Synthesis of 4-Amino-4-Deoxy-L-Arabinose C-Phosphonate Esters as Transferase Inhibitors

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1st EuroCarb Young Researcher (ECYR) Workshop

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Mini symposium: Glycobiology at the LUMC and beyond

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Synthesis of 4-Amino-4-Deoxy-L-Arabinose C-Phosphonate Esters as Transferase Inhibitors

Lukas Kerner 1 , Charlotte Olagnon1, Paul Kosma 1

1 University Of Natural Resources And Life Siences Vienna, Vienna, Austria

The group of 17 opportunistic pathogens linked to severe infections in cystic fibrosis and other immunocompromised conditions has been known as the Burkholderia cepacia complex.[1] The inner Kdo residue of Burkholderia lipopolysaccharide (LPS), which is highly conserved across the genus, is flanked by 4-amino-4-deoxy-L-arabinose units (Ara4N).[2] Furthermore, the binding of Ara4N to the phosphate groups of lipid A has been purported as one of the reasons for hindered interaction with cationic agents and consequently, to induce antibiotic resistance.[3] We set out to synthesize a series of tenable Ara4N transferase (ArnT) inhibitors with the prospect of impeding the biosynthetic pathway towards activated Ara4N species.[4] By the same token, we intend to inhibit the transfer of Ara4N residues both to Burkholderia LPS core and lipid A in vitro. Our synthetic endeavours en route to C-glycosidic derivatives mimicking either the transition state of glycosyl transfer or ArnT natural substrate will be presented.

During the course of the synthesis, selective monodemethylation of dimethyl phosphonate 1 was accomplished in a high yield, followed by alkylation of the arising intermediate 2. Interestingly, the latter base-promoted reaction resulted in the formation of isomeric endo- and exo-derivatives 3 and 4, respectively. Successful cleavage of the remaining methyl group allowed us to aim our efforts at the global deprotection of these advanced intermediates.

Synthetic route overview

Financial support from the Austrian Science Fund FWF (grant P 28826) is greatly acknowledged.

A. R. Hauser, M. Jain, M. Bar-Meir, S. A. McColley, Clin. Microbiol. Rev. 2011, 24, 29-70.

A. DeSoyza, A. Silipo, R. Lanzetta, J. R. Govan, A. Molinaro, Innate Immun. 2008, 14, 127-144.

S. A. Loutet, M. Valvano, Front. Microbiol. 2011, 2, 159.

B. D. Needham, S. M. Trent, Nat. Rev. Microbiol. 2013, 11, 467-481.

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