SOLID-PHASE METHODS FOR THE PREPARATION OF GLYCOPEPTIDES

一种制备模型糖肽的便捷途径

A convenient route for the preparation of model glycopeptides would be of enormous importance in developing an understanding of the chemical, biochemical, and biophysical properties of these materials. Solution-phase syntheses of some glycopeptides have been reported, but less work has been carried out on the use of solid-phase methods in this field, largely due to the chemical sensitivity of the glycosidic linkage. One possible approach to this problem is the use of the Kaiser-DeGrado procedure for solid- phase synthesis - this method involves the removal of a peptide chain from solid support under exceedingly mild conditions, using an amino acid ester as the cleaving agent. Investigation of the utility of this procedure in the synthesis of glycopeptides will involve two major approaches - the use of glycosylated amino acids as the cleaving agents, thus generating C-terminal glycopeptides, and the use of activatable aryl esters of amino acids as cleaving agents, thus providing a route to potential peptide active esters. Both of these approaches have the advantage of introducing a sensitive group in the final, mild step of the method, and a combination of these two strategies would provide a general route to glycopeptides. The study of the preparation of C-terminal glycopeptides will initially involve the preparation of a series of simple glycodipeptides, generated by the reaction of the acetate salt of a glycosylated serine derivative with various N-protected amino acids attached via oxime ester linkages to a polymer support. Structural features essential to the success of this process will be evaluated in this way. Later studies will extend to the preparation of increasingly larger glycopeptides, and practical points such as the ease of deprotection of these materials will be addressed. The reactions will be followed by IR and HPLC, and isolated product glycopeptides will be characterized by high-field NMR. A similar strategy (beginning first with simple dipeptides) will be developed for the study of the preparation of methylthiophenyl esters of peptides. Likely side-reactions which could complicate the solid-phase synthesis of these esters will be quantitatively investigated. The oxidation of the resulting esters to their electrophilic sulfone analogs will be carried out, and the use of these in fragment coupling processes will be evaluated.