Further studies on cation clock reactions in glycosylation: observation of a configuration specific intramolecular sulfenyl transfer and isolation and characterization of a tricyclic acetal

Abstract

The use of the 2-O-(2-trimethylsilylmethallyl) group as intramolecular nucleophile and cation clock reaction in the glucopyranose series depends on the nature of the glycosyl donor. As previously reported, with trichloroacetimidates the anticipated intramolecular Sakurai reaction proceeds efficiently and is an effective clock, whereas with sulfoxides complications arise. The source of these complications is now shown to be an intramolecular sulfenyl transfer reaction between the tethered allylsilane and the activated sulfoxide. These results illustrate how a different unimolecular clock reaction may be required for a given cation when it is generated from different donors in order to avoid side reactions. The synthesis and cyclization of a 2-O-(3-hydroxypropyl) glucopyranosyl sulfoxide leading on activation to the formation of a trans-fused acetal is also described. The formation of this crystallographically-established trans-fused acetal is discussed in terms of the high effective concentration of the intramolecular nucleophile which leads to a high degree of a SN2 character in the displacement of the α-glucsoyl triflate or at the level of the corresponding α-CIP. The possible use of such intramolecular alcohols as clock reactions and their limitations is discussed.

Acceptor reactivity in glycosylation reactions

“…Both methods have been used by the group of Crich, but only on the relatively nucleophilic and minimally intrusive iso-propanol. [103][104][105][106][107] An extension of these methods spanning a wider range of acceptors, will provide the much needed insight how the reactivity of the acceptors determines the position of the operational reaction mechanisms along the S N 2-S N 1-continuum. 108…”

The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1–SN2 Interface

“…In the corresponding glucopyranose series, the use of sulfoxide-based donors was not successful owing to an intramolecular sulfenyl transfer to the allylsilane on activation, 85 but the activation of the trichloroacetimidate afforded the cyclized product in the form of a single cis -fused isomer (Scheme 10). 84 Activation of a cognate 2- O -(3-hydroxypropyl)glucopyranosyl sulfoxide at low temperature resulted in the formation of a bicyclic acetal demonstrated to have the β-configuration by NMR and crystallographic methods (Scheme 11).…”

“…84 Activation of a cognate 2- O -(3-hydroxypropyl)glucopyranosyl sulfoxide at low temperature resulted in the formation of a bicyclic acetal demonstrated to have the β-configuration by NMR and crystallographic methods (Scheme 11). 85 The reversal of stereoselectivity on switching from the allylsilane to the more nucleophilic alcohol is best rationalized in terms of a change in mechanism. With the alcohol, direct nucleophilic attack on the intermediate α-glucosyl triflate formed on activation of the sulfoxide rationalizes the observed product, whereas the intramolecular Sakurai product, arising from the weaker nucleophile, is the result of an S N 1-type process on a transient oxocarbenium ion.…”

“…84,85 The β-selectivity of the acetal-forming reaction, which contrasts with the α-selective intermolecular O -glycosylation reactions of benzylidene-protected glucopyranosyl triflates, is explained in terms of the high effective molarity of the nucleophile in the cyclization. 85…”

Synthesis and intramolecular glycosylation of sialyl mono-esters of o-xylylene glycol. The importance of donor configuration and nitrogen protecting groups on cyclization yield and selectivity; isolation and characterization of a N-sialyl acetamide indicative of participation by acetonitrile

“…In continuation of our studies on the development of cyclization reactions for use as unimolecular clocks for estimating the molecularity of glycosylation reactions, 1–3 we report on the synthesis and cyclization of a series of o -(hydroxymethyl)benzyl (xylylene glycol monesters) of sialyl thioglycosides giving a series of spirocyclic eight-membered ring diolides. We report that the yield and stereoselectivity of these cyclizations is a function of the anomeric configuration of the initial thioglycoside and of the N5 protecting group.…”