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 beta-hydroxyketones. A potentially useful extension of the method--the use of beta-hydroxyketones as enolate synthons for effecting inter- or intramolecular aldol reactions under neutral conditions--is demonstrated.
Yang
W
W
ARIAD Gene Therapeutics, Inc, Cambridge, Massachusetts 02139-4234, USA.
Digits
C A
CA
Hatada
M
M
Narula
S
S
Rozamus
L W
LW
Huestis
C M
CM
Wong
J
J
Dalgarno
D
D
Holt
D A
DA
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002384:Catalysis; D007166:Immunosuppressive Agents / Q000737:chemistry*; D009942:Organometallic Compounds; D020123:Sirolimus / Q000737:chemistry*; D013237:Stereoisomerism; D014025:Titanium
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D009942:Organometallic Compounds; C102815:titanium isopropoxide; D014025:Titanium; D020123:Sirolimus