TY - DATA T1 - Design and Scale-Up of a Practical Enantioselective Route to 5-Phenylbicyclo[2.2.2]oct-5-en-2-one PY - 2012/01/20 AU - Stefan Abele AU - Roman Inauen AU - Jacques-Alexis Funel AU - Thomas Weller UR - https://acs.figshare.com/articles/journal_contribution/Design_and_Scale_Up_of_a_Practical_Enantioselective_Route_to_5_Phenylbicyclo_2_2_2_oct_5_en_2_one/2557891 DO - 10.1021/op200305y.s001 L4 - https://ndownloader.figshare.com/files/4200967 KW - reaction conditions KW - enantioselective route KW - target compound KW - chemical steps KW - Practical Enantioselective Route KW - intramolecular aldol reaction KW - CIDT KW - chiral purity KW - 1 kg KW - ketone aldehyde KW - enantiomeric ratio N2 - A practical enantioselective route to chiral 5-phenylbicyclo[2.2.2]­oct-5-en-2-one 1 has been designed and developed. The target compound has been obtained as colorless crystals in 22% yield from 2-cyclohexenone, with an enantiomeric ratio higher than 99.5:0.5 and notably high chemical purity (> 99%). Three intermediates out of nine chemical steps are isolated. It is noteworthy that this process is devoid of any chromatography or distillation although all but one intermediate are oils. Key to success was the optimization of an intramolecular aldol reaction of an in situ prepared ketone aldehyde leading to the solid intermediate (1R,4R,4S,6S)-6-hydroxybicyclo­[2.2.2]­octan-2-one 9a that is isolated in very high chemical and chiral purity. This is an example of an intramolecular crystallization-induced diastereomer transformation (CIDT). The dehydration of this secondary alcohol to 1 required an extensive screen of reaction conditions to secure an excellent purity, essential for crystallization of this low-melting compound. The final process is simple and concentrated as demonstrated by an expeditious synthesis of 1 kg of 1 in a 30-L reactor in 10 working days. ER -