Because of their inherent reactivity, cyclic enol ethers serve as precursors to a number of interesting heterocyclic compounds and have garnered the attention of the chemical synthesis community. Among the variety of methods that have been reported for their synthesis, there has been considerable interest in the cyclization chemistry of olefinic esters via the two-step metathesis sequence outlined in Scheme 1. 1,2 Clearly, a more efficient method of transforming 1 into 3 would bypass acyclic enol ether intermediates (e.g., 2). Along these lines, successes have been reported. In the mid 1980s, Grubbs, Stille, and Santarsiero successfully synthesized capnellene by utilizing strained olefinic esters (norbornenes) in ring-opening metathesis, carbonyl olefination reactions. 3 Subsequently, Grubbs and Fu reported the use of a tungsten alkylidene to generate a cyclic enol ether directly from an acyclic olefinic ester. 4 In 1996, Nicolaou and co-workers reported olefinic ester cyclization reactions using the Tebbe and Petasis reagents to generate fused ether compounds. 5 While Nicolaou's results were certainly impressive, the applicability of these reagents in olefinic ester cyclizations appears to be limited. A number of groups including ours have reported the reactions to be capricious and to lead, with some substrates, to a multitude of undesired side products. 6
An improved synthesis of the hexasaccharide MBr1 antigen (globo-H) is reported. Enhanced efficiency in the synthesis was necessary for the scale up production of globo-H, in order to advance globo-H based anticancer vaccines to clinical trials. The key features of the improved synthesis include preactivation-based glycosylations and a revised iodosulfonimidation/ rearrangement.The glycosphingolipid globo-H (1, Figure 1), first isolated by Hakomori and colleagues from the breast cancer cell line MCF-7, 1 is recognized by the monoclonal antibody MBr1. 2 This human breast cancer-associated antigen was found to be distinctively overexpressed on the surfaces of a variety of other epithelial cancer cells such as prostate, ovary, lung, colon, and small cell lung cancers. 3 For this reason, the globo-H antigen has played an important role in our ongoing carbohydrate-based cancer vaccine program. 4 Of particular interest to our laboratory was a recent report, indicating that globo-H and SSEA3 -the pentasaccharide precursor of globo-H -are also overexpressed in breast cancer stem cells. Interestingly, when co-administered with an immunological adjuvant (α-galactosylceramide), a globo-H based vaccine induces antibodies against both globo-H and SSEA3. 5 In the light of the fact that cancer stem cells are often responsible for relapse and metastasis of cancerous tissues,6 it is envisioned that globo-H based therapy might form the basis of an important new direction in cancer treatment. Indeed, the globo-H vaccine, 2, synthesized in our laboratories as a glycoconjugate appended to immunogenic carrier protein, has shown promise as a potential breast and prostate cancer vaccine, in preclinical, and even clinical settings.4a-e More recently, we also disclosed the synthesis and preclinical evaluation of the unimolecular pentavalent vaccine 34f-g, displaying globo-H and other antigens known to be overexpressed on prostate and breast cancer cell surfaces. The thought was to construct a single entity antigen system which reflects the actual degree of carbohydrate heterogeneity associated with most cancers. 7 Nonetheless, the accessibility of such complex carbohydrate antigens remained as an important question. Globo-H isolated from human cancer tissue collections is typically limited to sub-milligram levels, which impedes broader * s-danishefsky@ski.mskcc.org .Supporting Information Available: NMR spectra for 6, 7, 8, 9, and 10. This material is available free of charge via the Internet at http://pubs.acs.org. Figure 2). Although this concise and stereoselective strategy allows rapid access to globo-H, some steps, particularly those leading to DEF donor 7, still require further optimization if we are to secure the globo-H antigen in amounts required for our ongoing clinical trials with globo-H, both in monovalent and multivalent settings. NIH Public AccessIn this regard, we report herein our efforts to seek a much improved synthesis of the DEF donor 7 and ABC accepter 8. As described in our earlier report, 4b,13 DEF trisac...
Wie in freier Wildbahn: Die erste Totalsynthese des Wildtyp‐Glycoproteins Erythropoietin (siehe Bild) konnte abgeschlossen werden. Für das synthetisch gefaltete Protein wurde Erythropoietin‐Aktivität nachgewiesen.
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