Date of Graduation
2007
Document Type
Dissertation/Thesis
Abstract
De novo asymmetric synthesis is a strategy that uses asymmetric catalysis to construct chiral molecules from achiral starting materials. De novo approach to carbohydrate builds saccharides from commercially available achiral starting material which will enable the medicinal chemist to install a much broader range of carbohydrates on natural products and in a SAR-amenable fashion. The palladium-catalyzed glycosylation reaction stereoselectively converts 2-substituted 6-tert-butoxycarboxy-2H-pyran-3(6H)-ones into 2-substituted 6-alkoxy-2H-pyran-3(6H)-ones. By using this reaction, a divergent library of the natural and unnatural 1,4-manno-trisaccharides as well as branched 1,4- and 1,6-linked trisacchardes were synthesized. The 1,4-α-manno-disaccharides were achieved in eight total steps starting from achiral acylfuran. Similarly, 1,4-α-manno -trisaccharides were also synthesized in ten total steps. Key to the overall efficiency of this process was the use of highly diastereoselective palladium-catalyzed glycosylations, reductions, and dihydroxylations. A highly stereoselective synthesis of L-2-deoxy-β-ribo -hexopyranosyl nucleosides from 6-chloropurine and Boc-protected pyranone has been developed. Our approach relies on the iterative application of a palladium-catalyzed N-glycosylation, diastereoselective reduction, and reductive 1,3-transposition. This strategy is amenable to prepare various natural and unnatural hexopyranosyl nucleosides analogues. A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin has been developed. Key to this approach is the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The first total synthesis of natural product digoxose was accomplished in 19 total steps from achiral 2-acylfuran, and digitoxin was fashioned in 15 steps starting from digitoxigenin and β-Boc-pyranone. This flexible synthetic strategy also allows for the preparation of mono- and disaccharide analogues of digoxose and digitoxin. Landomycin A possesses a broad spectrum of bioactivity against 60 cancer cell lines in vitro. A highly enantioselective route to landomycin trisaccharide has been developed. The key transformations include: the palladium catalyzed glycosylation reaction, Myers’ reductive rearrangement, diastereoselective dihydroxylation, and regioselective Mitsunobu reaction. To the best of our knowledge, this is the first example of the chemoselective discrimination and stereoselective inversion of the 1,2-diol on sugar system using direct Mitsunobu reaction on diol. The trisaccharide was prepared from the achiral acylfuran in 21 steps and 5% overall yield.
Recommended Citation
Zhou, Maoquan, "De novo asymmetric syntheses of unnatural manno-trisaccharides, homo-adenosine, digitoxin and landomycin A." (2007). Graduate Theses, Dissertations, and Problem Reports. 10113.
https://researchrepository.wvu.edu/etd/10113