Guillaume Pelletier

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to N-Activated Pyridines

Stereoselective Addition to N-Activated Pyridines James A. Bull,‡ James J. Mousseau, Guillaume Pelletier,† and Andre ́ B. Charette*,† †Department of Chemistry, Universite ́ de Montreál, P.O. Box 6128, Station Downtown, Montreál, Queb́ec, Canada H3C 3J7 ‡Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K. Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Controlled and Chemoselective Reduction of Secondary Amides

This communication describes a metal-free methodology involving an efficient and controlled reduction of secondary amides to imines, aldehydes, and amines in good to excellent yields under ambient pressure and temperature. The process includes a chemoselective activation of a secondary amide with triflic anhydride in the presence of 2-fluoropyridine. The electrophilic activated amide can then be reduced to the corresponding iminium using triethylsilane, a cheap, rather inert, and commercially available reagent. Imines can be isolated after a basic workup or readily transformed to the aldehydes following an acidic workup. The amine moiety can be accessed via a sequential reductive amination by the addition of silane and Hantzsch ester hydride in a one-pot reaction. Moreover, this reduction tolerates various functional groups that are usually reactive under reductive conditions and is very selective to secondary amides.

Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides

The development of efficient and selective transformations is crucial in synthetic chemistry as it opens new possibilities in the total synthesis of complex molecules. Applying such reactions to the synthesis of ketones is of great importance, as this motif serves as a synthetic handle for the elaboration of numerous organic functionalities. In this context, we report a general and chemoselective method based on an activation/addition sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate was found to be pivotal in the observed exceptional functional group tolerance, allowing the facile addition of readily available Grignard and diorganozinc reagents to amides, and avoiding commonly observed over-addition or reduction side reactions. The methodology has been applied to the formal synthesis of analogues of the antineoplastic agent Bexarotene and to the rapid and efficient synthesis of unsymmetrical diketones in a one-pot procedure.

Intramolecular Pyridine Activation−Dearomatization Reaction: Highly Stereoselective Synthesis of Polysubstituted Indolizidines and Quinolizidines

An unprecedented intramolecular pyridine activation-asymmetric dearomatization reaction is described. This process produces 5-substituted indolizidines and 6-substituted quinolizidines in excellent yields and in a highly regio- and diastereoselective fashion. Formal syntheses of trans-indolizidine alkaloids are presented along with some preliminary results in the formation of C-5 quaternary centers.

Triflic Anhydride Mediated Synthesis of Imidazo[1,5-a]azines

Imidazo[1,5-a]azines are synthesized in moderate to excellent yields using a mild cyclodehydration/aromatization reaction triggered by the use of triflic anhydride (Tf2O) and 2-methoxypyridine (2-MeOPyr). Various substitution patterns and functional groups were found to be compatible under the optimized conditions. In addition, a 5-bromo-3-aryl derivative was also shown to be active in a Sonogashira cross-coupling and direct arylation reactions. A tertiary amide was compatible as a substrate leading to the synthesis of an imidazo[1,5-a]pyridinium triflate.

Enantioselective Synthesis of β-Trifluoromethyl α-Amino Acids

We report herein the three-step enantioselective synthesis of beta-trifluoromethyl alpha-amino acids including trifluorovaline (TFV) using stereoselective hydrogenation with [((R)-trichickenfootphos)Rh(cod)]BF(4) catalyst as the key step.

One-pot synthesis of 1-iodoalkynes and trisubstituted alkenes from benzylic and allylic bromides.

1-Iodoalkynes are formed in moderate to high yields from readily accessible benzylic and allylic alkyl bromides by a one-pot homologation/double elimination procedure with iodoform (CHI(3)). The developed conditions include facile purification and avoid the use of an excess of triphenylphosphine (PPh(3)), as described in classical Corey-Fuchs iodoalkynylation conditions. Replacing CHI(3) with CHI(2)Cl allows the isolation of the corresponding gem-(Z)-chloro-(E)-iodoalkene in good yield and stereoselectivity. Moreover, the use of benzhydryl bromides as nucleophiles enables the synthesis of trisubstituted alkenes under similar reaction conditions.

Cytosolic Triosephosphate Isomerase from Arabidopsis thaliana Is Reversibly Modified by Glutathione on Cysteines 127 and 218

In plant cells, an increase in cellular oxidants can have multiple effects, including the promotion of mixed disulfide bonds between glutathione and some proteins (S-glutathionylation). The present study focuses on the cytosolic isoform of the glycolytic enzyme triosephosphate isomerase (cTPI) from Arabidopsis thaliana and its reversible modification by glutathione. We used purified recombinant cTPI to demonstrate the enzyme sensitivity to inhibition by N-ethylmaleimide, hydrogen peroxide and diamide. Treatment of cTPI with diamide in the presence of reduced glutathione (GSH) led to a virtually complete inhibition of its enzymatic activity by S-glutathionylation. Recombinant cTPI was also sensitive to the oxidized form of glutathione (GSSG) in the micromolar range. Activity of cTPI was restored after reversion of S-glutathionylation by two purified recombinant A. thaliana cytosolic glutaredoxins (GRXs). GRXs-mediated deglutathionylation of cTPI was dependent on a GSH-regenerating system. Analysis of cTPI by mass spectrometry after S-glutathionylation by GSSG revealed that two Cys residues (Cys127 and Cys218) were modified by glutathione. The role of these two residues was assessed using site-directed mutagenesis. Mutation of Cys127 and Cys218 to Ser separately or together caused different levels of decrease in enzyme activity, loss of stability, as well as alteration of intrinsic fluorescence, underlining the importance of these Cys residues in protein conformation. Comparison of wild-type and mutant proteins modified with biotinyl glutathione ethyl ester (BioGEE) showed partial binding with single mutants and total loss of binding with the double mutant, demonstrating that both Cys residues were significantly S-glutathionylated. cTPI modification with BioGEE was reversed using DTT. Our study provides the first identification of the amino acid residues involved in cTPI S-glutathionylation and supports the hypothesis that this reversible modification could be part of an oxidative stress response pathway.

Highly regioselective intermolecular arylation of 1,2,3,4-tetrahydropyridines.

Using a catalytic amount of PdCl2(dppf) x CH2Cl2 in combination with Ag3PO4 and NaOAc, a range of arylated 1,2,3,4-tetrahydropyridines are synthesized in good yields and with complete selectivity at the beta-position. The reaction is compatible with a variety of electron-donating and electron-withdrawing aryl iodides as well as with heteroaryl iodides. The application of these tetrahydropyridines toward the synthesis of polysubstituted piperidines is also demonstrated.

Rapid phenolic O -glycosylation of small molecules and complex unprotected peptides in aqueous solvent

AbstractGlycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH)2, proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O-glycosylated peptides in water.Glycosylation is an attractive strategy to functionalize natural products and peptides for biomedical use, but non-enzymatic approaches usually require organic solvent and protecting groups. Now, an aqueous phenolic O-glycosylation reaction that uses glycosyl fluoride donors and a calcium salt has been developed for a wide range of substrates, including complex unprotected peptides.