FULL PAPER DOI: 10.1002/ejoc.200901445 Polymer-Supported Synthesis of Oligosaccharides Using a Diisopropylsiloxane Linker and Trichloroacetimidate Donors M. Mar Kayser, [a] José L. de Paz,* [a] and Pedro M. Nieto* [a] Keywords: Carbohydrates / Glycosylation / Oligosaccharides / Solid-phase synthesis We describe herein the polymer-supported synthesis of biolo- gically relevant oligosaccharides using a diisopropylsiloxane linker and trichloroacetimidates as glycosyl donors. Siloxane linkers offer important advantages over closely related silyl ethers since even sterically hindered alcohols can be directly loaded onto commercially available polymers, such as solu- ble polyethylene glycol (PEG), without prior manipulation of the support. Final products can be easily detached by mild Introduction The traditional synthesis of oligosaccharides is a time- consuming process, mainly due to the extensive need for purification steps and protecting-group manipulations. Polymer-supported, synthetic methodologies accelerate oli- gosaccharide production, facilitating intermediate purifica- tions by the simple washing of the support and, therefore, minimizing the number of chromatographic steps re- quired. [1,2] Additionally, the polymer-supported reactions can ideally be driven to completion by running several reac- tion cycles with excess reagents. The linker, the connection between the polymer support and the first monosaccharide, is of utmost importance for the entire synthetic process. Its chemical nature determines the reaction conditions that can be used during the oligosaccharide assembly and the cleav- age conditions required to release the final product from the support. Moreover, the linker should render the final oligosaccharide with an orthogonal functional group that allows for the creation of glycoconjugates. Among others, silyl ether linkers have been successfully employed for the polymer-supported synthesis of oligosac- charides. [3,4] Typically, sugar attachment to a solid support through a silyl ether linkage involves the synthesis of silyl halide resin by direct lithiation of polystyrene-like supports and reaction with dialkyldichlorosilane and subsequent silylation with a OH-bearing carbohydrate (see part A in Scheme 1). [5–9] Poor efficiencies are found when conducting [a] Instituto de Investigaciones Químicas, Centro de Investiga- ciones Científicas Isla de La Cartuja, CSIC-US, Americo Vespucio 49, 41092 Sevilla, Spain Fax: +34-954-460565 E-mail: jlpaz@iiq.csic.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.200901445. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2010, 2138–2147 2138 fluoridolysis to afford OH-tagged sugar probes. We followed an acceptor-bound approach that fixed the nucleophile on the polymer, and we selected soluble PEG as the support due to higher reactivity of bound sugars and easy reaction moni- toring. Following this strategy, the trisaccharide repeating unit of the capsular polysaccharide of Neisseria meningitidis (serogroup L) and the disaccharide containing the structural motif of hyaluronic acid were successfully synthesized. the loading at relatively hindered OH groups. To solve this problem, Danishefsky and coworkers described a new strat- egy for the solid-phase synthesis of oligosaccharides using a diisopropylsiloxane linker. [10] The siloxane linkage is formed by first reacting the sugar alcohol with dialkyldi- chlorosilane in solution prior to the attachment of the re- sultant chlorosiloxane intermediate to a polymer-bound alcohol (see part B in Scheme 1). This approach has been applied to the synthesis of glycopeptides following a donor- bound strategy and employing glycal-derived donors. [10] A siloxane linker has also been employed in the solid-phase synthesis of natural polyketide fragments, [11,12] oligonucleo- tides [13] and streptogramin antibiotics [14] and for the explo- ration of hetero-Diels–Alder reactions of dienes with poly- mer-supported acyl- and arylnitroso dienophiles. [15,16] Therefore, siloxane linkers [17,18] are attractive alternatives to silyl ethers. They exhibit stability under basic and acidic conditions, [19,20] and no prior manipulation of commer- cially available polymers is required (Scheme 1, B). This ad- vantage is particularly useful for soluble polyethylene glycol (PEG), since the preparation of noncommercially available silyl halide PEG is avoided, and OH-terminated PEG can be directly used. Siloxane linkers can be cleaved readily at the end of the synthesis by exposure to fluoride (Scheme 1, B). This treatment affords the original polymer support, which can be recycled for further use, dialkyldifluorosilane as a side product and a OH-functionalized sugar. This OH group, generated by fluoridolysis of the linker, can be con- sidered an orthogonal tag for further manipulation and bio- conjugation of the carbohydrate sample. [21] For instance, to- sylation and subsequent substitution by azide gives azido- terminated oligosaccharides ready for 1,3-dipolar cycload- dition with alkyne probes or Staudinger reduction to afford amines.