Synthesis of an optically active, bicyclic 2-pyridone dipeptide mimetic.
The eleven-step preparation of the bicyclic 2-pyridone dipeptide mimetic 1 [(3S)-6-(benzyloxycarbonylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid] in optically active form (60% ee) is described. Key steps in the synthesis of 1 include the osmium-catalyzed asymmetric dihydroxylation of olefin 13 [(6-but-3-enyl-2-methoxypyridin-3-yl)carbamic acid benzyl ester] and the intramolecular cyclization of protected diol 19 [(3'R)-[6-[4'-(tert-butyldimethylsilanyloxy)-3'-hydroxybutyl]-2-methoxypyridin-3-yl]carbamic acid benzyl ester] to afford the pyridinium salt 20 [(3S)-[3-(tert-butyldimethylsilanyloxymethyl)-5-methoxy-2,3-dihydro-1H-indolizin-6-yl]carbamic acid benzyl ester trifuoromethanesulfonic acid salt]. Several alternate methods to prepare olefin 13 are also discussed.
Dragovich
Peter S
PS
Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., 10777 Science Center Drive, San Diego, California 92121-1111, USA. peter.dragovich@pfizer.com
Zhou
Ru
R
Prins
Thomas J
TJ
D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D011728:Pyridones / Q000737:chemistry*; D013237:Stereoisomerism
D004151:Dipeptides; D011728:Pyridones; C017679:2-hydroxypyridine