Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors
yield
chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable
intermediates in organic synthesis. Of the various organocatalysts
examined, Singh’s catalyst [(2S)-N-[(1S)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide]
was found to efficiently promote this organocatalytic transformation
in a highly enantioselective manner. Detailed reaction monitoring
(19F-NMR, HPLC) showed that, up to full conversion, the
catalytic transformation proceeds under kinetic control and affords
up to 95% ee in a time-independent manner. At longer reaction times,
the catalyst effects racemization. For the product aldols, even weak
acids (such as ammonium chloride) or protic solvents, can induce racemization,
too. Thus, acid-free workup, at carefully chosen reaction time, is
crucial for the isolation of the aldols in high (and stable) enantiomeric
purity. As evidenced by 19F-NMR, X-ray structural analysis,
and independent synthesis of a stable intramolecular variant, Singh’s
catalyst reversibly forms a catalytically inactive (“parasitic”)
intermediate, namely a N,O-hemiacetal
with trifluoroacetophenones. X-ray crystallography also allowed the
determination of the product aldols’ absolute configuration
(S).