Synthesis of conformationally constrained glycosylated amino acids and synthesis of alpha-substituted serine amino acid analogs.

摘要

Glycosylation is a ubiquitous posttranslational modification of proteins and is associated with a number of processes both within cells and at cell surfaces. Aberrant glycosylation of cellular proteins and glycolipids is associated with various diseases, including cancerous and inflammatory conditions. Therefore, an understanding on a molecular level of the structural features of glycoproteins that are recognized by various enzymes and receptors would be valuable in developing inhibitor-based strategies to control carbohydrate-mediated cellular processes. The objective of this research was to synthesize constrained analogs of the α-N-acetylgalactosaminyl serine glycopeptide substructure for use in galactosyltransferase enzyme recognition studies. Additional studies were conducted in an effort to develop a method for the synthesis of novel α-substituted serine amino acid analogs.; Protected versions of two constrained glycopeptides bearing the L-serine and D-serine amino acid configurations were successfully synthesized through a convergent strategy. A key step in the synthesis entailed the nucleophilic coupling of appropriately protected carbohydrate and amino acid components of the target structure through an acetylide addition. These compounds illustrate a novel concept for constraining torsional angles in glycopeptides.; Although the aforementioned strategy was successful in producing the desired compounds, the initial synthesis failed to selectively establish the stereochemistry at Cα in the amino acid component of the target. In an effort to preferentially obtain one amino acid configuration and to improve the efficiency of the synthesis, a more stereoselective second-generation strategy was subsequently designed and executed. The new approach entailed a similar convergent coupling utilizing a differentially protected chiral amino acid component. The amino acid portion was in turn obtained from the enzymatic desymmetrization of an achiral substrate.; The enantioselective construction of quaternary amino acids has attracted a great deal of attention in the synthesis community for some time. In an effort to contribute to this field, an intermediate in the second-generation glycopeptide synthesis was employed in the synthesis of a series of α-disubstituted serine amino acids. The strategy employed palladium-catalyzed Sonogashira couplings as well as acetylide additions to achieve diversity at the α-position. A variety of functional groups, including alkyl chains, aromatics, and heteroaromatics, were successfully incorporated.