Neighboring-group participation by C-2 acyloxy groups: influence of the nucleophile and acyl group on the stereochemical outcome of acetal substitution reactions

Chun, Y.; Remmerswaal, W.A.; Codee, J.D.C.; Woerpel, K.A.

doi:doi:10.1002/chem.202301894

A single acyloxy group at C-2 can control the outcome of nucleophilic substitution reactions of pyran-derived acetals, but the extent of the neighboring-group participation depends on a number of factors. We show here that neighboring-group participation does not necessarily control the stereochemical outcome of acetal substitution reactions with weak nucleophiles. The 1,2-trans selectivity increased with increasing reactivity of the incoming nucleophile. This trend suggests the intermediacy of both cis-fused dioxolenium ions and oxocarbenium ions in the stereochemistry-determining step. In addition, as the electron-donating ability of the neighboring group decreased, the preference for the 1,2-trans products increased. Computational studies show how the barriers for the ring-opening reaction on the dioxolenium ions and the transition states to provide the oxocarbenium ions change with the electron-donating capacity of the C-2-acyloxy group and the reactivity of the nucleophile...Show moreA single acyloxy group at C-2 can control the outcome of nucleophilic substitution reactions of pyran-derived acetals, but the extent of the neighboring-group participation depends on a number of factors. We show here that neighboring-group participation does not necessarily control the stereochemical outcome of acetal substitution reactions with weak nucleophiles. The 1,2-trans selectivity increased with increasing reactivity of the incoming nucleophile. This trend suggests the intermediacy of both cis-fused dioxolenium ions and oxocarbenium ions in the stereochemistry-determining step. In addition, as the electron-donating ability of the neighboring group decreased, the preference for the 1,2-trans products increased. Computational studies show how the barriers for the ring-opening reaction on the dioxolenium ions and the transition states to provide the oxocarbenium ions change with the electron-donating capacity of the C-2-acyloxy group and the reactivity of the nucleophile.Neighboring-group participation by C-2 acyloxy groups can control the 1,2-trans stereoselectivity of acetal substitution reactions with the employment of strong nucleophiles. 1,2-Trans selectivity increases with decreased electron-donating ability of the acyloxy groups at C-2.image.Show less

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Neighboring-group participation by C-2 acyloxy groups: influence of the nucleophile and acyl group on the stereochemical outcome of acetal substitution reactions