Model studies on carboxypeptidase Y catalyzed peptide synthesis in an aqueous-organic two-phase system

Carboxypeptidase Y catalyzes in a biphasic system containing carbon tetrachloride and carbonate buffer the reaction ofZ-Phe-OMe and variousZ-andBoc-protected dipeptide methyl esters with Val-NH₂ and Leu-NH₂, respectively. This method has been applied to the synthesis of the corresponding N-protected tripeptide amides on a preparative scale. Using a substrate—nucleophile ratio of only 1:2 or 1:3 the peptide derivatives are obtained in yields of 56–97%.Abbreviations: IUPAC-IUB rules for peptides are followed, see Eur. J. Biochem.27, 201 (1972).Boc=tert-butyloxycarbonyl,Z=benzyloxycarbonyl,-OMe=methyl ester, HPLC=high performance liquid chromatography, TLC=thin layer chromatography,CPD-Y=carboxypeptidase Y.     

Investigation of racemisation in peptide synthesis within a micro reactor

We demonstrate that peptides derived from alpha-amino acids may be prepared in a micro reactor. The peptides were prepared in 20 min with quantitative conversion, compared to batch reactions which require prolonged reaction times. We illustrate that by using dilute reagent concentrations and short reaction times, less racemisation is observed in micro reactions than in bulk reactions.     

Tandem thiol switch synthesis of peptide thioesters via N-S acyl shift on thiazolidine

An efficient "thiol switch" approach for the synthesis of peptide thioesters via an acid-catalyzed N-S acyl shift and a thioester exchange reaction in tandem with concurrent removal of protecting groups is described. This method employs novel 2-(thiomethyl)thiazolidine (TMT)-anchored resins and is fully compatible with Fmoc chemistry.     

Tricarbonylchromium tryptophan derivatives and their use in peptide synthesis

Incorporation of a Cr(CO)₃ ligand into the indole ring of N-α-t-butoxycarbonyl-tryptophan methyl ester was achieved in 47% yield. The corresponding para-nitrophenyl ester was used in the solid phase synthesis of a peptidic hormone (LHRH) analogue with the aim of decreasing tryptophan alkylation. No improvement was observed.     

Synthesis of O-acylbenzohydroxamic acids and their use in peptide synthesis

The addition of N-protected amino acids to benzonitrile oxides yields activated esters, which on coupling with amino acid esters lead to peptides.     

The use of penicillin acylase for selective N-terminal deprotection in peptide synthesis

Penicillin acylase from E. coli (EC 3.5.1.11) accepts a broad range of N-phenylacetyl-dipeptide esters as substrates. The enzyme hydrolyses the N-terminal protecting group selectively at room temp. and pH=8.1 without affecting the peptide- or the ester-bonds. Alternatively methyl-, benzyl-, tert-butyl and allyl esters can be cleaved chemically leaving the phenylacetamido moiety intact.     

Tandem catalysis for the synthesis of 2-alkylidene cyclohexenones

(5R,6S,E)-5-Alkyl-2-(2-(methoxymethoxy)ethylidene)-6-(phenylsulfonyl)cyclohex-3-enones, have been obtained by a domino reaction using tandem catalysis with a Nazarov reagent 3, and several unsaturated aldehydes.     

Amphiphilic gels for peptide synthesis

A new class of “amphiphilic” copoly(styrene-acrylamide)s of potential interest for peptide synthesis is described. As examples of the new polymers, those carrying nitrophenol or piperazine functionality were used for model reactions in peptide synthesis, and were found to be substantially more efficient than similar reagents derived from polystyrene, polydimethylacrylamide or silica gel. Due to their amphiphilic structure, the new resins have general substrate compatibility and are permeated by all of the commonly used solvents, including toluene and ethyl acetate on the one hand, through dimethylformamide, to dimethylsulfoxide and water on the other. The improved performance of the new polymers is attributed to their alternating amphiphilic structure and favorable polymer–solvent–substrate interactions. © 1992 John Wiley & Sons, Inc.     

On the use of carboxamidomethyl esters in the protease-catalyzed peptide synthesis

Carboxamidomethyl esters (CAM esters) ofZ- andBoc-protected alanine and phenylalanine were prepared in order to investigate their usefulness as substrates for -chymotrypsin- and papain-catalyzed hydrolysis and peptide synthesis reactions. The easy removal of theCAM-C-protecting group under mild conditions and dependent on the enzyme specificity was demonstrated. Examples are given for the protease-catalyzed synthesis of various peptide derivatives usingCAM esters as C- and N-components in aqueous-organic media. Comparatively short reaction times were observed. Abbreviations: IUPAC-IUB rules for peptides are followed, see Eur. J. Biochem. (1972) 27: 201.Ac = acetyl,Bz = benzoyl,Boc =tert-butyloxycarbonyl,Z = benzyloxycarbonyl, -OBu ^t =tert-butyl ester, -CAM = carboxamidomethyl ester,-OEt = ethyl ester, -OMe = methyl ester, TLC = thin layer chromatography.     

A novel [60]fullerene amino acid for use in solid-phase peptide synthesis

[see structure]. A fullerene derivative containing a free amino group has been condensed with N-Fmoc-L-glutamic acid alpha-tert-butyl ester to give a C60-functionalized amino acid. The carboxylic end of this amino acid has been deprotected in acidic conditions, and the resulting acid has been used for solid-phase peptide synthesis. The final peptide, cleaved from the resin, was very soluble in water solutions and showed antimicrobial activity against two representative bacteria.     

Enzyme-cleavable linkers for peptide and glycopeptide synthesis

Hydroxymethylphenoxy linkers that are commonly used in solid phase peptide synthesis are surprisingly susceptible to efficient cleavage by the protease chymotrypsin with a broad range of amino acid residues being tolerated at the scissile bond; this enzyme-cleavable linker system has been applied to peptide and glycopeptide synthesis.     

Optimum catalytic reactor design for methanol synthesis with TEC MRF-Z® reactor

The concept of Multi-stage indirect cooling and Radial Flow (MRF) is ideal for designing a catalytic reactor in which an exothermic equilibrium reaction takes place. The reaction is controlled to go on along the path of the maximum reaction rate in the catalyst bed where synthesis gas flows radially in the catalyst beds from the outer side to an inner center pipe across boiler (cooling) tubes to recover the reaction heat as qualitative steam. The MRF concept has already been proven in a commercial scale methanol plant and is unique not only for saving energy but also for considerable scale-up for which the enhanced design, MRF-Z^®, provides. MRF-Z^® is now offered for single train 5,000 t/d reactors used in so-called jumbo methanol plants.     

Tandem one-pot intra- and inter-molecular McMurry coupling for the synthesis of bisindolostilbenophanes

Treatment of 3 equiv of indole-3-aldehyde with 1,3,5-trimethyl-2,4,6-tris(bromomethyl)benzene and 1,3,5-tris(bromomethyl)benzene gave the tris-alkylated products, which underwent both intra- and inter-molecular McMurry coupling in one-pot with low valent titanium to give indole-based stilbenophanes.     

A novel protecting/activating strategy for beta-hydroxy acids and its use in convergent peptide synthesis

beta-Hydroxy acids were reacted with hexafluoroacetone and carbodiimides to give carboxy-activated six-membered lactones in good yields. On reaction with amines, the corresponding amides were obtained. We demonstrate the following applications of this protecting/activating strategy: preparation of carboxamides in solution and on solid phase (both normal and reverse mode); recovery and reuse of the excess material in solid-phase synthesis; and convergent solid-phase peptide synthesis (CSPPS) with peptide segments bearing C-terminal Ser or Thr with very low levels of epimerization (<1%, HPLC).     

Tandem synthesis of 1-formyl-1,2,3-triazoles

A tandem method for preparing 4-formyl-1,2,3-triazoles via a two-step one-pot acetal cleavage/CuAAC reaction was developed. Using this method, 4-formyl-1,2,3-triazole analogs with both electron-withdrawing and electron-donating substituents were prepared in good yield and purity. Expansion of this method to a three-step tandem reaction that incorporates an additional step of azide substitution was also successful, circumventing the need for organic azide isolation. This one-pot method, noteworthy in its simplicity and mild conditions, utilizes practical, readily available reactants and relies on protic solvent to promote acid-catalyzed acetal cleavage.     

Peptides—XXXII: The use of phenyl esters in peptide synthesis

Phenyl esters of N-terminal amino-protected peptides are valuable intermediates in synthesis of polypeptides. The phenyl ester function is stable during the customary manipulations of chain extension, and it can be removed selectively by treatment with one equivalent of hydrogen peroxide at pH 10.5 in a variety of solvents such as 80% acetone, dimethylfonnamide, hexamethylphosphoramide or trifluoroethanol. The method has always been satisfactory providing that dimethylsulphide is used as a scavenger.     

Tandem indole C-H alkenylation/arylation for tetra-substituted alkene synthesis

Alkynyl indoles undergo a novel sequence of Pd-catalysed indole C-H activation/alkyne carbopalladation/arylation, with diaryliodonium salts providing the aryl components. An array of functionalised indole alkenes have been prepared in good to excellent yield, with the reaction being selective for the Z-alkene.