Stereoselective glycosylations using oxathiane spiroketal glycosyl donors

Abstract

Novel oxathiane spiroketal donors have been synthesised and activated via an umpolung Sarylation strategy using 1,3,5-trimethoxybenzene and 1,3-dimethoxybenzene.The comparative reactivity of the resulting 2,4,6-trimethoxyphenyl (TMP)-and 2,4-dimethoxyphenyl (DMP)-oxathiane spiroketal sulfonium ions is discussed, and theirstereoselectivity in glycosylation reactions are compared to the analogous TMP-and DMPsulfonium ions derived from a oxathiane glycosyl donors bearing a methyl ketal group. The results show that the stereoselectivity of the oxathiane glycosyl donors is dependent on the structure of the ketal group and reactivity can be tuned by varying the substituent on the sulfonium ion. IntroductionThe chemical synthesis of complex oligosaccharides presents many technical challenges ranging from lengthy reaction sequences through to problematic purification steps. Scheme 1 a) Umpolung S-arylation strategy for oxathiane ketal-S-oxide donors 1. b)Oxathiane ketal donor scaffold 4 and oxathiane spiroketal donor scaffold 6.Attempts to arylate glycosyl oxathianes with benzyne led to the formation of glycosyl 3 acetates. 21 However, oxidation of the oxathiane to give oxathiane ketal-S-oxides 1, and subsequent treatment with Tf 2 O, led to the formation of surprisingly stable activated intermediates which were sufficiently long-lived to undergo electrophilic aromatic substitution in the presence 1,3,5-trimethoxybenzene (TMB). Therefore, conversion of the previously nucleophilic sulfide into an electrophilic S(IV) centre facilitated an "umpolung" approach to S-arylation. The resulting 2,4,6-trimethoxyphenyl (TMP)-oxathiane ketal sulfonium ions 2 then afforded -glycosides 3 with complete stereoselectivity following heating at 50 °C. However, although glycosylation reactions with oxathiane ketal sulfonium ions 4 are notable for the formation of glycosides with complete -stereoselectivity, 19,21 the resulting O-2 acyclic ketal formed in the product 5 occasionally decomposed under the reaction conditions, diminishing yields in more challenging glycosylation reactions.Therefore, in an attempt to circumvent this issue, we set out to design a new oxathiane donor scaffold in which the axial methoxy group was replaced with an O-substituent constrained in a spirocyclic ring (Scheme 1b). It was anticipated that following glycosylation, spiroketal sulfonium ion 6 would afford glycosides 7 bearing an O-2 cyclic ketal which would be more stable than the corresponding O-2 acyclic ketal, but still sufficiently labile to be removed by Lewis acid catalysed cleavage. To this end, we present the synthesis and activation of oxathiane spiroketal-S-oxides via an umpolung S-arylation strategy, and compare theirstereoselectivities in glycosylation reactions with the analogous oxathiane ketal sulfoniumions. We also demonstrate that the stability and -stereoselectivity of oxathiane spiroketal sulfonium ions in glycosylation reactions can be modulated by changing the S-aryl appendage exogenous to the oxathiane ring. Both TMP and 2,4-dimet...

Do Glycosyl Sulfonium Ions Engage in Neighbouring‐Group Participation? A Study of Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity

“…Athough these observations appear to support the hypothesis, the presence of a ketal group in the oxathiane ring is not sufficient to ensure complete stereoselectivity. [54] Furthermore, the reactions of sulfonium ions 42 a and 42 b do not support the hypothesis (Scheme 5). Our DFT calculations indicate that the trimethoxyphenyl group in compound 42 a stabilises the sulfonium ion through a favourable interaction between a methoxy group and the sulfur atom (Figure 6).…”

Sulfonium Ions as Reactive Glycosylation Intermediates

“…This method is more practical because the carbonyl group selectively reacts with the hydroxyl group at the 2-position, and there is no need to prepare a chiral auxiliary. There are reports of the activation of the same decalin-type thioglycosides using the in situ generated benzyne as an activator (16) and a glycosyl donor equipped with a spiroketal structure (17). Alternatively, the intermolecular reaction between a sulfide and a trichloroacetimidate glycosyl donor 15 has been reported, and the generation of β-sulfonium ion 16 was confirmed by NMR ( Fig.…”

Stereocontrolled 1,2-cis glycosylation as the driving force of progress in synthetic carbohydrate chemistry

“…41 As in the previous methods, the oxathiane spiroketal donor is then activated viaS -arylation. Overall, the novel class of oxathiane glycosyl donors is easily accessible, highly α-selective in glycosylation, and offers high stability towards common protecting group manipulations.…”