N-Terminal peptide aldehydes as electrophiles in combinatorial solid phase synthesis of novel peptide isosteres

N-Terminal peptide aldehydes were synthesized on a solid support and utilized as electrophiles in nucleophilic reactions in order to furnish novel and diverse peptide isosteres. The aldehyde moiety of the peptide was synthesized by coupling a protected aldehyde building block to the peptide and deprotecting it quantitatively in less than 3 min. It was found that protection of the two succeeding amide nitrogens was necessary in order to avoid reaction between the aldehyde and backbone amides. The N-terminal peptide aldehydes were successfully reacted in the following way: (a) reductive amination with a large variety of amines, leading to N-alkyl-gamma-aminobutyric peptide isosteres positioned centrally in the peptide; (b) reductive amination with amino esters, leading to N-terminal 2,5-diketopiperazine peptides; (c) Horner-Wadsworth-Emmons olefination, leading to unsaturated peptide isosteres positioned centrally in the peptide; and (d) Pictet-Spengler condensations, leading to tetrahydro-beta-carbolines either positioned centrally in a peptide or fused with a diketopiperazine ring in the N-terminus of the peptide.     

Caged O-phosphorothioyl amino acids as building blocks for Fmoc-based solid phase peptide synthesis

The synthesis of 1-(2-nitrophenylethyl) caged O-phosphorothioylserine, -threonine, and -tyrosine derivatives is reported. These amino acid building blocks can be directly incorporated into peptides by Fmoc-based solid phase synthesis as their pentafluorophenyl esters or as symmetric anhydrides. Upon irradiation with UV light, the thiophosphate group, representing a hydrolysis resistant phosphate analog, is revealed.     

Phenols-useful templates for the synthesis of bi-functional orthogonally protected dendron building blocks via solid phase Mitsunobu reaction

Bi-functional dendritic building blocks for convergent dendrimer growth were successfully synthesized from phenolic templates in the solid phase via a Mitsunobu reaction. Each arm of the dendron building block carries an orthogonally protected secondary amine along the arm, and a peripheral primary amine or phenol group (building block type 1) or a tertiary amine junction with orthogonally protected peripheral primary amine or carboxyl groups (building block type 2). The synthetic routes reported in this work are general and applicable for the preparation of diverse building blocks, controlling protection, arm length, and peripheral moieties. These novel dendron units can form unusual dendritic architectures by solid-phase chemistry, which may be incorporated into specific complex structures expanding the scope of dendrimer science.     

Efficient microwave combinatorial parallel and nonparallel synthesis of N-alkylated glycine methyl esters as peptide building blocks

An easy and convenient microwave-assisted synthesis of N-alkylated glycine methyl esters is described. Parallel and nonparallel combinatorial methods are described and compared. The described reactions are reductive alkylations of several aldehydes and glycine methyl ester in the presence of NaBH3CN. Good yields and short reaction times are the main aspects of these procedures.     

Stepwise solid phase synthesis of uridylylated viral genome-linked peptides using uridylylated amino acid building blocks

The uridylylated amino acid building blocks 2-cyanoethyl-(N^α-9-fluorenylmethoxy-carbonyl-tyrosin-4-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate and 2-chlorophenyl-(N^α-fluorenyl-methoxycarbonyl-serin-3-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate have been used successfully in an on-line SPPS of the VPgpU from the polio, coxsackie and cowpea mosaic virus.     

Preparation and application of new acid labile anchor groups for the synthesis of peptide amides by FMOC solid phase synthesis

The synthesis and application of new linkage agents for the preparation of peptide amides using a modified Fmoc strategy is described.     

Synthesis of orthogonally protected optically pure ketopiperazine, diketopiperazine, ketodiazepane, and 3-aminopyrrolidone building blocks for peptidomimetic combinatorial chemistry

A simple and convenient synthesis of orthogonally protected multi-tethered, optically pure 2-ketopiperazine, diketopiperazine, 2-ketodiazepane and 3-aminopyrrolidone scaffolds for Fmoc combinatorial chemistry has been developed. It utilizes accessible chiral amino acid precursors, sequentially applying reductive alkylation, dipeptide coupling and regioselective ring formation as key steps. These scaffolds are expansion of our ‘pool of privileged building blocks’ and can introduce valuable drug-like properties in three independent directions to any medicinally relevant piperazine-, diazepane- and pyrrolidone-based motif by ‘around-the-scaffold’ drug optimization. The synthetic routes reported in this work are general and applicable for the preparation of a diverse library of scaffolds, controlling chirality, arm position and length as well as the nature of functional moieties at the arms for further diversification in three independent directions. In addition, these building blocks have a wide application scope in managing fast and efficient multi-cyclic optimization processes in the combinatorial chemistry and drug design fields.     

Convergent solid phase peptide synthesis. I. Synthesis of protected segments on a hydroxymethylphenyloxymethyl resin using the base labile FMOC α-amine protection. Model synthesis of LHRH.

Convergent solid phase peptide synthesis has been applied to yield LHRH. The segments 1–6 and 7–10 of LHRH were synthesized on a hydroxymethylphenyloxymethyl resin using the base labile Fmoc protecting group on the α-amines. The side chains were protected by HF labile groups. Purification of the segments was performed on Sephadex LH-20 columns and by HPLC on Silica Gel 60 columns. The two segments were then assembled on an α-aminobenzyl resin to yield entire sequence of LHRH. After HF treatment and standard purification on Sephadex G-15 and carboxymethylcellulose CM-52 the desired LHRH was obtained. Synthesis of the segments by the same strategy on carbazoyloxymethylphenyloxymethyl resin showed up unexpected difficulties.     

Synthesis of 5-aminothiazoles as building blocks for library synthesis

A convenient route to 4-phenyl-5-aminothiazoles is described, which offers control over substitution at the 2-position. 2-N-Acylglycinamides were dithionated and a subsequent TFAA-mediated cyclisation step was followed by removal of the 5-N-trifluoroacetyl group providing the free amines. Though applicable generally the method was found to be most effective when introducing aromatic substituents at the 2-position, whereupon moderate overall yields of the 5-amino compounds were obtained.     

Conversion of NGurethane protected arginine to ornithine in peptide solid phase synthesis

It is shown that Di-Adoc or Boc as guanidino protecting groups do not prevent the acylation and the subsequent conversion of arginine to ornithine in Fmoc solid phase peptide synthesis.     

Synthesis of lipophilic bisanthracene fluorophores: versatile building blocks toward the synthesis of new light-harvesting dendrimers

Lipophilic bisanthracene-based fluorophore and its derivatives were synthesized by the Suzuki-Miyaura cross-coupling reaction of 9-anthrylboronic acid with a substituted dibromobenzene. In addition to desirable fluorescent properties, these molecular systems were demonstrated to serve as versatile building blocks toward the synthesis of two types of new light-harvesting dendrimers due to their chemical stability.     

Binuclear ladder-type complexes as building blocks for the synthesis of novel polynuclear systems

Summarized are reactivity studies of binuclear ladder complexes in the metallation reaction that has been applied to prepare novel homo- and heteropolynuclear transition metal complexes. The electron transfer through π-ligand-metal-σ,π-ligand-metal chain has been studied by IR spectroscopy and cyclic voltammetry techniques.     

Synthesis of a novel silicon bearing linker for solid phase synthesis

A novel linker for solid phase synthesis is described, which exhibits rapid cleavage under selective, orthogonal conditions, including stability under acidic conditions. The linker incorporates a pyridyl propionate system, with a pendant β-silyl group. Rapid cleavage of the product is effected by elimination of the silyl group on treatment with fluoride. Two systems of this type have been synthesised, and the stability of the linkers has been tested under acidic and basic conditions in solution.     

Convergent solid phase peptide synthesis. II. Synthesis of the 1–6 apamin protected segment on a NBB-resin. Synthesis of apamin

The article deals with the use of the NBB-resin for synthesis of protected segments followed by solid phase segment condenstaion. Solid phse synthesis on a NBB-resin of the segment 1–6 of apamin yielded either the (1–6) apamin-OH segment after photolysis or (1–6) apamin-NH-NH₂ after hydrazinolysis. The two protected segments were purified on Sephaex LH-20 followed by Bio-Beads S-X1 chromatography and respectively coupled onto a resin on which the 7–18 sequence of apamin was assembled stepwise with the standard solid phase procedure. On a portion of the resin, stepwise synthesis was continued to complete apamin. After HF treatment, deprotection of the cysteines, formation of the disulfide bonds and purification, biologically active apamin was obtained in the three cases.     

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.     

New oxazole-based peptidomimetics: useful building blocks for the synthesis of orthogonally protected macrocyclic scaffolds

[structure: see text] The synthesis of a new family of densely functionalized oxazole-containing amino acids is described. These building blocks were employed for preparing macrocycles containing Lys and Glu residues by a combination of solid- and solution-phase synthesis. The resulting structures are presented as orthogonally protected scaffolds for supramolecular chemistry.     

1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics

Since the discovery of Cu(I)-catalysed click chemistry, the field of peptidomimetics has expanded to include 1,4-connected 1,2,3-triazoles as useful peptide bond isosteres. Here, we report the synthesis of triazole-containing analogues of the naturally occurring tyrosinase inhibitor cyclo-[Pro-Val-Pro-Tyr] and show that the analogues retain enzyme inhibitory activity, demonstrating the effectiveness of a 1,4-connected 1,2,3-triazole as a trans peptide bond isostere.