Sigmatropic Approaches

A. Introduction

This section focuses on the use of concerted processes in the preparation of C-glycosides. The topics covered are cycloaddition reactions and Wittig rearrangements as approaches to C-glycoside synthesis.

B. Cycloaddition Approaches

1. Diels-Alder

Several types of Diels-Alder reactions have been applied to the preparation of C-glycosides. Some of these include approaches to prepare the sugar ring or to append

Scheme 50

a ring on an existing C-glycosyl derivative. Dipolar cycloadditions have also been utilized.

(a) From Sugar Dienes or Glycals. Lubineau et al. reported an aqueous Diels-Alder approach to the trehalo derivative 281. Cycloaddition of 279 in water at 140°C gave a mixture of four isomers, of which the major compound, 280a, was separated, debenzoylated, and reduced to give 281. Compound 281 showed only modest activity (IC50 = 47 mM) as an inhibitor or porcine kidney trehalase (Km = 3 mM) (Scheme 50) [75].

In attempting to prepare sugar-based radical acceptors, Martin and Xie found that treatment of 282 with base to generate enone 283 gave instead the dimerized product 284; the result of a [4 + 2] cycloaddition reaction. Compound 283 was never isolated from the reaction mixture (Scheme 51) [76]. Quayle and coworkers used a Stille coupling approach to prepare a number of sugar-based dienes that then under-

Scheme 52

went a facile cycloaddition reaction with Cookson's reagent 287 to give good yields of the cycloadducts. The reaction shown in Scheme 51 is illustrative [77].

Work in this area has also been carried out with noncyclic carbohydrates. Reaction of the nitro sugar 289 with cyclopentanedienone gave a mixture of 291 and 290 in a 1.9:1 ratio (Scheme 52) [78]. Dondoni used his masked formyl derivative in a hetero-Diels-Alder approach to carbon-linked disaccharides. Cycloaddition of 293 with ethyl vinyl ether gave a mixture of isomers; the major compound, 294, is shown in Scheme 52. The cycloadduct was then converted to 295 via standard methods [79].

(b) De Novo Ring Formation. Varelis and Johnson utilized a hetero-Diels-Alder reaction to prepare the pyran ring system 300. The olefin diastereomers were separated, and reduction followed by acetylation gave 298. Ireland ester rearrangement of 299 proceeded with syn selectivity to deliver the 1,6-dialkyl C-glycoside-like structure 300 (Scheme 53) [80].

Hanna and coworkers used a [2+2] cycloaddition approach for the preparation of precursor en route to forskolin. Dichloroketene cycloaddition with glycal 301 was followed by reductive dechlorination to give 302 in 80% overall yield. Several steps were required to convert 302 into the forskolin (304) Diels-Alder precursor 303 (Scheme 54) [81].

(c) Other Cycloadditions. Holzapfel and van der Merwe utilized a palladium-mediated [3+2] cycloaddition of nitroglycal 305 to deliver the C-glycosides 306 and 307 in a 1:2.4 ratio (Scheme 55) [82]. The 1,3-dipolar nitrone cycloaddition has also been employed for the preparation of pseudo-aza-C-disaccharides from glycals. Ex-

Scheme 53

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