Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines by Lithiation and Substitution, with in Situ IR Spectroscopy and Configurational Stability Studies

Lithiation
of N-Boc-1-phenyltetrahydroisoquinolines was optimized
by in situ IR spectroscopy. The kinetics for rotation of the carbamate
group and for the enantiomerization of the organolithium were determined.
The organolithium is configurationally stable at low temperature,
and the asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines
can be achieved with high yields and high enantiomer ratios. The chemistry
was applied to the preparation of FR115427 and provides a way to recycle
the undesired enantiomer in the synthesis of solifenacin.