David J Dodsworth

NEW TRENDS IN PEPTIDE COUPLING REAGENTS

INTRODUCTION .............................................................................................................................. 205 I . PREPARATION OF REAGENTS ............................................................................................... 205 1 . Phosphonium Salts ............................................................................................................... 205 2 . Aminium Salts ....................................................................................................................... 209 3 . Phosphinic and Phosphoric Acid Derivatives ..................................................................... 214 4 . Other Coupling Reagents ..................................................................................................... 217 5 . Polymer-Supported Reagents .............................................................................................. 218 I1 . COUPLING MECHANISMS ...................................................................................................... 219 I . Carbodiimides ...................................................................................................................... 219 2 . Phosphonium Salts ............................................................................................................... 222 3 . Aminium Salts ....................................................................................................................... 222 4 . Phosphinic and Phosphoric Acid Derivatives ..................................................................... 223 5 . Other Coupling Reagents ..................................................................................................... 224 6 . Amino Arid Halides ............................................................................................................. 226 In . PEPTIDE SYNTHESIS ............................................................................. I . Carbodiimides ...................................................................................................................... 227 2 . Phosphonium Salts ............................................................................................................... 228 3 . Aminium Salts ....................................................................................................................... 237 4 . Phosphinic and Phosphoric Acid Derivatives ..................................................................... 244 5 . Other Coupling Reagents ..................................................................................................... 251 6 . Polymer-Supported Reagents ............................................... 7 . Active Esters ......................................................................................................................... 255 ................................................... 262 9 . Amino Acid Halides ............................................................................................................. 263 10 . Comparative Studies .......................................................................................................... 264 ..................................................... 267 1 . Carbodiimides ...................................................................................................................... 267 8 . Amino Acid Anhydrides ............................................

A new polymer-supported reagent for the Fmoc-protection of amino acids

A new polymer-supported Fmoc-OSu (Fmoc-P-OSu) has been prepared from polymer-bound N-hydroxysuccinimide (P-HOSu), and used as a solid-supported reagent for the Fmoc-protection of amino groups. The residual P-HOSu generated after the protection reaction can be separated by simple filtration and reused.

Polymer-bound TBTU as a new solid-supported reagent for peptide synthesis

Abstract A new polymer-supported TBTU (P-TBTU) has been prepared from polystyrene-bound 1-hydroxybenzotriazole (P-HOBT) and used efficiently as a solid-supported reagent for peptide-coupling reactions, and is even effective with wet solvents. The P-HOBT can be recovered by simple filtration and reused for the preparation of new P-TBTU.

Direct synthesis of hydroxamates from carboxylic acids using 2-mercaptopyridone-1-oxide-based thiouronium salts

Tetrafluoroborate and hexafluorophosphate thiouronium salts derived from 2-mercaptopyridone-1-oxide and tetramethylurea (TOTT and HOTT) or N,N′-dimethylpropyleneurea (TODT and HODT) convert carboxylic acids to Weinreb amides and N-methoxy or N-benzoxyamides in high yields by reaction with N,O-dimethylhydroxylamine and O-methyl- or O-benzyl-hydroxylamine hydrochlorides, respectively, in the presence of triethylamine or DIEA.

Efficient synthesis of primary amides using 2-mercaptopyridone-1-oxide-based uronium salts

S-(1-Oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium tetrafluoroborate (TOTT) and hexafluorophosphate (HOTT) are cheap and convenient reagents for the rapid and high-yielding preparation of primary amides when reacted with carboxylic acids and ammonium chloride in the presence of diisopropylethylamine. The reaction is chemoselective and undesired ammonolysis of other sensitive functional groups is not observed.

2,7-Di-tert-butyl-Fmoc-P-OSu: a new polymer-supported reagent for the protection of the amino group.

The polymer-supported (2,7-di-tert-butyl-9-fluorenyl)methyl succinimidyl carbonate (Dtb-Fmoc-P-OSu), derived from (2,7-di-tert-butyl-9-fluorenyl)methyl chloroformate (Fmoc-Cl) and a polymeric N-hydroxysuccinimide (P-HOSu), has been used for the preparation of Dtb-Fmoc-protected amines and amino acids. After the N-protection reaction, the liberated P-HOSu can be recovered and reused. This Dtb-Fmoc-protection improves the solubility of the Fmoc-protected analogues.

Polymer-bound N-hydroxysuccinimide as a solid-supported additive for DCC-mediated peptide synthesis

The use of 1,3-dicyclohexylcarbodiimide (DCC) in the presence of N-hydroxysuccinimide (HOSu) or other HOX compounds as racemization-reducing additives is a classical method for peptide bond formation, which involves the formation of active esters, 1 derivative 1 being an example of one of them prepared from HOSu. These activated species usually subsequently undergo smooth coupling reactions with amines for the forma- tion of amide bonds, and have been widely used in both solution and solid-phase peptide synthesis. 2 Isolated HOSu-derived active esters have been employed, for instance, for the preparation of leucyldemethylblasti- cidin S as part of a study of self-resistance mechanisms of Streptomyces bacteria, 3 or for the synthesis of a novel family of hairpin cyclic peptides. 4 In addition, they have been used in the final step of the synthesis of the immunomodulator galactosylceramide AGL-537, 5

2-Mercaptopyridine-1-oxide-based peptide coupling reagents

Abstract The thiouronium salts S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate (HOTT) and tetrafluoroborate (TOTT), and S-(1-oxido-2-pyridinyl)-1,3-dimethyl-1,3-trimethylenethiouronium hexafluorophosphate (HODT) and tetrafluoroborate (TODT), prepared from 2-mercaptopyridine-1-oxide and 1,1,3,3-tetramethylurea (TMU) or 1,3-dimethylpropyleneurea (DMPU), have been employed as reagents in solution and solid-phase peptide coupling chemistry. Furthermore, 2-mercaptopyridine-1-oxide has been employed as racemization-reducing additive combined with the new thiouronium salts and other frequently used peptide coupling reagents such as DCC or TBTU.

Ammonium salts from polymer-bound N-hydroxysuccinimide as solid-supported reagents for EDC-mediated amidations

Abstract New ammonium and alkylammonium salts derived from a polymeric N -hydroxysuccinimide (P-HOSu) have been prepared and used for the amidation of carboxylic acids and amino acids mediated by 1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide hydrochloride (EDC). These polymer-supported ammonium salts afforded the corresponding amides in good yield, without detectable α-racemization and with easy recovery of the P-HOSu after the amidation reaction, being especially suitable for the amidation of Fmoc-protected amino acids.

O-Succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis

Abstract The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.