Pyroglutamic Derivatives Research Articles

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines.

A procedure for the enantioselective synthesis of α-substituted glutamates and pyroglutamates via a cyclopropenimine-catalyzed Michael addition of amino ester imines is described. Enantioselectivities of up to 94% have been achieved, and a variety of functional groups were found to be compatible. The impact of the catalyst structure and imine substitution is discussed. Compared to other methods, this protocol allows for a broader and more enantioselective access to pyroglutamate derivatives.

On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives

In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.

4-Hydroxybenzyl-substituted amino acid derivatives from Gastrodia elata

Seven new 4-hydroxybenzyl-substituted amino acid derivatives (1−7), together with 11 known compounds, were isolated from an aqueous extract of the rhizomes of Gastrodia elata Blume. Their structures were determined by spectroscopic and chemical methods. Compounds 1−3 are pyroglutamate derivatives containing 4-hydroxybenzyl units at the N atom and 4−7 are the first examples of natural products with the 4-hydroxybenzyl unit linked via a thioether bond to 2-hydroxy-3-mercaptopropanoic acid (4−6) and 2-hydroxy-4-mercaptobutanoic acid (7), which would be biogenetically derived from cysteine and homocysteine, respectively. The structures of 1 and 2 were verified by synthesis, while the absolute configurations of 4, 5 and 7 were assigned using Mosher’s method based on the MPA determination rule of ΔδRS values. The known compound 4-(hydroxymethyl)-5-nitrobenzene-1,2-diol (8) exhibited activity against Fe2+-cysteine induced rat liver microsomal lipid peroxidation with IC50 values of 9.99×10−6mol/L.

Uncatalysed diaryldiazo cyclopropanations on bicyclic lactams: access to annulated prolines.

The uncatalysed cycloaddition of substituted diaryldiazo compounds onto bicyclic unsaturated lactams derived from pyroglutamic acid efficiently leads to highly functionalised azatricyclononanes. The products are readily elaborated to deprotected pyroglutamate derivatives, providing rapid access to conformationally constrained amino acids and their analogues. Preliminary assessment of antibacterial activity against one Gram positive and one Gram negative organism indicated high levels of efficacy in some cases.

The revisited synthesis of tert-butyl pyroglutamate derivatives

The very common protection reactions of scaffolds by introduction of Boc or tert-butyl groups on lactams or acids in the pyroglutamic series have been revisited in a green perspective. Particularly, reaction conditions allowing a quantitative yield in substitution of bromine in tert-butyl bromide were discovered for the first time, allowing the synthesis of tert-butyl pyroglutamate 4. This synthesis of tert-butyl ester by nucleophilic substitution, realized without using concentrated perchloric or sulfuric acid, could be of interest for acid sensitive compounds. On the other hand, we demonstrated that non toxic N-methylimidazole and tert-butanol can pleasantly replace the problematic toxic 4-dimethylaminopyridine (DMAP) and dichloromethane utilized for the N-carbamoylation of lactam 4. This environmentally improved route to compound 4 allowed the development of a multi-gram supply of protected N-aminoethyl and N-hydroxyethyl γ-glutamine 1 and 2.

Straightforward synthesis of non-natural l-chalcogen and l-diselenide N-Boc-protected-γ-amino acid derivatives

The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-γ-amino acids is described herein. These new compounds were prepared through a simple and short synthetic route, from the inexpensive and commercially-available amino acid L-glutamic acid. The products, with a highly modular character, were obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall retention of the L-glutamic acid stereochemistry. Also, an L-diselenide-N-Boc-γ-amino acid was prepared in good yield. This new synthetic route represents an efficient method for preparing new L-chalcogen- and L-diselenide-γ-amino acids with biological potential.

ChemInform Abstract: A Facile Cu(I)/BINAP‐Catalyzed Asymmetric Approach to Functionalized Pyroglutamate Derivatives Bearing a Unique Quaternary Stereogenic Center.

AbstractThe tandem Micheal addition—elimination [ ‐< conditions A)] is followed by deprotection [‐< conditions B)] and lactamization [‐< conditions C)].

First chemoenzymatic synthesis of (+)‐2‐carboxypyrrolidine‐3‐acetic acid, the nucleus of kainoid amino acids

The distinctive nucleus of kainoid amino acids, (2S,3R)-(+)-2-carboxypyrrolidine-3-acetic acid 6, was synthesized by a chemoenzymatic process, exploiting the diastereomeric cis/trans methyl pyroglutamate derivatives 10a-c/11a-c as key intermediates. These mixtures, when subjected to a kinetic resolution mediated by α-chymotrypsin, reacted diastereo-, regio-, and enantioselectively to give the trans derivatives (+)-10a-c possessing the correct (2S,3R) configuration. Subsequently, the desired product (2S,3R)-(+)-6 could be obtained after well-established transformations.

Cu(I)/BINAP-Catalyzed Synthesis of Pyro-glutamates

A facile protocol for the rapid construction of pyroglutamate derivatives is reported. A Cu(I)/BINAP-catalyzed tandem Michael addition-elimination sequence followed by deprotection-lactamization affords the products bearing a quaternary stereogenic center in good yields with high enantioselectivities. The general reaction scale for this transformation is 0.3 mmol.

A Facile Cu(I)/BINAP-Catalyzed Asymmetric Approach to Functionalized Pyroglutamate Derivatives Bearing a Unique Quaternary Stereogenic Center

A direct and facile access to enantioenriched pyroglutamate derivatives bearing a unique quaternary stereogenic center has been developed via Cu(I)/BINAP-catalyzed tandem Michael addition-elimination of α-substituted aldimino esters with Morita-Baylis-Hillman (MBH) carbonates followed by a deprotection/lactamization protocol, which performs well over a broad scope of substrates and provides biologically active pyroglutamate derivatives in good yields and excellent enantioselectivities.

ChemInform Abstract: Protection by Pyroglutamic Acid and Some of Its Newly Synthesized Derivatives Against Glutamate-Induced Seizures in Mice.

The protection by pyroglutamic acid (CAS 98-79-3) and derivatives Ia-i (injected i.p.) against glutamate- and NMDA (N-methyl-D-aspartate) (i.c.v.) induced seizures in mice has been studied in comparison with known antiepileptics and antagonists of excitatory aminoacids. The potency of pyroglutamic acid and some derivatives (Id,f,g,h) against glutamate-induced convulsions was similar to that shown by glutamic acid diethylester and by valproic acid. Interestingly, pyroglutamic acid did not affect NMDA-induced convulsions which were well antagonized by both 2-amino-5-phosphono valeric acid and by diazepam. Thus, pyroglutamic acid may represent the starting for synthesis of excitatory aminoacid antagonists acting at non NMDA receptors.

ChemInform Abstract: Asymmetric Synthesis from α-Amino Acids. Some Reactions of (S)- Pyroglutamate.

Abstract Reactions at C-3, C-4, and C-5 of pyroglutamate derivative ( 10 ) are presented.

Synthesis of condensed pyridones by using a new ring switching reaction

Abstractmagnified imageA new ring‐switching reaction of enaminoesters behaving as bisnucleophiles towards other enaminoesters behaving as biselectrophiles is described. By starting from pyroglutamic derivatives, this reaction provided easy access to methyl 5‐oxo‐1,2,3,5‐tetrahydro‐3‐indolizinecarboxylates substituted by an aminoester side chain in position 6.

Diastereoselective Synthesis of Glutamate-Appended Oxolane Rings: Synthesis of (S)-(+)-Lycoperdic Acid

The stereocontrolled synthesis of the glutamate-containing natural product (S)-(+)-lycoperdic acid is described. The key transformation in the synthetic route was an efficient diastereoselective annulation of an oxolane ring onto a pyroglutamate scaffold to construct either a gamma,gamma-disubstituted glutamate-appended tetrahydrofuran or a gamma-lactone. The reaction sequence also featured an improved method for the halogenation of pyroglutamate derivatives in high yield with enhanced stereoselection.

Convenient synthesis of deuterated glutamic acid, proline and leucine via catalytic deuteration of unsaturated pyroglutamate derivatives

AbstractNovel 3,4‐didehydropyroglutamate derivatives, the key intermediates in this synthesis, were obtained from a protected pyroglutamate by the well‐known selenenylation‐oxidative deselenenylation method and were catalytically deuterated using a slow‐addition technique. The obtained deuterated pyroglutamates were converted to [3,4‐2H2]glutamic acid, [3,4,5‐2H3]proline, and [3,4,5,5,5‐2H5]leucine via an appropriate functional group interconversions followed by the standard deprotection procedure. Copyright © 2006 John Wiley & Sons, Ltd.

Synthesis of (2S,3R)-[3',3',3'-2H3]-valine and (2S,3S)-4-fluorovaline.

A new synthesis of (2S,3R)-[3',3',3'-2H3]-valine has been completed and (2S,3S)-4-fluorovaline has been synthesised for the first time. Both compounds have been prepared by routes involving stereoselective addition to the (S)-pyroglutamate derivative and are available for studies in several areas of bio-organic chemistry.

Synthesis and Reactions of a Novel 3,4‐Didehydropyroglutamate Derivative.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of new bicyclic lactam peptidomimetics by ring-closing metathesis reactions

An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams 3a and 3b is described. The spirane cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative 18 followed by ring-closing metathesis (RCM). A more practical and stereoselective method for the allylation of the α-methoxy carbamate 21 , involving the use of InCl 3 as a Lewis acid, was developed. In the crucial coupling reaction of the diastereomeric mixture of cis- and trans-pirrolidine derivatives 5a and 5b with N-Cbz vinyl phenylalanine only the cis isomer was found to react. An RCM reaction on the dipeptides 25a and 25b followed by catalytic hydrogenation, gave the final epimeric bicyclic lactams 3a and 3b . The same synthetic sequence on the model compound 7 , lacking the spiro cyclopentane nucleus, is also reported.

Synthesis and reactions of a novel 3,4-didehydropyroglutamate derivative.

Some reactions such as catalytic hydrogenation, Diels-Alder reaction, cyclopropanation, dihydroxylation, and Michael addition of a novel 3,4-didehydropyroglutamate derivative, in which the carboxylic group is protected as an ABO ester, are examined and found to take place in a stereospecific manner giving 3- and/or 4-substituted pyroglutamate derivatives without loss of enantiomeric purity at the alpha-position.

ChemInform Abstract: Diastereoselective Formation of a Quaternary Center in a Pyroglutamate Derivative. Formal Synthesis of Monatin.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.