Investigation Of The Effects Of A 3-Deoxy-3-Thio Substituent On Glycosylation Mechanisms

Author

Timothy F. Mcmillan, Wayne State University

Access Type

WSU Access

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

The beginning of chapter one provides information on the importance of sugars to the field of organic chemistry. A general background to carbohydrates is then explored such as the denotation of α and β anomers, and the glycosylation reaction. A more in-depth description to the glycosylation reaction is then described, breaking down the glycosylation mechanism and the importance of the oxocarbenium ion. A brief history of glycosyl donors and their corresponding activation systems is also explained. The second half of chapter one focuses on the importance of selectivity when conducting glycosylation reactions, and the strategies that have been employed to influence it. Concepts such as the benzylidene effect, O2-C2-C3-O3 torsion angle strain, C-2 and C-3 substituent influence and hydrogen bonding capabilities are described. Chapter two describes the synthesis of several novel 3-deoxy-3-thioalkyl-based mannosyl donors, and the study of their corresponding glycosylation reactions. The benzyl ether typically found on the O3 position of a 4,6-di-O-benzylidene acetal protected mannoside is replaced by a thioalkyl group with the hopes to mimic the β-selectivity often attributed with glycosylation reactions involving these mannopyranosyl donors. Key steps for the synthesis of these donors include a selective benzylation of a cis diol, inversion of the C-3 position, and the installation of a thioacetate group, allowing for late-stage functionalization. Hydrogen bonding studies were conducted using model pyridine-based compounds with the idea of discerning the impact that hydrogen bonding has on the overall selectivity of glycosylation mechanisms involving a pyridine moiety. Long-range participation of the C-3 substituent was also hypothesized in this chapter, inspired by the isolation and characterization of a novel tricyclic pyridinium ion. Finally, Raney nickel cleavage was conducted on a few disaccharides post-glycosylation, in turn producing unique 3-deoxy-β-mannosides. The first half of chapter three presents the possible advantages of using an altrosyl donor in glycosylation reactions as a replacement for the mannosyl donors used in chapter two. This chapter describes the synthesis of a series of 3-deoxy-3-thioacyl altrosyl donors, and the study of their corresponding glycosylation reactions. Key steps for the synthesis of these donors includes a selective benzylation, and the installation of the thioacetate group on the C-3 position, allowing for late-stage functionalization of these compounds. Further investigation of the long-range participation hypothesis was conducted in the form of low temperature NMR spectroscopy studies on a 13C enriched S-benzoyl donor, showing potential carbonyl group participation as evidenced by a 13C resonance of δ210.6 ppm. Additional evidence of long-range participation by the C-3 substituent is further supported by the isolation and characterization of an intramolecular thioorthoester as well as a migration product involving the swapping of the anomeric p-methylphenylthiol group with that of the C-3 thioester benzofuranyl system giving an anomeric ester and a disulfide on the C-3 position. Overall, despite the evidence supporting long-range participation by the C-3 substituent, low β-selectivity was witnessed during the investigation of all the glycosylation reactions involving the 3-deoxy-3-thioacyl altrose series of donors. The second part of chapter three describes the deviation from thioester substituents on C-3 of the altrose donor in favor of using a thioether, the synthesis of these 3-deoxy-3-alkylthio altrosyl donors, and the study of their corresponding glycosylation reactions. Key steps for the synthesis of these donors includes a selective benzylation, and the installation of the thioacetate group on the C-3 position, allowing for late-stage functionalization of these compounds. Sterically bulky substituents were used, including methyladamantyl, and 2-napthyl, with the idea of increasing the 1,3-diaxial interactions present in the altrose molecule. This strategy proves to be moderately effective, providing higher β-selectivity than previously observed in the earlier chapters, with a β:α ratio as high as (3.3:1). Isolation and characterization of an altrosyl tricyclic pyridinium ion further supports the long-range participation hypothesis. The isolation and characterization of a disulfide akin to the migration product from earlier in the chapter is hypothesized to have originated from a bridged disulfide intermediate arising from participation from the sulfur on the 3-position. Lastly, Raney nickel cleavage was conducted on a few altrosyl disaccharides post-glycosylation, producing 3-deoxy-β-mannosides. Chapter four describes the successful synthesis of a 1,3-disulfide bridged altrosyl donor. The chapter begins with background information on previously synthesized 1,6-disulfide bridged sugars and applying that concept with the concepts of β-selective glycosylation and long-range participation. Key steps during the synthesis of these 1,3-disulfide bridged altropyranosides includes selective thioacetate deprotection in the presence of acetate groups, selective PMB protection of a cis diol, thioacetate installation, and oxidation of a 1,3-dithiol to a 1,3-disulfide. Finally, a plan implementing the 1,3-disulfide bridged altropyranoside as a β-selective donor is described. Chapter six provides comprehensive experimental instructions and characterization data for all compounds synthesized.

Recommended Citation

Mcmillan, Timothy F., "Investigation Of The Effects Of A 3-Deoxy-3-Thio Substituent On Glycosylation Mechanisms" (2022). Wayne State University Dissertations. 3601.
https://digitalcommons.wayne.edu/oa_dissertations/3601