Objectives The stereocontrolled synthesis of O-2-deoxyglycosides is challenging owing to the absence of a C2 substituent to control stereoselectivity. We sought to develop a mechanistically-distinct glycosylation reaction to access these products. Methods and results. We developed a novel umpolung glycosylation reaction that provides O-2-deoxyglycosides with high stereoselectivity (typically >50:1). Our approach proceeds by reductive lithiation of bench- and air-stable thiophenyl glycosides. In most instances, the α (axial) anomeric anion is the kinetically-favored anion diastereomer. The addition of an alkyl 2-(2-methyltetrahydropyranyl) peroxide, a formal alkoxenium ion equivalent, to this anion then provides the α-linked O-2-deoxyglycoside. Alternatively, the α (axial) anion may be thermally isomerized to the more stable β (equatorial) anion. Recooling, followed by addition of a peroxide, then provides the β-linked O-2-deoxyglycoside. By this approach, either diastereomer of product is accessible from a common reagent. The reaction was extended to the synthesis of O-glycosides bearing basic nitrogen and free hydroxyl substituents on the carbohydrate donor. Conclusion. Scheme 1. Classical (top) and our umpolung (bottom) glycosylation strategiesThe umpolung glycosylation we developed provides efficient access to α- or β-linked O-2-deoxyglycosides that are difficult to prepare by other methods. Current research is focused on expanding the accessibility of the requisite peroxide electrophiles and employing less reactive organometallic intermediates in places of the anomeric organolithium species.IntroductionImmense efforts have been directed toward synthetic glycosylations. In a typical transformation, the anomeric (C1) position of the glycoside donor 1 is activated by a Lewis acid promoter to form an electrophilic intermediate. This intermediate is trapped by an alcohol acceptor to form the glycoside products (3 and 4 in Scheme 1). Control of stereoselectivity at the anomeric center has been deemed “the central topic” in synthetic carbohydrate chemistry.1 The substituent at C2 has been used strategically to guide the formation of α- or β-linked products. 2-Deoxyglycosides, which lack a C2 substituent, are more difficult to synthesize owing to the absence of a 2-substituent. Indeed, the synthesis of these glycosides was recently identified as one of the most challenging problems in carbohydrate chemistry1) .Ultimately, we realized an efficient and diastereoselective O-glycosylation via addition of Development of an umpolung glycosylation2)Our laboratory is interested in developing strategies for the synthesis of 2-deoxyglycosides, owing to their presence in a large number of natural products3). The synthesis of β-2-deoxyglycosides is particularly problematic as this is often the thermodynamically- and kinetically-disfavored product in classical glycosylations. We conceived alternative methods of C–O bond formation with the reasoning that these might circumvent the limitations of classical methods. 102Development of an umpolung glycosylation for the synthesis of α- or β-linked O-2-deoxyglycosidesSeth B. Herzon1Kevin M. Hoang, 1Nicholas R. Lees, 1Xiaoying Zheng, and 1,2Seth B. Herzon1Department of Chemistry, Yale University. 2Departments of Pharmacology and Therapeutic Radiology, Yale School of Medicine
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