Reactive resin facilitated preparation of an enantiopure fluorobicycloketone.
A facile preparation of enantiopure ethyl (1S,5S,6S)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate is described. The key feature of the synthesis involves copper-catalyzed enantioselective intramolecular cyclopropanation of a diazoketone to form endo-fluorocyclopropane in a single operation. Removal of a problematic chloroketone impurity using a reactive resin treatment enabled a high throughput enantiopurity upgrade by chiral HPLC. The development of a scalable synthesis of is presented, including details of the selection of catalyst and ligand optimization, incorporation of a reactive resin treatment and selection of chiral HPLC media and conditions.
Wong
Audrey
A
Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, New Jersey 07065, USA. audrey_wong@merck.com
Welch
Christopher J
CJ
Kuethe
Jeffrey T
JT
Vazquez
Enrique
E
Shaimi
Mohamed
M
Henderson
Derek
D
Davies
Ian W
IW
Hughes
David L
DL