Date

Thursday 22 Oct 2026

Time

15:15 - 15:45

Location

BW020

Supervisor

Jeroen Codee

2nd reviewer

Dmitri Filippov

Jury

Anthe Janssen

Long-range participation from the 4-position of galactosyl donors has been proposed as a means of controlling glycosylation stereoselectivity, but its mechanistic role remains controversial. In particular, it is unclear whether 4-O-acyl groups promote α-selectivity through formation of a 1,4-dioxepanium ion or through indirect electronic effects. Here, we investigate this question in galactosyl and fucosyl donor systems using a combination of glycosylation experiments, in situ NMR spectroscopy, and computational chemistry. A series of thioglycoside donors was activated under Ph₂SO/Tf₂O conditions and evaluated for their stereoselectivity using an array of acceptors of varying nucleophilicity. ¹H CEST and ¹⁹F EXSY NMR were used to characterize reactive species in solution, while conformational energy landscapes were calculated to assess the accessibility of the proposed dioxepanium ion. The results show that 4-O-acyl groups enable formation of a 1,4-dioxepanium ion, providing an additional pathway to the α-glycoside alongside the triflate pathways available to all donors. The proposed ion is both energetically accessible and detectable in solution, and the influence on the stereoselectivity persists when its population in solution is increased by a 4-C-methyl substituent. Conversely, replacing the 2-O substituent with an electron-withdrawing azide prevents formation of the dioxepanium ion and eliminates the additional α-selectivity associated with the 4-O-acyl group. These findings establish long-range participation through a 1,4-dioxepanium ion as the common mechanistic origin of the α-directing effect of 4-O-acyl groups in galactosyl and fucosyl glycosylations.