Search

Presentation of synthetic methods for novel, unnatural sulfur and selenium containing amino acids

PRESENTATION OF NEW RESULTS CONCERNIG THE SYNTHESIS OF ENANTIOPURE ORTHOGONALLY PROTECTED EITHER S-(AMINOALKYL) OR Se-(AMINOALKYL) ALPHA-AMINO ACIDS FROM BETA-IODOAMINES AND CYSTEINE OR SELENOCYSTINE RESPECTIVELY IN CONCERT WITH THE PROGRESS IN THE SYNTHESIS OF ENANTIOPURE BETA2,3-AMINO ACIDS FROM n-PROTECTED BETA3-AMINO NITRILES.

An efficient approach for the synthesis of cyclic peptides containing unnatural thioether side-chain bridges, based on the use of (2 S )-9-fluorenylmethyl-2-[( tert -butoxycarbonyl)amino]-4-iodobutanoate and its homologue 5-iodopentanoate, derived from Boc- l -Asp-OFm and Boc- l -Glu-OFm, respectively, is reported. The synthesis was performed by a tandem combination of solid-phase peptide synthesis and microwave-assisted cyclization strategy.

E' STATA PRESENTATA UNA NUOVA METODOLOGIA SINTETICA PER OTTENERE TIOMETILENPSEUDOPEPTIDI UTILIZZANDO GLI ENANTIOPURI N-FMOC BETA-IODOAMMINE E L'ACIDO TIOGLICOLICO, ANCH'ESSO PROTETTO ALL'ATOMO DI ZOLFO CON IL GRUPPO FMOC.

Presentation of a synthetic procedure for large scale homologation of alpha-amino acids

A novelprocedurefor reductionandsimultaneousprotectionof phenolgroupsof hydroxycinnamicacidsto therelatedalcoholshas beendeveloped.Duringthe formationof mixedanhydridesfromtheacidsandan alkylchloroformate,thephenolwasprotectedas carbonate,andthe mixedanhydrideswerereducedwithan aqueoussolutionof sodiumborohydride.Freephenolswereobtainedby deprotectionundermildconditionswith30%aq.NH4OHin methanol.O-protectedphenolicalcoholscan be convertedby standardmethodsintoorthogonalprotectedderivatives.Thisrapidandefficientsyntheticmethodoffersa simpleandhigh-yieldpreparationoftheseimportantfinechemicals,overcomingthetediousandcostlyproceduresassociatewiththeuseof strongreducingagentssuchas LiAlH4andDIBALH.

Hydroxycinnamic acids such as p-coumaric, ferulic, sinapic and caffeic acids were protected as carbonates and activated as mixed carbonic anhydrides in water at RT by adding a base and isobutyl chloroformate. These anhydrides were used for amine and C-protected α-amino acid acylation to give O-carbonate protected phenolic amides. Acylation of free α-amino acids was performed in acetone-water in high yields producing the O- carbonate protected N-hydroxycinnamoyl-α-amino acids. Pure derivatives were obtained in many cases directly by crystallization. Free phenolic compounds were rapidly obtained by carbonate deprotection with piperidine. The method offers a novel route for amide bond formation in water and the direct functionalization of hydroxycinnamic acid families with free α- amino acids, providing a facile preparation of precious natural bioactive derivatives.

Natural L-homocysteine and L,L-cystathionine, along with a series of unnatural analogues, have been prepared from L-aspartic and L-glutamic acid. Manipulation of the protected derivatives provided ω-iodoamino acids, which were used in thioalkylation reactions of sulfur nucleophiles, such as the ester of L-cysteine and potassium thioacetate.

Developing seeds from Triticum aestivum (wheat) cultivars were collected after flowering and analysed for puroindoline a and b gene expression by Real Time RT-PCR. Mature seeds were investigated for the presence and the amount of starch-associated puroindoline a and b proteins by flow cytometry. Puroindoline a gene and protein were found to have a predominant role in controlling wheat kernel hardness.

A peptidomics approach was developed to identify transglutaminase-susceptible Q residues within a pepsin-trypsin gliadin digest. Based on tagging with a monodansylcadaverine fluorescent probe, six alpha/beta-, gamma-gliadin, and low molecular weight glutenin peptides were identified by nanospray tandem mass spectrometry. In functioning as an acyl acceptor, tissue transglutaminase was able to form complexes with the glutamine-rich gliadin peptides, whereas by lowering pH, the peptides were deamidated by transglutaminase at the same Q residues, which were previously transamidated. The main common feature shared by the peptides was the consensus sequence Q-X-P. Our findings offer relevant information for the understanding of how dietary peptides interact with the host organism in celiac disease.

The general synthesis of a new class of non-natural diamino acids, 2-amino-3-[(2′-aminoalkyl)seleno]propanoic acids, or Se-(aminoalkyl)selenocysteines, is reported. Under the conditions devised, enantiopure N -Boc-protected β- l -iodoamines, which are readily generated from proteinogenic α-amino acids, were treated with the selenolate anion obtained from NaBH 4 splitting of the Se–Se bond in commercial l -selenocystine. The Se-alkylation products were enantiomerically pure and the reaction is high yielding (92–98%), without any detectable traces of accompanying by-products.

A new strategy is designed to synthesize polyhydroxyl compounds (and/or carbohydrates) by coupling of 5,6-dihydro-1,4-dithiins - carrying a vinylic hydrogen atom - with chiral aldehydes and, in sequence, stereoselective removal of the dithiodimethylene dithiin bridge and stereospecific hydroxylation of the resulting polyhydroxyl alkenes. In this paper the study of both coupling and desulfurization steps is reported by the use of 2-phenyl-5,6-dihydro-1,4-dithiin (5) as a model compound in the reactions with three chiral aldehydes, 3a,b and 4.

The synthesis of new substituted prolines carrying at C-4 a second alpha-amino acid residue is reported. The amino acid, L-cysteine or L-selenocysteine, is linked to the proline ring through the sulfur or the selenium atom, respectively. The products were prepared with different stereochemistry at C-4, in few and clean high-yielding steps, with suitable protections for solid phase applications. The introduction of both sulfur and selenium atoms at C-4 of the proline ring seems to enhance significantly the cis geometry at the prolyl amide bond.

The general synthesis of a new class of non-natural diamino acids, 2-amino-3-[(2′-aminoalkyl)thio]propanoic acids or S-(aminoalkyl)cysteines, is reported. Under the conditions devised, enantiopure N-Boc-protected β-iodoamines, readily generated from proteinogenic α-amino acids, are treated with L-cysteine ethyl ester hydrochloride, using Cs2CO3 as a base. The S-alkylation products, obtained in high yields (96–98 %) and without any detectable traces of accompanying byproducts, are hydrolysed to yield the free carboxyl group. An orthogonal protection is then introduced on the free amino group by treatment with Fmoc-OSu under standard conditions. The inclusion of one of these orthogonally protected diamino acids in a solid-phase growing pentapeptide is also reported. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Background Celiac disease is a widely prevalent enteropathy caused by intolerance to gliadin, one of the gluten proteins. We developed two methods for the analysis of gliadin levels. Both methods use flow cytometry and rat antibodies against a 16-residue peptide of gliadin. The peptide is common to the α-, β-, γ-, and ω-gliadins. Methods In the one-site assay, the antigen (gliadin standard or food extract) was adsorbed on 3-μm latex particles. Sensitized particles were then incubated, in this order, with rat anti-gliadin peptide antibodies and anti-rat immunoglobulin G antibodies labeled with fluorescein isothiocyanate. In the two-site assay, the antigen was trapped on the latex particles by rat anti-gliadin antibodies and then measured by the same antibodies labeled with fluorescein. Results Detection limits were 1 ng/ml for the one-site assay and 10 pg/ml for the two-site assay. The two-site assay displayed gliadin at concentrations above the limit proposed by the Codex Alimentarius in 2 of 40 gluten-free products. Conclusion There is a growing concern that gliadin, even when present in gluten-free foods within the limit fixed by the Codex Alimentarius, over the long term may become toxic to patients with celiac disease. The techniques described in this study provide an opportunity to further decrease the acceptable limit of gliadin in gluten-free foods. © 2005 Wiley-Liss, Inc.

Aldehydes and methyl ketones readily afford 5,6-dihydro-1,4-dithiins that can be converted by n-butyllithium into their corresponding sulfur stabilized carbanions. Coupling of the latter with alkyl halides leads to species having a cis-configurated, disubstituted double bond tied up by the sulfur-containing ring which is known to be susceptible of selective removal.

N-Acetyl-1,3-thiazolidine derivatives of cyclohexanones, when treated with a threefold excess N-bromosuccinimide in anhydrous chloroform at room temperature, smoothly afford N-acetyl-2,3-dihydro-1,4-benzothiazines. This represents the first general route to such heterocyclic system in one step from aliphatic precursors. The synthesis of optically active N-acetyl-2,3-dihydro-1,4-benzothiazines is also reported