Synthetic strategies to α-trifluoromethyl and α-difluoromethyl substituted α-amino acids

Smits, René; Cadicamo, Cosimo D.; Burger, Klaus; Koksch, Beate

doi:10.1039/b800310f

Cited by 253 publications

(62 citation statements)

References 96 publications

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“…To date, elaboration of prochiral electrophiles bearing pre-installed CHF 2 groups has been the most widely studied strategy for generating enantioenriched CHF 2 -containing small molecules (Fig. 1B) (10, 11, 12, 13). Deoxyfluorination of aldehydes (14, 15, 16) is a conceptually straightforward approach to constructing CHF 2 groups, but α-branched chiral aldehydes are prone to epimerization and other decomposition pathways (15, 17, 18), whereas α-quaternary aldehydes are susceptible to rearrangement reactions (14, 19, 20, 21) (Fig.…”

mentioning

confidence: 99%

Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters

Banik

Medley

Jacobsen

2016

Science

287

134

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Difluoromethyl groups possess specific steric and electronic properties that invite their use as chemically inert surrogates of alcohols, thiols, and other polar functional groups important in a wide assortment of molecular recognition processes. We report here a method for the catalytic, asymmetric, migratory geminal difluorination of β-substituted styrenes to access a variety of products bearing difluoromethylated tertiary or quaternary stereocenters. The reaction uses commercially available reagents (mCPBA and HF•pyridine) and a simple chiral aryl iodide catalyst, and is carried out readily on gram scale. Substituent effects and temperature-dependent variations in enantioselectivity suggest that cation-π interactions play an important role in stereodifferentiation by the catalyst.

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mentioning

confidence: 99%

Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters

Banik

Medley

Jacobsen

2016

Science

287

134

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“…Nevertheless, the connection of the strong electron withdrawing and sterically hindered trifluoromethyl group directly on the backbone provides important modifications in terms of hydrophobicity, preferred conformations and increased hydrogen bonding donating effect. Firstly synthesized in their racemic form (Osipov et al 1986;Burger and Gaa 1990;Burger and Sewald 1990;Kukhar et al 1990), α-Tfm-AAs can now be prepared in their enantiopure form (Smits et al 2008;Acena et al 2012). However, α-TfmAAs have mainly been incorporated into peptides in their racemic form.…”

Section: Introductionmentioning

confidence: 98%

Synthesis of protected enantiopure (R) and (S)-α-trifluoromethylalanine containing dipeptide building blocks ready to use for solid phase peptide synthesis

et al. 2016

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Considering the increasing importance of fluorinated peptides, the development of efficient and reliable synthetic methods for the incorporation of unnatural fluorinated amino acids into peptides is a current matter of interest. In this study, we report the convenient Boc/benzyl and Cbz/tert-butyl protection of both enantiomers of the quaternarized amino acid α-trifluoromethylalanine [(R)- and (S)-α-Tfm-Ala]. Because of the deactivation of the nitrogen atom of this synthetic amino acid by the strong electron withdrawing trifluoromethyl group, the peptide coupling on this position is a challenge. In order to provide a robust synthetic methodology for the incorporation of enantiopure (R)- and (S)-α-trifluoromethylalanines into peptides, we report herein the preparation of dipeptides ready to use for solid phase peptide synthesis. The difficult peptide coupling on the nitrogen atom of the α-trifluoromethylalanines was performed in solution phase by means of highly electrophilic amino acid chlorides or mixed anhydrides. The synthetic effectiveness of this fluorinated dipeptide building block strategy is illustrated by the solid phase peptide synthesis (SPPS) of the Ac-Ala-Phe-(R)-α-Tfm-Ala-Ala-NH2 tetrapeptide.

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“…1,2,3-Triazoles could be easily constructed by click chemistry reaction25 and which yielded small molecules with special properties, such as moderate dipole character, hydrogen bonding capability, rigidity, and stability 26. Heterocyclic27–29 fluorine-containing compounds have been shown to exhibit promising anti-tuberculosis (anti-TB) activity,30 including 1,2,3-triazole analogs, for their promising anti-TB activity 31. Keeping this in mind and considering the pharmacological significance of dihydropyrimidine and 1,2,3-triazole pharmacophores, in the present investigation it was decided to design and synthesize a series of novel 1,2,3-triazole hybrid with dihydropyrimidinone (DHPM) scaffolds in accordance with Lipinski rule except compound 7d 32.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and characterization of (1-(4-aryl)-1<em>H</em>-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against <em>Mycobacterium tuberculosis</em>

Venugopala¹,

Rao²,

Bhandary³

et al. 2016

DDDT

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The novel (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of Cu(OAc)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. The newly synthesized compounds were characterized by a number of spectroscopic techniques, such as infrared, liquid chromatography-mass spectrometry, 1H, and 13C nuclear magnetic resonance along with single crystal X-ray diffraction. The current procedure for the synthesis of 1,2,3-triazole hybrids with dihydropyrimidinones is appropriate for the synthesis of a library of analogs 7a-l and the method accessible here is operationally simple and has excellent yields. The title compounds 7a-l were evaluated for their in vitro antitubercular activity against H37RV and multidrug-resistant strains of Mycobacterium tuberculosis by resazurin microplate assay plate method and it was found that compound 7d was promising against H37RV and multidrug-resistant strains of M. tuberculosis at 10 and 15 μg/mL, respectively.

show abstract

Synthetic strategies to α-trifluoromethyl and α-difluoromethyl substituted α-amino acids

Cited by 253 publications

References 96 publications

Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters

Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters

Synthesis of protected enantiopure (R) and (S)-α-trifluoromethylalanine containing dipeptide building blocks ready to use for solid phase peptide synthesis

Design, synthesis, and characterization of (1-(4-aryl)-1<em>H</em>-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against <em>Mycobacterium tuberculosis</em>

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