Total Synthesis of Legionaminic Acid as Basis for Serological Studies

Abstract

Legionaminic acid is a nine-carbon diamino monosaccharide that is found coating the surface of various bacterial human pathogens. Its unique structure makes it a valuable biological probe, but access via isolation is difficult and no practical synthesis has been reported. We describe a stereoselective synthesis that yields a legionaminic acid building block as well as linker-equipped conjugation-ready legionaminic acid starting from cheap d-threonine. To set the desired amino and hydroxyl group pattern of the target, we designed a concise sequence of stereoselective reactions. The key transformations rely on chelation-controlled organometallic additions and a Petasis multicomponent reaction. The legionaminic acid was synthesized in a form that enables attachment to surfaces. Glycan microarray containing legionaminic acid revealed that human antibodies bind the synthetic glycoside. The synthetic bacterial monosaccharide is a valuable probe to detect an immune response to bacterial pathogens such as Legionella pneumophila, the causative agent of Legionnaire's disease.

Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis

“…In this review, many applications of α-amino acids as chiral inducers in a substrate-controlled manner were specifically discussed. To establish challenging stereocenters in natural product architectures, the chirality of α-amino acids was applied to a remarkable variety of reactions, such as rearrangement, cyclization, cycloaddition, [50,51]. Conventional protection of chiral pool reagent 77, followed by DIBAL-H reduction, provided chiral aldehyde 78 in high yield [52].…”

“…Recently, Seeberger et al published the total synthesis of protected legionaminic acid 80 from D-threonine as a starting material (Scheme 16) [50,51]. Conventional protection of chiral pool reagent 77, followed by DIBAL-H reduction, provided chiral aldehyde 78 in high yield [52].…”

Preparation of legionaminic acid analogs of sialo-glycoconjugates by means of mammalian sialyltransferases

“…These are all considerably larger substrates than the ones we examined previously [1,2] so their successful modification extends the scope of these reactions to more biologically interesting substances, which was not possible with the bacterial sialyltransferases. However the recent finding of natural antibodies to legionaminic acid in human sera [21] rules out their use as therapeutics, though its known derivatives such as the 5-acetamidino form [22] may not be as reactive. (upper panel) and the GM1a starting material (lower panel).…”

Stereoselective Synthesis of 5-epi-α-Sialosides Related to the Pseudaminic Acid Glycosides. Reassessment of the Stereoselectivity of the 5-Azido-5-deacetamidosialyl Thioglycosides and Use of Triflate as Nucleophile in the Zbiral Deamination of Sialic Acids

“…Indeed, only two simple glycosides have been prepared chemically to date – one each of Leg and Pse, both involving formation of very simple axial glycosides with primary alcohols. 13–14 Seeberger has presented a synthesis of Leg in eleven steps from d -threonine 13 with numerous subsequent steps needed to prepare a simple axial glycoside; the more difficult equatorial glycosides were not addressed. 13 Earlier syntheses by Tsvetkov and by Ito involved homologation of suitable hexoses and subsequent adjustment of functionality and were longer.…”