The cyclohexyl-subunit of rapamycin was cleaved by a sequence involving a Baeyer-Villiger reaction and acid hydrolysis of the resulting lactone-acetal as key steps. Binding of this new rapamycin derivative to FKBP12 was only slightly reduced by this modification, whereas the loss of antiproliferative and immunosuppressive activity was dramatic. These findings indicate that part of the cyclohexyl-subunit of rapamycin could belong to its effector domain.