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Access to complex C2-branched glycoconjugates via palladiumcatalyzed aminocarbonylation reaction of 2-iodoglycals. Andrea Bordessa, Angélique Ferry, and Nadege Lubin-Germain J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02278 • Publication Date (Web): 22 Nov 2016 Downloaded from http://pubs.acs.org on November 23, 2016
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The Journal of Organic Chemistry
Access
to
complex
palladium-catalyzed
C2-branched
glycoconjugates
aminocarbonylation
reaction
of
via 2-
iodoglycals. Andrea Bordessa, Angélique Ferry*, Nadège Lubin-Germain*. Laboratoire de Chimie Biologique (LCB), Université de Cergy-Pontoise, EA 4505, 5 Mail Gay-Lussac, 95031 Cergy-Pontoise cedex, France.
ABSTRACT: A convenient straightforward synthesis of 2-amido-glycals through a palladiumcatalyzed aminocarbonylation reaction between 2-iodoglycal partners and diverse amines in presence of a “CO” source has been developed. Several amines such as aliphatics, benzylics or aromatics are compatible with our reaction conditions as well as sulfonamides. Further deprotection steps have been successfully applied leading to glycoside mimics. This method constitutes a new route to access to original glycopeptide- and glycolipid-type analogs possessing a C-C bond at the C2-position. The well-known ubiquity of carbohydrates and glycoconjugates (glycopeptides and glycolipids) in biological processes such as cell adhesion, cell recognition or immunity led chemists to develop new synthetic methodologies to build them or their analogs efficiently.1 In particular, the replacement of natural glycosidic linkages by mimic carbon-carbon bonds
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The Journal of Organic Chemistry
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(C-branched sugars) is widely explored due to the discovery of interesting natural bioactive C-glycosides such as Palytoxin or Spongistatin.2 Moreover, the enzymatic and chemical stability of C-C bonds as well as conformational similarity compared to C-O and C-N links are major strengths in carbohydrate-type mimic design in particular as sugar processing enzymes inhibitors.2c These promising properties led our laboratory to develop new synthetic access to C-branched glycoside and nucleoside analogs.3 Few years ago, we described the synthesis of a potential antiviral C-nucleoside mimic of Ribavirin via a key indium-mediated alkynylglycosylation step.3b Recently, C2-branched carbohydrates have been proved to mimic N-acetylglycosides which are key intermediates of lipid biosynthesis.4 In the literature, the preparation of C2-branched analogs of carbohydrate have been extensively described.5 However, access to C2-amidoglycoconjugates is still limited despite their proved potential inhibitory activity as stable glycoside mimics.6 Indeed, scarce C2-amidosugar examples are described where the amide link was generally inserted by cycloaddition reactions between a glycal-type starting material and an isocyanate or an azomethine imine partner (Figure 1).6,7 However, these methods require the synthesis of the suitable isocyanate or azomethine imine compound. These last decades, the development of versatile methods to build amide function via
metal-catalyzed
reactions
became
more
and
more
attractive.
In
particular,
aminocarbonylation process was proved to be a useful and powerful tool to insert amide parts.8 In glycoside chemistry, the formation of C2-branched analogs by metal-catalyzed cross-coupling steps is less explored. Indeed, only few examples of Suzuki-Miyaura, Sonogashira, Heck or Stille cross-couplings reactions were described on 2-halogenated compounds.9 However, to the best of our knowledge, access to C2-branched glycoconjugate analogs by an aminocarbonylation strategy has not been described so far despite usefulness. We describe thus a new convenient access to C2-amido glycosides by a palladium-catalyzed
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The Journal of Organic Chemistry
aminocarbonylation reaction from 2-iodoglycals and commercially available amines leading to original C2-branched glycoconjugates (Figure 1).
Figure 1. Synthesis of C2-amido-glycal scaffolds. We started our aminocarbonylation methodological study using classical catalytic system: Pd(OAc)2 (10 mol%), PPh3 (20 mol%), K2CO3 (2 equiv.) in DMF.9l To these conditions were added an amine partner (BnNH2) and a “CO” source (molybdenum hexacarbonyl Mo(CO)6). Table 1. Optimization of the aminocarbonylation reactiona
Solvent
Yieldb (%)
K2CO3
DMF
