Synthesis of PPAR agonist via asymmetric hydrogenation of a cinnamic acid derivative and stereospecific displacement of (S)-2-chloropropionic acid.
The synthesis of the peroxime proliferator activated receptor (PPAR) alpha,gamma-agonist (1) was accomplished with high enantio- and diastereoselectivity by employing an asymmetric hydrogenation strategy, of an alpha-alkoxy cinnamic acid derivative, to set the C-2 chiral center. A diastereospecific S(N)2 displacement under mild basic conditions established the C-10 stereochemistry without any detectable racemization of the two epimerizable chiral centers.
Houpis
Ioannis N
IN
Chemical Product Research and Development, Lilly Development Center, Mont. St. Guibert, Belgium. houpis_ioannis@lilly.com
Patterson
Lawrence E
LE
Alt
Charles A
CA
Rizzo
John R
JR
Zhang
Tony Y
TY
Haurez
Michael
M
D002934:Cinnamates / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D006865:Hydrogenation; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D002934:Cinnamates; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; C501950:S-2-ethoxy-3-(4-(R-1-(2-(4-ethyl-phenyl)-ethylcarbamoyl)-ethoxy)-phenyl)- propionic Acid; C029010:cinnamic acid