Conformational studies on peptides having chiral five-membered ring amino acid with two azido or triazole functional groups within the sequence of Aib residues

The chiral cyclic α,α-disubstituted α-amino acid, (3R,4R)-1-amino-3,4-diazido-1-cyclopentanecarboxylic acid [(R,R)-Ac₅c^dN3], was introduced into achiral α-aminoisobutyric acid (Aib) peptides. The azido groups of (R,R)-Ac₅c^dN3 in the peptides were efficiently converted into 1,2,3-triazole functional groups. FTIR, ¹H NMR, and CD spectra revealed that the dominant conformations of all peptides in solution were 3₁₀-helical structures without controlling the helical-screw sense. X-ray crystallographic analyses of peptides containing (R,R)-Ac₅c^dN3 showed that both the right-handed (P) and left-handed (M) 3₁₀-helical structures were present in the crystal state.     

Synthesis of the 3-methyl and 4-methyl derivatives of 3-amino-3,4-dihydro-1-hydroxycarbostyril and related compounds

The 3-methyl and 4-methyl derivatives of 3-amino-3,4-dihydro-1-hydroxycarbostyril were synthesized by the reductive cyclization of α-methyl-β-(o-nitrophenyl)alanine and α-amino-β-(o-nitrophenyl)butyric acid hydrohalides, respectively, under conditions of catalytic hydrogenation in acidic solution. The free bases of the latter two o-nitroaromatic amino acids were also catalytically hydrogenated under neutral conditions to yield the respective α-methyl-β-(o-aminophenyl)alanine and α-amino-β-(o-aminophenyl)butyric acid which were converted to the corresponding lactams, 3-methyl- and 4-methyl-3-amino-3,4-dihydrocarbostyrils. α-Methyl-β-(o-nitrophenyl)alanine was obtained by acid hydrolysis of 5-methy)-5-(o-nitrobenzyl)hydantoin which was prepared by treatment of o-nitrophenylacetone with potassium cyanide and ammonium carbonate. α-Amino-β-(o-nitrophenyl)butyric acid was synthesized by condensation of α-bromo-o-nitroethylbenzene with diethyl acetamidomalonate, followed by acid hydrolysis of the condensation product. The 4-methylated compounds were obtained as synthetic mixtures of two diasteromeric racemates in nearly the same amounts as shown by nmr spectral analysis. Unlike the demethylated parent compound, 3-amino-3,4-dihydro-1-hydroxycarbostyril, neither the 3-methyl nor 4-methyl analog was found to possess any antibacterial activity.     

Semi-synthetic Heparins with 2-Deoxy-2-sulfamino-α-l-iduronic Acid Residues: Chemical Reactivity and Biological Activity1

Abstract

Ammonolysis of the epoxide rings of 2,3-anhydro-α-L-guluronic acid residues, generated in alkaline medium from 2-O-sulfated α-L-iduronic acid residues of heparin, quantitatively afforded 2-amino-2-deoxy-α-L-iduronic acid residues. N-sulfation of these residues by TMA·SO₃ complex led to a formal replacement of the original 2-O-sulfate groups of heparin with N-sulfates, without configurational changes. These modified uronic acid residues (no longer amenable to alkaline epoxidation) can be easily N-desulfated. The presence of negative or positive charges at position 2 of the newly generated 2-amino-2-deoxy-α-L-iduronic acid residues influences the in vivo antithrombotic activity and haemorrhagic effects in different ways. A free amino group mainly decreases the haemorrhagic properties of heparin, while a negatively charged N-sulfate group decreases the coagulation parameters.     

Palladium Complexes with Aminophosphonates. K2PdC14 Coordination to Aminophosphonic Acid Analogues of Aspartic and Glutamic Acids

Abstract

²¹P and ¹⁹C NMR spectroscopy is applied to study the reaction of the K₂PdCl₄ with 3-amino-3-phosphono- -propionic acid(α-PAsp), 2-amino-3-phosphonopropionic acid(β-Pasp). 4-amino-4-phosphonobutyric acid(α-PGlut) and 2-amino-4-phosphonobutyric acid(γ-PGlut) in a wide PH range.     

Synthesis of protected derivatives and short peptides of antAib, a novel C-tetrasubstituted α-amino acid of the Ac5c type possessing a fused anthracene fluorophore

The N^α-Boc and N^α-Fmoc protected derivatives of 2-amino-2,3-dihydro-1H-cyclopenta[b]anthracene-2-carboxylic acid (antAib), a novel fluorescent, achiral, α-amino acid, rigid analogue of the known 9-antAla and 2-antAla residues, and belonging to the class of C_i^α→C_i^α cyclized, C^α,α-disubstituted glycines (strong β-turn and helix inducers in peptides), were synthesized in seven steps from 1,2,4-trimethylbenzene. The UV absorption and fluorescence properties of Boc-antAib-OEt and Boc-antAib-OH are also described. Solution syntheses of the short peptides Boc-antAib-l-Ala-OMe, Fmoc-l-Ala-antAib-l-Ala-OMe, as well as Boc-Aib-antAib-l-Ala-OMe and the side product 2,5-dioxopiperazine cyclo-[antAib-l-Ala], are presented as examples of the coupling ability at both C- and N-termini of the antAib residue.     

Synthesis of some 7-α-carboxyethyl-1,3-dihydro-(2H)-1,4-benzodiazepin-2-ones

1,4-Benzodiazepin-2-ones possessing an α-carboxyethyl group in 7-position (21-25) were prepared from a key compound, 2-amino-5-α-carboxyethylbenzophenone (8) or from its O-benzyl derivative 14 , using methods developed previously. An optimized route to 8 starting from 2-nitro-5-chlorobenzophenone ( 1 ), as well as some unsuccessful attempts are described. Compound 8 was deaminated into racemic α-(3-benzoyl)-phenylpropionic acid ( 9 ), a well-known antiinflammatory agent.     

Synthesis of new racemic α-heterocyclic α,α-diaminoesters and α-aminoester carboxylic

New racemic α-aminoester and α,α-diaminoesters derivatives were synthesized by nucleophilic substitution of methyl α-azido glycinate N-benzoylated with 3-amino-1,2,4-triazole, 2-tetrahydrofuran-2-ylmethan-amine and 2-methyl quinolin-4-amine.     

Resolution of enantiomers of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid via diastereomeric salt formation with enantiopure 1-phenylethylamines

The resolution of racemic α-hydroxy-H-phosphinic acid with enantiopure 1-phenylethylamines via diastereomeric salt formation was investigated. X-Ray crystallographic analysis of the salt revealed that (R)-1-phenylethylamine to be efficient resolving agent for obtaining a single enantiomer of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid. Resolving racemic α-hydroxy-H-phosphinic acid with (S)-2-phenylethylamine also gave access to (S)-α-hydroxyalkylphosphinic acid in good yield.     

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane as a difluoromethyl building block: A general strategy to α,α-difluoromethyl aryl ketones

The synthetic utility of α,α-difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF₂SiMe₃; 1) as a difluoromethyl building block providing a general strategy to α,α-difluoromethyl aryl ketones was demonstrated. Oxidation, by using m-chloroperoxybenzoic acid, of the readily available 1-aryl-2,2-difluoro-2-phenylsulfanyl-1-trimethylsiloxyethanes obtained from fluoride-catalyzed nucleophilic addition of PhSCF₂SiMe₃ with aromatic aldehydes followed by flash vacuum pyrolytic elimination provided α,α-difluoromethyl aryl ketones in moderate overall yields.     

Alpha-glucosidase inhibitory activity of ethanol extract,fractions and purified compounds from the wood of Albizia myriophylla

Albizia myriophylla Benth. is a medicinal herb which is used as a traditional remedy for various ailments including diabetes in Thailand. In our continued investigation of the biological activity of A. myriophylla, the ethanol extract, fractions and the isolated compounds from the wood of this plant were evaluated for in vitro α-glucosidase inhibition using spectrophotometric method. The plant ethanol extract and its different fractions possessed α-glucosidase inhibitory activity in a concentration-dependent manner. Dichloromethane fraction of the wood ethanol extract exhibited the highest percent inhibition against α-glucosidase (69.30%) among all fractions. Subsequent α-glucosidase inhibition assay proved that indenoic acid (1), 8-methoxy-7, 3′,4′-trihydroxyflavone (2) and 3,4,7,3′-tetrahydroxyflavan (3) were partially rational for antidiabetic effect of this plant species. Among these compounds, 3 (IC₅₀ 98.59 μg/mL) exhibited potent inhibition of α-glucosidase, compared with a positive control acarbose (IC₅₀ 125 μg/mL). The inhibitory effect towards α-glucosidase of compounds 1–3 was reported herein for the first time.     

Absolute Configuration and Crystal Structure of a Phosphonate Analogue of Tyrosine Produced by Actinomycetes

Abstract

Levorotatory 1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid (TyrP) of unknown configuration is a part of hypotensive tri-peptides produced by Actinomycetes¹ and is the only 1-aminoalkane phosphonate found so far in living organisms. Nitration of enantiomers of PheP followed by reduction of the p-nitro group and diazotization yielded enantiomers of TyrP of specific rotations +67 and ?67° (c.0.9;1n HCl). Single crystal X-ray analysis showed S configuration for dextrorotatory TyrP. Thus, natural levorotatory TyrP has the R configuration and belongs to the L series of aminoacids.     

A Convenient,Large-Scale Preparation of a Differentially Protected α-Aminoglycine Suitable for the Synthesis of α-Aminoglycine-Containing Peptides

α-Boc-amino-Fmoc-glycine 6 was prepared in two steps from 9-fluorenyl-methylcarbamate 1, glyoxylic acid 3 and t-butyl carbamate 5. This compound is useful in Solid Phase Peptide Synthesis to prepare α-aminoglycine-containing peptides using Fmoc-strategy.     

Synthesis of [D-alanine, 4'-azido-3',5'-ditritio-L-phenylalanine, norvaline4[alpha-melanotropin as a 'photoaffinity probe' for hormone-receptor interactions (author's transl)]

Synthesis of [D -alanine¹, 4′-azido-3′, 5′-ditritio-L -phenylalanine², norvaline⁴]α-melanotropin as a ‘photoaffinity probe’ for hormone-receptor interactions. The synthesis of an α-MSH derivative containing 4′-azido-3′,5′-ditritio-L -phenylalanine is described: Ac · D -Ala-Pap(³H₂)-Ser-Nva-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val · NH₂. This hormone analogue is being used for specific photoaffinity labelling of receptor molecules. The synthesis was performed in a way to minimize the number of radioactive steps and to introduce the radio-active and the photoaffinity label exclusively into position 2. The dipeptide N(α)-acetyl-D -alanyl- (4′-amino-3′,5′-diiodo)-L -phenylalanine was tritriated and transformed into the azido compound, N(α)-acetyl-D -alanyl-(4′-azido-3′,5′-ditritio)-L -phenylalanine which was then condensed with H · Ser-Nva-Glu(OtBu)-His-Phe-Arg-Trp-Gly-Lys(BOC)-Pro-Val · NH₂ to the tridecapeptide. The α-MSH analog displayed a specific activity of 11 Ci/mmol, and a biological activity of about 4 · 10⁹ U/mmol (10% of α-MSH).     

Chiral α-Amino Acid-Based NMR Solvating Agents

Four new chiral α-(nonafluoro-tert-butoxy)carboxylic acids were synthesized from naturally occurring α-amino acids (alanine, valine, leucine and isoleucine, respectively), and tested in ¹H- and ¹⁹F-NMR experiments as chiral NMR shift reagents. The NMR studies were carried out at room temperature, using CDCl₃ and C₆D₆ as solvents, and (RS)-α-phenylethylamine and (RS)-α-(1-naphthyl)ethylamine as racemic model compounds. To demonstrate the applicability of the reagents, the racemic drugs ketamine and prasugrel were also tested.     

Purification and Characterization of Pepsin-Solubilized Collagen from Skin of Sea Cucumber Holothuria parva

Pepsin-solubilized collagen (PSC) was extracted from the skin of sea cucumber Holothuria parva and was fractionally characterized. The PSC from H. parva skin consisted of three α₁ chains (α₁)₃, in contrast to calf skin collagen type I with two α₁ and one α₂ chains (α₁)₂α₂ with approximately 130 kDa each. The maximum transition (T_m) and denaturation temperature (T_d) of PSC were determined to be 46.94 and 32.5 °C, respectively. The amino acid composition analysis revealed that glycine, proline, alanine, and hydroxyproline were the abundant amino acids available in extracted PSC. The results showed that the isolated collagen from H. parva has some similar characteristics to previously reported collagens used in food and pharmaceutical industries.     

The First Fully Planar C5‐Conformation of Homooligopeptides Prepared from a Chiral α‐Ethylated α,α‐Disubstituted Amino Acid: (S)‐Butylethylglycine (=(2S)‐2‐Amino‐2‐ethylhexanoic Acid)

An optically active α‐ethylated α,α‐disubstituted amino acid, (S)‐butylethylglycine (=(2S)‐2‐amino‐2‐ethylhexanoic acid; (S)‐Beg; (S)‐ 2 ), was prepared starting from butyl ethyl ketone ( 1 ) by the Strecker method and enzymatic kinetic resolution of the racemic amino acid. Homooligopeptides containing (S)‐Beg (up to hexapeptide) were synthesized by conventional solution methods. An ethyl ester was used for the protection at the C‐terminus, and a trifluoroacetyl group was used for the N‐terminus of the peptides. The structures of tri‐ and tetrapeptides 5 and 6 in the solid state were solved by X‐ray crystallographic analysis, and were shown to have a bent planar C₅‐conformation (tripeptide) and a fully planar C₅‐conformation (tetrapeptide) (see Figs. 1 and 2, resp.). The IR and ¹H‐NMR spectra of hexapeptide 8 revealed that the dominant conformation in CDCl₃ solution was also a fully planar C₅‐conformation. These results show for the first time that the preferred conformation of homopeptides containing a chiral α‐ethylated α,α‐disubstituted amino acid is a planar C₅‐conformation.     

Synthesis of Cyclic Depsipeptides and Peptides via Direct Amide Cyclization

The 2,2-disubstituted 2H-azirin-3-amines 7 (2,2-disubstituted 3-amino-2H-azirines) were used as amino-acid synthons in the preparation of medium-sized cyclic depsipeptides and peptides derived from salicylic acids 6 and anthranilic acid 19 , respectively (Schemes 2--4 and 5, resp.). The combination of the ‘azirine/oxazolone method’ for the synthesis of linear peptides containing α,α-disubstituted α-amino acids and the acid-catalyzed amide cyclization in DMF at 60° proved to be an excellent preparative route to ten-membered cyclic depsipeptides and peptides. In the case of the anthranilic-acid derivative, a transannular ring-closure reaction was observed ( 24 → 25 ). Larger rings proved to be extremely sensitive to hydrolysis.     

α,α-Dialkylglycines obtained by solid phase Ugi reaction performed over isocyanide functionalized resins

The multicomponent Ugi reaction is a straightforward method that can be used for the synthesis of highly hindered C-tetrasubstituted amino acids by reacting an amine, a ketone or aldehyde, a carboxylic acid and an isocyanide. In the present work, the synthesis of several α,α-dialkylglycines (α,α-diethylglycine, Deg; α,α-dipropylglycine, Dpg; 1-amino-1-cyclohexanecarboxylic acid, Ac₆c) was achieved by solid phase Ugi reaction using resins functionalized with the isocyanide group. Since no resins with these features were available commercially, the functionalization of an aminomethylated resin started by the use of glycine (Gly), β-alanine (β-Ala) and γ-aminobutyric acid (GABA) as spacers. After spacer N-formylation, followed by dehydration, isocyanide functionalised resins were obtained. The resins were then used in solid phase Ugi reaction, using phenylacetic acid as the acid component, 4-methoxybenzylamine as the amine component and different ketones, to afford the desired N-acylated α,α-dialkylglycines in good overall yields (60–80%), after acidolytic cleavage from the resin, thus proving the feasibility of this approach.     

Synthesis of Ureido-Linked Glycosylated Amino Acids from N α-Fmoc-Asp/Glu-5-oxazolidinones and Their Application to Neoglycopeptide Synthesis

A simple route for the synthesis of ureido-linked glycosylated amino acids has been described. The key step involves the reaction of isocyanates derived from N ^α-Fmoc-Asp/Glu-5-oxazolidinones 1 with glycosyl amines followed by hydrolysis. The resulting ureido-linked glycosylated amino acids have been incorporated into peptides. The overall procedure is simple, high-yielding, and involves fewer steps.     

Trading N and O: asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters

Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl₃CCO₂H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.