Stereoselective Synthesis of 2-Deoxy-β-glycosides Using Anomeric O-Alkylation/Arylation

Abstract

Anomeric O-alkylation/arylation is applied to the synthesis of 2-deoxy-β-glycosides. Treatment of lactols with NaH in dioxane followed by the addition of electrophiles leads to the formation of 2-deoxy-β-glycosides in high yield and high selectivity. The high β-selectivity observed here demonstrates a powerful stereoelectronic effect for the stereoselective formation of acetals under kinetic control.2-Deoxy-β-glycosides are present in biologically active natural products such as the lomaiviticins, olivomycin A, OSW-1, and durhamycin. The stereoselective preparation of 2-deoxy-β-glycosides is difficult 1 because substituents at C2 often serve as directing groups during the glycosylation event. The synthesis challenge posed by 2-deoxy-β-glycosides coupled with their presence in nature has inspired a variety of approaches aimed at accessing these important glycosides. The most common methods involve the use of a heteroatom substituent at C2 of the glycosyl donor followed by its reductive removal after glycosylation. 2 Other methods include the use of α-glycosyl phosphites, 3 displacement of α-glycosylhalides, *E-mail: shair@chemistry.harvard.edu. Supporting Information Available: Experimental procedures and spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. We became interested in the synthesis of 2-deoxy-β-glycosides since they are present in the lomaiviticins, molecules we are targeting for synthesis (Figure 1). In particular, our recent synthesis of the central ring system of the lomaiviticins involves incorporation of the C4 and C4′ carbinols by S N 2 displacement of allylic sulfones with methoxide anions. 8 This raised the possiblity that the 2-deoxy-β-glycosides at C4 and C4′ might be incorporated via an anomeric O-alkylation using glycosyl-1-alkoxides. NIH Public AccessAnomeric O-alkylation with glycosyl-1-alkoxides generally affords high levels of β-glycosides. 9 An explanation for this selectivity involves rapid equilibrium between axial and equatorial alkoxides with the enhanced nucleophilicity of the equatorial alkoxide leading to selective generation of β-glycosides (Scheme 1). It has been proposed that the enhanced nucleophilicity of the equatorial alkoxide (II), compared to the axial alkoxide (I), is due to increased electron-electron repulsion resulting from the alkoxide of II being gauche to both electron lone pairs of the ring oxygen compared to a single gauche interaction in I. This phenomenon has been referred to as the kinetic anomeric effect, 9 or the β-effect, and may be similar to the α-effect, which is observed in molecules where the nucleophilic atom is directly attached to another heteroatom. To date, most examples of anomeric O-alkylation have been performed with substituents in the C2 position. 10 This has made it difficult to assess the contribution of the β-effect versus steric (or electronic) influences of C2 substitutents in the selective formation of β-glycosides by anomeric O-alkylation. In this paper we r...

Enantioselective Syntheses of (-)-Kinamycin F and (-)-Lomaiviticin Aglycon

“…Shair and co-workers used this as motivation to develop a new method for the direct construction of such bonds. 16 The same group reported two syntheses of the protected pyrrolosamine residue of the lomaiviticins. 16,17 Many groups have also conducted studies aimed at elucidating the origins of the cytotoxic effects of the kinamycins and lomaiviticins, 18 although a complete understanding of the fate of these metabolites in vivo has not yet been obtained.…”

“…Moreover, the 2,6-dideoxyaminosugar of the lomaiviticins is b-linked, and most methods to establish this glycosidic bond rely on reductive removal of a C-2 substituent, 31 conditions that are expected to be incompatible with the diazofluorene 18c,d,i (for exceptions, see ref. 16,32 ). Finally, while we were able to relay the stereochemistry of the diol protecting group to that of the bridging carbon-carbon bond, the natural stereochemical bias in the dimerization of glycosylated lomaiviticin monomers is certainly not unambiguous.…”

Synthetic study of 3-fluorinated sialic acid derivatives

“…23e25 This effect was utilized for the synthesis of 2-deoxy-b-glycosides. 26 However, the applicability of this approach to sialic acid derivatives has not been clarified. In the case of sialic acid derivatives, it is necessary to consider the presence of the carboxyl group, often protected as a methyl ester, at a position opposite to the anomeric alkoxide.…”

Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-d-pyrrolosamine glycal of lomaiviticins A and B via epimerization of l-Threonine

“…Recently, the synthesis of the N , N -dimethylpyrrolosamine carbohydrate found in both 1 and 2 has been addressed by our group5 as well as Herzon and coworkers 6. In this communication, we describe an alternative synthesis of the N , N -dimethylpyrrolosamine sugar that utilizes an interesting and useful epimerization reaction.…”