A Double Ring‐Closing Metathesis Approach for the Synthesis of β‐C‐Trisaccharides

Abstract

The synthesis of C-glycosides, compounds in which the interglycosidic oxygen atom has been replaced by a carbon atom, has received considerable attention from both the synthetic [1] and biological [2] point of view. They comprise an important class of stable carbohydrate mimics and the debate regarding their validity as conformational mimics of the parent O-glycosides is ongoing. [3] Although there have been many interesting and unique approaches to the synthesis of C-glycosides, [4] the preparation of C-saccharides, [5] whether they are C-disaccharides or higher homologues, has been considerably more challenging. The first C-trisaccharide synthesis by Kishi and co-workers [6] clearly showed that these compounds could be prepared and, since that time, several other research groups [7] have targeted these carbohydrate-based compounds for synthesis. There are two main challenges associated with the synthesis of Csaccharides. The first challenge is the difficulty associated in functionalizing one carbohydrate ring (or open chain) followed by its subsequent attachment to the anomeric center of a second (or more) monosaccharide unit(s). To address this, several approaches to the synthesis of a variety of differentially linked C-saccharides [5] have been developed and we have recently published a unified and versatile strategy for a convergent and efficient synthesis of (1!6)-b-C-disaccharides [8] and a variety of differentially linked b-C-disaccharides.[9] Our ring-closing-metathesis (RCM) [10] approach is flexible enough to deliver a wide variety of C-glycoside-type structures.[11] We now report that our metathesis-based approach can be used to efficiently synthesize a variety of b-C-trisaccharides through a highly efficient double enol ether-olefin RCM cyclization [12] that provides the products in excellent overall yield after functionalization of the newly formed double bonds.The general approach begins with dehydrative coupling of olefin alcohol 1 with a suitable carbohydrate-based diacid such as 2 to give diester 3 (Scheme 1). Methylenation of 3 is followed by a double RCM reaction to give bis-C-glycal 5. Functionalization of the bis-glycal double bonds then delivers the b-C-trisaccharide 6.In our previous C-disaccharide work [8,9] the installation of only one acetyl group onto the pyranose ring was needed, whereas in this case the preparation of a diacetyl derivative was required. We permitted the nature of the diacid to dictate the type of chemistry that would be used for its preparation. Scheme 2 shows the use of both Wittig-and Keck-type allylation chemistry for the synthesis of diacid 2 a. The primary alcohol on 7[13] was oxidized, olefinated, and hydrogenated, which served to reduce the double bond and cleave the benzyl group, to furnish 8. The Robins-based [14] radical precursor was then installed by using the N-hydroxysuccinimide method [15] and Keck allylation [16] then delivered compound 9 as the sole isomer. Two-step oxidative cleavage of the olefin in 9 to an intermediate monoacid was followed by sa...