Efficient peptide coupling method of conjugated carboxylic acids with methyl ester amino acids hydrochloride. Application to the synthesis of Fa-Met, an important enzymatic substrate

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate reagent (BOP) serves as an efficient and versatile coupling reagent for the coupling of conjugated carboxylic acid with methyl ester amino acids hydrochloride allowing the synthesis of various substituted amino acid derivatives in high chemical yields of up to 90%. The usefulness of this method is illustrated in the synthesis of Fa-Met, an important enzymatic substrate.     

Phenyltrisalanine: a new,C3-symmetric,trifunctional amino acid

Two derivatives of phenyltrisalanine, a new, trifunctional amino acid, were synthesised in optically active forms. Two complementary techniques were employed, an HWE olefination reaction or a Heck coupling reaction, and the resulting dehydroamino acids were hydrogenated using a chiral Rh(I)–Et-DuPHOS catalyst. Phenyltrisalanine derivatives of excellent stereoisomeric purities were thus obtained.     

PHOTOCHEMICAL COUPLING OF 5-BROMOURACIL TO TRYPTOPHAN, TYROSINE AND HISTIDINE, PEPTIDE-LIKE DERIVATIVES IN AQUEOUS FLUID SOLUTION

Direct irradiation of 5-bromouracil (BU) in aqueous fluid solution in the presence of tryptophan (trp), tyrosine (tyr) or histidine (his) derivatives using a XeCl excimer laser at 308 nm yielded photocoupling of BU to the aromatic ring of each amino acid. Irradiation of BU at 308 nm most likely results in excitation of the n-φ* transition, intersystem crossing to the triplet manifold, and coupling via electron transfer from the aromatic amino acid. The coupling observed was regiospecific between the 5-position of uracil (U) and the 2-position of the indole and phenol rings and the 5-position of the imidazole ring of the respective amino acids. Quantum yields of photocoupling to BU ranged from 1 × 10^-3 to 7 × 10^-3 and paralleled known rates of electron transfer and ionization potentials of the aromatic rings. The photocoupling between BU and some of the aromatic amino acid peptide-like derivatives possibly mimics photocrosslinking of BU-DNA to associated proteins, a potentially useful photoreaction for studying nucleic acid-protein interactions. Formation of crosslinks of the type proposed here might be detected by the characteristic fluorescence emission of the uracil amino acid adducts.     

Synthesis of Novel and Thermally Stable Water Insoluble Coumarin‐based Azo Dyes via a Mild and Green Procedure

A series of novel azo coumarin dyes were synthesized by the diazotization of 7‐amino coumarins in the presence of catalytic amounts of tungstate sulfuric acid (TSA) followed by coupling with phenol derivatives. Tungstate sulfuric acid catalyzes this reaction at room temperature and short reaction time with high yields.     

Synthesis of a New Class of High‐Molecular‐Weight Soluble Poly(amino acid)s by Oxidative Polymerization of Polyfunctional Macromolecules

Oxidative coupling of phenol‐containing macromolecules, polyglutamine and polyasparagine derivatives, has been examined to produce a new class of poly(amino acid)s. Under the conditions applied, the Fe‐salen‐catalyzed oxidative coupling of the polymers proceeded homogeneously, yielding exclusively soluble polymers of high molecular weight, avoiding the formation of insoluble gels.     

Indolizine Studies,Part 5: Indolizine-2-carboxamides as Potential HIV-1 Protease Inhibitors[ 1 ]

1,1-Carbonyldiimidazole-promoted coupling of Baylis–Hillman-derived indolizine-2-carboxylic acids with a range of amine and amino acid derivatives has provided access to the corresponding carboxamides in moderate to excellent yield.     

Cyclic homooligomers from sugar amino acids: synthesis, conformational analysis, and significance

Sugar amino acids (SAAs) were designed as new building blocks carrying an amino group and a carboxyl group on a carbohydrate scaffold. By exploiting standard solid- and solution-phase coupling procedures, linear and cyclic homooligomers containing glucosyluronic acid methylamine (Gum) were synthesized. We achieved a high yield and a very short coupling time for the oligomerization and cyclization of sequences encompassing two, three, four, and six Gum units. The synthesis of cyclic oligomers containing only SAAs as repetitive units has not been reported before. The conformational preferences in aqueous solution of the cyclic derivatives and their applications as potential host molecules are described herein. Benzoic acid and p-nitrophenol were chosen as model guest molecules to study the formation of cyclodextrin-like inclusion complexes. The complexation behavior of the cyclic hexamer was proved from three different points of view: chemical shifts, longitudinal relaxations (T(1)), and diffusion coefficients. All of them showed different values for host and guest molecules measured independently and in the presence of each other.     

Biphenomycin B and Derivatives: Total Synthesis and Translation Inhibition

A full account on the synthesis of the antibiotic natural product biphenomycin B and several derivatives is reported, which employs a Suzuki coupling reaction of a free carboxylic acid and macrolactam formation as key transformations. Liberal exchange of the central amino acid was demonstrated. This procedure gave derivatives to study the influence of the polar side chain of the central amino acids on translation inhibition.     

Synthesis of N alpha-(1-phenyl-2-mercaptoethyl) amino acids, new building blocks for ligation and cyclization at non-cysteine sites: scope and limitations in peptide synthesis

A new and convenient method for the synthesis and incorporation of N(alpha)-(1-phenyl-2-mercaptoethyl)-derivatized amino acids applicable to chemical ligation at non-cysteine sites is presented. N(alpha)-Auxiliary derivatives of glycine and alanine were easily prepared using reductive amination approaches. Several strategies for the incorporation of these derivatives into peptide chains were investigated: coupling without protection, with acid-labile protection, with base-labile protection, and via a novel protection strategy using the thiazolidine derivative. All amino acid derivatives were successfully coupled to various peptide resins, and with the exception of those incorporating Boc-protected derivatives, all resins yielded the desired peptide fragments. However, the coupling of the two alanine derivative diastereomers generated some epimerization. Finally, N-terminal auxiliary glycine and alanine peptides were cyclized, and the corresponding native circular peptides were obtained upon successful removal of the auxiliary.     

Synthesis,Characterization and Application of Some Axially Chiral Binaphthyl Phosphoric Acids in Asymmetric Mannich Reaction

Two novel chiral Br?nsted acids 3b and 3c were prepared without involving the complexity of Suzuki coupling. Catalyst 3c bearing two additional hydroxyl groups at 3 and 3′ positions of axially chiral 1,1‐binaphthalene‐2,2′‐diol phosphoric acid was applied in a model Mannich reaction to afford β‐amino ester in high yield (92%) and enantiomeric excess (91%) at low reacting temperature of ?40°C. In addition, those β‐amino ester derivatives with high yields and excellent enatioselectivities were obtained in the presence of catalyst 3c under the above condition.     

对氨基苯甲酸拟二肽酯的简易合成及其抗糖尿病活性初步研究

以未保护的对氨基苯甲酸和氨基酸酯直接反应, 一步法合成了9个未见报道的氨基酸修饰的对氨基苯甲酸衍生物(对氨基苯甲酸拟二肽酯), 合成方法简捷, 产物收率较高(78%～91%). 产物的结构经IR, 1H NMR, 13C NMR, MS, HRMS表征和证实. 初步的生物活性筛选结果表明, 这些化合物抗糖尿病活性较弱.     

Natural and synthetic polymers as reagents. I. Diazonium salt derivatives of polycarboxylic resins (insoluble diazonium salt chromogens)

A method is described for the preparation of insoluble polymeric diazonium-salt chromogens which have a precise composition and well-defined specific reactivity and which are capable of undergoing coupling reactions to produce highly colored azo derivatives. The technique involves reaction of the acid chloride of an acrylic or methacrylic acid polymer crosslinked with divinylbenzene with an aromatic diamine, followed by diazotization of the free amino groups of the resultant aminoarylamido resin to give an insoluble diazonium salt. The aminoarylamido derivatives, the corresponding diazonium salts, and colors of the azo derivatives obtained in coupling reactions are tabulated.     

Three component coupling of alpha-iminoesters via umpolung addition of organometals: synthesis of alpha,alpha-disubstituted alpha-amino acids

The synthesis of alpha,alpha-disubstituted alpha-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting enolate intermediates subsequently react with electrophiles (aldehydes, imines, alpha,beta-unsaturated nitro, alkyl halides, acyl cyanides) to form a quaternary center. Tethering of the electrophile and nucleophile components provides cyclic alpha,alpha-disubstituted alpha-amino acid derivatives.     

Synthesis of ortho-substituted nitroaromatics via improved Negishi coupling conditions

We describe modified Negishi coupling conditions that allow improved access to ortho-nitrophenylalanine derivatives. These useful amino acid intermediates can be further elaborated into biologically active lactams and cyclic hydroxamic acid targets.     

Oxidative coupling of indoles with ethyl 2-(disubstituted amino)acetates: an approach to achieve indolylglycine derivatives

An efficient method for the synthesis of indolylglycine derivatives is described. The oxidative coupling reactions of ethyl 2-(disubstituted amino)acetates with indoles proceeded smoothly in the presence of meta-chloroperoxybenzoic acid (mCPBA) under ambient conditions to produce indolylglycine derivatives in satisfactory to excellent yields.     

Copper/DIPEA-catalyzed, aldehyde-induced tandem decarboxylation-coupling of natural α-amino acids and phosphites or secondary phosphine oxides

A copper/DIPEA-catalyzed, aldehyde-induced intermolecular decarboxylative coupling reaction of natural α-amino acids and phosphites or secondary phosphine oxides was developed. In this process, a series of potentially useful ligands for organic synthesis and biologically important unnatural amino acid derivatives (tertiary amino phosphorus compounds) were obtained.     

Amino acid derivatives,part 2: Synthesis,antiviral, and antitumor activity of simple protected amino acids functionalized at N‐terminus with naphthalene side chain

Coupling of various acylated amino acid derivatives with (naphthalen‐2‐lyloxy)acetic acid ( 3 ) in the presence of 1‐hydroxy‐benzoteriazole (HOBt) and DCC afforded the new amides 6–12 . Alternatively, the latter compounds were prepared from reaction of the corresponding hydrazide 5 , via the azide‐coupling method, with the acylated amino acid derivatives. Treatment of 6, 10–12 with N₂H₄ċH₂O afforded the hydrazides 13–16 , respectively, as key intermediates for the synthesis of peptide derivatives. Reaction of 12 , as a acceptor, with the glycosyl‐trichloroimidate 18 , as donors in the presence of TMSOTf gave the new glycoside 19 . The new compounds were evaluated for their anti‐HIV‐1, antibovine viral diarrhea virus (BVDV), and antitumor activity. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:148–222, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20082     

Gas chromatographic quantification of amino acid enantiomers in food matrices by their N(O,S)-ethoxycarbonyl heptafluorobutyl ester derivatives

Several amino acid enantiomer derivatives were prepared with different chloroformates and analysed by gas chromatography (GC) on a Chirasil-L-Val GC column, at a temperature below 200 degrees C. Among them the N(O,S)-ethoxycarbonyl heptafluorobutyl esters presented the best compromise between short retention times, high yield responses and good resolution for almost all the tested amino acids. These derivatives proved to be suited for quantification of amino acids in aqueous media, with L-p-chlorophenylalanine as internal standard. The developed procedure was applied to several food samples for determination of their free amino acid profiles.     

Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone

In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.     

Utility of tetrathiomolybdate and tetraselenotungstate: efficient synthesis of cystine, selenocystine, and their higher homologues

Efficient synthesis of cystine, selenocystine, and their higher homologues like homo and bishomo amino acid derivatives from natural amino acid derivatives using tetrathiomolybdate and tetraselenotungstate reagents under mild and neutral conditions is reported. The generality of the reaction has been studied by capping various groups to amino and carboxyl components of canonical amino acids.