Regioselective lipase-catalyzed acylation of 41-desmethoxy-rapamycin without vinyl esters

New acyl donors have been found enabling the first regioselective acylation of a rapamycin derivative without the use of vinyl esters. Selective lipase-catalyzed acylation of 41-desmethoxyrapamycin has been achieved with a quaternary carboxylic acid avoiding the use of vinyl ester activation. Among the acyl donors investigated, the novel butanedione-monooxime and the N-acetylhydroxamate ester proved to be the most efficient donors, comparable in reactivity to the undesired vinyl ester and allowing selective, preparative acylation on gram scale in excellent yields. These new donors are proposed as sustainable and process-friendly alternatives to the widely used vinyl ester substrate activation in lipase-catalyzed acylations of secondary alcohols.