Linkages, unnatural

Because of this situation, the prospect of synthesizing D-rhamnosyl cardenolides containing the unnatural, a-D-linkage was investigated. D-Rhamnose has not been reported to occur naturally, but it has been synthesized by Hudson and co-workers (4) in six steps, starting with methyl a-D-mannopyranoside. An intermediate in the synthesis is methyl... 

Assay results with the two new 1,2-cis (ft-d) cardenolides show enhanced activity as compared with the two unnatural, a-D-rhamnosides. They have potencies that fall well within the range for those of the naturally occurring cardenolides. These results support the postulate that the a-D-glycosidic linkage in cardenolides containing D-sugars is unfavorable for cardiotonic activity. 

The result was quite disappointing, as instead of the required 3 -5 -phosphodiester linkage, which is found in nucleic acids today, the main products obtained were those with the unnatural 2 -5 -bond between the nucleotides. Further experiments showed that the presence of divalent metal ions had a clear positive effect on the matrix-dependent polycondensation. The addition of l-10mMPb2+ to 100 mM of poly(U) as the matrix and 50 mM of ImpA monomer caused the yield of oligomeric product (pentamers and longer) to increase by a factor of four (Sleeper et al., 1979). 

The ether linkage is a major structural motif found in a broad range of natural and unnatural structures. Due to the biomedical and industrial importance of these molecules, the efficient and selective construction of ether bonds has been a topic of long-standing interest. While numerous etherification processes have been developed ever since the discovery of the Williamson ether synthesis,1 an increasingly large number of examples have employed transition... 

Hoadley, K. A., Purtha, W. E., Wolf, A. C., Flynn-Charlebois, A., and Silverman, S. K. (2005). Zn2+-dependent deoxyribozymes that form natural and unnatural RNA linkages. Biochemistry 44, 9217—9231. 

Since calotropagenine, the aglycone of uscharidine, is accessible only with difficulty, model experiments have been carried out with the more readily available cholestan-2oc,3P-diol 21. On Ag2C03-mediated reaction with actino-spectosyl chloride 18 two isomers formed smoothly in an approximate 3 1 ratio, of which the major one - as evidenced by H- and 13C-NMR data, corroborated by NOE experiments - proved to be the "unnatural" anellation product 23. The minor product 22, however, could be readily debenzoylated by treatment with butylammonium acetate in aqueous acetonitrile to afford the uscharidine analog 24 albeit in modest yield (46), yet crystalline form so that its linkage geometry could be secured by an X-ray structure analysis (47). 

We have developed two methods for the synthesis of natural and unnatural products from D-glucose. Enantio-and diastereo-switching method established a new strategy for the synthesis of four possible stereomers for natural products synthesis, and this powerful method was successfully applied to the synthesis of unnatural protein phosphatase inhibitors. The second synthetic method involved the preparation of the urea-glycosidic linkages for the synthesis of glycopeptide mimics. 

This chapter first examines the different methods for the preparation of relevant synthetic glycoproteins largely where the linkage between the proteic part and the saccharidic moiety is unnatural. The later discussion focuses on the application of... 

This section highlights the currently most common and important unnatural linkages used to prepare glycoproteins (Fig. 19.1). The increasing demand for new therapeutics will lead to new members on this list. 

FIGURE 19.1 Examples of unnatural linkages used to prepare glycoproteins. 

SCHEME 19.9 Endo-A-catalyzed glycosylation of glycoproteins bearing unnatural linkages. 

Other conversions to unnatural residues occur when most proteins are exposed to high pH (80, 81,82). The high pH causes a -elimination of a cystine (see Figure 16) or O-substituted serine or threonine, with the formation of a dehydroalanine or a dehydro-a-aminobutyrate. Such products are subject to nucleophilic attack by the e-amino group of a lysine to form a cross-linkage, such as lysinoalanine, or attack by cysteine to form lanthionine. Walsh et al. (81) have taken advantage of the formation of these cross-links to produce avian ovomucoids that have nonreducible cross-links and have lost the antiprotease activity of one of their two inhibitory sites (see Figure 17). 

---