DMOBO: an improvement on the OBO orthoester protecting group.

[reaction: see text] Conversion of a carboxylic acid to an orthoester provides protection toward nucleophiles and strong bases. The addition of methyl substituents to the oxetane precursor of the commonly used [2.2.2]-bicyclic OBO orthoester significantly increased the ease of orthoester formation and its resistance to hydrolysis. NMR kinetics show the DMOBO protecting group is formed 85 times faster than the OBO group, and that its stability toward aqueous hydrolysis is 36 times greater. Nucleophilic attack of the ester carbonyl on the oxetane ring was shown by 18O-labeling to take place at the most substituted position.