Glycosylations of unprotected sugars.We saw our method as a potential avenue to address glycoside Single-flask synthesis of oligosaccharides2)Additionally we synthesized bifunctional substrates that contained both electrophilic (MTHP peroxide) and pronucleophilic (thiophenylsulfide) residues (Figure 4). The disaccharide products shown can be further transformed to trisaccharides. For example, reductive lithiation of thioglycoside 23, addition of 24α, further reductive lithiation, and addition of 25 the trisaccharide 26 in 54% yield and as a single diastereomer (as determined by 1H NMR analysis). The reaction mixture was extended to other diastereomers of 26 and to the tetrasaccharide 27. Conclusion and outlookWe have developed a novel approach to the synthesis of 2-deoxyglycosides. The use of an umpolung strategy provides access to either α- or β-linked glycosides in synthetically useful yields and near-perfect diastereoselectivities from a single bearing acidic protonsDevelopment of an umpolung glycosylation for the synthesis of α- or β-linked O-2-deoxyglycosidesSeth B. HerzonTable 1. Inirial optimization of the β-glycosylation reaction for unprotected sugarstable toward acidic hydrolysis; this effect is exacerbated for 2-deoxyaminoglycosides. Our umpolung glycosylation provides access to a range of aminoglycosides, including forosamine, pyrrolosamine, acosamine, and ristosamine derivatives, in yields of 60‒90% for the α-linked products and 45‒94% for the β-linked products (Figure 2). To highlight the applicability of this method, the forosamine derivative 12β was synthesized in 69% yield and 5.3:1 β:α selectivity, which represents the best β-selective introduction of a forosyl donor reported to date (a related glycosylation was reported to proceed in 71% yield and with 1:1 β:α selectivity)10). Interestingly, ristosamine derivatives (in which the amine substituent lies in the axial orientation) favored β-products at low temperature (Table 2, vide infra). Figure 3. Selected substrates for the umpolung glycosylation for carbohydrates bond formation using donors bearing free hydroxyl groups. Deprotonation with methyllithium prior to the reductive lithiation followed by treatment with the alkyl MTHP peroxides allowed for efficient glycosylation reactions of unprotected sugars or carbohydrates. Currently, we are optimizing the β-selective conditions (Table 1) and working on the substrate scope of these reactions (Figure 3). For unprotected substrates, we are able to achieve efficient α-reactivity, but we believe the di-anionic intermediates are slower to equilibrate to the respective β anions, thus leading to less efficient β-selective reactions. In tandem with ongoing experimental work, we are conducting computational modelling of the intermediates in order to gauge the energy profiles of the α- and β-dianions.104
元のページ ../index.html#104