Semester

Spring

Date of Graduation

2009

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

George A. O'Doherty.

Abstract

The carbohydrate portion of natural products plays a crucial role in biology, such as target binding, solubility, tissue targeting, and membrane transportation. The O'Doherty group has developed a de novo methodology to build the desired functionality and stereochemistry within each sugar, in contrast to the traditional approach using known carbohydrates as starting materials. 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.;Continuing our investigations on the utility of this strategy, we turned our attention to the syntheses of the bioactive carbohydrate-based natural product analogues. The targets we chose are the p90 ribosomal S6 kinase (RSK) inhibitors SL0101 and its analogues. We developed a practical 7-10 step diastereoselective route for the syntheses of six different analogues of SL0101 in either enantiomeric form without using any protecting groups in the sugar moieties.;C-glycosides are carbohydrates where one of the acetal oxygens has been replaced with a methylene group. These non-hydrolyzable sugar mimics have long been recognized as an important pharmacophore. Cyclitols/Carbasugars are an important subset of the C-glycoside structural motif where the endo-acetal ring oxygen has been replaced with a methylene group. In particular, polyhydroxylated cyclohexane cyclitols that mimic pyrano-sugars are ubiquitous in many biologically important natural products. We successfully developed a pratical route to achieve rhamno-carbasugars in either enantiomeric and diastereomeric form (e.g., alpha-L, beta- L, alpha-D, beta-D) starting with quinic acid. Three cyclitol/carbasugar monosaccharides and five carbasugar C-1 phosphates have been synthesized.;In order to further facilitate the medicinal structure-activity relationship (SAR) study of SL0101, we also turned our attention to the synthesis of carbsugar glycoside analogues of SL0101. A practical palladium(0)-catalyzed cyclitolization/C-in ring-glycosylation and a post-cyclitolization transformation has been successfully developed. This methodology has been utilized to synthesize six carbasugar analogues of SL0101 in either enantiomeric form.;Efforts have been made toward the synthesis of biologically important jadomycin A and B. A practical approach has been successfully developed to achieve alpha-digitoxose, the sugar moiety of jadomycin B by employing a new post-glycosylation reactions following palladium(0)-catalyzed glycosylation reaction. Jadomycin A, the aglycone part of jadomycin B, has been successfully synthesized. The key transformations included an oxidative ring closure of dihydropyridine followed by acid induced lactonization to form an oxazolone ring.

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