Fluorination-free synthesis of a 4,4-difluoro-3,3-dimethylproline derivative.
A Claisen rearrangement/iodolactamization sequence starting from commercially available trifluoroacetaldehyde methyl hemiacetal, followed by a classical chemical resolution, provided enantiomerically pure 4,4-difluoro-3,3-dimethylproline (S)-1. No hazardous fluorination reagents were used, and the overall yield over 12 steps was greater than 28%.
Chen
Lijian
L
Chemical Research and Development, La Jolla Laboratories, Pfizer, Inc., 10578 Science Center Drive, San Diego, California 92121-1111, USA. lijianc@amgen.com
Kim
Young Mi
YM
Kucera
David J
DJ
Harrison
Katheryn E
KE
Bahmanyar
Sogole
S
Scott
Jill M
JM
Yazbeck
Daniel
D
D002384:Catalysis; D005461:Fluorine / Q000737:chemistry*; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
D005461:Fluorine; D011392:Proline; C003342:stachydrine