Strain-release glycosylation using donor-acceptor cyclopropanes: development and applications in carbohydrate synthesis

• Main Author: Ding, Han
• Other Authors: Liu Xuewei
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Chemistry; Glycosylation; Donor-acceptor cyclopropane; Ring-strain release
• Online Access: https://hdl.handle.net/10356/181814
• Institution: Nanyang Technological University

Carbohydrates are essential biological molecules that can mediate diversified biological processes including cell-cell signalling, adhesion, and growth. Vital utilities in drug and vaccine development of these essential compounds translate to keen demand for their acquisitions. However, the relatively low-concentration natural occurrence and microheterogeneity prohibit the direct isolation of significant amounts of sugar molecules from biological resources. Therefore chemical glycosylation becomes one of the most reliable approaches for large-scale preparations of carbohydrates with well-defined structures. Donor–acceptor cyclopropanes (DACs) are a multifunctional three-carbon building block that can undergo divergent organic transformations of cycloaddition, nucleophilic ringopening and/or electrophilic ring-opening reactions driven by ring-strain release. Recognizing the potential of nucleophilic ring-opening reactions of DAC, this thesis described the development of a series of DAC-strain-release-initiated glycosylation protocols, aiming to address the availability problems of sugar molecules by chemical approaches. To initiate the strain-release glycosylation, the DAC-mediated thioglycoside activation reactions utilizing the mixed promoter of Sc(OTf)3 catalyst and a DAC reagent featuring a para-nitrobenzene donor moiety were developed. The reaction applies to diverse armed and disarmed glycosyl donor for oligosaccharide assembly. Mechanistic experiments disclosed that a reversible, unbiased nucleophilic ring-opening of DAC by anomeric sulfide is the key to the glycosylation reactions. Inspired by the new activation, an SN2-like glycosylation with selenoglycosaminoside donor, equipped with a C-2-(2,4-dinitrobenzenesulfonamide (DNs)) group, was established. The utility of the glycosylation reaction was effectively showcased by the one-pot synthesis of two trisaccharides. Chapter 3 describes the evolution of strain-release glycosylation by merging the ester type glycosyl donor with DAC-mediated glycosylation to generate a novel class of glycosyl donors, i.e., glycosyl ortho-2,2-dimethoxycarbonylcyclopropylbenzoates (CCBz), a catalytically, remotely activable glycosyl donors. The glycosylation with glycosyl CCBz enables facile and efficient coupling with O-, N-, and S-nucleophiles. The gram-scale assembly of chitooligosaccharides demonstrated the usefulness of this elegant protocol in the assembly of oligosaccharides of biological relevance. By replacing the nucleophilic ester in the anomeric leaving group with a sulfide and subjecting the donor to Sc(OTf)3 catalysis, a novel genre of catalytic glycosylation was established by employing the rationally designed ortho-2,2-dimethoxycarbonylcyclopropylbenzyl (CCPB) thioglycoside donors. The current glycosylating agent overcame limitations that the glycosyl thiols cannot be used for the glycosylation with glycosyl CCBz donors, enabling the effective synthesis of 1,1'-S-linked glycosides, as exemplified by the total synthesis of TD139. Meanwhile, the reactivity of the current donor significantly increased, as evidenced by the kinetic one-pot glycosylation with the glycosyl CCBz donor. Steroidal glycosides widely occurred as functional molecules with divergent medicinal activities while they are sensitive to acidic and enzymatic hydrolysis in human bodies. Attaching steroids to sugar with ether linkages generates a novel class of pseudo-steroidal glycosides that exhibit enhanced metabolic stability. However, their synthesis is mainly plagued by lacking effective protocols. By introducing the CCBz ester into steroids, chapter 5 developed a steroidation reaction, which is useful in the synthesis of chimeric steroids with O-, C-, N-, S-, and P-nucleophiles. Notably, all types of O-nucleophiles gave C-3 steroids invariably. DFT calculations were conducted to delineate the mechanism leading to the unique regioselectivity. Finally, two well-designed pseudo-cholesteryl disaccharides were subjected to biological studies and demonstrated excellent anti-inflammatory reactivities, showing promising prospects for novel anti-inflammation agent development.