Glycosylidene carbenes

Vasella et al. introduced an approach to glycoside synthesis using the glycosylidene carbene generated from the diazirine sugar as a novel type of glycosyl donor. The... 

Highly electrophilic nitromethylenes [ CRN02 (R = H, CF3, COPh, C02R, CN, S02Ar)] are added to alkenes via Rh2 (OAc)4-catalyzed decomposition of the corresponding diazo precursors. The reaction works best with electron-rich, sterically undemanding alkenes (equation 106)225-227. The addition of chiral glycosylidene carbenes to electron-deficient... 

A similar method has been used to synthesize spirocyclic glycosyl diaziridines and diazirines (e.g., 66 and 67), which are used as glycosylidene carbene precursors. The diaziridine is made by reaction of the sulfonylated oxime 65 with ammonia, followed by oxidation to the diazirine with iodine (Scheme 23). 

Vasella, A, Waldraff, C A A, Glycosylidene carbenes. Part 3. Synthesis of spirocyclopropanes, Helv. Chim. Acta, 74, 585-593, 1991. 

Dotz and coworkers prepared several interesting and novel glycosylidene carbenes (259-261) by reaction of lithiated glycal 258 with the appropriate metal carbonyl derivative. The synthetic utility of the formed carbenes was demonstrated by reaction with 3-hexyne to give a mixture of complexed and uncomplexed adducts 262 and 263, respectively. The anomeric chromium carhene 264 was converted to 265 hy exposure to ethoxy ethyne (Scheme 48) [70]. The same workers have carried out a similar chromium-mediated henzannulation (266 —> 268), this time with the chromium on the aromatic fragment [71]. Other sugar-hased carhenes have also been prepared [72]. 

Figure 7.41 Mechanisms of reaction of glycosylidene carbenes with alcohols.

K. Briner and A. Vasella, Glycosylidene carbenes. Part 6. Synthesis of alkyl and fluoroalkyl glycosides, Helv. Chim. Acta, 75 (1992) 621-625. 

S. E. Mangholtz and A. Vasella, Synthesis of glycono-1,5-lactone tosylhydrazones as precursors of glycosylidene carbenes, Helv. Chim. Acta, 73 (1990) 2100-2111. 

A. Vaselia, Pure Appl. Client., 65 (1993) 731-752 A. Vaselia, Glycosylidene Carbenes in Bioorganic Chemistry, Vol. 3. S. Hecht. ed Oxford Press, New York. 1999. p56-88. 

Carba disaccharide 97 has been prepared by insertion of a sugar glycosylidene carbene (made in situ from a glycosyl diazirine derivative) into OH groups of protected deoxy m o-inositoI orthoformate derivatives. ... 

C-glycosides Vasella has reviewed his work on glycosylidene carbenes which is of relevance to the subject, and the use of glycosyl carbanions in C-glycoside synthesis has also been surveyed. ... 

An entirely novel approach to glycosylation uses glycosylideneaziridines which can be oxidised to the relatively unstable diazirines from which glycosylidene carbenes are produced on warming to room temperature. In the presence of alcohols these give glycosides by insertion reactions (Scheme 1) attempts to... 

The glycosylideneaziridines (Vol. 23, p, 16), on photolysis, give glycosylidene carbenes which react with alcohols to give glycosides (Scheme 2). ... 

The diazirine (83) (see Vol. 23, p.l6 and 114) reacts (by way of the glycosylidene carbene) on heating with acrylonitrile to give all four isomeric glycosyl cyanocyclopropanes (Scheme 28). Trapping of the intermediate carbene with N-phenylmaleimide, dimethyl maleate and dimethyl fumarate are also described. 

Deprotonation of the glycosyl acceptor by a glycosylidene carbene ought to lead to a highly reactive, initially unsolvated ion pair, where both donor and acceptor are activated and should react readily with each other. Stereoelectronic effects dictate that deprotonation of the acceptor occurs in the a-plane of the carbene (more or less equivalent to the plane of the pyranoside ring), whereas addition of the oxy-anion to the oxycarbenium cation has to occm in the n-plane, i.e. more or less perpendicular to the a-plane, and preferentially from the axial direction (illustrated in Scheme 2 by the carbene derived from the benzylated g/wco-diazirine 7). 

Scheme 2. Glycosidation of alcohols by glycosylidene carbenes derived from diazirines.

The high reactivity of glycosylidene carbenes enables rapid access to the first representatives of intermediates or products for which more convenient routes might subsequently be developed. 

Exploratory experiments have shown that glycosylidene carbenes also insert into the N-H bond of sulfonamides, whereas carboxamides yield esters, as illustrated by the product obtained from an A-Boc-asparagine benzyl ester (Figure 7c) [32]. Presumably, such esters are formed by hydrolysis of the initially formed imino ether 0-glycosides, suggesting that glycosylidene diazirines may be used for (selective ) cleavage of peptidic bonds. 

Nucleophilic addition of glycosylidene carbenes to triligated boron compounds followed by migration of a boron substituent to the glycosidic center should lead to... 

Treatment of the cellobiose-derived diazirine 26 with XeF2 in dichloromethane yielded a maximum of 22% of the desired difluoride and large amounts of azines (Scheme 8) [16]. In the presence of small amounts of MeOH, these azines were replaced by, mostly, the equatorial monofluoride. These results show that the reactivity of glycosylidene carbenes towards XeF2 is not pronounced, but sufficient to furnish the amounts of the desired difluoride required for the enzymatic tests [55]. 

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