CRYSTAL GROWTH & DESIGN
·
2024
·
IF 3.2
Yujiang Xie,Shubo Liu,Jie Sun,Weiwei Tang,Junbo Gong
Processes that allow access to enantiomerically pure drugs are of the utmost importance to maximize pharmacological activity while minimizing the side effects. This work develops a novel diastereomeric cocrystallization-induced spontaneous deracemization process for a racemic compound, dihydromyricetin (DMY), which contains two stereocenters. A pair of diastereomeric cocrystals, (2R,3R-DMY)2:R-N-benzyl-1-phenylethylamine and (2R,3R-DMY)2:S-N-benzyl-1-phenylethylamine, the latter of which is equivalent to (2S,3S-DMY)2:R-N-benzyl-1-phenylethylamine, was discovered via a complete screening of 12 chiral coformers using both slurry and liquid-assisted grinding methods. Crystal structure of these cocrystals was determined using single-crystal X-ray diffraction and reported for the first time. Enantioseparation of rac-DMY by virtue of diastereomeric cocrystals was designed and optimized through slurry and cooling crystallization methods, resulting in a product of 81% enantiomeric purity with a yield of only 31%. Further, the racemization process of DMY enantiomers with various influence factors was examined, and the optimal racemization condition that achieves simultaneous racemization of the two stereocenters was determined. Finally, a stepwise cocrystallization-induced deracemization process of rac-DMY that combines chiral resolution by cocrystallization and racemization of recycling mother liquor was developed, producing an enantiomeric purity of 97.5% and a maximal yield of 68%.
研究领域:
药学
·
有机化学
·
药物化学
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产品关联
DOI
高影响因子
JOURNAL OF BIOTECHNOLOGY
·
2023
·
IF 4.1
Fang-Ying Zhu,Qing Yang,Min Cao,Ken Zheng,Xiao-Jian Zhang,Qi Shen,Xue Cai,Zhi-Qiang Liu,Yu-Guo Zheng
d -(−)-Pantolactone (DPL) is a key intermediate for the production of d -(+)-pantothenate (vitamin B5). Deracemization of d , l -pantolactone (D, L -PL) through oxidizing l -(+)-pantolactone (LPL) to ketopantoyl lactone (KPL) and subsequently reducing KPL to DPL is a promising route for synthesizing DPL. Herein, a newly mined l -pantolactone dehydrogenase from Rhodococcus hoagie ( Rho LPLDH) was used for the oxidative dehydrogenation of LPL. To alleviate inclusion bodies formed by membrane-bound Rho LPLDH intracellular expression in E. coli , strategies involving chaperone assistance and decreasing induction temperature were used to achieve Rho LPLDH soluble expression. To enhance its activity, directed evolution and hydrophilicity-based engineering yielded increased catalytic activity and thermostability . 1 M LPL was efficiently converted to KPL by engineering strain CM5 co-expressing Rho LPLDH L254I/V241I/I156L/F224Q/N164K and chaperone. A “two stages in one-pot” method was employed in deracemization of 1 M D, L -PL with 91.2% yield. These results demonstrated that CM5 catalyst exhibits great potential in enzyme cascade deracemization for the production of DPL.
研究领域:
生物技术
·
生物化学
·
酶工程
·
微生物生物技术
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产品关联
DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
·
2023
·
IF 3.8
Li Wang,Na Wang,Jingchen Sui,Shiyu Sun,Ziwei Feng,Guangyan Li,Hongxun Hao,Lina Zhou
The formation of a conglomerate is always attractive, which is a prerequisite for chiral resolution by a flexible and productive preferential crystallization. This present study is aimed at exploring the possibility of chiral resolution in a two racemic compound system. The racemic conglomerate of S–S and R–R was prepared by slurring RS-naproxen (RS-NAP) with RS-1-(2-naphthyl) ethylamine (RS-NEA), which was determined by powder X-ray diffraction, differential scanning calorimetry, single-crystal X-ray diffraction, and ternary solubility phase diagram. Moreover, comparative analysis of the molecular structure, stacking patterns, thermodynamic properties, and intermolecular interactions of S–S and R–S indicates that the S–S crystal is more stable. Finally, the feasibility of chiral resolution in isopropanol was explored through a seeded isothermal preferential crystallization mode, and alternative crystallization of S–S and R–R was achieved with recycling the mother liquors.
研究领域:
化学
·
药学
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DOI
高影响因子
FORENSIC SCIENCE INTERNATIONAL
·
2016
·
IF 1.95
Shisheng Chen,Yanyi Lv,Dian Wang,Xiaojun Yu
Aspartic acid racemization in teeth has been increasingly used to estimate chronological age with a considerably high accuracy in forensic practice. The Chaoshan population in South China is relatively isolated in geography, and has specific lifestyle and dietary inhibits. It is still unknown whether this method is suitable for this population. The aim of this study was to analyze the relationship between chronological age and the d / l aspartic acid ratio in dentin in the third molar tooth of the Chaoshan population. Fifty-eight non-carious third molar teeth (31 mandibles and 27 maxillae), from 58 living individuals of known age (24 males and 34 females), were retrieved. Dentin was extracted from these teeth. The d - and l -aspartic acids in dentins were separated and detected by high performance liquid chromatography (HPLC). Linear regression was performed between the d / l aspartic acid ratio of dentins and chronological age. Results showed that the correlation coefficient (r) was 0.969, and the mean absolute error (MAE) was 2.19 years, its standard deviation (SD) was ±1.53 years, indicating excellent correlation. There was no significant difference in racemization rates of dentin between sexes ( P = 0.113, F = 2.6), or between mandibles and maxillae ( P = 0.964, F = 0.000). Results indicate that the ratio of the d and l forms of aspartic acid of dentins, in the third molar, is closely correlated with chronological age, special lifestyle do no obviously affect the accuracy of the age estimations by aspartic acid racemization of the dentin in the third molar and that aspartic acid racemization in the third molar dentin can be used as an accurate method to estimate chronological age in the Chaoshan population in South China.
研究领域:
法医学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED POLYMER SCIENCE
·
2023
·Vol. 140
·期 17
·e53762
·
IF 3
Guiying Tian,Huiqing Wang,Yuanyuan Song,Jun Xiang,Yiran Ying,Xurui Han,Songbo Wang,Lei Zhang,Jianping Zhang,Na Tang
Lactide is the crucial intermediate for polylactic acid (PLA) synthesis via ring-open polymerization, but it suffers low yield and low purity induced by racemization reaction. In this work, we have developed a zinc oxide-creatinine (ZnO-CR) hybrid catalyst, which offers high yield (the distilled lactide yield and pure l -lactide yield are 95.73% and 61.64%) and high purity (81.53%) for green l -lactide synthesis at the cyclization temperature of 240°C. Furthermore, NMR and HPLC results show that CR addition significantly restrains the racemization by reducing α-proton abstraction, where guanidine derived from the CR plays a main catalytic role to provide a tight association with the carbonyl oxygen in the carboxyl of L n A oligomers. Therefore, carbonyl-carbon with the enhanced electrophilicity is easier being attacked by a hydroxyl terminal of L n A oligomers, leading to high yield and high purity for lactide synthesis.
研究领域:
化学工程
·
材料科学
·
催化化学
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产品关联
DOI
高影响因子
ADVANCED SYNTHESIS & CATALYSIS
·
2019
·Vol. 361
·期 13
·3191-3199
·
IF 5.451
Shuyun Ju,Mingxin Qian,Gang Xu,Lirong Yang,Jianping Wu
Optically pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids constitute an important class of building blocks for the synthesis of natural products and synthetic pharmaceuticals. However, redox deracemization of racemic 1,2,3,4-tetrahydroisoquinoline carboxylic acids as an attractive method is still challenging for the lack of suitable oxidoreductases. Herein, a D-amino acid oxidase from Fusarium solani M-0718 ( Fs DAAO) with broad substrate scope and excellent enantioselectivity was exploited through genome mining, and applied for the kinetic resolution of a number of racemic 1- and 3-carboxyl substituted tetrahydroisoquinolines to yield the corresponding ( S )-enantiomers with excellent enantiomeric excess ( ee ) values (up to >99%). By using Fs DAAO in combination with ammonia-borane in one pot, deracemization of these racemic carboxyl-substituted tetrahydroisoquinolines was achieved with conversions up to >98% and >99% ee . Preparative-scale deracemization of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was also demonstrated with good isolated yields (82% and 73%, respectively) and ee >99%. Our study provides an effective method for the synthesis of enantiomeric pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids. This method is expected to provide access to chiral carboxyl-substituted 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-ß-carbolines.
研究领域:
生物化学
·
有机合成
·
酶工程
✓ 已验证
产品关联
DOI
高影响因子
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2017
·Vol. 33
·期 1
·24-30
·
IF 1.024
Li Lang,Xie Shengming,Zhang Junhui,Chen Ling,Zhu Pengjing,Yuan Liming
Homochiral metal-organic frameworks(HMOFs) have special properties, such as high surface area, fasci-nating structures and excellent chemical and thermal stability and they have broad application prospects. In this work, we reported the use of HMOF Co- L -GG( L -GG, dipeptide H-Gly- L -Glu) as the stationary phase for separating race-mates in gas chromatography. Co- L -GG coated fused silica capillary column(10 m×250 μm i.d.) was prepared via a dynamic coating method. Thirty racemates belonging to different classes of organic compounds were resolved in-cluding halohydrocarbons, ketones, esters, ethers, organic acids, epoxyalkanes, alcohols and sulfoxides. When com-pared with the previously reported chiral MOFs-coated capillary columns, the Co- L -GG coated column exhibited broader chiral resolution ability towards chiral compounds.
研究领域:
分析化学
·
材料科学
·
色谱技术
·
金属有机框架材料
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DOI
高影响因子
GREEN CHEMISTRY
·
2019
·Vol. 21
·期 20
·5579-5585
·
IF 9.405
Shuyun Ju,Mingxin Qian,Jing Li,Gang Xu,Lirong Yang,Jianping Wu
Optically pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids are important chiral building blocks in the pharmaceutical and fine chemical industries. However, the existing chemo-enzymatic deracemization method employing D-amino acid oxidase from Fusarium solani M-0718 (FsDAAO) suffers from the requirement for a large excess of a nonselective chemical reducing agent. To explore an alternative method, we envisaged a concurrent biocatalytic oxidation and reduction cascade in one pot. Herein, we report a novel biocatalytic route for the asymmetric reduction of 3,4-dihydroisoquinoline-1-carboxylic acids employing Δ1-piperidine-2-carboxylate/Δ1-pyrrolidine-2-carboxylate reductase from Pseudomonas putida KT2440 (PpDpkA) as a biocatalyst, yielding the corresponding (S)-1-carboxyl-substituted tetrahydroisoquinolines with high conversions and enantiomeric excess (>99% ee). By combining FsDAAO and PpDpkA in one pot, a fully biocatalytic method was demonstrated for the deracemization of a range of racemic 1-carboxyl substituted tetrahydroisoquinolines to produce the corresponding (S)-enantiomers with >99% conversions and >99% ee. Furthermore, preparative-scale biotransformation of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid gave the (S)-enantiomer with 89% isolated yield and >99% ee. Taken together, we provide an enantioselective biocatalytic redox cascade method for the one-pot synthesis of enantiopure 1,2,3,4-tetrahydroisoquinoline carboxylic acids.
研究领域:
生物催化
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有机化学
·
制药
·
精细化工
✓ 已验证
产品关联
DOI
高影响因子
BIOTECHNOLOGY AND BIOENGINEERING
·
2024
·
IF 3.5
Feng Cheng,Ke-Xiang Sun,Xiao-Xiao Gong,Wei Peng,Hua-Yue Zhang,Xi-Hang Liang,Ya-Ping Xue,Yu-Guo Zheng
D-amino acid oxidase (DAAO)-catalyzed selective oxidative deamination is a very promising process for synthesizing l -amino acids including l -phosphinothricin ( l -PPT, a high-efficiency and broad-spectrum herbicide). However, the wild-type DAAO's low activity toward unnatural substrates like d -phosphinothricin ( d -PPT) hampers its application. Herein, a DAAO from Caenorhabditis elegans ( Ce DAAO) was screened and engineered to improve the catalytic potential on d -PPT. First, we designed a novel growth selection system, taking into account the intricate relationship between the growth of Escherichia coli ( E. coli ) and the catalytic mechanism of DAAO. The developed system was used for high-throughput screening of gene libraries, resulting in the discovery of a variant (M6) with significantly increased catalytic activity against d -PPT. The variant displays different catalytic properties on substrates with varying hydrophobicity and hydrophilicity. Analysis using Alphafold2 modeling and molecular dynamic simulations showed that the reason for the enhanced activity was the substrate-binding pocket with enlarged size and suitable charge distribution. Further QM/MM calculations revealed that the crucial factor for enhancing activity lies in reducing the initial energy barrier of the reductive half reaction. Finally, a comprehensive binding-model index to predict the enhanced activity of DAAO toward d -PPT, and an enzymatic deracemization approach was developed, enabling the efficient synthesis of l -PPT with remarkable efficiency.
研究领域:
生物技术
·
酶学
·
蛋白质工程
·
计算生物学
·
化学生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ORGANIC PROCESS RESEARCH & DEVELOPMENT
·
2024
·
IF 3.1
Chao-Ping Lin,Chen-Hui Xu,Fan-Yu Meng,Shi-Ping Song,Zhe-Ming Wu,Ren-Chao Zheng,Yu-Guo Zheng
A chemoenzymatic process combing nitrilase-catalyzed hydrolysis and continuous flow racemization was developed for highly efficient manufacturing of (S)-pregabalin. Nitrilase was immobilized on epoxy resin and employed for the biosynthesis of (S)-3-cyano-5-methylhexanoic acid ((S)-CMHA), the precursor of (S)-pregabalin. Isobutylsuccinonitrile (IBSN) (700 mM) was converted to (S)-CMHA with a conversion of 45.3% and ee of 99.5%. Meanwhile, the unreacted (R)-IBSN was continuously racemized by the γ-alumina-based solid base catalysts (ASBCs) in a packed bed reactor, and an outstanding space-time yield of 6.76 mol L–1 day–1 was achieved. Moreover, the ASBCs exhibited excellent operational stability in the racemization system and retained 85.9% catalytic activity after 20 days of continuous racemization operation. (S)-CMHA was subsequently separated and purified by a membrane separation system in 95% yield and was hydrogenated in one step to (S)-pregabalin in a yield of 88%. These obtained results exhibited the efficiency of the chemoenzymatic process and the great potential for industrialization of (S)-pregabalin.
研究领域:
化学工程
·
生物催化
·
药物化学
✓ 已验证
DOI
高影响因子
JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY
·
2022
·
IF 6.76
Jie Sun,Yaping Wang,Zhenguo Gao,Junbo Gong,Weiwei Tang
Herein, we report a successful resolution of L-norvaline, a racemic compound system, performed near the eutectic composition by coupling preferential crystallization with tailor-made additives. The structures of enantiomer and racemate were characterized by PXRD, DSC , and the enantiomeric purity were measured by Chiral HPLC. The preferential crystallization process was designed and established from binary melting phase diagram and ternary solution phase diagram. The effects of supersaturation, solution enantiomer composition, and seed quantity on the preferential crystallization process were investigated. However, the significant improvements of enantiomeric purity and product yield were demonstrated by additive-assisted preferential crystallization approach using tailor-made additives. These additives bearing similar structure motifs to norvaline a highly selective binding to the racemate rather than enantiomer and remarkably suppress nucleation of DL-norvaline, the key factor determining the resultant enantiomer purity and separation efficiency. The underly inhibition principle was revealed due to the centrosymmetric packing of the racemate while the polarity of enantiomer leads to only partial or slight crystallization suppression. The interesting inhibition mode by tailor-made additives is also believed to be applicable for other racemic crystallization systems. Our established additive-assisted preferential crystallization has showed great potential in the development of separation technology and resolution of enantiomer from racemic compounds.
研究领域:
化学
·
材料科学
·
药学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）