Organic Letters
Letter
and high enantioselectivities. Notably, the N-alkyl benzosul-
tams (N-cyclohexyl and N- butyl) worked well for the DKR
quenched before the full consumption of hemiaminal 1a, the
ester 3aa with high ee was isolated and hemiaminal 1a without
enantioexcess was recovered (reaction a). This result suggests
that the racemization of 1a is much faster than the O-acylation
reaction under the NHC catalysis conditions. Then we tried to
synthesize optically active hemiaminal 1a by the alcoholysis of
its optical active ester 3aa (94% ee) under basic conditions,
which gave hemiaminal 1a without enantioexcess (reaction b).
The hydrolysis of 3aa under acidic conditions gave the racemic
hemiaminal, and some loss of the enantiopurity of the ester
3aa was observed, which was possibly due to the re-O-acylation
of the resulted racemic hemiaminal (reaction c). No hydrolysis
or racemization of 3aa was observed in the presence of 2 equiv
n
reaction (3hd−3id). Both electron-withdrawing groups and
electron-donating groups (X = Ph, CF , OMe, Me) at the
3
phenyl ring of benzosultams were tolerated but gave the
products (3jd−3mf) with some decreased enantioselectivities,
which could be improved to 92% ee after recrystallization
(3mf). The absolute (R)-configuration of product 3mf was
assigned via single-crystal X-ray analysis.
To further expand the scope of the hemiaminals, those with
-difluoromethyl (1n) and 3-pentafluoroethyl (1o) instead of
3
trifluoromethyl were also tested for the DKR reaction, which
afforded the desired products (3nd and 3od) in high yields
with some decreased but still high enantioselectivities (Scheme
of K CO in the mixed solvent of ethyl acetate/water (9:1) at
2
3
room temperature (reaction d).
4
).
Based on the control experiments, we proposed a
mechanism for racemization of hemiaminals via ketones II
under basic conditions (Scheme 7a). The electron-with-
Stereocontrol Modes
The reaction could be easily scaled up to 2.4 mmol of
benzosultam-derived hemiaminal 1a, giving 1.2 g of the desired
product 3aa in 99% yield with 94% ee under standard
conditions (Scheme 5).
Scheme 5. Gram-Scale Synthesis
drawing N-sulfonyl and trifluoromethyl groups can enhance
the acidity of the α-hydroxyl in hemiamianls 1, thus facilitating
the racemization. The addition of (R)-3-hydroxy-3-trifluor-
omethyl benzosultams (mode A) are kinetically favored over
their (S)-enantiomers (mode B) to attack the acyl azolium,
which is generated from aldehyde under oxidative NHC
catalysis (Scheme 7b). The additional bulky aryl group of the
NHC catalyst can increase the repulsion in unfavored
stereocontrol mode B and play an important role in
differentiating the two enantiomers of the hemiaminals.
In summary, a dynamic kinetic resolution of hemiaminals
without α-hydrogen was developed via the chiral NHC-
catalyzed O-acylation of 3-hydroxy-3-trifluoromethylbenzosul-
tams. The racemic hemiaminals without α-hydrogen were
effectively racemized and differentiated by chiral NHCs under
basic conditions. This protocol provides a wide range of
enriched benzosultam derivatives in excellent yields with good
to excellent enantioselectivities. Other related NHC-catalyzed
dynamic kinetic resolution reactions are underway in our
laboratory.
Several control experiments were carried out to clarify the
mechanism of the racemization of α-hydroxy-α-trifluorome-
thylbenzosultams (Scheme 6). When the reaction was
Scheme 6. Investigation on Racemization
1
363
Org. Lett. 2021, 23, 1361−1366
Gao, Yuan-Yuan
