op200305y_si_001.pdf (2.42 MB)
Design and Scale-Up of a Practical Enantioselective Route to 5-Phenylbicyclo[2.2.2]oct-5-en-2-one
journal contribution
posted on 2012-01-20, 00:00 authored by Stefan Abele, Roman Inauen, Jacques-Alexis Funel, Thomas WellerA 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.