Synthesis of the Hexasaccharide Fragment of Landomycin A Using a Mild, Reagent-Controlled Approach

Abstract

The synthesis of the hexasaccharide fragment of landomycin A is reported. Using ptoluenesulfonyl chloride mediated dehydrative glycosylation, we constructed the deoxy-sugar linkages in a stereoselective fashion without the need for temporary prosthetic groups to control selectivity. Through this approach, the hexasaccharide was obtained in 28 steps and 8.9% overall yield, which is an order of magnitude higher than that of previously reported approaches.

Evolution of a Reagent-Controlled Strategy for β-Selective C-Glycoside Synthesis

“…In the case of landomycin, we chose to examine a more convergent approach to the target. 24 To this end we initially targeted trisaccharide 19, which could serve as a precursor to both donor 20 and acceptor 21 required for oligosaccharide synthesis (Scheme 4). Following an iterative sequence of glycosylation and deprotection, the synthesis of 19 proceeded smoothly, as did the subsequent deprotections to provide 20 and 21.…”

Glycosyl Sulfonates Beyond Triflates

“…Concurrent with these studies, we also studied the application of our sulfonate‐mediated glycosylation chemistry to the synthesis of the landomycin A hexasaccharide (Scheme 6). We envisioned that this target could be obtained through a [3+3] approach where the two coupling partners were derived from the same trisaccharide precursor [24] . In the forward direction the synthesis commenced with the coupling of olivose donor 16 with acceptor 6 to afford disaccharide 24 in 81 % yield as a 16 : 1 (β : α) mixture of anomers.…”

“…We envisioned that this target could be obtained through a [3 + 3] approach where the two coupling partners were derived from the same trisaccharide precursor. [24] In the forward direction the synthesis commenced with the coupling of olivose donor 16 with acceptor 6 to afford disaccharide 24 in 81 % yield as a 16 : 1 (β : α) mixture of anomers. Removal of the Nap protecting group using DDQ and β-pinene as an acid scavenger afforded acceptor 25.…”

Catalytic Site-Selective Carbamoylation of Pyranosides

“…The two galactoside anomers 6a – b were converted into the corresponding products 7a – b where the carbamate function was selectively incorporated onto the equatorial O -3 position with no traces of anomeric epimerization. Various 4-methoxyphenyl (PMP) glycosides from the manno and galacto series were then envisioned, as the anomeric 4-methoxyphenyl group could be readily removed under oxidative conditions using ceric ammonium nitrate, thus enabling a straightforward preparation of glycoside donors . The d -mannose, d -galactose, l -arabinose, l -lyxose, and l -rhamnose derivatives 8a – e underwent the intended catalyst-controlled carbamoylation, providing the carbamates 9a – e in good yields ranging from 56% to 82%, with some substrates needing a longer reaction time to improve conversion.…”