C-disaccharide analog

C-Disaccharide analogs of trehalose were recently [20c] prepared by using as a key step an aqueous Diels-Alder reaction between the sodium salt of glyoxylic acid and the water soluble homochiral glucopyranosil-l,3-pentadiene 19 (Equation 6.1). A mixture of four diastereoisomers in a 41 24 21 14 proportion was obtained after esterification with methanol and acetylation. The main diaster-eoisomer 20 was isolated and characterized as benzoyl-derivative. 

As shown in Eq. 12.54, with glyoxylate as the dienophile, if the attack is on the si face of the diene, it would lead to the skeleton of KDO if the attack is on the re face, it would lead to the skeleton of KDN. C-Disaccharide analogs of trehalose were prepared using an... 

Isomerization of the C-allyl glycoside 302 provides the corresponding C-(l-propenyl) derivative 303 as a major E-isomer. Cross metathesis proceeds in high yield only with the Grubbs II catalyst to deliver the homodimer 304, transformed to C-disaccharide analog 305 of the mycobacterial motif. 

A phosporamidic linker also proved viable, as reported in the synthesis of the C-disaccharide analog of a-D-GalNAc(l-4)-D-Glc (Scheme 34) [64]. Intermediate 131 prepared in two steps from the galactosamine derivative 130 and the unsaturated... 

Initial Wittig reaction of the readily available arabinose derivative 138 and the phosphonium salt 139 led to the cis alkene 140 (Scheme 38). Stereoselective dihy-droxylation, exploiting the 1,3-allylic strain effect, then monoprotection of the diol, oxidation and cleavage led to the cyclic hemiacetal 142 after protection of the primary alcohol. Reduction of the hemiacetal was best performed with /j-PrsSiH, affording exclusively the p anomer 143. Deprotection and acidic methanolysis then led to the C-disaccharide analog 144 of p-D-Man(l-4)-D-Glc. On the other hand, simple oxidation of the C2-hydroxyl group in 143 followed by stereoselective reduction converted the manno series to the gluco series with the eventual formation of C-cellobioside 145. 

The importance of substituent and conformational effects in glycal additions was also demonstrated in attempting Michael addition of an alkoxide to the O-linked 2-nitrogalactal 1S3 and its C-linked analog 154. The a-toio-isomer 156 was obtained from 154 in contrast to the result of Michael addition to the analogous O-linked disaccharide 153, which eventually gave the 2-acetamido-a-galactoside-terminated disaccharide 155. 

P. Vogel, S. Gerber-Lemaire and L. Juillerat-Jeanneret, Imino -C- disaccharides and analogs synthesis and biological activity, in Imino sugars, from synthesis to therapeutic applications, ed. P. Compain and O. Martin, Wiley, 2007, pp. 87-130. 

Glycals can also be obtained from suitable substrates, by ring-closing olefin metathesis reactions. In a general approach to variously linked C-disaccharides, illustrated in O Scheme 48, nonreducing-end glycals are typical intermediates, finally subjected to hydroboration or dihy-droxylation to afford the desired C-analogs of O-disaccharides [238,239]. 

Coupling of sulfone 187 with aldehyde 175 provides a mixture of four isomers which, after oxidation, epimerization and reacetylation produce the 8-linked C-disaccharide 188, a protected analog of the /3-D-GlcNAc-(l— 6)-D-Man motif of tri- and tefra-antennary complex-type... 

Thioacetal 418 was used by Mootoo to access several C-linked disaccharides [153,154] including the C-hnked analog of a Sialyl Lewis x mimetic [155] (O Scheme 82). 

Diels-Alder methodology is well suited to the preparation of C-monosaccharides and higher carbohydrate analogs. In general, these reactions provide products with high degrees of stereochemical induction as well as exhibiting synthetically useful yields. Further examples of Diels-Alder reactions applied to the preparation of C-disaccharides will be elaborated upon in Chapter 8. 

Additional work in 1987 centered around studies of the preferred conformations of various C-disaccharides. Preliminary work by Kishi, era/.,13 was subsequently confirmed by the same group in 1991.14 In these reports, utilizing C-glycosidic analogs of isomaltose and gentiobiose (Figure 8.5.1), it was determined that conformations of C-disaccharides can be predicted on the basis of steric interactions alone. This conclusion, based, in part, on similarities regarding the conformations and behaviors of conventional disaccharides in variable temperature proton NMR studies, was later extended to the conformations of C-trisaccharides introduced in Chapter 1. 

Among the most important C-disaccharide syntheses reported in 1989 is the preparation of C-sucrose. This analog of table sugar is interesting in that unlike natural sucrose, it cannot be metabolized to lower sugars. An actual synthesis of C-sucrose was reported by Nicotra, et ai.,22>23 and is illustrated in Scheme 8.7.5. As shown, the C-glucoside, prepared as discussed in Chapter 2, was converted to a metallated alcohol in 97% yield. Subsequent oxidation of the metal with iodine followed by oxidation of the alcohol to a ketone and... 

FIGURE 8.11 Bactericidal effect of moenomycin and disaccharide analog 31 on Gram-positive bacteria (S. aureus and S. epidermidis). Moenomycin was added to 100 times MIC and disaccharide analog 31 added to 8 times MIC. C.f.u. s were determined by plating serial dilutions at various times following drug addition. 

FIGURE 11.7 Moenomycin A disaccharide analogs. (From Nicolaou, K.C. et al., Radiofrequency encoded combinatorial chemistry, Angew. Chem., hit. Ed. Engl., 34, 2289, 1995.)... 

French A.D., Kelterer A.-M., Johnson G.R, Dowd M.K., and Cramer C.J. 2001a. HF/6-31G" energy surfaces for disaccharide analogs. J Comput Chem 22 65-78. 

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