Glycosylation orthoesters

Glycosyl orthoesters of the type 223 (Table 4.12) have been introduced for the syntheses of 1,2-trans-glycosidts [77,78]. Orthoesters can be converted into the corresponding glycosides by... 

Allen, J G, Fraser-Reid, B, -Pentenyl glycosyl orthoesters as versatile intermediates in oligosaccharide synthesis. The proteoglycan hnkage region, J. Am. Chem. Soc., 121,468-469,1999. 

When neighboring-group participation is a feature of the glycosylation reaction, the use of a base in this manner frequently results in the isolation of orthoesters rather than the desired glycosides. In the case of activation by triflic anhydride, it is possible to avoid this problem by simply omitting the base. Alternatively, with more sensitive substrates, the hindered base may be retained and boron trifluoride ethe-rate be added to promote the rearrangement of the orthoester to the glycoside, as in... 

From a historic perspective glycosyl chlorides and bromides introduced, respectively, by Michael [2] and Koenigs and Knorr [3] were the most widely used donors in the saccharide synthesis for a very long time. The introduction of 1,2-orthoesters in 1964 [4] was the first important attempt to find an alternative to the Koenigs-Knorr method. However, Paulsen in his 1990 review of reliable donors for glycosyl... 

Scheme 5.5 1,2-O-Alkyl orthoesters in glycosylation (a) polar or nonpolar solvents, high amount of acid (b) low polarity solvents, minor amounts of acid catalyst. 

In 1964, Kochetkov, Khorlin and Bochkov reported that the reaction of 1,2-alky-lorthoacetates with alcohols in the presence of catalytic amounts of HgBr2 and pTsOH furnished acetylated 1,2-trans glycosides or isomeric orthoesters depending on the reaction conditions [4]. Polar solvents (nitromethane, acetonitrile) and large amounts of catalyst promoted glycosylation (a, Scheme 5.5), whereas solvents of low polarity (dichloroethane) and the use of small amounts of catalyst favored transorthoesterification (b, Scheme 5.5) [16]. 

The application of these optimized conditions permitted Kochetkov et al. to prepare, among others, [1-cholcstcryl glucoside in 45% yield. However, with low reactive agly-cons (R OH) the yield was poor (10-20%) owing to the competing glycosylation of the extruded alcohol (ROH) from the initial orthoesters (Scheme 5.6). 

To address this problem, the authors devised two modifications. [30] The first one, two-stage glycosylation (Scheme 5.7), employed an initial, reversible trans-orthoes-terification step (12 —> 14, Scheme 5.7) in which the departing alcohol was removed either azeotropically or by molecular sieves [31]. The new orthoester 14 was then processed to give the glycoside (6) under the conditions developed in their previous work. The second variation consisted of the use of orthoacetates of hindered alcohols (isopropyl and tert-butyl) that minimize the return of the alcohol that is split off. 

Scheme 5.6 The competing glycosylation issue with orthoesters.

Scheme 5.7 The two-stage modification for glycosylation with orthoesters.

These modifications met with only limited success however, they set the basis for the future applications of orthoesters as glycosyl donors. 

Scheme 5.15 Alternative strategies for efficient glycosylation with orthoesters.

Orthoester to Glycoside Rearrangement - The Two-Stage Glycosylation Method Revisited... 

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