Pyruvoyl, a novel amino protecting group on the solid phase peptide synthesis and the peptide condensation reaction

In one of the peptide condensation methods termed thioester method, an amino protecting group is required in the lysine side chain. In this study, to investigate the efficiency of the pyruvoyl group as an amino protecting group, we synthesized N^α-fluorenylmethoxycarbonyl (Fmoc)-N^ε-pyruvoyl-lysine and introduced it into peptides and glycopeptides by the ordinary Fmoc-based solid phase peptide synthesis. The pyruvoyl peptide could be condensed with a peptide thioester by the thioester method, and this protecting group was easily removed by o-phenylenediamine treatment without significant side reactions.     

A facile one-pot synthesis of Nα-Z/Boc-protected S-linked 1,3,4-oxadiazole tethered peptidomimetics

A new class of S-linked 1,3,4-oxadiazole-tethered N^α-protected peptidomimetics is designed and synthesized by a reaction of N^α-Z/Boc-protected 1,3,4-oxadiazole-2-thiol with α-bromo ester derived from amino acid. The protocol has also been employed for the synthesis of glycosylated amino acids and N,N′-orthogonally protected dipeptidomimetics bearing S-linked 1,3,4-oxadiazole mimetics as well. The intermediate 5-alkyl amino-1,3,4-oxadiazole-2-thiols have been isolated as stable compounds. Further, the chain extension at both N- and C-termini of N-protected S-linked 1,3,4-oxadiazole tethered dipeptidomimetics was also demonstrated.     

New chiral NiII complexes of Schiff’s bases of glycine and alanine for efficient asymmetric synthesis of α-amino acids

New modified chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2-chlorobenzyl)pyrrolidine-2-carboxamide (2-CBPB) and (S)-N-(2-benzoylphenyl)-1-(3,4-dimethylbenzyl)pyrrolidine-2-carboxamide (3,4-DMBPB) and their Ni^II complexes of Schiff’s base with glycine and alanine have been synthesized and tested in asymmetric C-alkylation and aldol condensation reactions of amino acid moieties. The tests proved that both new auxiliaries were efficient with the ee’s of the final amino acids as high as 98% even in case of α-methyl-α-amino acid synthesis.     

Facile synthesis of pseudo-C-glycosyl p-amino-dl-phenylalanine building blocks via Amadori rearrangement

We studied the synthesis of pseudo-C-glycosyl amino acid via an Amadori rearrangement in aqueous solution using unprotected d-lactose and a tyrosine analogue: the p-amino-dl-phenylalanine. Two steps were necessary. In the first step, the N-glycosylation of d-lactose was carried out in aqueous conditions. The synthesized N-glycosylamine was stabilized in a second step by the formation of Amadori compound, the N-[β-d-galactosyl-1-4-(1-deoxyfructos-1-yl)]-p-amino-dl-phenylalanine. Products were purified and characterized by mass spectrometry and by ¹H and ¹³C NMR. The influence of the temperature, the pH, the nature of acid and the concentration of the acid on the synthesis yield was examined in order to determine the optimum conditions of Amadori rearrangement. In the best conditions, 35% of p-amino-dl-phenylalanine was converted into N-[β-d-galactosyl-1-4-(1-deoxyfructos-1-yl)]-p-amino-dl-phenylalanine. For the N-glycosylation, a specific base catalysis took place in the media whereas a general acid catalysis was observed for the Amadori rearrangement using weak acids and with a temperature close to 75 °C. The Amadori compound from glucose [N-(1-deoxyfructopyranos-1-yl)-p-amino-dl-phenylalanine] was also synthesized and characterized by mass spectrometry and by ¹H and ¹³C NMR.     

A one-step synthesis of N-Fmoc-4-O-[O′,O″-di-tert-butyl-2-(2-fluoromalonyl)]-l-tyrosine from commercially available starting material

A one-step high yield synthesis from commercially available starting material is reported for the novel phosphotyrosyl mimetic, N^α-Fmoc-4-O-[O′,O″-di-tert-butyl-2-(2-fluoromalonyl)]-l-tyrosine. The conditions employed for this transformation may also be applicable for the direct electrophilic fluorination of other N^α-Fmoc-protected amino acids.     

Stereoselective synthesis of novel N-(α-l-arabinofuranos-1-yl)-l-amino acids

In lead detoxification, the α-anomer of N-glycocyl-l-amino acid is more potent than its β-anomer. Here a six-step-reaction route for stereoselectively preparing N-(α-l-arabinose-1-yl)-l-amino acids is reported. Treating l-arabinose with acetic anhydride and sodium acetate provided 1,2,3,5-tetra-O-acetyl-l-arabinofuranose in 90% yield. After removing the 1-acetyl group, the thus formed 2,3,5-tri-O-acetyl-l-arabinofuranose and N-(2-nitrophenylsulfonyl)-l-amino acid t-butylesters were treated with triphenylphosphine to perform Mitsunobu dehydration and form 2,3,5-tri-O-acetyl-l-arabinofuranosyl-l-[N-(2-nitrophenylsulfonyl)]amino acid t-butylesters 2a–f, and the ratios of their α- to β-anomer ranged from 8/1 to 9/1. Chromatographic separation provided epimerically pure 2a–f-α and 2a–f-β. In the presence of CF₃CO₂H, 2a–f-α and 2a–f-β were converted to α- and β-anomers of N-(2,3,5-tri-O-acetyl-l-arabinofuranosyl)-N-(2-nitrobenzenesulfonyl)-l-amino acids, 3a–f-α and 3a–f-β, in 87–92% yields. While in the presence of NaOCH₃, 3a–f-α and 3a–f-β were converted to α- and β-anomers of N-(l-arabinofuranosyl)-N-(2-nitrobenzenesulfonyl)-l-amino acids, 4a–f-α and 4a–f-β, in 90–96% yields. Treating 4a–f-α and 4a–f-β with N-ethyldiisopropylamine (DIPEA) and thiophenol, their 2-nitrophenylsulfonyl groups were removed, and the α- and β-anomers of N-(l-arabinose-1-yl)-l-amino acids were formed in 70–79% yields. The bioassay confirmed that the lead detoxification activity of the α-anomer was significantly higher than that of the β-anomer.     

A convenient [2+2] cycloaddition-cycloreversion reaction for the synthesis of 1,1-dicyanobuta-1,3-diene-scaffolded peptides as new imaging chromophores

We report on the chemoselective coupling between colorless peptide fragments functionalized with a mutually reactive electron-rich N^α-(4-ethynylphenyl)-N^α-(methyl)-glycyl- and an electron-deficient [4-(2,2-dicyanovinyl)]benzoyl moiety. The resulting donor-substituted 1,1-dicyanobuta-1,3-dienes represent a new class of orange-red colored (λ_max = 450-500 nm, with molar extinction coefficients (ε) above 5,000 mol⁻¹ dm³ cm⁻¹) peptide-based imaging chromophores.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Rate constants for 1,n-hydrogen transfer reactions in some amino acid derived radicals

Absolute rate constants for 1,n-hydrogen atom transfers in some substituted amino acid derived radicals have been determined in benzene through the use of competitive kinetic experiments. Radicals derived from methyl N-(2-iodobenzoyl)-N-(tert-butyloxycarbonyl)glycinate, -alaninate, -leucinate, -tert-leucinate and -phenylglycinate undergo intramolecular 1,5-hydrogen atom transfer to afford the corresponding α-amino acid ester radicals with rate constants in the range: 1.0-4.3 × 10⁷ s⁻¹ at 80 °C. Where abstractable hydrogen atoms exist in the amino acid side-chain, 1,6- and 1,7-translocations are competitive processes.     

An improved synthesis of enantiomerically pure CIP-AS,a potent and selective AMPA-kainate receptor agonist

CIP-AS (−)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to N-BOC-3,4-didehydro-(S)-proline methyl ester (−)-6. Herein, we report an alternative strategy based on the cycloaddition of the same dipolarophile to N-(4-methoxybenzyl)-α-ethoxycarbonylnitrone 12. The mixture of stereoisomeric 3-ethoxycarbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines 13 was then converted into the corresponding 3-ethoxycarbonyl-Δ²-isoxazolinyl prolines by DDQ mediated oxidation. The new strategy yielded the precursor of CIP-AS in satisfactory overall yield and represents an improvement upon the existing procedure in terms of yield and efficiency.     

Complexes of dibenzo-24-crown-8 with some sodium monoalkyl benzeneazophosphonates

Syntheses and properties of complexes of dibenzo-24-crown-8 with the sodium monoethyl ester and the sodium monobutyl ester of [α-(4-benzeneazoanilino)-N-benzyl]phosphonic acid, [α-(4-benzeneazoanilino)-N-4-hydroxybenzyl]phosphonic acid and [α-(4-benzeneazoanilino)-N-4-methoxybenzyl]phosphonic acid have been studied. The crystalline complexes formed were found to depend not only on the size of the cation and the crown ether cavity but also on the choice of anion and the reaction solvent. It was shown that the molecular structure and electronic configuration of the anion are important factors in a salt-ligand system which influence the case of solubilization and charge separation in solution. The complexes obtained were characterized on the basis of conductance measurements and UV, IR and ¹H NMR spectra.     

Facile rearrangement of N-(α-aminoacyl)cytidines to N-(4-cytidinyl)amino acid amides

Under near neutral and mildly basic conditions, primary N⁴-(α-aminoacyl)cytidines (4a-g) undergo a facile rearrangement to form N-(4-cytidinyl)amino acid amides (5a-g). Secondary aminoacyl derivatives rearrange with other competing pathways. Tertiary aminoacyl derivatives do not rearrange.     

Synthesis of chiral β2-amino acids by asymmetric hydrogenation

The synthesis of chiral β²-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepared by a Baylis–Hillman reaction, followed by acylation and amination. For the asymmetric hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing commercially available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H₂-pressure, temperature, solvent), full conversions and products with up to 99% ee were achieved.     

An expedient and short synthesis of chiral α-hydrazinoesters: synthesis and conformational analysis of 1:1 [α/α-Nα-hydrazino]mers

Different α-hydrazinoesters with high optical purity have been obtained in large scale via an S_N2 protocol. A coupling reaction with a natural amino acid leads to the corresponding dimers, which have been oligomerized in order to obtain the 1:1 [α/α-N^α-hydrazino]mer series. Conformational studies show that these mixed oligomers are self-organized in solution via a succession of γ-turn and hydrazinoturn whatever the absolute configuration of the chiral carbons.     

Chemoenzymatic synthesis of sialylated oligosaccharides for their evaluation in a polysialyltransferase assay

A series of sialylated β-d-Gal-(1→3)-α-d-GalNAc-octyl containing oligosaccharides representative of those found on mucin type complex O-glycans were synthesized by a chemoenzymatic approach for use in the kinetic characterization of recently cloned polysialyltransferases. Enzymatic incorporation of N-acetylneuraminic acid (sialic acid) into the synthetic acceptors was accomplished by 2,3-(N) and (O)-sialyltransferases to give the target compounds 6-10 in a practical yield.     

Mass spectra of partially n-acetylated derivatives of kanamycin a

As part of a program concerned with the chemistry and biochemistry of aminocyclitol antibiotics, a number of selectively N-acetylated kanamycins have been prepared from kanamycin monosulfate and characterized by a study of the electron impact induced fragmentation of two types of derivatives. In one of these, the remaining free amino groups were N-trideuteroacetylated and the N-acylated kanamycins thus obtained, were N.O-methylated. The spectra of these derivatives were useful for the location of the N-acetyl and N-trideu-teroacetyl groups, except in the 2-deoxystreptamine unit. In a second type of derivative, the partially N-acetylated kanamycins were N.O-permethylated converting the free amino groups into dimethylamino groups. In this form, it was possible to locate the site of N-aeelylation on the 2-deoxystreptamine ring. The partially N-acetylated kanamycins have been identified as 1,3,6'-tri-N-acetyl, 3,6',3'-tri-N-acetyl, 3,6'-di-N-acetyl, 1,6'-di-N-acetyl and 6'-N-acetyl kanamycin, from a study of the mass spectra of these two types of derivatives.     

Measurements of the solubilities of derivatized amino acids in supercritical carbon dioxide

The solubilities of phenylalanine and tyrosine in supercritical carbon dioxide (SCCO₂) were measured after derivatization as the N-acetyl amino acid ethyl ester, N-carbobenzoxy amino acid and N-acetyl amino acid. Using an SCCO₂ flow system, a measuring method of the saturated solubilities of the derivatized amino acids was established in which the contact height of the extraction cell, i.e. a packed column, is increased till the concentration of a derivatized amino acid at the exit of the cell reaches a plateau. The solubilities of N-acetyl phenylalanine ethyl ester (APEE) exceeded 0.001 mole fraction, which is higher than those of caffeine produced in industrial SCCO₂ processes. A possible way of separating the amino acid mixtures using polarity differences in different amino acid side chains was demonstrated using the solubility data of the N-acetyl-amino acid ethyl esters in SCCO₂, as the solubilities of APEE are higher than those of N-acetyl tyrosine ethyl ester by two orders of magnitude.     

Concise and diastereoselective approach to syn- and anti-N-tosyl-α-hydroxy β-amino acid derivatives

The methyl diazoacetate and aryl (N-tosyl)imines can be transformed into syn or anti α-hydroxy β-amino esters with high diastereoselectivities in three steps: the base promoted nucleophilic condensation of the methyl diazoacetate and aryl (N-tosyl)imines to give β-(N-tosyl)amino α-diazoesters, followed by oxidation with Oxone^® to generate α-oxo esters, which were reduced with NaBH₄ to yield the anti-N-tosyl-α-hydroxy β-amino ester, or hydrogenated with Pd/C (10%) as the catalyst to yield corresponding syn isomer, both in high diastereoselectivity.     

Enzymatic synthesis of novel quercetin sialyllactoside derivatives

Quercetin and its derivatives are important flavonols that show diverse biological activity, such as antioxidant, anticarcinogenic, anti-inflammatory, and antiviral activities. Adding different substituents to quercetin may change the biochemical activity and bioavailability of molecules, when compared to the aglycone. Here, we have synthesised two novel derivatives of quercetin, quercetin-3-O-β-d-glucopyranosyl, 4′′-O-d-galactopyranosyl 3′′′-O-α-N-acetyl neuraminic acid i.e. 3′-sialyllactosyl quercetin (3′SL-Q) and quercetin-3-O-β-d-glucopyranosyl, 4′′-O-β-d-galactopyranosyl 6′′′-O-α-N-acetyl neuraminic acid i.e. 6′-sialyllactosyl quercetin (6′SL-Q) with the use of glycosyltransferases and sialyltransferases enzymes. These derivatives of quercetin were characterised by high-resolution quadrupole-time-of-flight electrospray ionisation mass spectrometry (HR-QTOF-ESI/MS) and ¹H and ¹³C nuclear magnetic resonance (NMR) analyses.