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42397-G1
Development of the Thiazolyl Methodology for Convergent Synthesis of Complex Glycostructures

Alexei V. Demchenko, University of Missouri (St. Louis)

Thanks to the generous support provided by Petroleum Research Foundation, we have already acquired important results and significantly advanced in the direction of the development of a general glycosylation methodology and expeditious oligosaccharide synthesis. Based on the preliminary results that have been acquired in our laboratory with novel S-thiazolinyl (STaz) glycosyl donors, we conclude that the STaz glycosides can be successfully prepared from a variety of synthetic precursors and applied as building blocks in glycosylations. It has been determined that the STaz moiety can be selectively activated over conventional thioglycosides and O-pentenyl glycosides, while bromides, trichloroacetimidates, and thioglycosides could be activated over the STaz moiety (Scheme 1). Based on these studies, we discovered fully orthogonal character of STaz and S-ethyl/phenyl anomeric moieties. This discovery led to the synthesis of a model pentasaccharide derivative.1

Scheme 1. (sorry I could not bypass the firewall, would be happy to send the file by e-mail)

Many other synthetic strategies could be developed with these unique glycosyl donors, amongst which is inverse armed-disarmed concept. So far, we demonstrated that complete 1,2-trans selectivity can be achieved with the use of a 2-O-picolyl moiety, a novel neighboring group that is capable of efficient participation via a six-membered intermediate while retaining the glycosyl donor in the armed state, as opposed to conventional acyl participating moieties. The application of a novel arming participating moiety to complementary chemoselective oligosaccharide synthesis has been also developed. This new armed-disarmed glycosylation strategy allows chemoselective introduction of a 1,2-trans glycosidic linkage prior to other linkages (Scheme 2), as opposed to classic Fraser-Reid's approach. We expect that the developed technique, along with the classic armed-disarmed approach, would allow a convergent access to virtually any oligosaccharide sequence from only one type of a leaving group. We expect to publish a full article describing the extended studies and further application of the methodology developed.

Scheme 2.

Further application of the developed glycosylation approach emerged for the synthesis of target oligosaccharides of biological importance and medicinal relevance. We already reported the synthesis of the spacer-containing carbohydrate antigens Gb3 and SSEA-3 using STaz glycosides.3 The methodological importance of synthesizing the SSEA-3 pentasaccharide derives from the fact that its pentasaccharide backbone structure is structurally related to other complex glycosphingolipids of the globo series (see Figure 1). This strategy can be applied for the synthesis of the other tumor-associated antigens, the syntheses of which are currently under pursuit in our laboratory. These endeavors will be published in due course.

Scheme 3.

The method developed was also used for an efficient expeditious synthesis of pneumococcal oligosaccharides of Streptococcus pneumoniae (SPn) serotypes 6A and 6B (Scheme 4).4 Rapid oligosaccharide assembly was accomplished by selective activation of the STaz and SBox leaving group of glycosyl donors over the S-ethyl anomeric moiety of glycosyl acceptors. Application of the STaz and SBox methodology has also allowed completely stereoselective introduction of two challenging 1,2-cis glycosidic moieties. It is to be expected that the protocol reported herein will be suitable for the synthesis of recently discovered structurally similar serotypes SPn6C and 6D.

Scheme 4.

Further studies involving the synthesis of oligosaccharides, mimicking dimeric repeating unit motif of SPn14 have been nearly completed in our laboratory. A communication article describing the synthesis of the SPn14 oligosaccharides (Scheme 4) via the temporary deactivation concept is currently in preparation.5 Application of the thioimidoyl methodology in combination with the temporary deactivation principle allowed rapid oligosaccharide assembly. The use of the bidentate S-(2-pyridinium) Taz anomeric moiety (SPT, Scheme 4) as ligand for palladium(II) deactivation has proven to be advantageous in comparison with the STaz moiety. The article describing this discovery is currently in preparation with planned submission to Angewandte Chemie in Nov-Dec 2007 (Pornsuriyasak, P.; Rath, N. P.; Demchenko, A. V., "Temporary deactivation concept for a highly expeditious oligosaccharide synthesis." 2007, In preparation).

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