Date of Graduation
Eberly College of Arts and Sciences
John H Penn
The carbohydrate portion of natural products plays an important role in its biological activity, such as solubility, target binding, tissue targeting, and membrane transportation. Over the last fourteen years, Dr. O'Doherty's group has been developing de novo methodologies to build the desired carbohydrate functionality and stereochemistry within each sugar from simple achiral starting materials in stark contrast to the traditional carbohydrate approach using known sugar isomers as starting materials. The methodologies depend on a highly diasteroselective palladium-catalyzed glycosylation reaction to control the anomeric stereochemistry, and a highly enantioselective Noyori reduction to install the sugar absolute stereochemistry. Appropriate post-glycosylation transformations create the remaining stereochemistry in the sugar moiety. This thesis reports application of these methods to the following five projects discussed below.;Macrolides are an important class of polyketide antibiotics used for treatment of infections caused by Gram-positive bacteria. Four variously (amino/azido/dideoxy) substituted methymycin analogues have been achieved via a divergent yet highly stereoselective route. The key to the success of this method is the iterative use of the Pd-catalyzed glycosylation reaction, Luche reduction/Myers' reductive rearrangement, diastereoselective dihydroxylation, and regioselective reductions. The samples were sent to our collaborator Prof. Hung-wen Liu at the University of Texas at Austin for biological testing.;Cleistrisides and cleistetrosides are biologically active partially acylated rhamnoside natural products. A short and diastereoselective total synthesis of one cleistrioside and six cleistetrosides including two new analogue cleistetrosides has been achieved via our group's de novo asymmetric approach. The synthesis features an organotin mediated regioselective glycosylation achieving the desired reversed diol glycosylation regioselectivity with only two protecting groups used. Anti-cancer activities of these compounds have also been evaluated.;SL0101 was discovered to be the first specific p90 ribosomal S6 kinase (RSK) inhibitor. As part of an effort to elucidate the role of the sugar and acetyl portions of SL0101 to its activity, three D-sugar analogues with different acylation have been made via our group's de novo asymmetric approach. Biological testing indicated that the D-sugar analogues were inactive.;To prepare analogues of SL0101 with improved RSK inhibition and anti-cancer activity, we tried C6" modifications on SL0101 by preparing various C6"-alkyl substituted L-rhamno-sugar analogues. Six C6"-ethyl-alpha-L-sugar analogues of SL0101 have been synthesized via a highly enantio- and diastereoselective de novo asymmetric approach which is amenable to synthesis of other C6"-alkyl substituted analogue in both D- and L-sugar forms. Biological testing indicated that C6"-ethyl substituted modification were more valuable modification with C6"-ethyl -C3",C4"-diacetate (SL0101-type) being the most potent one, which killed 70% of the human breast cancer cell line MCF-7 without affecting non-cancer cell line MCF-10A, being more efficient than SL0101 which inhibited the growth of MCF-7 by 80% without altering the growth of MCF-10A. A patent application for this work has been submitted.;Encouraged by our successful C6"-ethyl substituted modification of SL0101, we continued our investigation on C4"-amido substituted modification to further improve the resistance to ester hydrolysis. Four targeted C4"-amido-alpha-L-sugar analogues of SL0101 have been synthesized via a highly enantio- and diastereoselective de novo asymmetric approach. The key to the success of this method is the highly diastereoselective t-butyl carbonate formation of allylic azide hemiacetal followed by highly diastereoselective Pd-catalyzed glycosylation which is successfully applied to the Boc-protected allylic azide pyranone. Upjohn dihydroxylation combined with Zn/AcOH reduction of azide as well as regioselective acylation provided the desired SL0101-type analogue, in 4 steps fewer than the original route to same type analogue. All these samples were sent to our collaborator Dr. Lannigan at UVA for biological testing.
Wu, Bulan, "De Novo Asymmetric Synthesis of Biologically Active Carbohydrate Natural Products and Related SAR studies" (2011). Graduate Theses, Dissertations, and Problem Reports. 4816.