description, and the substitution group is a carbon atom at the end or the secondary end. The NAD analogue is synthesized from 1-(2',4'-dinitrophenyl)-3-carbamoylpyridine and L-alpha-amino acid under the catalysis of an alkali; and the NAD analog can be used as NAD(P)-dependent oxidoreductase coenzyme. The method has the advantages of mild reaction conditions during synthesis of the NAD analogue, and simple and easily available raw materials, and allows the reaction product to completely reserve the stereostructure of the raw material L-alpha-amino acid without racemization. The NAD analog obtained in the present invention can beused in biocatalysis, bioanalytical chemistry, metabolic engineering and synthetic biology researches.
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Paragraph 0106-0110
(2019/07/04)
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- Characterization of one novel microbial esterase WDEst9 and its use to make l-methyl lactate
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Chiral lactic acids and their ester derivatives are crucial building blocks and intermediates for the synthesis of a great variety of valuable functional materials and pharmaceuticals. Before our study, the reports about the enantioselective preparation of pure L-lactic acid and its ester derivatives through direct hydrolysis of racemic substrate were quite rare. Herein, we heterologously expressed and functionally characterized one novel microbial esterase WDEst9 from Dactylosporangium aurantiacum, which exhibited high resistance to diverse metal ions, organic solvents, surfactants, NaCl and KCl. We further utilized WDEst9 as a green biocatalyst in the kinetic resolution of (±)-methyl lactate through direct hydrolysis and generated L-methyl lactate with high enantiomeric excess (e.e. >99%) and high yield (>86%) after process optimization. Notably, the enantioselectivity of WDEst9 was opposite than that of two previously reported esterases PHE14 and BSE01701 that can generate D-methyl lactate though kinetic resolution of (±)-methyl lactate. Microbial esterase WDEst9 is a promising green biocatalyst in the preparation of valuable chiral chemicals and opens the door for the identification of useful industrial enzymes and biocatalysts from the genus Dactylosporangium.
- Wang, Yilong,Xu, Shan,Li, Renqiang,Sun, Aijun,Zhang, Yun,Sai, Ke,Hu, Yunfeng
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p. 190 - 200
(2018/12/11)
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- Functional Models of the Nickel Pincer Nucleotide Cofactor of Lactate Racemase
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A novel nickel pincer cofactor was recently discovered in lactate racemase. Reported here are three synthetic nickel pincer complexes that are both structural and functional models of the pincer cofactor in lactate racemase. DFT computations suggest the ipso-carbon atom of the pyridinium pincer ligands act as a hydride acceptor for lactate isomerization, whereas an organometallic pathway involving nickel-mediated β-hydride elimination is less favored.
- Shi, Renyi,Wodrich, Matthew D.,Pan, Hui-Jie,Tirani, Farzaneh Fadaei,Hu, Xile
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supporting information
p. 16869 - 16872
(2019/11/13)
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- BIOLOGICAL FERMENTATION USING DIHYDROXYACETONE AS A SOURCE OF CARBON
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The present invention relates to the use of hydrocarbons derived from natural gas in the fermentative production of biochemicals including biofuels. More specifically, the present invention provides the method for manufacturing dihydroxyacetone ("DHA") from natural gas, biogas, biomass and CO2 released from industrial plants including electricity-generating plants, steel mills and cement factories and the use of DHA as a source of organic carbon in the fermentative production of biochemicals including biofuels. The present invention comprises three stages. In the first stage of the present invention, syngas and formaldehyde are produced from natural gas, biogas, biomass and CO2 released from industrial plants. In the second stage of the present invention, formaldehyde and syngas are condensed to produce DHA. In the third stage of the present invention, biochemicals including biofuels are produced from DHA using fermentation process involving wild type or genetically modified microbial biocatalysts.
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- Enrichment of D-lactic acid from organic wastes catalyzed by zero-valent iron: An approach for sustainable lactate isomerization
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Recently, food waste and waste activated sludge (WAS) have been bio-valorized to lactic acid, an important industrial intermediate and widely used precursor for biodegradable plastic. Although optically pure l-lactic acid could be efficiently fermented previously, the bio-conversion of d-lactic acid with high optical activity is still difficult. In this study, we introduce a green approach catalyzed by zero-valent iron (ZVI), in which a high yield of optical activity (81%) of d-lactic acid (6.4-fold versus the Blank) was successfully obtained from organic wastes. On studying the mechanism, it was revealed that the enhancement of lactic acid yield was because of the acceleration of solubilization and hydrolysis in the presence of ZVI. In addition, proper dosage of ZVI (60 mg g-1 TSS) was beneficial for the proliferation of Burkholderia, which overwhelmingly produced d-lactic acid under facultative conditions. Moreover, electron transfer during Fe(ii)→Fe(iii) was thermodynamically favorable when adding ZVI, and, during this process, the isomerization of l-lactate → d-lactate was observed simultaneously. Finally, a bioelectrochemical system with two electrodes was employed instead of adding ZVI to disclose the catalytic role of electron transfer on the high OA of D-lactic acid generation. This finding provides an efficient way for the sustainable enrichment of d-lactic acid, from waste streams, with high optical activity.
- Li, Xiang,Zhang, Wenjuan,Xue, Shunli,Lai, Sizhou,Li, Jun,Chen, Hong,Liu, Zhenhong,Xue, Gang
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p. 928 - 936
(2017/08/14)
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- Fructose conversion in the presence of Sn(iv) catalysts exhibiting high selectivity to lactic acid
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The catalytic performance of a series of Sn(iv)-based organometallic complexes in fructose conversion was studied under several reaction conditions, and the conversion, yields, and selectivity measurements of this transformation have been evaluated. The results were compared to those obtained from non-catalysed reactions and those in the presence of a conventional catalyst (H2SO4). These organometallic Sn(iv)-based catalysts demonstrated the ability to fully convert fructose into valuable chemicals. Under particular reaction conditions, lactic acid is obtained in good yields and selectivity.
- Dos Santos, Jailma Barros,De Albuquerque, Nilson José Araújo,De Paiva E Silva Zanta, Carmen Lúcia,Meneghetti, Mario Roberto,Meneghetti, Simoni Margareti Plentz
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p. 90952 - 90959
(2015/11/11)
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- Au/Pt/TiO2 catalysts prepared by redox method for the chemoselective 1,2-propanediol oxidation to lactic acid and an NMR spectroscopy approach for analyzing the product mixture
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1,2-propanediol obtained from the waste glycerol is the most prominent substrate to produce lactic acid (LA) through the sustainable "green" catalytic oxidative route. We showed that bimetallic Au/Pt/TiO2 catalysts that could be easily prepared by the redox reaction with preadsorbed hydrogen possessed a high activity in the formation of lactic acid from 1,2-propanediol through selective primary hydroxyl group oxidation by an oxygen-air mixture or an air. The most efficient catalyst with the highest TON value was the sample with the lowest Au content. Even the addition of 0.025 wt.% of gold to the 1%Pt/TiO2 catalyst by the redox method resulted in the enhanced 1,2-propanediol conversion up to 96% with the 91% selectivity to LA. The high oxidation activity of the Au/Pt/TiO2 catalysts was ascribed to the strong interaction between the two metals in Au/Pt bimetallic particles and between the bimetallic particles and the support, which was proved by X-ray photoelectron spectroscopy (XPS) analysis, Fourier transform infrared spectroscopy of adsorbed CO (DRIFTS) technique, and temperature programmed reduction method (TPR-H2). The reaction products were identified and analyzed with the use of 1D and 2D nuclear magnetic resonance spectroscopy (NMR) methods, which also allowed suggesting a plausible up-to-date scheme of 1,2-propanediol catalytic oxidation.
- Redina, Elena,Greish, Alexander,Novikov, Roman,Strelkova, Anastasiya,Kirichenko, Olga,Tkachenko, Olga,Kapustin, Gennady,Sinev, Ilya,Kustov, Leonid
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p. 170 - 183
(2015/05/05)
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- Synthesis of tertiary and quaternary amine derivatives from wood resin as chiral NMR solvating agents
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Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher's acid (3) and its n-Bu4N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient.
- Laaksonen, Tiina,Heikkinen, Sami,W?h?l?, Kristiina
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supporting information
p. 20873 - 20886
(2015/12/23)
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- Solid-phase synthesis of tetrahydropyridazinedione-constrained peptides
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The design and solid-phase synthesis of tetrahydropyridazine-3,6-dione (Tpd) peptidomimetics derived from backbone-aminated peptides is reported. The described protocol features the synthesis of chiral α-hydrazino acids suitable for chemoselective incorporation into growing peptide chains. Acid-catalyzed cyclization to form the Tpd ring during cleavage affords the target peptidomimetics in good yield and purity. The scope of Tpd incorporation is demonstrated through the synthesis of constrained peptides featuring nucleophilic/electrophilic side chains and sterically encumbered α-substituted hydrazino acid residues. (Chemical Equation Presented).
- Kang, Chang Won,Ranatunga, Sujeewa,Sarnowski, Matthew P.,Del Valle, Juan R.
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supporting information
p. 5434 - 5437
(2015/02/19)
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- Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX
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VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC50 of 0.48-8.21 mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.
- Jia, Chao,Yang, Ke-Wu,Liu, Cheng-Cheng,Feng, Lei,Xiao, Jian-Min,Zhou, Li-Sheng,Zhang, Yi-Lin
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supporting information; experimental part
p. 482 - 484
(2012/03/11)
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- Extraction and separation of (D,L)-lactic acid in simulated fermentation broth
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The recovery of lactic acid from fermentation broth plays an important part in production of lactic acid. In this case, the extraction of lactic acid from simulated fermentation broth was processed by tri-n-octylamine dissolved in oleyl alcohol. The extraction efficiency was investigated with several variables, and the optimal condition of extraction of lactic acid (10 mg/mL) from aqueous solution was tri-n-octylamine/oleyl alcohol (30/70, v/v) and solvent phase/fermentation (1/2, v/v) stirring for 60 min under room temperature. The optimal back extraction of lactic acid was obtained by hot water (～90°C) with solvent phase/water (1/4, v/v). The back extracted racemic lactic acid was direct enantiomeric analyzed and separated by chiral ligand chromatography due to strict requirement of absolute configuration in pharmaceutical field and food science. The effect of various parameters on enantioselectivity was discussed and the (L)-phenylalaninamide·HCl (6.0 mmol/L) and CuSO4·5H2O (3.0 mmol/L) dissolved in methanol/water (5/95, v/v) at pH 6.0 was the suitable mobile phase for chiral ligand exchange separation of (D,L)-lactic acids. By the investigations, a convenient systemic method was established for extraction and separation of (D,L)-lactic acid.
- Zhou, Jun,Bi, Wentao,Row, Kyung-Ho
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p. 631 - 636
(2012/10/30)
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- Total syntheses of the gregatins A-D and aspertetronin A: Structure revisions of these compounds and of aspertetronin B, together with plausible structure revisions of gregatin E, cyclogregatin, graminin A, the penicilliols A and B, and the huaspenones A and B
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Comprehensive comparisons of 1H and 13C NMR chemical shift values in the furanone cores a, b, and c provide plausible support for a reassessment of the furanone nuclei of the title compounds from b to c. Total syntheses via enantiomerically pure lactic esters were based on the Seebach-Frater "self-reproduction of stereocenters" methodology. Attachment of the hexadienyl side-chain in a trans,trans-selective manner was achieved by addition of the Seebach-Frater enolate to trans-hex-4-en-1-al rather than to trans-hex-3-en-1-al. The type-c furanone cores of the synthetic materials were reached by single or double acylation of a model γ-hydroxy-β-oxo ester (compound 50) and its hexadiene-containing counterpart 29. Our syntheses confirmed the novel connectivities in six compounds. In addition, they required revision of the configuration of a quaternary carbon atom in five cases. Moreover, they allowed elucidation of the configurations of four previously unassigned stereocenters. Hindsight analyses of why the furanone cores of the title compounds had been misinterpreted as a and/or b instead of c are given. Why the stereocenters in the heterocycles had been incorrectly configured, on the bases (a) of relay studies in the 1960s, and (b) of a 1984 total synthesis of gregatin B, is also discussed.
- Burghart-Stoll, Heike,Brueckner, Reinhard
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supporting information; experimental part
p. 3978 - 4017
(2012/10/18)
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- Continuous multiple liquid-liquid separation: Diazotization of amino acids in flow
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A second-generation laboratory-scale, modular liquid-liquid separation device based on computer-controlled high-pressure pumps and a high-resolution digital camera has been invented. The diazotization of amino acids to produce valuable chiral hydroxyacids is demonstrated in flow for the first time. The use of a triple-separator system in conjuction with the developed diazotization process allows the safe and efficient production and automated isolation of multigram quantities of valuable chiral hydroxyacids.
- Hu, Dennis X.,O'Brien, Matthew,Ley, Steven V.
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supporting information; experimental part
p. 4246 - 4249
(2012/10/08)
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- N,N-diarylammonium pyrosulfate as a highly effective reverse micelle-type catalyst for hydrolysis of esters
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Reverse micelle-type N,N-diarylammonium pyrosulfate (3-5 mol %) efficiently catalyzes the hydrolysis of esters (up to 100 mmol scale) under organic solvent-free conditions. The present method is successfully applied to the hydrolysis of various esters without the decomposition of the base-sensitive moieties and without any loss of optical purity for α-heterosubstituted carboxylic acids.
- Koshikari, Yoshiki,Sakakura, Akira,Ishihara, Kazuaki
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supporting information; experimental part
p. 3194 - 3197
(2012/07/31)
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- Metal-ligand cooperation in the catalytic dehydrogenative coupling (DHC) of polyalcohols to carboxylic acid derivatives
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Several polyols, which are easily available from sugars through biochemical conversion or hydrogenolytic cleavage, are directly converted into carboxylic acids and amides. This efficient dehydrogenative coupling process, catalyzed by a rhodium(I) diolefin amido complex, is an attractive approach for the production of organic fine chemicals from renewable resources. This method tolerates the presence of several hydroxy groups and can be extended to the direct synthesis of lactams from the corresponding amino alcohols under mild conditions.
- Trincado, Monica,Kuehlein, Klaus,Gruetzmacher, Hansjoerg
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supporting information; experimental part
p. 11905 - 11913
(2011/11/06)
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Serendipitous discovery of α-hydroxyalkyl esters as β-lactamase substrates
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O-(1-Carboxy-1-alkyloxycarbonyl) hydroxamates were found to spontaneously decarboxylate in aqueous neutral buffer to form O-(2-hydroxyalkylcarbonyl) hydroxamates. While the former molecules do not react rapidly with serine β-lactamases, the latter are quite good substrates of representative class A and C, but not D, enzymes, and particularly of a class C enzyme. The enzymes catalyze hydrolysis of these compounds to a mixture of the α-hydroxy acid and hydroxamate. Analogous compounds containing aryloxy leaving groups rather that hydroxamates are also substrates. Structure-activity experiments showed that the α-hydroxyl group was required for any substantial substrate activity. Although both d- and l-α-hydroxy acid derivatives were substrates, the former were preferred. The response of the class C activity to pH and to alternative nucleophiles (methanol and d-phenylalanine) suggested that the same active site functional groups participated in catalysis as for classical substrates. Molecular modeling was employed to explore how the α-hydroxy group might interact with the class C β-lactamase active site. Incorporation of the α-hydroxyalkyl moiety into novel inhibitors will be of considerable interest.
- Pelto, Ryan B.,Pratt
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experimental part
p. 10496 - 10506
(2011/10/18)
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- Chiral mono boronic acid as fluorescent enantioselective sensor for mono α-hydroxyl carboxylic acids
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(Graph Presented) New mono boronic acid was found to be an enantioselective fluorescent chemosensor for mono α-hydroxyl carboxylic acids, such as mandelic acid and lactic acid. The chiral sensor shows lower background fluorescence, higher fluorescence enh
- Chi, Lina,Zhao, Jianzhang,James, Tony D.
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p. 4684 - 4687
(2008/09/21)
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- A surprising mechanistic "switch" in Lewis acid activation: A bifunctional, asymmetric approach to α-hydroxy acid derivatives
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We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels-Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, α-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph3P)2PdCl2 was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV, and NMR spectroscopy. Our observations document a fundamental mechanistic "switch", namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.
- Abraham, Ciby J.,Paull, Daniel H.,Bekele, Tefsit,Scerba, Michael T.,Dudding, Travis,Lectka, Thomas
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supporting information; experimental part
p. 17085 - 17094
(2009/04/13)
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- Quinazolinone-based fungal efflux pump inhibitors. Part 1: Discovery of an (N-methylpiperazine)-containing derivative with activity in clinically relevant Candida spp.
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The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.
- Lemoine, Rémy C.,Glinka, Tomasz W.,Watkins, William J.,Cho, Aesop,Yang, Jessie,Iqbal, Nadeem,Singh, Rajeshwar,Madsen, Deidre,Lolans, Karen,Lomovskaya, Olga,Oza, Uma,Dudley, Michael N.
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p. 5127 - 5131
(2007/10/03)
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- Isolation and structure determination of obyanamide, a novel cytotoxic cyclic depsipeptide from the marine cyanobacterium Lyngbya confervoides
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Obyanamide (1) was isolated from a variety of the marine cyanobacterium Lyngbya confervoides collected in Saipan, Commonwealth of the Northern Mariana Islands. Gross structure elucidation of this novel cyclic depsipeptide relied on extensive application of 2D NMR techniques. The absolute stereochemistry was deduced by chiral chromatography of the hydrolysis products and comparison with authentic and synthetic standards. Obyanamide (1) was cytotoxic against KB cells with an IC50 of 0.58 μg/mL.
- Williams, Philip G.,Yoshida, Wesley Y.,Moore, Richard E.,Paul, Valerie J.
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- Mapping the substrate selectivity of new hydrolases using colorimetric screening: Lipases from Bacillus thermocatenulatus and Ophiostoma piliferum, esterases from Pseudomonas fluorescens and Streptomyces diastatochromogenes
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Recent advances in biochemistry and molecular biology have simplified the discovery and preparation of new hydrolases. Although these hydrolases might solve problems in organic synthesis, measuring their selectivity, especially enantioselectivity, remains tedious and time consuming. Recently, we developed a colorimetric screening method to measure the enantioselectivity of hydrolases. Here we apply this rapid screening method to map the substrate selectivity of four new hydrolases: lipases from the thermophilic Bacillus thermocatenulatus (DSM 730, BTL2) and a filamentous fungus Ophiostoma piliferum (NRRL 18917, OPL) and esterases from two bacteria, Pseudomonas fluorescens (SIK-W1, esterase I, PFE) and Streptomyces diastatochromogenes (Tue 20, SDE). We screened a general library of 29 substrates and a chiral library of 23 pairs of enantiomers. All four hydrolases catalysed the hydrolysis of unnatural substrates, but the two lipases accepted a broader range of substrates than the two esterases. As expected, the two lipases favoured more hydrophobic substrates, while the two esterases showed a preference for smaller substrates. Several moderately enantioselective reactions were identified for the solketal esters: BTL2, butyrate, E = 7.9 (R); octanoate, E = 4.9 (R) and 3-bromo-2-methyl propionate methyl esters, PFE, E = 12 (S); SDE, E = 5.6 (S). OPL showed low enantioselectivity toward all substrates tested. The current colorimetric screen could not measure the selectivity for several slow-reacting substrates. Traditional screening identified high enantioselectivity of BTL2 and PFE toward one of these slow substrates, 1-phenylethyl acetate (E>50).
- Liu, Andrew Man Fai,Somers, Neil A.,Kazlauskas, Romas J.,Brush, Terry S.,Zocher, Frank,Enzelberger, Markus M.,Bornscheuer, Uwe T.,Horsman, Geoff P.,Mezzetti, Alessandra,Schmidt-Dannert, Claudia,Schmid, Rolf D.
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p. 545 - 556
(2007/10/03)
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- Purification process of lactic acid
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A process for treating pyruvic acid and other impurities of lactic acid by reduction treatment of an aqueous lactic acid solution and for obtaining high quality lactic acid having a substantially no pyruvic acid content, high purity, excellent heat stability and improved smell. Further, a high molecular weight polylactic acid having low coloration and consistent quality can be prepared by dehydration polycondensation of lactic acid obtained by the reduction treatment.
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- Synthesis and utilisation of chiral 3-hydroxy perhydropyrrolo [2,1-c] [1,4] oxazin-4-one as a novel precursor for the enantioselective synthesis of α-hydroxy carboxylic acids
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A novel strategy for the enantioselective synthesis of several α- hydroxy carboxylic acids by the nucleophilic alkylation of chiral 3-hydroxy- (3S, 8aS)-perhydropyrrolo [2,1-C] [1,4] oxazin -4 one is reported.
- Pandey, Ganesh,Das, Parthasarathi,Reddy, Paidi Y.
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p. 7153 - 7154
(2007/10/03)
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- (R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries for the asymmetric synthesis of α-hydroxy acids
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Rac-α-bromo acids, rac-4, have been converted into(R)- or(S)-α-hydroxy acids, (R)- or (S)-9 by DCC-induced esterification with the chiral auxiliaries (R)or (S)-1, followed by reaction with sodium p-methoxyphenoxide in the presence of tetra-n-hexylammonium iodide, conditions of dynamic kinetic resolution, to give quite diastereoselectively the (αR,3S)- or (αS,3R)-α-(p-methoxyphenoxy) esters, 7, which were then oxidized with eerie ammonium nitrate and hydrolyzed under controlled acid conditions.
- Camps, Pelayo,Perez, Francesc,Soldevilla, Nuria
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p. 1877 - 1894
(2007/10/03)
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