Showing papers by "Fernando Albericio published in 1996"

3-(1-Piperidinyl)alanine formation during the preparation ofC-terminal cysteine peptides with the Fmoc/t-Bu strategy

Abstract: Several side reactions have been detected for cysteine-containing peptides. During the synthesis ofC-terminal cysteine peptides, a base-catalyzed elimination of the sulfhydryl-protected side-chain to afford the dehydroalanine derivative followed by a nucleophilic addition to the alkene was observed. MALDI-TOF analysis was a useful analytical technique to determine this phenomenon.

Preparation and Applications of Xanthenylamide (XAL) Handles for Solid-Phase Synthesis of C-Terminal Peptide Amides under Particularly Mild Conditions(1-3).

Abstract: [[9-[(9-Fluorenylmethyloxycarbonyl)amino]xanthen-2(or 3)-yl]oxy]alkanoic acid (XAL) handles have been prepared by efficient four-step routes from 2- or 3-hydroxyxanthone and coupled onto a range of amino-functionalized supports. The resultant XAL supports are the starting points for solid-phase peptide synthesis by Fmoc chemistry. Upon completion of chain assembly, C-terminal peptide amides are released in excellent yields and purities by use of low concentrations [1-5% (v/v)] of trifluoroacetic acid (TFA) in dichloromethane, often without a need for added carbocation scavengers. These cleavage conditions allow retention of all or a significant portion of tert-butyl type and related side-chain protecting groups, which subsequently may be removed fully in a solution process carried out at higher acid concentration. XAL supports are particularly useful for the synthesis of acid-sensitive peptides, including tryptophan-containing sequences that are known to be susceptible to yield- and/or purity-reducing alkylation side reactions. The effectiveness of this chemistry was shown with the syntheses of prothrombin (1-9), acyl carrier protein (65-74), Tabanus atratus adipokinetic hormone, fragments of the protein RHK 1, CCK-8 sulfate, and oxytocin. Furthermore, the application of XAL supports for the preparation of fully protected peptide amides has been demonstrated.

Optimized preparation of deca(L-Alanyl)-L-valinamide by 9-fluorenylmethyloxycarbonyl (fmoc) solid-phase synthesis on polyethylene glycol-polystyrene (PEG-PS) graft supports, with 1,8-diazobicyclo[5.4.0]-undec-7-ene (DBU) deprotection

Abstract: Deca(L-alanyl)-L-valinamide is known to be a challenging model target for solidphase peptide synthesis, due to its hydrophobicity and its tendency to form secondary structures which inhibit acylation and deprotection. Here we report systematic studies on the synthesis of this peptide on an automated continuous-flow instrument, using the 9-fluorenylmethyloxycarbonyl (Fmoc) group for N alpha-amino protection and a polyethylene-glycol polystyrene (PEGPS) graft support. The optimal deprotection reagent proved to be DBU-piperidine-DMF (1:1:48, vol/vol/vol). The synthetic peptides were analyzed and characterized by high-performance liquid chromatography and several mass spectrometric techniques.

A comparative study of supports for the synthesis of oligonucleotides without using ammonia

Abstract: A comparative study of the cleavage efficiency of succinyl, phthaloyl, oxalyl, 2-(2-nitrophenyl)ethyl, 9-fluorenylmethyl, and 2-nitrobenzyl supports in 0.5M DBU solutions is described. A decrease in cleavage efficiency is observed when small oligonucleotides containing thymidine are linked to the supports. In these conditions oxalyl supports gave the best yields followed by 2-(2-nitrophenyl)ethyl and 9-fluorenylmethyl supports.

On the use of novel coupling reagents for solid-phase peptide synthesis

Abstract: Publisher Summary This chapter discusses the use of novel coupling reagents for solid-phase peptide synthesis. Common coupling reagents used for the construction of peptide bonds include carbodiimides, N , N -dicyclohexylcarbodiimide (DCC) and N , N -diisopropylcarbodiimide (DIPCDI) for butyloxycarbonyl (Boc) and 9-fluorenylmethyloxycarbonyl (Fmoc) strategies, respectively, active esters such as pentafluorophenyl derivatives (OPfp) and uronium and phosphonium salts based on N -hydroxybenzotriazole (HOBt). Fmoc amino acid fluorides and urethane-protected N-carboxyanhydrides (UNCA's) are also efficient reagents for rapid peptide coupling under both solution and solid-phase conditions. l-hydroxy-7-azabenzotriazole (HOAt), HATU, PyAOP, HAPyU and tetramethyl fluoroformamidinium hexafluorophosphate (TFFH) are efficient coupling reagents for solution- and solid-phase peptide synthesis. These derivatives enhance reactivity, reduce racemization and are suited for peptides containing either natural or hindered amino acids. These reagents are compatible with both manual and automated batch and continuous-flow techniques.

Synthesis of derivatives of (2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoic acid, a constituent of the didemnins

Abstract: The syntheses of the two protected derivatives 7 and 16 of (2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoic acid, a constituent of the didemnin family of antineoplastic macrocyclic depsipeptides are described. The preparation of 7 was carried out by modification of a previously reported synthetic route whereas the use of derivative 16 represents a novel approach to the management of this sub-unit. Removal of the carboxy protecting groups from 7 or 16, followed by amide bond formation with derivatives of (S)-leucine, and oxidation in the cases of compounds deriving from 16, generates the diastereoisomeric intermediates 11, 22 and 23. In each of these either of the protecting groups can be removed in the presence of the other, allowing them to be elaborated further at either terminus. Previous work indicates that diastereoisomeric mixtures of such intermediates can, in principle, be used to obtain optically pure didemnins.

Support material for solid phase organic synthesis

Abstract: A support material for solid phase synthesis is provided having an amine-containing organic group attached to it through a linker The support material is of the following general formula (Formula I): ##STR1##

Lips symposia in print and other issues

Abstract: Peptide chemistry has evolved to allow for the incorporation of unique amino acids, distinct secondary structural elements, and sophisticated peptidomimetics. A variety of biological problems may be approached in a systematic and logical fashion by designing peptides that more closely resemble native proteins. Posttranslational modifications, such as hydroxylation, phosphorylation, glycosylation, and sulfation, are readily incorporated into synthetic peptides via appropriate amino acid derivatives or by modification of peptide-resins. Peptide chemists have also become more proficient at designing simple secondary structures, such as (x-helices, [3-sheets, and [3-turns, and even super-secondary structures such as collagen-like triple helices. The efficacy of peptides can be greatly enhanced by cyclization and/or replacement of peptide bonds and amino acid side chains by nonhydrolyzable mimics. The combination of these approaches represents a powerful tool for dissecting the mechanisms of processes such as cellular recognition and enzyme binding and for developing efficient therapeutics.