Synthesis of monophosphoryl lipid A using 2-naphtylmethyl ethers as permanent protecting groups

Abstract

Lipid A, which is a conserved component of lipopolysaccharides of gram-negative bacteria, has attracted considerable interest for the development of immuno-adjuvants. Most approaches for lipid A synthesis rely on the use of benzyl ethers as permanent protecting groups. Due to the amphiphilic character of lipid A, these compounds aggregate during the hydrogenation step to remove benzyl ethers, resulting in a sluggish reaction and by-product formation. To address this problem, we have developed a synthetic approach based on the use of 2-naphtylmethyl ether (Nap) ethers as permanent protecting group for hydroxyls. At the end of a synthetic sequence, multiple of these protecting groups can readily be removed by oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Di-allyl N,N-diisopropylphosphoramidite was employed to install the phosphate ester and the resulting allyl esters were cleaved using palladium tetrakistriphenylphosphine. The synthetic strategy allows late stage introduction of different fatty acids at the amines of the target compound, which is facilitated by Troc and Fmoc as orthogonal amino-protecting groups.