AITF (4-acetamidophenyl triflimide) mediated synthesis of amides, peptides and esters.

A simple, broadly applicable protocol for amidation and esterification reactions is described. Thereby, 4-acetamidophenyl triflimide (AITF), a crystalline stable reagent, is employed for the activation of carboxylic acids. The use of AITF as a coupling agent is demonstrated in the synthesis of peptides, amides and esters under mild conditions in good to excellent yields. Notably, peptide segment condensations were also accomplished. A diverse array of synthetic protocols showcasing a broad substrate scope and good functional group compatibility were accomplished. Herein, we systematically summarized the use of AITF in peptide synthesis strategies.

Synthesis of Nß-Protected Amino Sulfenyl Methyl Formamides and Sulfonyl Methyl Formamides: A Simple Protocol.

Chiral amino acid-derived formamides represent one of the most versatile components in multicomponent reactions. Herein, we describe a facile synthesis of Nß-protected amino sulfenyl methyl formamides and sulfonyl methyl formamides via the Mannich reaction of Nα-protected amino alkyl thiols followed by oxidation using 3-chloroperbenzoic acid (m-CPBA). This protocol is applicable to a wide range of Fmoc- and Cbz-protected amino acids. Notably, the reaction provides high yield and retains the stereochemistry of the chiral center of the starting component.

Staudinger/aza-Wittig reaction to access Nß-protected amino alkyl isothiocyanates.

A unified approach to access Nß-protected amino alkyl isothiocyanates using Nß-protected amino alkyl azides through a general strategy of Staudinger/aza-Wittig reaction is described. The type of protocol used to access isothiocyanates depends on the availability of precursors and also, especially in the amino acid chemistry, on the behavior of other labile groups towards the reagents used in the protocols; fortunately, we were not concerned about both these factors as precursor-azides were prepared easily by standard protocols, and the present protocol can pave the way for accessing title compounds without affecting Boc, Cbz and Fmoc protecting groups, and benzyl and tertiary butyl groups in the side chains. The present strategy eliminates the need for the use of amines to obtain title compounds and thus, this method is step-economical; additional advantages include retention of chirality, convenient handling and easy purification. A few hitherto unreported compounds were also prepared, and all final compounds were completely characterized by IR, mass, optical rotation, and 1H and 13C NMR studies.

Thioacids - synthons for amide bond formation and ligation reactions: assembly of peptides and peptidomimetics.

The synthesis of α-amino thioacids and peptide thioacids and their applications in chemoselective amide bond formation, ligation of peptides/proteins/glycopeptides and synthesis of peptidomimetics are reviewed. A variety of successful methods including both C-terminal and N-terminal activations for the coupling of α-amino thioacids and peptide thioacids have ascertained the thioacid-based protocol as a benign alternative to some of the traditional methods of amide/peptide bond formation which employs carboxyl activation. In addition to the couplings involving unprotected peptide fragments and solid phase synthesis, their use in the synthesis of different classes of peptidomimetics such as thioxopeptides, imide conjugates and acylsulfonamide-peptide conjugates only illustrates the versatility of this functionality in generating diverse classes of molecules, some of which are relevant to drug discovery and chemical biology. A note on more reactive seleno counterparts of thioacids, which can be useful in selective cases, is provided.

Synthesis of thioureido peptidomimetics employing alkyl azides and dithiocarbamates.

An unprecedented approach for the assembly of thioureido peptidomimetics is developed employing alkyl azides and dithiocarbamates. Dithiocarbamates react with alkyl azides with the liberation of N2 and elemental sulfur thereby leading to thiourea in a traceless manner. Thioureido peptidomimetics are thus furnished in good yields with no epimerization. This process is mild, free from the use of a base, scalable and step economic. The practicability of this methodology has been highlighted by the synthesis of N,N'-orthogonally protected thioureido peptidomimetics.

Computational studies on ground and excited state charge transfer properties of peptidomimetics.

Chemical modifications at various peptide positions result in peptidomimetics with unique physical and chemical properties that can be used for a range of applications. Among many peptidomimetics, ureidopeptides are interesting due to their ability to act as donor-bridge-acceptor systems through which charge transfer occurs in one direction and can be triggered by an electrochemical pulse without perturbing the nuclear position. In this regard, some UP mimetics with different chromophoric units are studied in this work to understand their role using DFT based methods. Computational results and natural charge analysis provide evidence for the extensive contribution of the substituents to the excitation and hole migration dynamics. Further, the results show that the UP backbone preserves its uni-directional charge transfer phenomenon from the ureido to carboxylate terminal irrespective of the terminal groups and position. However, the substituent affects the excitation energies and the time scales of the hole migration. Among the substituents studied here, fluorine migrates to the hole within a shorter time scale while phenyl groups take longer.

N-Chlorosuccinimide-Mediated Oxidative Chlorination of Thiols to Nα -Protected Amino Alkyl Sulfonyl Azides and Their Utility in the Synthesis of Sulfonyl Triazole Acids

An efficient oxidative chlorination of thiols to Nα-protected amino alkyl sulfonyl azides is delineated. The reaction involves in situ generation of sulfonyl chloride employing Nchlorosuccinimide and tetrabutylammonium chloride-water in acetonitrile, followed by the reaction with sodium azide. The protocol is simple, straight forward, mild and high yielding. Amino acids with simple as well as bifunctional side chains were used to obtain Nα-protected amino alkyl sulfonyl azides. Further, sulfonyl azides were utilized to synthesize unnatural amino acids via Cu(OAc)2.H2O/2-amino phenol catalyzed Click reaction with propiolic acid.

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics.

Peptides with ureido group enclosing backbones are considered peptidomimetics and are known for their higher stabilities, biocompatibilities, antibiotic, inhibitor, and charge-transduction activities. These peptidomimetics have some unique applications, which are quite different from those of natural peptides. Hence, it is imperative to appreciate their properties at a microscopic level. In this regard, this work outlines, in detail, the charge transfer (CT) properties, hole-migration dynamics, and electronic structures of various experimentally comprehended ureidopeptidomimetic models using density functional theory (DFT). Time-dependent DFT and complete active space self-consistent field computations on basic models provide the necessary evidence for the viability of CT from the end enfolding the ureido group to the other end with a carboxylate entity. This donor-to-acceptor CT has been reflected in excitation studies, in which the higher intensity band corresponds to CT from the π orbital of the ureido group to the π* orbital of the carboxylate entity. Further, hole-migration studies have shown that charge can evolve from the ureido end, whereas the hole generated at the carboxylate end does not migrate. However, hole migration has been reported to occur from both ends (amino and carboxylate ends) in glycine oligopeptides, and our studies show that the ability to transfer and migrate charge can be tuned by modifying the donor and acceptor functional groups in both the neutral and cationic charge states. We have analyzed the possibility of hole migration following ionization using DFT-based wave-packet propagation and found its occurrence on a ∼2-5 fs time scale, which reflects the charge-transduction ability of peptidomimetics.

A facile one pot route for the synthesis of imide tethered peptidomimetics.

A simple and efficient method for the synthesis of N,N'-orthogonally protected imide tethered peptidomimetics is presented. The imide peptidomimetics were synthesized by coupling the in situ generated selenocarboxylate of N(α)-protected amino acids with N(α)-protected amino acid azides in good yields. The protocol was also successfully applied for the synthesis of hybrid tripeptidomimetics bearing both amide and imide functionalities. In addition, coumarinic imide conjugates of amino acids have been accomplished by employing this protocol. The present method provides a convenient and easy access to imide tethered peptidomimetics and is compatible with common protecting groups employed in peptide chemistry.

Observation of a reversible isomorphous phase transition and an interplay of "σ-holes" and "π-holes" in Fmoc-Leu-ψ[CH2-NCS].

Fmoc-Leu-ψ[CH2NCS] undergoes a reversible isomorphous phase transition upon cooling. The crystal structure at 100 K displays a short N=C=S···N=C=S intermolecular interaction, which has been characterized based on experimental charge density analysis, as a stabilizing interaction with both σ-holes and π-holes acting cooperatively.

Synthesis and stereochemistry-activity relationship of chiral thiourea derivatives as potential anticancer agents.

Synthesis of new chiral thiourea derivatives (27 examples) as anticancer agents has been described. Three compound 7d (NSC code 761448/1), 7e1 (NSC code 767161/1), and 7e3 (NSC code 767160/1) were found to exhibit higher anticancer activity than 5-fluorouracil against Colon cancer, Melanoma, Ovarian cancer, and Breast cancer subpanels. The effect of stereochemistry of amino acid residues on the tumor growth inhibitory activity has also been studied.

Epimerization free synthesis of O-acyl isodipeptides employing COMU.

O-Acyl isodipeptides are prepared by coupling Boc-Ser/Thr-OBzl with Fmoc-Xaa-OH employing COMU, well known third generation peptide coupling agent. The reaction proceeds with high yield and the chemical homogeneity of the synthesized molecules were established via chiral HPLC analyses. The O-acyl isodipeptide units play crucial role in the success of ' click peptide' protocol employed for assembling ' difficult sequence' peptides.

Synthesis of selenoxo peptides and oligoselenoxo peptides employing LiAlHSeH.

Synthesis of selenoxo peptides by the treatment of N(α)-protected peptide esters with a combination of PCl(5) and LiAlHSeH is delineated. The method is simple, high-yielding, and free from racemization. Thus obtained selenoxo peptides are used as units for N-terminal chain extension through N(α)-deprotection/coupling to yield peptide-selenoxo peptide hybrids. Multiple selenation is demonstrated by conversion of two peptide bonds of tripeptides into selenoxo peptide bonds. Amino acid derived arylamides are also converted into aryl selenoamides. C(6)H(5)-CSeNH-Val-OMe 8f is obtained as single crystal, and its structure was determined through X-ray diffraction study.

Iron(III) catalysed synthesis of unsymmetrical di and trisubstituted ureas--a variation of classical Ritter reaction.

An application of the classical Ritter reaction for the synthesis of unsymmetrical di and trisubstituted ureas catalyzed by FeCl(3) is described. The protocol is of significant interest in view of the easy availability of precursors, mild reaction conditions employed and interestingly its applicability for the alkylation of alcohols capable of forming stable carbocationic intermediates even to the sterically hindered moieties.

CuI-promoted one-pot synthesis of N-Boc protected ß-ketotriazole amino acids: application in the synthesis of new class of dipeptidomimetics.

One-pot click chemistry of N(α)-Boc-bromomethylketones, NaN3 and propiolic acid affords N-Boc protected 1,4-disubstituted 1,2,3-ß-ketotriazole acids in good to excellent yield. The use of CuI as catalyst and DMSO as solvent leads the click reaction to efficient, practical and column-free preparation of the title compounds. The utility of the resulting unnatural amino acids as building blocks to prepare triazole possessing peptidomimetics is also delineated.

Carbonyldiimidazole (CDI) mediated synthesis of Nα-protected amino acid azides: application to the one-pot preparation of ureidopeptides.

Synthesis of Nα-protected amino acyl azides starting from corresponding acids via the carbonyldiimidazole (CDI) activation is described. The protocol is extended for a one-pot preparation of ureido peptides that circumvents the isolation of acyl azide and isocyanate intermediates. The reaction was accomplished without using any additives and base. The protocol is simple, clean, high yielding and free from racemization.

Poly(vinyl)chloride supported palladium nanoparticles: catalyst for rapid hydrogenation reactions.

Palladium nanoparticles supported over poly(vinyl)chloride matrix (PVC-Pd(0)) are prepared through an efficient and inexpensive protocol. The catalyst has been characterized by XRD, SEM and TEM and its utility for the reduction of a range of functional groups as well as for the removal of some common protecting groups employed in peptide chemistry is demonstrated.

Synthesis of oligopeptides through O-acyl isopeptide method.

The O-acyl isopeptide method has recently gained attention as an efficient protocol for the synthesis of 'difficult sequence' peptides. Herein, synthesis of three oligopeptides of different length, a pentapeptide Gly-Leu-Leu-Ser-Val, a heptapeptide fragment 285-291 of transmembrane (M7-24-T40) Ala-Val-Leu-Ser-Leu-Pro-Leu and a decapeptide, Gly-Leu-Leu-Ser-Val-Leu-Gly-Ser-Val-Ala were demonstrated in solution phase by employing O-acyl isopeptide method. The peptides were established through an efficient pH triggered intramolecular O→N acyl migration under physiological conditions. The reactions were clean and complete in appreciable length of time.

Isoselenocyanates derived from amino acid esters: an expedient synthesis and application to the assembly of selenoureidopeptidomimetics, unsymmetrical selenoureas and selenohydantoins.

An important class of organoselenium compounds-α-isoselenocyanato esters 4 has been prepared by a reaction of α-isocyano esters with elemental selenium powder. The reaction issimple, rapid and all the isoselenocyanates have been isolated as stable ones after chromatographic purification. These hitherto unreported classes of molecules would be useful building blocks for the preparation of variety of selenium containing peptidomimetics. In this study, the utility of the title molecules in the preparation of selenoureidopeptidomimetics 6, unsymmetrical selenoureas 8 and selenohydantoins 10 is demonstrated.

New and simple synthesis of acid azides, ureas and carbamates from carboxylic acids: application of peptide coupling agents EDC and HBTU.

Conversion of carboxylic acids into acid azides using peptide coupling agents, EDC and HBTU is described. The procedure is efficient, practical and applicable to a diverse range of carboxylic acids including N-protected amino acids. Using the same reagents, one-pot synthesis of ureas, dipeptidyl urea esters and carbamates from acids has also been achieved.