Semester

Spring

Date of Graduation

2010

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Kung K. Wang.

Abstract

The carbohydrate portions of natural products play a crucial role in their pharmacological properties. These properties can vary from improved water solubility, improved membrane transport properties, improved tissue targeting, as well as improved target binding. Herein we describe our efforts to use de novo synthesis to help elucidate the various roles carbohydrates play in biologically active glycosylated natural products.;The O'Doherty group has developed a method that uses asymmetric synthesis for the de novo synthesis of carbohydrates. In contrast to traditional carbohydrate methods, this de novo approach builds the desired functionality and stereochemistry within each sugar. This methodology relies on a highly diastereoselective palladium(0)-catalyzed glycosylation reaction to control the stereochemistry at the anomeric center and post-glycosylation transformation to introduce the corresponding functionality in the sugar moiety.;This de novo approach was first used in a highly enantio- and diastereoselective synthesis of Vineomycin C and PI-080. The trisaccharide was made up of three rare sugars, an alpha-L-aculose, an alpha-L-rhodinose and a beta-D-olivose. The key transformations include: the palladium-catalyzed glycosylation, Myers' reductive rearrangement, diastereoselective dihydroxylation, and regioselective Mitsunobu inversion. Material from this synthetic effort was used in several biological studies, such as 60-cell line cytotoxicity screens and apoptosis/necrosis mechanism of cell death studies. Significant apoptotic antitumor activity was found for this trisaccharide, which has implication for Vineomycin C and PI-080's structure-activity relationship. To further elucidate the structural activity relationship for this trissacharide, we also prepared the enantiomeric D/D/L-trisaccharide, which is made up of alpha-D-aculose, alpha-D-rhodinose and beta-L-olivose sugars.;To further study the structure activity relationship of these C-aryl glycoside natural products, an effort was undertaken to develop a selective method for the installation of a beta-C-aryl glycoside bond to an intact di- and tri-sacchardes. This began with a de novo synthesis of the disaccharide portion of two new C-aryl glycoside natural products, SCH-47554 and SCH-47555. Unfortunately, despite the exhaustive screening of Lewis acid, no method was found for the formation of the desired beta- C-aryl glycoside bond that did not occur with hydrolysis of the di- and tri-saccharide glycosidic bonds.;In the final chapter, an effort was described that was aimed at the synthesis of hydroxyl-substituted analogues of two biologically important natural products for further glycosylation. The two natural products that were chosen for these studies were the poly-aromatic alkaloids ellipticine and camptothecin. This effort was aimed at trying to improve the water solubility/membrane transport properties of these anticancer natural products. While the efforts to prepare the required hydroxy-substituted aza-ellipticin failed, a glycosylated camptothecin was prepared. Unfortunately, the acid sestivity of the glycosylated camptothecin limits its use in biological studies.

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