The chemistry of C-glycoside compounds has been of considerable interest over the last 20 years. This class of compounds is defined as compounds in which the exo-cyclic oxygen atom of an O-glycoside has been replaced by a carbon atom (Fig. 1). C-Glycosides are not solely man-made, but are the creation of nature, as attested by the occurrence of many C-glycoside natural products. Unlike the corresponding O-glycosides, C-glycosides are unaffected by hydrolytic or enzymatic cleavage and therefore would seem to be ideally suited for use as stable sugar mimics. They possess a level of chemical stability comparable to that of cyclic ethers. Several reviews have appeared on the subject of C-glycoside preparation, as well as two monographs.

Many methods for the preparation of both the a- and ^-C-glycosides have been developed, and new approaches are still appearing in the literature. This chapter covers the literature from the end of 1994 to early 1999, with other inclusions as deemed appropriate. Following the organization of earlier work [1], we select the mode reactivity of the anomeric center to define the category. The chapter discusses free radical chemistry, C1 anions, Wittig chemistry-cyclization chemistry, transition metal mediated chemistry, sigmatropic chemistry, and approaches based on cationic chemistry. The chapter focuses on the most recent and novel developments in the field, but all the relevant references are included whenever possible.

Figure 1

O-methyl glycoside methyl C-glycoside

Figure 1


The use of free radical chemistry at the anomeric center to produce carbon-carbon bonds, especially in an intramolecular fashion, remains a popular method for C-glycoside synthesis. A review entitled ''C-Glycosidation Technology with Free Radical Reactions'' appeared in early 1998, and the reader is referred to that source [2] as well as to the more traditional ones for complete overviews on the subject. Again, the coverage here focuses on the most recent developments.

B. Intermolecular Approaches

1. Anomeric Radicals

Wang has studied the trapping of anomeric pyranosyl radicals with f-butylisocyanide to give anomeric cyanides. The readily available acetylated gluco derivative 1 when exposed to f-butylisocyanide in the presence of AIBN and tris(trimethylsilylsilane), gave a 73% yield of the a isomer 2. Other sugars were examined and gave products with yields in the range of 22-71%, (Scheme 1) [3]. Junker and Fessner examined the addition of anomeric radicals to vinyl phosphonic dialkyl esters to deliver C-glycosyl-phosphonates directly. Thus exposure of 3 to standard radical conditions in the presence of vinyl phosphonic dimethyl ester gave 4 in 31% yield. Several other sugars were examined and generally gave yields of similar magnitude with excellent ratios, (Scheme 1) [4].

Scheme 2

The use and application to C-glycoside preparation of a different radical initiator also have been reported [5]. Schwartz has reported that treatment of glycosyl halides with (Cp2TiCl2)2 leads to glycals, presumably via the anomeric organometallic intermediate 6. However, if the reaction is carried out in the presence of a Michael acceptor, such as MVK, then the initially formed radical can be trapped and undergo carbon-carbon bond formation to give the a-C-glycoside 9. Methyl acrylate and acrylonitrile were also examined as radical traps. The product is presumably formed as the titanium enolate 8, which should be useful for further transformations (Scheme 2) [6].

Witzack et al. also carried out the following intermolecular radical addition to the levoglucosenone 11. The addition was highly exo-face selective and product 12 was obtained in 26% yield along with the remainder of product being that of direct reduction of 10, (Scheme 3) [7].

Allylations have continued to serve as useful reactions, and Bertozzi et al., found that radical allylation of the 2-deoxy-2-phthalimido derivatives 13 and 14 gives good to excellent selectivity of the ^-allylated isomers 15 and 16, (Scheme 4). This is contrasted to allylations of the 2-deoxy-2-acetyl derivative, which gives mainly the a product, which is the normal stereochemical course for additions of these types. Presumably the steric bulk of the phthalimido group plays a role in directing the stereochemistry of the addition [8].

Praly et al. cleverly used radical allylation of sugars to obtain ^-C-glycosides. Treatment of the 1-bromoglucopyranosyl chloride 18 with tri-ra-butylallyltin under photolytic conditions gave the intermediate ^-allyl compound 19. When 19 was further exposed to standard radical reducing conditions (Bu3SnH, hv) the expected ^-allyl C-glycoside 20 was formed in good yield. Alternatively, 19 could be treated

Scheme 4

O Ac

O Ac

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