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Stereoselective Synthesis of Digitoxin and S-Linked Glycosides

Baryal, Kedar N
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438174529

Abstract Details

, Doctor of Philosophy, University of Toledo, Chemistry.
Deoxy-sugars are an important class of carbohydrates in which one or more hydroxyl group/s are replaced by hydrogen atom/s. 2-Deoxy sugars exist in a wide range of bioactive natural products and clinical agents including antimicrobial and antitumor antibiotics. These sugars play critical roles in biological activity by serving as additional binding sites or changing the pharmacokinetics of molecules. Digitoxin is a cardiac glycoside isolated from Digitalis purpurea and has been in use for the treatment of congestive heart failure and cardiac arrhythmia for a long period of time. However, the clinical use of digitoxin is limited due to the narrow therapeutic window. Over the years, antiproliferative activity against cancer cells has been known and recently, more attention has focused on the direction of this research. Structurally, digitoxin contains two subunits: ß-linked digitoxose trisaccharide and aglycon (digitoxigenin). In this study, we described a rhenium(V)-catalyzed stereoselective synthesis of ß-D-digitoxosides from 6-deoxy-D-allal. The ß-selectivity may be due to the disfavored formation of a-D-digitoxosides by 1,3-diaxial interactions. In addition, Re(V)-catalysis had been applied to the synthesis of the digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1'-epi-digitoxin. Moreover, the O-glycosidic linkage of 2-deoxy glycosides is known to be susceptible to acid hydrolysis and enzymatic cleavage, which results in the increased toxicity and reduced activity of the parent molecules. Thioglycosides (S-linked glycosides), in which the glycosidic oxygen is replaced by a sulfur atom, are carbohydrate mimics resistant towards chemical and enzymatic cleavage. In addition, thioglycosides maintain the biological activity of their parent O-glycosides. Therefore, it is appealing to synthesize S-linked 2-deoxy sugars and comparatively study their chemical and biological properties with their O-linked counterparts. Due to the absence of a directing group at C-2, stereoselective synthesis of S-linked 2-deoxy sugars is challenging. To overcome this problem, we devised the sulfenylation of stereochemically defined glycosyl lithium with sugar-derived asymmetric disulfides to furnish S-linked 2-deoxy a- and ß-glycosides in excellent yield and stereoselectivity. The stereochemically defined 2-deoxy glycosyl lithiums can be readily formed by reductive lithiation of glycosylphenylsulfide at low temperature by lithium di-4,4’-tert-butylbiphenylide (LiDBB) and subsequent temperature-controlled anomerization. A complex S-linked trisaccharide, and a hexasaccharide analog of landomycin A have been successfully synthesized by employing this newly developed method.
Jianglong Zhu, Dr. (Committee Chair)
Steven Sucheck, Dr. (Committee Member)
Joseph Schmidt, Dr. (Committee Member)
James Slama, Dr. (Committee Member)
316 p.
Chemistry; Organic Chemistry

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Citations

  • Baryal, K. N. (2015). Stereoselective Synthesis of Digitoxin and S-Linked Glycosides [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438174529

    APA Style (7th edition)

  • Baryal, Kedar. Stereoselective Synthesis of Digitoxin and S-Linked Glycosides. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438174529.

    MLA Style (8th edition)

  • Baryal, Kedar. "Stereoselective Synthesis of Digitoxin and S-Linked Glycosides." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438174529

    Chicago Manual of Style (17th edition)

toledo1438174529
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This open access ETD is published by University of Toledo and OhioLINK.