Chapter 10
Oligosaccharide Synthesis with Glycosyl Phosphates Jeroen D. C. Codée and Peter H. Seeberger*
Downloaded by UNIV OF ARIZONA on August 6, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch010
Laboratory for Organic Chemistry, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
This chapter desribes the synthesis of glycosyl phosphates and their use as glycosylating agents. Their use in the construction of complex oligosaccharides, both in solution and on solid support, is presented. Their ease of synthesis in combination with their rapid activation have made them ideal glycosylating agents to be used for automated solid phase oligosaccharide synthesis.
Introduction The preparation of synthetic oligosaccharide sequences presents a significant challenge to the organic chemist.(1) The desired structures possess a myriad of hydroxyl groups, are often highly branched and require the stereospecific formation of glycosidic linkages. Nature employs glycosyltransferases to catalyze the formation of a new glycosidic linkage. These enzymes utilize nucleotide diphosphosugars (NDPs) as substrates/2) The preparation of NDPs is most commonly accomplished by the coupling of glycosyl 1-phosphates and nucleoside 5'-monophosphates. The variety of procedures available for the synthesis of anomeric phosphates was in stark contrast to the limited uses of glycosyl phosphates as glycosylating agents. Recent advancements, however, have resulted in an increased interest in phosphorus based glycosyl donors (3) that was initiated by Ikegami and co workers.^ 150
© 2007 American Chemical Society In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
151 Here we discuss the chemical synthesis of glycosyl 1-phosphates and their application in oligosaccharide construction. The focus of this review is on chemical methods and not enzymatic approaches, which have been the subject of excellent reviews/5) The synthesis of anomeric phosphates from glycal starting materials and the utilization of glycosyl phosphate triesters in the construction of O-glycosides is discussed. Finally, solid phase techniques employing glycosyl phosphates for the automated synthesis of complex structures are presented.
Downloaded by UNIV OF ARIZONA on August 6, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch010
Synthesis of Glycosyl Phosphate Triesters Generation of anomeric phosphate triesters for use as glycosylating agents and for the synthesis of NDPs has been accomplished from a variety of intermediates/J) Anomeric lactols and 1,2-anhydro sugars are commonly employed, while derivitization of other glycosylating agents (glycosyl imidates, w-pentenyl-, bromo- and thioglycosides), has also seen use in generating glycosyl phosphates. These methods allow for the construction of phosphate triesters containing various alkyl and aryl substituents. Glycals are attractive starting materials for the synthesis of glycosylating agents since they possess only three hydroxyl groups that need to be differentiated. Furthermore glycal derived 1,2-anhydrosugars can be transformed into fully protected glycosyl phosphates in a one-pot procedure/*?, 7) Thus, generation of the anhydrosugar with dimethyldioxirane followed by epoxide opening at low temperature and in situ acylation afforded building blocks 2-4 (Scheme 1A). This method worked well for both monosaccharide and disaccharide glycal moieties. Alpha or beta-enriched phosphates can be generated with this method depending on the solvent employed for the 1,2anhydrosugar opening. Coordinating solvents such as THF afforded predominantly a-phosphates while less polar solvents such as dichloromethane resulted in P-selective epoxide opening. The latter can be rationalized by the finding that anomerization takes place more rapidly in THF (Scheme \B).(7b) For example, when the ring-opening of 1,2-anhydrosugar 5 was carried out in CH C1 followed by acylation, P-phosphate 6 was obtained exclusively. Similarly, when the ring-opening was performed in THF and the newly generated C2-OH was immediately acylated, only the p-phosphate was obtained. When the ring-opening was allowed to stir at ambient temperature for 8 h and then acylated, a 1:1 mixture of anomers 6a and 6b was obtained. These results support earlier findings that a-phosphates could be formed from the P-isomers by acid-catalyzed anomerization. The possibility to create different types of 2
2
In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
152 anomeric phosphates proved particularly important with respect to the glycosylation properties of the ensuing species, since (as with most types of glycosyl donors) the P-phosphates are a lot more reactive than their ctcounterparts.(76) The installation of C2 protecting groups other than esters proved challenging. ' Benzylation employing sodium hydride and benzyl bromide resulted in migration of the phosphate to yield the C2-phosphoryl benzyl glycoside. Triethylsilyl ethers, on the other hand, were readily prepared by reaction of the C2-hydroxyl group of the glycosyl phosphate with triethylsilyl chloride and imidazole in DMF. In pure form, a- and P-glycosyl phosphates were found to be completely stable to storage for several months at 0°C. Downloaded by UNIV OF ARIZONA on August 6, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch010
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