Louis A. Carpino

Racemization studies during solid-phase peptide synthesis using azabenzotriazole-based coupling reagents

Abstract 1-Hydroxy-7-azabenzotriazole (HOAt) and its corresponding uronium salts are shown to be more effective in avoiding racemization in a model solid-phase peptide segment coupling process than their benzotriazole analogs.

The diisopropylcarbodiimide/ 1-hydroxy-7-azabenzotriazole system: Segment coupling and stepwise peptide assembly

Abstract For a group of model peptide segments, coupling reactions carried out via solution or solid phase techniques have demonstrated the advantages of the system DIC HOAt over DIC HOBt and in addition for systems involving other selected carbodiimides and substituted HOBt derivatives bearing electron-withdrawing substituents. Very little, if any, loss of configuration occurred in DCM regardless of the additive used, although the relative order of efficiency was similar in solvents such as DMF in which more extensive epimerization resulted. In application of DIC HOAt to stepwise peptide assembly by solid phase techniques, it was found that the hindered pyridine base collidine enhanced the step involying preactivation of the carboxylic acid residue in contrast to the normal situation in which bases such as DIEA, NMM, or non-hindered pyridine bases inhibit this step. These results led to development of a stepwise procedure for peptide assembly in which collidine is added to enhance activation and subsequently DIEA is added to enhance coupling.

On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis

Abstract Phosphonium derivatives of HOAt such as PyAOP are useful for the solid-phase preparation of a range of peptides that include those incorporating hindered amino acids, difficult short sequences, and cyclic peptides. An advantage relative to uronium salts is that excess PyAOP does not undergo the detrimental side-reaction at the amino terminus which blocks further chain assembly.

Advantageous applications of azabenzotriazole (triazolopyridine)-based coupling reagents to solid-phase peptide synthesis

1-Hydroxy-7-azabenzotriazole (HOAt) and its corresponding uronium and phosphonium salts are shown to be superior to their benzotriazole analogs in solid-phase peptide synthesis, thereby making possible the automated synthesis of peptides containing hindered amino acids.

Coupling reagents and activation.

Publisher Summary This chapter discusses the coupling methods most commonly used in solid-phase peptide synthesis (SPPS). The two main classes of coupling technique involve (1) those that require in situ activation of the carboxylic acid and (2) those that depend on an activated species that has previously been prepared, isolated, purified, and characterized. The controlled formation of a peptide bond (the so called coupling reaction) between two amino acids requires activation of the carboxyl group of one for facile reaction with the amino group of the other. The process of activation is the aspect of peptide synthesis—that is most extensively developed in recent years. An essential feature of all coupling methods is that—in addition to giving the peptide bond in good yield, the configurational integrity of the carboxylic component should be maintained.

The 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group (Pbf) as arginine side chain protectant☆

Abstract The 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl residue (Pbf) is more easily deblocked by trifluoroacetic acid (TFA) than the corresponding Pmc analog and can be used efficiently in the synthesis of arginine-containing peptides.

Synthesis of cyclic peptides via efficient new coupling reagents

Abstract The efficiency of various coupling reagents in promoting the cyclization of linear peptides has been compared. Newly developed reagents based on 1-hydroxy-7-azabenzotriazole were found to be highly effective and led to remarkably diminished racemization.

Synthesis of Fmoc-amino acid fluorides via DAST, an alternative fluorinating agent

DAST [(diethylamino)sulfur trifluoride] has shown to be an excellent alternative fluorinating agent for synthesis of Fmoc-amino acid fluorides. The use of DAST is advantageous relative to other fluorinating agents, such as cyanuric fluoride, since handling and isolation of the acid fluorides are facile.

The β-(trimethylsilyl)ethoxycarbonyl amino-protecting group

The β-(trimethylsilyl)ethoxycarbonyl amino-protecting group is de-blocked in acetonitrile at 50 °C by the specific reagent tetraethylammonium fluoride with the formation of gaseous by-products.

Synthesis and 1H NMR studies of some pentacoordinate tin(IV) complexes derived from triphenyltin halides

Abstract Several anionic—cationic and neutral pentacoordinate tin(IV) complexes were prepared by the reaction of triorganotin(IV) halides, R 3 SnX (R =Me and X =Cl; R =Ph and X =F, Cl, Br) with tetraalkylammonium halides and neutral ligands (pyridine, 4-(dimethylamino)pyridine, hexamethylphosphoramide and triphenylphosphine oxide). The complexes were examined in solution by 1 H NMR spectroscopy and characterized as having trigonal bipyramidal geometry around tin where the phenyl groups occupy the equatorial sites and more electronegative ligands are at axial positions. The 1 H NMR spectra of these complexes showed two distinct sets of aromatic multiplets arising from ortho -protons at low field, and meta - and para -protons at high field. A possible rationale has been offered for this observation. The upward shift of the tetraalkylammonium proton resonances in the phenyl-substituted complexes has been postulated to arise from shielding caused by the aromatic ring.