Journal of the American Chemical Society
Article
ization mechanism is consistent with the isolation of
S6).
Table 2. Control Experiments Confirm Kinetic and
Thermodynamic Product Formation
a
A computational study was undertaken at the M06-2X/6-
311+G(d,p)//M06-2X/6-31G(d) level of theory in order to get
deeper insight into the mechanism and importantly to rationalize
the observed stereochemistry of 5. Initial calculations inves-
tigated according to the above mechanism did however furnish a
conflicting result, as it provided systematically the wrong
enantiomer. The details are provided in the Supporting
Information (Schemes S3 to S6). As such, it questioned the
dual activation of the vinyliminium and the dienecarbamate by
the chiral phosphoric acid 1a (TS-8, Scheme 4). This finding
required the reevaluation of the mechanism of this spirocycliza-
tion. Our novel set of computations clearly indicated that the
process of water abstraction from the indolyl alcohol had to be
taken into account, and that the resulting H-bonded water
molecule could play a major role in the stereoselectivity.13,14
Figure 1 shows what we believe fully rationalizes our
experimental findings. As a reference system, we chose
indolylmethanol 2a, the s-trans diene 3a, and the model catalyst
1b. The s-cis diene 3a′ was found to be 3.0 kcal/mol less stable
than 3a. The formation of a H-bond between the alcohol
functionality of 2a andthe acidic proton of 1b leads to B, with the
release of 4.8 kcal/mol of free energy. Cleavage of the C−O bond
provides intermediate C,15 which is of course axially chiral by the
phosphate side, but this especially induces planar chirality as the
water molecule is located on the lower face of the vinyl-
indoliniminium ion framework when the Me group is oriented to
the right. The corresponding transition state, TSBC, lies at 12.5
kcal/mol on the free energy surface, and this step is endergonic
by 4.3 kcal/mol. The diastereomers of B and C, B′ and C′, are
shown on the lower energy profile. While these intermediates are
virtually as stable as B and C, TSB′C′ is 0.9 kcal/mol less stable
than TSBC. An adduct is then formed between 3a′ and the
vinylindoliniminium species C or C′, which can only occur on
the face opposite water. Of note, in D and D′, the carbamate is
oriented as to give an endo-adduct in the Diels−Alder sense of
the word. The exo-orientation did not allow any subsequent C−
C bond formation. D′ is markedly less stable than D by 4.3 kcal/
mol (from −0.9 to 3.4 kcal/mol). The last step is an
asynchronous [4+2] cycloaddition furnishing the spiro-adduct
E or E′, which are equally stable. However, TSDE is 4.2 kcal/mol
more stable than TSD′E′ (from 12.1 to 16.3 kcal/mol).
Comparison of these two profiles clearly indicates that the
formation of E is kinetically preferred over that of E′. The
absolute configuration of E matches that of the experimentally
observed kinetic product (KP) 4a (R,R configuration), located at
−12.5 kcal/mol on the free energy surface. The corresponding
thermodynamic product (TP) 5a was found at −14.3 kcal/mol.
While the S enantiomer of B shown in the upper part of Figure 1
reacts faster than the R enantiomer depicted in the lower part, we
observed no kinetic resolution in this transformation. Thus, the
two profiles must be connected in some way by transition states
of lower energies than those already discussed to allow a dynamic
kinetic resolution. We found indeed that C and C′ are in fast
based on these computations and all the other options
that the planar chirality of the vinylindoliniminium ion
intermediate controls the enantioselectivity of the formal
cycloaddition reaction.
b
b
entry 1a (x mol %) T, °C
time
15 h
5a conv (%)
5a yield (%)
1
2
3
4
5
6
7
0
5
0
0
0
0
5
rt
rt
0
100
0
100
20
15 h
15 h
100
35
35
35
60
60
c
6 h
80
ND
100
100
cd
,
18 h
15 h
100
100
5 min
a
General conditions: 4a (0.05 mmol) and 1a (5 mol %) in DCE (0.05
M). Conversion and yields determined by H NMR spectroscopy
using Bn2O as standard. Irradiated with EvoluChem, P206-18-1 at
b
1
c
d
405 nm, 28 mW/cm2. In MeOH.
7) in the presence of 5 mol % of 1a. In addition, the isomerization
of 4a was complete at 35 °C in the absence of catalyst 1a applying
a 405 nm irradiation (80% NMR yield of 5a after 6 h, entry 4).
Interestingly, the reaction performed in MeOH under such
conditions resulted in the formation of the hemiaminal 10a; this
trapped iminium intermediate spontaneous cyclizes after its
isolation (15% yield) in the NMR tube (entry 5).
Based on these experiments and our previous mechanistic
studies,6 a catalytic cycle of the enantioselective spirocyclization
was proposed. Even though we were not able to identify any
iminium (or trapped intermediate 10a) under the catalyzed
stepwise mechanism. The vinylindoliniminium ion is formed
upon initial chiral phosphoric acid 1a-mediated dehydration of
2-alkyl-3-indolylarlymethanols 2, furnishing complex 7 (Scheme
4). Then, dienecarbamate 3 reacts with the vinyliminium
Scheme 4. Plausible Reaction Mechanism
complex 7 to form the iminium intermediate 8. The latter
undergoes an intramolecular C3 aza-alkylation of indolyl-
methane, delivering iminium 9, which produces the desired β
spirocyclohexyl-indolenines 4. Finally, the kinetic product
isomerizes to yield the thermodynamically more stable spiro-
product 5 via iminium intermediate 9′. The stepwise isomer-
11614
J. Am. Chem. Soc. 2021, 143, 11611−11619