New catalysts for the synthesis of C-Glycosides
C-Glycosides
C-Glycosides are analogs of carbohydrates wherein a C-C bond is used to replace the usual C-O glycosidic linkage. This change engenders resistance of C-glycosides to enzymatic degradation. For example, the C-glycoside analog of the immuno-stimulant α-galactosylceramide, KRN 7000, shows a striking enhancement of activity. The C-glycoside analog was approximately 1000 times more effective than KRN7000 itself.
Although numerous synthetic methods have been developed for C-glycoside synthesis, most focus on conventional nucleophilic or electrophilic additions to the anomeric position of carbohydrates. Transition metal-catalyzed cross-coupling methods are considerably less developed despite providing a straightforward approach to these targets. One reason is that fully oxygenated carbohydrates are susceptible to β-elimination processes (hydride or alkoxy), which complicates any reaction that generates nucleophilic character at C1 or involves a C1-M intermediate; see scheme I.
One strategy for inhibiting beta-H elimination is to block the cis sites needed for formal transfer of the H to the metal center. Pincer ligands have accomplished this in a number of organometallic catalysts (see also the organo-Pt research section), and they have found utility in addressing this same problem in the cross-coupling reaction of elimination prone carbohydrates. Thus, NiCl2-PyBox complexes are efficient catalysts for the cross coupling of α-glycosidic halides and organozinc reagents; see scheme II. Yields and diastereoselectivities were particularly high for mannosides, while glucosides were slightly less so; scheme II. Representative examples of the transfer of functionalized alkyl zinc reagents is shown.
We continue to expand the type of compatible alkyl sources continue (e.g. to boronic acids), to additionally include aryl sources (C1-aryl glycosides are ubiquitous), and to examine furanose reactive partners.