The asymmetric borane reduction of carbonyl compounds using chiral catalysts is one of the most active research. Among them,Oxazaborolidines developed by Corey are most significant- Herein. we report the use of sufony...The asymmetric borane reduction of carbonyl compounds using chiral catalysts is one of the most active research. Among them,Oxazaborolidines developed by Corey are most significant- Herein. we report the use of sufonylamides as chiral catalysts to reduce aromatic ketone in high yield and with e.e. of up to 91 %. Scheme:展开更多
Asymmetric reduction of 3,5-bistrifluoromethyl acetophenone to produce(S)-3,5-bistrifluoromethylphenyl ethanol was successfully carried out with sodium alginate immobilized Saccharomyces rhodotorula cells in an aqueou...Asymmetric reduction of 3,5-bistrifluoromethyl acetophenone to produce(S)-3,5-bistrifluoromethylphenyl ethanol was successfully carried out with sodium alginate immobilized Saccharomyces rhodotorula cells in an aqueous-organic solvent biphasic system.The possible influential factors were examined thoroughly according to their effects on conversion rate and e.e of the product.Organic solvents were rated by their biocompatibility and conversion potential.The immobilized cells [125 mg/mL in 20 mmol/L Tris-HCl buffer and 5%(j) octane at pH 8] showed the best conversion with a substrate concentration of 1.42 g/L at 30℃ with glucose as co-substrate for cofactor regeneration.Sequential 8-batch process was carried out with immobilized cells with a slow decrease in conversion and e.e.The immobilized cells showed stable catalytic activity with 50% reserved activity and are superior especially in reusability in comparison with resting cells.展开更多
Optically pure(R)-γ-and(R)-δ-lactones can be prepared by intramolecular cyclization of chiral hydroxy acids/esters reduced asymmetrically from γ-and δ-keto acids/esters using Saccharomyces cerevisiae(S.cerevisiae)...Optically pure(R)-γ-and(R)-δ-lactones can be prepared by intramolecular cyclization of chiral hydroxy acids/esters reduced asymmetrically from γ-and δ-keto acids/esters using Saccharomyces cerevisiae(S.cerevisiae) as a whole-cell biocatalyst.However,some of the enzymes catalyzing these reactions in S.cerevisiae are still unknown up to date.In this report,two carbonyl reductases,OdCRl and OdCR2,were successfully discovered,and cloned from S.cerevisiae using a genome-mining approach,and overexpressed in Escherichia coli(E.coli).Compared with OdCR1,OdCR2 can reduce 4-oxodecanoic acid and 5-oxodecanoic acid asymmetrically with higher stereoselectivity,generating(R)-γ-decalactone(99% ee) and(R)-δ-decalactone(98% ee) in 85% and 92%yields,respectively.This is the first report of native enzymes from S.cerevisiae for the enzymatic synthesis of chiral γ-and δ-lactones which is of wide uses in food and cosmetic industries.展开更多
The favorable microbes for the asymmetric reduction of prochiral aromatic ketones was isolated from soil using acetophenone as the sole carbon source,when the asymmetric reduction of acetophenone(ACP)to chiral a-phene...The favorable microbes for the asymmetric reduction of prochiral aromatic ketones was isolated from soil using acetophenone as the sole carbon source,when the asymmetric reduction of acetophenone(ACP)to chiral a-phenethyl alcohol(PEA)was chosen as the model reaction.Two microbe strains with excellent catalytic activity were obtained.They were Geotrichum candidum and Pichia pastoris identified by bacteria identification.The product of the asymmetric reduction of ACP catalyzed by Pichia pastoris was mainly R-PEA and that by Geotrichum candidum was mainly S-PEA.The yield and enantiomeric excesses(e.e.)could respectively reach 75%and 90%for Pichia pastoris,and 80%and 70%for Geotrichum candidum,much higher than those catalyzed by baker’s yeast.展开更多
(R)-1,3-butanediol is an important pharmaceutical intermediate, and the synthesis of(R)-1,3-butanediol using green biological methods has recently been of interest for industrial application. Here, a novel strain QC-1...(R)-1,3-butanediol is an important pharmaceutical intermediate, and the synthesis of(R)-1,3-butanediol using green biological methods has recently been of interest for industrial application. Here, a novel strain QC-1 that efficiently transforms 4-hydroxy-2-butanone to(R)-1,3-butanediol was isolated from soil samples. Based on morphological, physiological, and biochemical tests and 5.8 S-internal transcribed spacer sequencing, the strain was identified as Pichia kudriavzevii QC-1. The reaction conditions were optimized to 35 ℃, pH 8.0, rotation speed 200 rpm, and 6:5 mass ratio of glucose to 4-hydroxy-2-butanone. Evaluation of the effects of 4-hydroxy-2-butanone concentrations on yield and cell survival rate showed that 85.60 g·L^-1 product accumulated, with an enantiomeric excess of more than 99%, when 30 g·L^-14-hydroxy-2-butanone was added at 0, 10, and 30 h in a 3-L bioreactor. Thus, strain QC-1 showed excellent catalytic activity and stereoselectivity for the synthesis of(R)-1,3-butanediol from 4-hydroxy-2-butanone.展开更多
A new continuous-flow process for the enzymatic synthesis of optically pureγ-lactones,which are used as flavors and fragrances in the food and cosmetic industries,was developed in a three-dimensional microfluidic rea...A new continuous-flow process for the enzymatic synthesis of optically pureγ-lactones,which are used as flavors and fragrances in the food and cosmetic industries,was developed in a three-dimensional microfluidic reactor.The microchannels(175 mm in length,0.9 mm in depth,and 1.72 mL in volume)were carved precisely inside a single borosilicate glass(90 mm×75 mm×12 mm)with ultrafast femtosecond laser micromachining.The flow field analysis and reaction simulation showed that the mixing of substrates and enzymes was enhanced,allowing the adjustment of residence time in a wide window.SmCR_(V4),a carbonyl reductase with excellent catalytic activity and enantioselectivity towardγ/δ-keto acids,was employed for the asymmetric synthesis of various chiral lactones.30 mmol/L(R)-γ-decalactone(3g)can be obtained in 26 s with a space-time yield(STY)up to 16,877 g L^(-1)d^(-1),which is 14.4 times higher than the highest STY of batch reaction reported previously.This continuous-flow process was applied to the synthesis of 6 chiral lactones.In addition,the scaled-up synthesis of 3g was carried out in 6 cascade microreactors continuously for 6 h,demonstrating the feasibility and stability of the 3D continuous-flow process in enzymatic synthesis of optically pure compounds.展开更多
The developments of hydrogen sources stand at the forefront of asymmetric reduction. In contrast to the well-studied alcohols as hydrogen sources via β-hydride elimination, the direct utilization of the proton of alc...The developments of hydrogen sources stand at the forefront of asymmetric reduction. In contrast to the well-studied alcohols as hydrogen sources via β-hydride elimination, the direct utilization of the proton of alcohols as a hydrogen source for activatormediated asymmetric reduction is rarely explored. Herein we report the proton of alcohols as a hydrogen source in diboronmediated palladium-catalyzed asymmetric transfer hydrogenation of 1,3-diketones and indoles, providing a series of chiral β-hydroxy ketones and indolines with excellent yields and enantioselectivities. This strategy would be useful for the synthesis of chiral deuterium-labelled compounds due to the ready availability of deuterium-labelled alcohols. Mechanistic investigations and DFT calculations revealed that active chiral Pd-H species was generated from the proton of alcohols by activating of tetrahydroxydiboron, hydrogen transfer was the rate-determining step, and the reaction preferred Pd(0)-catalyzed mechanism.展开更多
A highly efficient and enantioselective method for the asymmetric reductive amination ofβ-keto phosphine de-rivatives was disclosed,and the correspondingβ-amino phosphine oxides could be obtained in high yields(up t...A highly efficient and enantioselective method for the asymmetric reductive amination ofβ-keto phosphine de-rivatives was disclosed,and the correspondingβ-amino phosphine oxides could be obtained in high yields(up to 97%yield)and excellent enantioselectivities(up to 97%ee).Moreover,the reaction worked well on a gram scale,indicating that our protocol has potential applications in the synthesis of chiral ligands and organocatalysts.展开更多
(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important...(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important compound.Through screening the available carbonyl reductases,we obtained a carbonyl reductase from Novosphingobium aromaticivorans(CBR),which could completely convert 100 g/L of 1a to(S)-1b.Furthermore,a carbonyl reductase from Novosphingobium sp.Leaf2(NoCR)was identified to completely convert 200 g/L of 1a to(S)-1b with excellent enantioselectivity(>99%ee)and 77%isolated yield using FDH/formate system for NADH regeneration.The K_(m) and k_(cat) of recombinant NoCR towards 1a were 0.66 mmol/L and 7.5 s-1,and the catalytic efficiency k_(cat)/K_(m) was 11.3 mmol/s.L.Meanwhile,NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring,indicating that NoCR is a valuable biocatalyst with potential practical applications.展开更多
The gene which encodes(R)-specific carbonyl reductase(rCR)from Candida parapsilosis CCTCC M203011 was cloned,sequenced and compared with genes from the GenBank.The results indicated that rCR gene was 1011 bp,encoding ...The gene which encodes(R)-specific carbonyl reductase(rCR)from Candida parapsilosis CCTCC M203011 was cloned,sequenced and compared with genes from the GenBank.The results indicated that rCR gene was 1011 bp,encoding a protein of 336 amino acids with a molecular weight of 35.9 kDa,and its nucleotide sequence showed 99%similarity to those of other members of the alcohol dehydrogenase superfamily.The rCR gene could express in recombinant strain Escherichia coli JM109,and the expression plasmid could produce(R)-1-pheny-1,2-ethanediol(100%e.e.,80.14%yield)from b-hydroxyacetophenone without any additive to regenerate NAD+from NADH.展开更多
文摘The asymmetric borane reduction of carbonyl compounds using chiral catalysts is one of the most active research. Among them,Oxazaborolidines developed by Corey are most significant- Herein. we report the use of sufonylamides as chiral catalysts to reduce aromatic ketone in high yield and with e.e. of up to 91 %. Scheme:
文摘Asymmetric reduction of 3,5-bistrifluoromethyl acetophenone to produce(S)-3,5-bistrifluoromethylphenyl ethanol was successfully carried out with sodium alginate immobilized Saccharomyces rhodotorula cells in an aqueous-organic solvent biphasic system.The possible influential factors were examined thoroughly according to their effects on conversion rate and e.e of the product.Organic solvents were rated by their biocompatibility and conversion potential.The immobilized cells [125 mg/mL in 20 mmol/L Tris-HCl buffer and 5%(j) octane at pH 8] showed the best conversion with a substrate concentration of 1.42 g/L at 30℃ with glucose as co-substrate for cofactor regeneration.Sequential 8-batch process was carried out with immobilized cells with a slow decrease in conversion and e.e.The immobilized cells showed stable catalytic activity with 50% reserved activity and are superior especially in reusability in comparison with resting cells.
基金financially sponsored by the National Key Research and Development Program of China (2016YFA0204300, 2019YFA09005000)the National Natural Science Foundation of China (21536004, 21776085, 21871085)+2 种基金the Natural Science Foundation of Shanghai (18ZR1409900)Key Project of the Shanghai Science and Technology Committee (18DZ1112703)the Fundamental Research Funds for the Central Universities (WF1714026)。
文摘Optically pure(R)-γ-and(R)-δ-lactones can be prepared by intramolecular cyclization of chiral hydroxy acids/esters reduced asymmetrically from γ-and δ-keto acids/esters using Saccharomyces cerevisiae(S.cerevisiae) as a whole-cell biocatalyst.However,some of the enzymes catalyzing these reactions in S.cerevisiae are still unknown up to date.In this report,two carbonyl reductases,OdCRl and OdCR2,were successfully discovered,and cloned from S.cerevisiae using a genome-mining approach,and overexpressed in Escherichia coli(E.coli).Compared with OdCR1,OdCR2 can reduce 4-oxodecanoic acid and 5-oxodecanoic acid asymmetrically with higher stereoselectivity,generating(R)-γ-decalactone(99% ee) and(R)-δ-decalactone(98% ee) in 85% and 92%yields,respectively.This is the first report of native enzymes from S.cerevisiae for the enzymatic synthesis of chiral γ-and δ-lactones which is of wide uses in food and cosmetic industries.
基金This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China(Grant No.20050335131)Wuhan Youth Scientist Dawn Foundation(200750731288)Natural Science Foundation of Wuhan University of Science and Technology(2005XY15).
文摘The favorable microbes for the asymmetric reduction of prochiral aromatic ketones was isolated from soil using acetophenone as the sole carbon source,when the asymmetric reduction of acetophenone(ACP)to chiral a-phenethyl alcohol(PEA)was chosen as the model reaction.Two microbe strains with excellent catalytic activity were obtained.They were Geotrichum candidum and Pichia pastoris identified by bacteria identification.The product of the asymmetric reduction of ACP catalyzed by Pichia pastoris was mainly R-PEA and that by Geotrichum candidum was mainly S-PEA.The yield and enantiomeric excesses(e.e.)could respectively reach 75%and 90%for Pichia pastoris,and 80%and 70%for Geotrichum candidum,much higher than those catalyzed by baker’s yeast.
基金Financial supports from the National Key R&D Program of China(2018YFC1604100)the National Natural Science Foundation of China(NSFC)[21676120,31872891]+8 种基金the 111 Project[111-2-06]the Highend Foreign Experts Recruitment Program[G20190010083]the Program for Advanced Talents within Six Industries of Jiangsu Province[2015-NY007]the National Program for Support of Top-notch Young Professionalsthe Fundamental Research Funds for the Central Universities[JUSRP51504]the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education InstitutionsTop-notch Academic Programs Project of Jiangsu Higher Education Institutionsthe Jiangsu Province“Collaborative Innovation Center for Advanced Industrial Fermentation”Industry Development Programthe National First-Class Discipline Program of Light Industry Technology and Engineering[LITE2018-09]。
文摘(R)-1,3-butanediol is an important pharmaceutical intermediate, and the synthesis of(R)-1,3-butanediol using green biological methods has recently been of interest for industrial application. Here, a novel strain QC-1 that efficiently transforms 4-hydroxy-2-butanone to(R)-1,3-butanediol was isolated from soil samples. Based on morphological, physiological, and biochemical tests and 5.8 S-internal transcribed spacer sequencing, the strain was identified as Pichia kudriavzevii QC-1. The reaction conditions were optimized to 35 ℃, pH 8.0, rotation speed 200 rpm, and 6:5 mass ratio of glucose to 4-hydroxy-2-butanone. Evaluation of the effects of 4-hydroxy-2-butanone concentrations on yield and cell survival rate showed that 85.60 g·L^-1 product accumulated, with an enantiomeric excess of more than 99%, when 30 g·L^-14-hydroxy-2-butanone was added at 0, 10, and 30 h in a 3-L bioreactor. Thus, strain QC-1 showed excellent catalytic activity and stereoselectivity for the synthesis of(R)-1,3-butanediol from 4-hydroxy-2-butanone.
基金financially sponsored by the National Key Research and Development Program of China(No.2021YFC2102804)the National Natural Science Foundation of China(No.22078096)。
文摘A new continuous-flow process for the enzymatic synthesis of optically pureγ-lactones,which are used as flavors and fragrances in the food and cosmetic industries,was developed in a three-dimensional microfluidic reactor.The microchannels(175 mm in length,0.9 mm in depth,and 1.72 mL in volume)were carved precisely inside a single borosilicate glass(90 mm×75 mm×12 mm)with ultrafast femtosecond laser micromachining.The flow field analysis and reaction simulation showed that the mixing of substrates and enzymes was enhanced,allowing the adjustment of residence time in a wide window.SmCR_(V4),a carbonyl reductase with excellent catalytic activity and enantioselectivity towardγ/δ-keto acids,was employed for the asymmetric synthesis of various chiral lactones.30 mmol/L(R)-γ-decalactone(3g)can be obtained in 26 s with a space-time yield(STY)up to 16,877 g L^(-1)d^(-1),which is 14.4 times higher than the highest STY of batch reaction reported previously.This continuous-flow process was applied to the synthesis of 6 chiral lactones.In addition,the scaled-up synthesis of 3g was carried out in 6 cascade microreactors continuously for 6 h,demonstrating the feasibility and stability of the 3D continuous-flow process in enzymatic synthesis of optically pure compounds.
基金the National Natural Science Foundation of China(21901239,21532006)the Strategic Priority Program of Chinese Academy of Sciences(XDB17020300,QYZDJ-SSW-SLH035)。
文摘The developments of hydrogen sources stand at the forefront of asymmetric reduction. In contrast to the well-studied alcohols as hydrogen sources via β-hydride elimination, the direct utilization of the proton of alcohols as a hydrogen source for activatormediated asymmetric reduction is rarely explored. Herein we report the proton of alcohols as a hydrogen source in diboronmediated palladium-catalyzed asymmetric transfer hydrogenation of 1,3-diketones and indoles, providing a series of chiral β-hydroxy ketones and indolines with excellent yields and enantioselectivities. This strategy would be useful for the synthesis of chiral deuterium-labelled compounds due to the ready availability of deuterium-labelled alcohols. Mechanistic investigations and DFT calculations revealed that active chiral Pd-H species was generated from the proton of alcohols by activating of tetrahydroxydiboron, hydrogen transfer was the rate-determining step, and the reaction preferred Pd(0)-catalyzed mechanism.
基金the National Natural Science Foundation of China(No.21901107)Shenzhen Bay Laboratory(No.SZBL2019062801006)+5 种基金Shenzhen Science and Technology Innovation Committee(No.KQTD20150717103157174)Key-Area Research and Development Program of Guangdong Province(No.2020B010188001)Stable Support Plan Program of Shenzhen Science and Technology Innovation Committee(No.20200925161222002)Innovative Team of Universities in Guangdong Province(No.2020KCXTD016).G.Q.Chen gratefully acknowledges the National Natural Science Foundation of China(Nos.21901107 and 22171129)the Guangdong Basic and Applied Basic Research Foundation(No.2022B1515020055)the Shenzhen Science and Technology Innovation Committee(No.JCYJ20210324104202007)for financial support.B.Ma is indebted to the financial support from the National Natural Science Foundation of China(No.22001113)B.Ma is the National Natural Science Foundation of China(No.22001113).
文摘A highly efficient and enantioselective method for the asymmetric reductive amination ofβ-keto phosphine de-rivatives was disclosed,and the correspondingβ-amino phosphine oxides could be obtained in high yields(up to 97%yield)and excellent enantioselectivities(up to 97%ee).Moreover,the reaction worked well on a gram scale,indicating that our protocol has potential applications in the synthesis of chiral ligands and organocatalysts.
基金supported by the National Key R&D Program of China(No.2021YFC2102000)the Strategic Priority Research Program of the Chinese Academy of Sciences,and Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(No.TSBICIPKJGG-009).
文摘(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important compound.Through screening the available carbonyl reductases,we obtained a carbonyl reductase from Novosphingobium aromaticivorans(CBR),which could completely convert 100 g/L of 1a to(S)-1b.Furthermore,a carbonyl reductase from Novosphingobium sp.Leaf2(NoCR)was identified to completely convert 200 g/L of 1a to(S)-1b with excellent enantioselectivity(>99%ee)and 77%isolated yield using FDH/formate system for NADH regeneration.The K_(m) and k_(cat) of recombinant NoCR towards 1a were 0.66 mmol/L and 7.5 s-1,and the catalytic efficiency k_(cat)/K_(m) was 11.3 mmol/s.L.Meanwhile,NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring,indicating that NoCR is a valuable biocatalyst with potential practical applications.
基金This study was supported by the National Basic Research Program of China(No.2003CB716008)the Program for Changjiang Scholars and Innovative Research Team in University(PCSIRT,IRT0532).
文摘The gene which encodes(R)-specific carbonyl reductase(rCR)from Candida parapsilosis CCTCC M203011 was cloned,sequenced and compared with genes from the GenBank.The results indicated that rCR gene was 1011 bp,encoding a protein of 336 amino acids with a molecular weight of 35.9 kDa,and its nucleotide sequence showed 99%similarity to those of other members of the alcohol dehydrogenase superfamily.The rCR gene could express in recombinant strain Escherichia coli JM109,and the expression plasmid could produce(R)-1-pheny-1,2-ethanediol(100%e.e.,80.14%yield)from b-hydroxyacetophenone without any additive to regenerate NAD+from NADH.
