Temperature-Controlled Regioselectivity in the Reductive Cleavage of p-Methoxybenzylidene Acetals

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Abstract
The regioselective ring opening of pyranosidic 4,6-p-methoxybenzylidene acetals with BH3/Bu2BOTf in THF can be tuned by adjusting the reaction temperature and reagent concentrations. Reductive cleavage at 0 °C resulted in the exclusive formation of 4-O-p-methoxybenzyl (PMB) ethers, whereas reaction at −78 °C produced 6-O-PMB ethers in high yields. The latter condition was observed to be compatible with a variety of acid-sensitive functional groups, including allyl and enol ethers. The presence of water does not interfere with reductive ring opening and may contribute toward in situ generation of H+ as a catalyst for 6-O-PMB ether formation. Reductive cleavage under rigorously aprotic conditions is greatly decelerated, and yields only the 4-O-PMB ether. The temperature-dependent reductive cleavage of the 4,6-acetal can be described in terms of kinetic versus thermodynamic control: Lewis-acid coordination of the more accessible O-6 is favored at higher temperatures, whereas protonation of the more basic but sterically encumbered O-4 predominates at low temperatures.