Peptide-heterocycle hybrid molecules: solid-phase-supported synthesis of substituted N-terminal 5-aminotetrazole peptides via electrocyclization of peptidic imidoylazides.
A method for the synthesis of polypeptides modified with a tetrazole ring at the N-terminus is described. Reaction of the N-terminal amino group of solid-supported peptides with arylisothiocyanates generates thiourea intermediates, which upon treatment with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) generate electrophilic carbodiimide functionality. Trapping by the azide anion and electrocyclization of the intermediate imidoylazide generates an aryl-substituted 5-aminotetrazole at the N-terminus of the peptide. To prevent competitive cyclization of a neighboring amide N-H into the carbodiimide, there should not be a free N-H at the [X-1] position relative to the activated carbodiimide. Protection of the N-H group at this position or incorporation of a secondary amino acid is thus required for optimal tetrazole formation. Cleavage from the resin releases the hybrid molecules incorporating a 5-aminotetrazole ring conjugated onto a peptidic fragment.
Gavrilyuk
Julia I
JI
Davenport Chemical Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada M5S 3H6.
Evindar
Ghotas
G
Chen
Jin Yu
JY
Batey
Robert A
RA
D001386:Azides / Q000737:chemistry*; D003500:Cyclization; D030562:Databases, Protein; D004583:Electrons; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006827:Hydantoins / Q000737:chemistry; D007094:Imides / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D013777:Tetrazoles / Q000737:chemistry*; D013890:Thiourea / Q000737:chemistry
D001386:Azides; D006571:Heterocyclic Compounds; D006827:Hydantoins; D007094:Imides; D010455:Peptides; D013777:Tetrazoles; C001573:5-amino-1H-tetrazole; D013890:Thiourea