High Throughput Enzymatic Enantiomeric Excess: Quick-ee

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High throughput screening techniques (HTS) are fast and efficient alternatives to evaluate enzymatic activities. Here, this technique is applied to obtain enantiomeric excess and conversions values with chiral fluorogenic probes and a non fluorogenic competitor, which was named Quick-ee. The fluorescent signal reveals of the enantioselectivity of the enzyme. Details are presented in the Article High Throughput Enzymatic Enantiomeric Excess: Quick-ee by Maria L. S. de O. Lima, Caroline C. da S. Gonçalves, Juliana C. Barreiro, Quezia Bezerra Cass and Anita Jocelyne Marsaioli on page 319.

http://dx.doi.org/10.5935/0103-5053.20140282

Cover Article

J. Braz. Chem. Soc. 2015, 26(2), 319-324

High Throughput Enzymatic Enantiomeric Excess: Quick-ee

Maria L. S. O. Lima; Caroline C. S. Gonçalves; Juliana C. Barreiro; Quezia B. Cass; Anita J. Marsaioli

Lima MLSO, Gonçalves CCS, Barreiro JC, Cass QB, Marsaioli AJ. High Throughput Enzymatic Enantiomeric Excess: Quick-ee.J. Braz. Chem. Soc. 2015;26(2):319-324

/////////////High Throughput,  Enzymatic,  Enantiomeric Excess,  Quick-ee

http://jbcs.sbq.org.br/imagebank/pdf/v26n2a14.pdf

http://jbcs.sbq.org.br/imagebank/pdf/v26n2a14-Sup01.pdf

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

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Abstract Image

Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States
Org. Process Res. Dev., Article ASAP

//////////Flow Grignard,  Lithiation, Screening Tools,  Development, Continuous Processes,  Benzyl Alcohol, Starting Material

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The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

A key pharmaceutical intermediate (1) for production of edivoxetine·HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solventcomposition, stoichiometry, and operations temperature were optimized to produce 12 g h−1crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h−1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000–6000 L batch reactors.

A continuous flow Barbier reaction was employed for the production of a key pharmaceutical intermediate (1) in the synthesis of edivoxetine·HCl (a highly selective norepinephrine re-uptake inhibitor).

US scientists from Eli Lilly and Company and D&M Continuous Solutions, led by Michael Kopach, report the development of a continuous Barbier reaction which preserves chirality and the product obtained in >99% ee.  The team ran the process in a series of continuous stirred tank reactors, where residence time, solvent composition, stoichiometry and operations temperature were optimised to produce 12 g per hour of the ketone precursor to 1 with 98% ee and 88% in situ yield for 47 hours total flow time.  Continuous salt formation and isolation of 1 could then be achieved from the ketone solution with >99% purity.

This process offers up several significant advantages over a traditional Grignard batch process.  This continuous flow method gave greater than 30% reduced process mass intensity and magnesium usage relative to the batch method.  Equally, the flow process resulted in >100 x less excess magnesium to quench and >100 x less diisobutylaluminum hydride to initiate giving significant safety benefits.  The authors expect that the maximum long-term scale of the process is 50 L which would replace 4000-6000 L batch reactors.

Continuous Flow Barbier Reaction

Figure 2. Continuous Barbier Laboratory Setup

For 100 years, Grignard reactions have been one of the most powerful and effi cient organic chemistry methodologies for C-C bond formation. However, Grignard reactions are also among the most challenging reactions from both operational and potential safety issues due to initiation diffi culties and runaway potential. A close variation to the Grignard reaction is the Barbier reaction wherein the Grignard reagent is prepared in the presence of an electrophile resulting in the immediate consumption of the Grignard. A Barbier reaction using a CSTR was developed for a key pharmaceutical intermediate in production of edivoxetine·HCl (Scheme 4) [9]. In the fl ow setup (Figure 2), solid magnesium is sequestered in the fi rst tank where the Grignard initiation event takes place. CSTR 2 was used as an aging tank and CSTR 3 was the quench tank. CSTRs were used for Grignard reaction rather than a PFDR because of the solid Mg reagent.

Scheme 4: Barbier Reaction to form Ketone 15

Continuous reaction improved process safety, product quality, and process greenness. The continuous reaction achieved >99% ee in situ versus 95% ee batch because of immediate conversion of unstable intermediate. Solvent volumes were reduced 30%. The safety hazards were reduced by decreasing the reactor size by 50X, which reduced chemical potential and also increased heat transfer surface area per unit volume by 4X. DIBAL-H initiating agent was reduced by more than 100X, and excess Mg that must be quenched at the end of reaction was almost eliminated. When run continuously, the commercial scale Grignard formation reactor was expected to be 50L, which replaces 4000-6000L batch reactor.

The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

*Corresponding authors
aChemical Product Research and Development, Eli Lilly and Company, Indianapolis, USA
E-mail: kopach_michael@lilly.com
bD&M Continuous Solutions, Indianapolis, USA
Green Chem., 2012,14, 1524-1536

DOI: 10.1039/C2GC35050E

http://pubs.rsc.org/en/Content/ArticleLanding/2012/GC/C2GC35050E#!divAbstract

Three vessel Grignard CSTR process train.

Grignard synthesis of compound 1.

Retrosynthesis of edivoxetine·HCl.

Flow diagram for the whole continuous process from amide 3 to product 1.

Continuous crystallization of compound 1.

Distillation and continuous crystallization of compound 1.

Entry, Rxn temp. (°C), Vol. ratio THF–toluene (%), Conversion (%), ee (%)

//////////The continuous flow,  Barbier reaction,  improved environmental alternative,  Grignard reaction, FLOW SYNTHESIS

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Commercial Production of Semi-Synthetic Artemisinin

New Drug Approvals

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Figure 1. Production of artemisinic acid or β-farnesene by engineered yeast. The sesquiterpene alkenes β-farnesene and amorphadiene are both derived from FPP (farnesyl diphosphate) by the action of specific enzymes introduced from plants: amorphadiene synthase (ADS) generates amorphadiene and β-farnesene synthase (FS) generates β-farnesene. Production strains express either ADS or FS, not both. Oxidation of amorphadiene to artemisinic acid is accomplished by the action of five plant enzymes expressed in the engineered yeast.17 Conversion of purified artemisinic acid to artemisinin is accomplished by in vitro organic chemistry. Isoprenoid production strains make little ethanol.

The antimalarial drug artemisinin and the specialty chemical β-farnesene are examples of natural product isoprenoids that can help solve global challenges, but whose usage has previously been limited by supply and cost impediments. This review describes the path to commercial production of these compounds utilizing fermentation of engineered yeast. Development of commercially viable yeast strains was a…

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Directed alkynylation of unactivated C(sp3)-H bonds with ethynylbenziodoxolones mediated by DTBP

Directed alkynylation of unactivated C(sp3)-H bonds with ethynylbenziodoxolones mediated by DTBP

Green Chem., 2016, 18,4185-4188

DOI: 10.1039/C6GC01336H, Communication
Zhi-Fei Cheng, Yi-Si Feng, Chun Rong, Tao Xu, Peng-Fei Wang, Jun Xu, Jian-Jun Dai, Hua-Jian Xu
A general and efficient alkynylation of unactivated C(sp3)-H bonds under metal-free conditions was developed herein.

Directed alkynylation of unactivated C(sp3)–H bonds with ethynylbenziodoxolones mediated by DTBP

Zhi-Fei Cheng,a   Yi-Si Feng,*abc   Chun Rong,a   Tao Xu,a  Peng-Fei Wang,a   Jun Xu,a   Jian-Jun Daia and   Hua-Jian Xu*abc  
*Corresponding authors
aSchool of Chemistry and Chemical Engineering, School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, P. R. China
bAnhui Key Laboratory of Controllable Chemical Reaction and Material Chemical Engineering, Hefei 230009, P. R. China
E-mail: hjxu@hfut.edu.cn
Fax: (+86)-551-62904405
cAnhui Provincial Laboratory of Heterocyclic Chemistry, Maanshan 243110, China
Green Chem., 2016,18, 4185-4188

DOI: 10.1039/C6GC01336H, http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01336H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A general and efficient method for the direct alkynylation of unactivated C(sp3)–H bonds under metal-free conditions is described. The reaction performs smoothly under mild conditions and shows excellent functional-group tolerance. Initial mechanistic investigation indicates that the reaction may involve a radical pathway.
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2-((4-chlorophenyl)ethynyl)tetrahydrofuran (3cg) ref 1 : Following general procedure, The product was purified by flash column chromatography on silica gel (petroleum ether) and 1c : 2g = 1:69, obtained in 70 % yield as a pale yellow oil (28.8 mg).
1H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 8.4 Hz, 2H), 7.28 – 7.25 (m, 2H), 4.82 – 4.77 (m, 1H), 4.00 (dd, J = 14.6, 7.1 Hz, 1H), 3.85 (dd, J = 13.6, 7.8 Hz, 1H), 2.26 – 2.19 (m, 1H), 2.11 – 2.04 (m, 2H), 1.95 (dd, J = 13.3, 5.8 Hz, 1H).
 Wan, M.; Meng, Z.; Lou, H.; Liu, L. Angew. Chem. Int. Ed. 2014, 126, 14065.
STR1
13C NMR (151 MHz, CDCl3) δ 134.2, 132.9, 128.5, 121.2, 90.0, 83.3, 68.5, 67.9, 33.3, 25.4.
STR2

//////////Directed alkynylation, unactivated C(sp3)-H bonds,  ethynylbenziodoxolones,  DTBP

An efficient Passerini tetrazole reaction (PT-3CR)

Graphical abstract: An efficient Passerini tetrazole reaction (PT-3CR)

An efficient Passerini tetrazole reaction (PT-3CR)

Green Chem., 2016, 18,3718-3721

DOI: 10.1039/C6GC00910G, Communication

Ajay L. Chandgude, Alexander Domling

A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-type three-component reaction (PT-3CR) has been developed.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00910G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-type three-component reaction (PT-3CR) has been developed. It comprises the reaction of an aldehyde/ketone, an isocyanide and a TMS-azide in methanol : water (1 : 1) as the solvent system. The use of sonication not only accelerated the rate of the reaction but also provided good to excellent quantitative yields. This reaction is applicable to a broad scope of aldehydes/ketones and isocyanides.

An efficient Passerini tetrazole reaction (PT-3CR)

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Corresponding authors
a
Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
E-mail: a.s.s.domling@rug.nl
Web: http://www.drugdesign.nl/
Green Chem., 2016,18, 3718-3721

DOI: 10.1039/C6GC00910G

/////////////Passerini tetrazole reaction (PT-3CR)

Oxidation of refractory sulfur compounds with molecular oxygen over a Ce-Mo-O catalyst

Oxidation of refractory sulfur compounds with molecular oxygen over a Ce-Mo-O catalyst

 Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC01357K, Paper
Yawei Shi, Guozhu Liu, Bofeng Zhang, Xiangwen Zhang
A Ce-Mo-O catalyst showed remarkable performance for aerobic oxidative desulfurization without sacrificial agents at 100 [degree]C and atmospheric pressure.

Oxidation of refractory sulfur compounds with molecular oxygen over a Ce–Mo–O catalyst

Yawei Shi,a   Guozhu Liu,*a   Bofeng Zhanga and  Xiangwen Zhang*a  
*
Corresponding authors
a
Key Laboratory for Green Chemical Technology of Ministry of Education, School of Chemical Engineering and Technology, Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin 300072, China
E-mail: gliu@tju.edu.cnzhangxiangwen@tju.edu.cn
Fax: +86 22 27892340
Tel: +86 22 27892340
Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC01357K

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01357K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A Ce–Mo–O catalyst prepared by a simple sol–gel method was proved to be highly active for aerobic oxidative desulfurization. Almost complete conversions of dibenzothiophene and 4,6-dimethyldibenzothiophene were achieved without any additional sacrificial agent at 100 °C and atmospheric pressure, and the conversion of benzothiophene could reach 97%. Reusability of the catalyst was also conducted, and >99% conversions could be achieved in three consecutive runs. As supported by carefully-designed control experiments, oxygen was activated by Ce species in the catalyst first, forming some reactive oxygen species, which oxidized DBT into DBTO2 with the assistance of Mo species. Furthermore, selective quenching experiments indicated the generation of superoxide species during the reaction.

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