Selective epimerization of rapamycin via a retroaldol/aldol mechanism mediated by titanium tetraisopropoxide

[GRAPHICS] We describe the efficient and selective epimerization of the immunosuppress ant rapamycin to 28-epirapamycin under mild conditions, The mechanism of ep imerization involves an equilibrium of the four C28/C29 diastereomers throu gh a two-step retroaldol/aldol (macrocycle ring-opening/ring-closing) seque nce. This retroaldol/aldol equilibration is not restricted to rapamycin but is also applicable to acyclic beta-hydroxyketones, A potentially useful ex tension of this method-the use of beta-hydroxyketones as enolate synthons f or effecting inter- or intramolecular aldol reactions under neutral conditi ons-is demonstrated.