Synthetic Studies toward 2,3-di-N-Acyl-2,4,6-Trideoxy-L-Altropyranoses as Synthetic Precursors to Pseudaminic Acid
Creators: name: Niedzwiecka, Anna
Publisher: name: Graduate Studies
Year: 2023
Subjects: subject: Total Synthesis
subject: Carbohydrates
subject: Antibiotics
subject: Polysaccharide Conjugate Vaccines
subject: Pseudaminic Acid
subject: Nonulosonic Acid
subject: Chemistry--Organic

description: With the growing therapeutic inefficiency of traditional antibiotics by rapidly spreading antimicrobial resistance (AMR) through different mechanisms, and a significant slow-down in the development of novel antimicrobials, especially in the pharmaceutical industry during recent years, it is of utmost importance to maintain research to address this global challenge. The chemical synthesis of carbohydrate antigens that are unique to pathogenic bacteria can benefit the search for antibacterial therapeutics with the development of prophylactic vaccines such as polysaccharide conjugates. Bacterial nonulosonic acids (NonAs) that include pseudaminic (Pse) and legionaminic (Leg) acids are found in important structural components that contribute to certain pathogens’ virulence, like Pseudomonas aeruginosa and Campylobacter jejuni: they have been recently shown to be good candidates for use as antigen epitopes in vaccination, and their biosynthetic precursors can also be used towards the development of other types of antibacterial therapeutics. The research presented here begins with preliminary investigations into a synthesis from L-arabinose that has the potential to produce 5 different NonA structures with only a few appropriate variations in the scheme. The synthesis of two C5-(R)/(S) hexose diastereomers was achieved with different selectivity, and those can further undergo an inversion and installation of nitrogen functionalities on C-2 and C-4, before the final three-carbon extension with a phosphoenolpyruvate (PEP) equivalent to produce the target NonA. The work showed promise, justifying future development. Next, a short, mild and scalable synthetic scheme towards 2,4-di-acetamido-2,4,6-trideoxy-L-altrose (Alt-diNAc), the biosynthetic precursor to Pse, is presented: the desired product was obtained from commercially available L-fucose in 10 steps and 23% overall yield, making it the most efficient synthesis published to-date. A further optimized shorter version of synthesis is described as well through regioselective sulfonyl activation to form a key epoxide intermediate, ultimately giving Alt-diNAc in 7 steps and 27% overall yield. Based on these achievements, a new and elegant methodology for the differentiable functionalization of the N2/N4 amide groups of Alt-diNAc was developed, which relies on a regiospecific O→N migration of acyl groups during a Staudinger reduction of the O-acylated di-azido precursor. The new methodology was proved to have broad scope and provides unprecedented versatility to introduce different N-acyl functionalities to the N5 and N7 positions of Pse. Finally, preliminary work towards a potentially stereoselective three-carbon extension of hexose precursors to NonAs is described, with the synthesis of a phenol-based cleavable linker containing an α-methyl ketone that can potentially undergo aldol addition intramolecularly, and then ruthenium-catalyzed oxidation to produce the required carboxylic functionalities for Pse. A successful selective coupling of this linker to one of the two amido groups on the L-altro-configuration precursor was then achieved, paving the way to investigate the diastereoselectivity of intramolecular aldol additions with this strategy in the future. Several possible variations to the linker functional groups and length can easily be incorporated in this synthetic plan , and provide an exciting prospect for future developments.