Expedient synthesis of l-heptose derived septacidin building blocks from l-glucose

Lien DOI – 10.1016/j.carres.2023.108985

Carbohydr. Res. 2023, 534, 108985

Bacterial natural products containing heptosides such as septacidin represent interesting scaffolds for the development of drugs to combat antimicrobial resistance. However, very few synthetic strategies have been reported to grant access to these derivatives. Here, we have devised a synthetic pathway to l-glycero-l-glucoheptoside, a key building block en route to septacidin, directly from l-glucose. Importantly, we show that carbon homologation at C6, encompassing oxidation of the C6-OH followed by methylenation, is significantly influenced by the nature of the C4-moiety. In order to observe the effect of various patterns, namely azide (N₃), p-methoxybenzyloxy (OPMB), and benzyloxy (OBn), a thorough analysis was conducted on the corresponding l-glucosides. The results unveiled a distinct trend where the efficiency of methylenation followed the trend OBn > OPMB > N₃. Finally, the C6-alkene was dihydroxylated in the presence of osmium tetroxide to yield the expected l/d-glycero-l-glucoheptosides. The lead building block, which features a C-4 azide, was delivered as a phenyl thioglycoside. Added to the suitable masking of the 6,7-diol, this combination enables further functionalization to achieve versatile compounds of biological interest. The study insights into the interplay between substitution at C-4 and carbon homologation at C-6 provide valuable guidance for future endeavors in the synthesis of these carbohydrate molecules.