Benzyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate, a versatile intermediate for the synthesis of 3,3-dimethylproline derivatives.
The synthesis of racemic nitrile (+/-)-9 was accomplished in four steps and 58% overall yield from the known pyrrolidinone 5. Nitrile (+/-)-9 was resolved via preparative chiral HPLC to afford optically pure nitriles (+)-9 and (-)-9, from which 3,3-dimethylprolines (+)-1 and (-)-1 and 3,3-dimethylprolinamides (+)-2 and (-)-2 could be accessed in nearly quantitative yield, without loss of optical purity. The absolute configurations of the resolved prolines and prolinamides were determined by correlation with an intermediate of known absolute stereochemistry.
Medina
Jesus R
JR
Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, PA 19426, USA. jesus.r.medina@gsk.com
Blackledge
Charles W
CW
Erhard
Karl F
KF
Axten
Jeffrey M
JM
Miller
William H
WH
D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry*; D013237:Stereoisomerism
D011759:Pyrrolidines; C530612:benzyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate; D011392:Proline