(2R,4R)-Methyl-2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate

(2R,4R)-Methyl-2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate (18)

the resulting crude was purified by flash chromatography on silica gel (eluted by 30–50% ethyl acetate in hexane). The collected fractions were evaporated and recrystallized from diethyl ether–hexanes (1:1, v/v) to afford N-formyl thazolidine 18 (300 g, 90% yield, 97% HPLC purity) as colorless crystals.

 

1H NMR (400 MHz, CDCl3, mixture of conformers (7:1), major): δ 8.35 (s, 1H), 4.89 (t, J = 8.0 Hz, 1H), 4.74 (s, 1H), 3.77 (s, 3H), 3.34–3.24 (m, 2H), 1.03 (s, 9H) ppm.

 

13C NMR (100 MHz, CDCl3, mixture of conformers (7:1), major): δ 170.1, 162.8, 75.3, 61.6, 52.8, 38.7, 33.0, 26.5 ppm. HRMS (ESI) m/z calcd for C10H17NO3S (M+H)+ 232.1002, found 232.1001.

 

Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor

Qi-Yin Chen†‡§, Pravin R. Chaturvedi§, and Hendrik Luesch*†‡§ 

†Department of Medicinal Chemistry and ‡Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida 32610, United States

§ Oceanyx Pharmaceuticals, Inc., Sid Martin Biotechnology Incubator, 12085 Research Drive, Alachua, Florida 32615, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00352

 

*E-Mail: luesch@cop.ufl.edu; Tel.: +1-352-273-7738; Fax: +1-352-273-7741.

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00352

Abstract

Herein we describe the research and development of the process for the scale-up total synthesis of largazole, a potent class I selective histone deacetylase (HDAC) inhibitor, a potential anticancer agent and also useful for the treatment of other disorders where transcriptional reprogramming might be beneficial. The synthetic route and conditions for each fragment and final product were modified and optimized to make them suitable for larger-scale synthesis. With the process we developed, hundreds of grams of each fragment and decagrams of final product largazole were synthesized in good to excellent yields. The final target largazole was obtained in 21% overall yield over eight steps based on the longest sequence with over 95% HPLC purity.

 

 

//////////

Methyl (S)-2-(benzylideneamino)propanoate

Alanine, N-(phenylmethylene)-, methyl ester; AC1LRVOF; D-Alanine, N-(phenylmethylene)-, methyl ester; Methyl benzylidenealaninate; SCHEMBL8125280; N-[(E)-Benzylidene]-Ala-OMe
Molecular Formula:	C11H13NO2
Molecular Weight:	191.23 g/mol

1. 112674-72-3
2. 53933-42-9

Methyl (S)-2-(benzylideneamino)propanoate (1g)
970 mg (6.95 mmol, 1.0 eq) L-Alanine methyl ester hydrochloride, 700 µL (6.88 mmol, 0.99 eq) benzaldehyde, 1.06 mL (7.65 mmol, 1.1 eq) triethylamine and 7 mL CHCl3. Yield: 1.289 g (6.74 mmol, 97%), yellow viscous oil.

1 H-NMR (300 MHz, CDCl3): δ = 8.31 (s, 1H), 7.81-7.74 (m, 2H), 7.48-7.38 (m, 3H), 4.16 (q, 3 JHH = 6.8 Hz, 1H), 3.75 (s, 3H), 1.53 (d, 3 JHH = 6.8 Hz, 3H).

13C NMR (75 MHz, CDCl3): δ = 173.1, 163.1, 135.8, 131.3, 128.7, 128.6, 68.2, 52.4, 19.6.


1H NMR PREDICT

13 C NMR PREDICT

/////////////////
O=C(OC)[C@H](C)/N=C/c1ccccc1

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids

 

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of [small alpha]-difluoromethyl-amino acids

Green Chem., 2018, 20,108-112
DOI: 10.1039/C7GC02913F, Communication

 Open Access

  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Manuel Kockinger, Tanja Ciaglia, Michael Bersier, Paul Hanselmann, Bernhard Gutmann, C. Oliver Kappe
Difluoromethylated esters, malonates and amino acids (including the drug eflornithine) are obtained by a gas-liquid continuous flow protocol employing the abundant waste product fluoroform as an atom-efficient reagent.

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids

 

Manuel Köckinger,^a  Tanja Ciaglia,^a  Michael Bersier,^b  Paul Hanselmann,^b  Bernhard Gutmann*^ac  and  C. Oliver Kappe*^ac 

Author affiliations

* Corresponding authors

^a Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
E-mail: bernhard.gutmann@uni-graz.at, oliver.kappe@uni-graz.at

^b Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland

^c Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria

Abstract

Fluoroform (CHF₃) can be considered as an ideal reagent for difluoromethylation reactions. However, due to the low reactivity of fluoroform, only very few applications have been reported so far. Herein we report a continuous flow difluoromethylation protocol on sp³ carbons employing fluoroform as a reagent. The protocol is applicable for the direct C^α-difluoromethylation of protected α-amino acids, and enables a highly atom efficient synthesis of the active pharmaceutical ingredient eflornithine.
Methyl 3,3-(difluoro)-2,2-diphenylpropanoate (2a) The product mixtures were collected and the solvent removed in vacuo. The products were isolated by thin layer chromatography (dichloromethane/hexane = 3/2 (v/v)). Yield: 173 mg (0.62 mmol, 62%); 93% by 19F NMR ;light yellow viscous liquid. 1 H NMR (300 MHz, D2O): δ = 7.45 – 7.19 (m, 10H), 6.90 (t, 2 JHF = 55.0 Hz, 1H), 3.79 (s, 3H). 13C NMR (75 MHz, D2O): δ = 171.1, 136.3, 129.8, 128.3, 128.2, 115.6 (t, 1 JCF = 246.2 Hz), 64.7, 53.1.19F NMR (282 MHz, D2O):δ = -123.0 (d, 2 JHF = 55.0 Hz).
  

Conclusions

A gas–liquid continuous flow difluoromethylation protocol employing fluoroform as a reagent was reported. Fluoroform, a by-product of Teflon manufacture with little current synthetic value, is the most attractive reagent for difluoromethylation reactions. The continuous flow process allows this reaction to be performed within reaction times of 20 min with 2 equiv. of base and 3 equiv. of fluoroform. Importantly, the protocol allows the direct C^α-difluoromethylation of protected α-amino acids. These compounds are highly selective and potent inhibitors of pyridoxal phosphate-dependent decarboxylases. The starting materials are conveniently derived from the commercially available α-amino acid methyl esters, and the final products are obtained in excellent purities and yields after simple hydrolysis and precipitation. The developed process appears to be especially appealing for industrial applications, where atom economy, sustainability, reagent cost and reagent availability are important factors.

//////////

Bio-derived production of cinnamyl alcohol via a three step biocatalytic cascade and metabolic engineering

 

Bio-derived production of cinnamyl alcohol via a three step biocatalytic cascade and metabolic engineering

Green Chem., 2018, Advance Article
DOI: 10.1039/C7GC03325G, Paper

Evaldas Klumbys, Ziga Zebec, Nicholas J. Weise, Nicholas J. Turner, Nigel S. Scrutton
Cascade biocatalysis and metabolic engineering provide routes to cinnamyl alcohol.

Bio-derived production of cinnamyl alcohol via a three step biocatalytic cascade and metabolic engineering

 

Evaldas Klumbys,^a  Ziga Zebec,^a  Nicholas J. Weise,^a  Nicholas J. Turner^a  and  Nigel S. Scrutton*^a 

* Corresponding authors

^a Manchester Institute of Biotechnology (MIB), School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, UK
E-mail:nigel.scrutton@manchester.ac.uk

Evaldas Klumbys

Prof Nigel ScruttonScD, FRSC, FRSB

Professor of Enzymology and Biophysical Chemistry

• Affiliations:
• Chemical Biology and Biological ChemistrySchool of Chemistry
• Manchester Institute of BiotechnologyFaculty of Science and Engineering

• Links:
• Manchester Centre for Biophysics and Catalysis
• Manchester Institute of Biotechnology
• Scrutton Laboratory website
• SYNBIOCHEM Synthetic Biology Research Centre

• Email:
• Nigel.Scrutton@manchester.ac.uk

Phone: +44 (0) 161 306 5152

Full contact details

ORCID: 0000-0002-4182-3500

Abstract

The construction of biocatalytic cascades for the production of chemical precursors is fast becoming one of the most efficient approaches to multi-step synthesis in modern chemistry. However, despite the use of low solvent systems and renewably resourced catalysts in reported examples, many cascades are still dependent on petrochemical starting materials, which as of yet cannot be accessed in a sustainable fashion. Herein, we report the production of the versatile chemical building block cinnamyl alcohol from the primary metabolite and the fermentation product L-phenylalanine. Through the combination of three biocatalyst classes (phenylalanine ammonia lyase, carboxylic acid reductase and alcohol dehydrogenase) the target compound could be obtained in high purity, demonstrable at the 100 mg scale and achieving 53% yield using ambient temperature and pressure in an aqueous solution. This system represents a synthetic strategy in which all components present at time zero are biogenic and thus minimises damage to the environment. Furthermore we extend this biocatalytic cascade by its inclusion in an L-phenylalanine overproducing strain of Escherichia coli. This metabolically engineered strain produces cinnamyl alcohol in mineral media using glycerol and glucose as the carbon sources. This study demonstrates the potential to establish green routes to the synthesis of cinnamyl alcohol from a waste stream such as glycerol derived, for example, from lipase treated biodiesel.
(R)-3-amino-3-(3-fluorophenyl)propanoic acid (1c) 1H NMR (CDCl3): δ 7.16-7.31 (m, 5H, ArH), 6.50-6.54 (d, 1H, J = 16 Hz, C=CH), 6.23-6.30 (dt, 1H, J = 16, 8 Hz, C=CHCH2 ), 4.21-4.23 (dd, 2H, J = 8, 4 Hz, C=CHCH2); 13C NMR (CDCl3): 136.70, 131.09, 128.60, 128.54, 127.69, 126.48, 63.65.
 

////////////cinnamyl alcohol,  biocatalytic, metabolic engineering

(2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one

CAS 1672658-93-3

C24 H25 F O6 S, 460.52

D-Glucopyranose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-

 

 

CAS 1809403-04-0

C24 H25 F O6 S, 460.52

D-Glucose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-

WO2017/93949

 

 

 

(2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one    12

From the FT-IR spectra of 12 contain a signal at 1674 cm–1, this signal is strongly indicative of a carbonyl ketone being present in 12

In 13C NMR and HMBC correlations spectra, the chemical shift at 199.75 ppm was observed. Analysis of the NMR data  confirmed that the structure of 12 is a ring-opened keto form

Synthesis of (2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one 12

title compound 12 (84.23% yield) and having 99.4% purity by HPLC;

 

DSC: 160.84–166.44 °C;

 

Mass: m/z 459 (M+–H);

 

IR (KBr, cm–1): 3313, 2982, 1674.7, 1601, 1507.5, 1232.7;

 

1H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.80 (dd, J = 1.8 Hz, 1H), 7.61–7.58 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.21–7.18 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 3.6, 3.0 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.57 (d, J = 4.8 Hz, 1H), 4.43–4.39 (m, 3H), 4.22 (s, 2H), 4.02–4.01 (m, 1H), 3.53–3.51 (m, 3H), 3.38–3.37 (m, 1H), 2.35 (s, 3H);

 

13C NMR (101 MHz, DMSO-d6) δ 199.7, 162.6, 160.2, 142.8, 142.1, 140.5, 138.8, 133.3, 130.5, 130.4, 130.4, 129.3, 127.2, 127.0, 127.0, 126.7, 123.5, 116.0, 115.8, 75.2, 72.3, 71.8, 71.3, 63.2, 33.2, 19.2.

 

HRMS (ESI): calcd m/zfor [C24H25FO6S + Na]+ = 483.1248, found m/z 483.1244.

 

 

 

 

 

 

 

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00281

////////////