Ring-opening of Aziridine-2-carboxamides by Carbohydrate C1-O Nucleophiles: Stereoselective Preparation of O-linked Glycopeptides
ProQuest, 2009 - 205 pages
A new method for the synthesis of O-linked glycopeptides is described. The method uses the carbohydrate C1-O nucleophilic ring-opening of aziridine-2-carboxamides to access the target O-linked glycopeptides. The synthesis of the alpha-GalNAc-Ser class of glycopeptides is emphasized and either the alpha- or beta-glycoside can be accessed by judicious selection of solvent and metal counter-ion, even in the presence of the native carbohydrate C2-NHAc group. Other classes of 0-glycosyl serine constructs, such as the beta-GlcNAc-Ser and alpha-Man-Ser linkages, are also prepared by this approach. In the course of these studies, the ortho-allylbenzyl (ABn) moiety was developed as a new C-terminus secondary amide protective group for carboxylic acids, which allows for oxidative C-terminus extension of amino acids following the carbohydrate-aziridine coupling reaction. A new protocol for deprotection of p-nitrobenzenesulfonamides with in situ peptide coupling is also reported. This reaction allows for direct N-terminus extension of p-nitrobenzenesulfonyl protected amino acids, or glycosyl amino acids, in one synthetic step.
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RINGOPENING OF AZIRIDINE2CARBOXAMIDES
with Oxygen Nucleophiles
REALIZATION OF THE SYNTHETIC METHOD
13C NMR a-GalNAc a-selective AA'BB acetone in dichloromethane alkylation amino acid anomers aziridine Aziridine C-Terminal Peptides benzyl BnO^OBn byproduct C-terminal C2-acetamido carbohydrate carboxylic acid CDCI3 chloride chloroform coupling reactions crude product deprotection dichloromethane diethyl ether diluted with dichloromethane dipeptide dried magnesium sulfate equiv ester ethyl acetate filtered flash column chromatography free aziridine FTIR neat film gel flash column glycoconjugate glycopeptides glycoside glycosyl glycosyl donors H NMR hCH2 hemiacetal hemiacetal 115 hexanes:ethyl acetate HRMS layer was dried m/z calcd M+Na magnesium sulfate mmol NMR 126 MHz NMR 500 MHz NMR analysis nosyl nucleophiles O-linked glycopeptides organic layer peptide peptide coupling reactions pNsHN potassium hydride prepared procedure product was purified provide the desired provided the crude purified by silica reaction was stirred reagent ring-opening reactions Scheme secondary amide serine silica gel flash stereoselectivity substrates Synthesis triethylamine white solid yield