Selective Epimerization of Rapamycin via a Retroaldol/Aldol Mechanism Mediated by Titanium Tetraisopropoxide

We describe the efficient and selective epimerization of the immunosuppressant rapamycin to 28-epirapamycin under mild conditions. The mechanism of epimerization involves an equilibrium of the four C28/C29 diastereomers through a two-step retroaldol/aldol (macrocycle ring-opening/ring-closing) sequence. This retroaldol/aldol equilibration is not restricted to rapamycin but is also applicable to acyclic β-hydroxyketones. A potentially useful extension of this methodthe use of β-hydroxyketones as enolate synthons for effecting inter- or intramolecular aldol reactions under neutral conditionsis demonstrated.