A combined theoretical and experimental investigation into the highly stereoselective migration of spiroindolenines

Article abstract of DOI:10.1021/jo400365e

This paper describes a combined theoretical and experimental investigation into the acid-catalyzed migration of spiroindolenines to the corresponding fused cyclic products. It is suggested that the three-center-two- electron -type transition state is the crucial reason accounting for the highly stereoselective phenomenon. Further studies demonstrated that the electronic property of the migratory group as well as the ring size may have a major influence on the reaction profile of the migration process. Some predictions based on the computational results were supported by additional experiments.

Full text of DOI:10.1021/jo400365e

Article
pubs.acs.org/joc
A Combined Theoretical and Experimental Investigation into the
Highly Stereoselective Migration of Spiroindolenines
Chao Zheng,* Qing-Feng Wu, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: This paper describes a combined theoretical and experimental investigation into the acid-catalyzed migration of
spiroindolenines to the corresponding fused cyclic products. It is suggested that the “three-center-two-electron”-type transition
state is the crucial reason accounting for the highly stereoselective phenomenon. Further studies demonstrated that the electronic
property of the migratory group as well as the ring size may have a major influence on the reaction profile of the migration
process. Some predictions based on the computational results were supported by additional experiments.
the spiroindolenine species that could undergo subsequent
migration process (path b).
INTRODUCTION
■
The Pictet−Spengler reaction1 is among the most powerful
methods for functionalization at the C2 position of indoles. It
also provides quick access to various polycyclic indole
derivatives including tetrahydro-β-carbolines2 that are widely
distributed in natural products as well as molecules of
pharmaceutical interests. However, the detailed mechanism of
the Pictet−Spengler reaction and related functionalization at
the C2 position of indoles still remains a debate.1f In general,
two mechanistic scenarios have been proposed (Scheme 1): the
product of Pictet−Spengler-type reaction can be obtained
either via the direct attack of the C2 position of indole to the
iminium moiety (path a) or, alternatively, through the
nucleophilic addition of the C3 position of indole, affording
A large amount of experimental evidence supporting path b
has been reported. It is known that the five-membered aza-
spiroindolines can be generated by the condensation of
tryptamine and the corresponding aldehyde under reductive
conditions.3 The pioneering works of Jackson et al.4 showed
that the independently synthesized 3,3-disubstituted spiroindo-
lenines undergo an intramolecular rearrangement affording the
2,3-disubstituted indole counterparts in acidic media.5
Computational methods have also been employed to probe
the mechanism of Pictet−Spengler reaction, but the results
seemed not to support the spiroindolization/migration
mechanism.6 In a recent mechanistic study, Stockigt, Peters,
̈
O’Connor, and co-workers7 calculated a nonenzyme-catalyzed
Pictet−Spengler reaction with the DFT method (PW1PW91)
and showed that the protonated spiroindolenine (B, R = Me) is
a nonproductive intermediate. The migration process (B → C,
R = Me) does not occur, and the spiroindolenine only
rearranges to reform the iminium species (A, R = Me). Indeed,
the nature of the migration of the spiroindolenines still remains
unclear and requires further exploration. Meanwhile, the direct
stereochemistry information associated is also not fully
uncovered, probably due to the difficulty in synthesizing
enantioenriched spiroindolenines.
Scheme 1. Two Different Mechanisms Commonly Proposed
for Pictet−Spengler and Related Reactions
Recently, we8 disclosed that chiral five-membered spiroindo-
line 3a could be synthesized by Ir-catalyzed intramolecular
asymmetric allylic dearomatization9 of indol-3-yl allylic
Received: February 19, 2013
Published: April 11, 2013
© 2013 American Chemical Society
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Scheme 2. Ir-Catalyzed Intramolecular Asymmetric Allylic Dearomatization of Indol-3-yl Allylic Carbonate and Acid-Catalyzed
a
Highly Stereoselective Allyl Migration of Spiroindolenine
a
ΔGTHF and ΔETHF (in parentheses) of compounds 2a, 4a, and 4b are in kcal/mol. Calculated at the PBE1PBE/6-311+G(d,p) level of theory.
carbonate 1a and subsequent NaBH3CN reduction of the
spiroindolenine compound 2a (Scheme 2). The products were
obtained in excellent yields and stereoselectivities (up to 96%
yield, 99% ee and 16:1 dr) under mild conditions. More
intriguingly, on treatment of catalytic amount of TsOH, the
spiroindolenine 2a was converted to the corresponding
tetrahydrocarbazole 4a smoothly, with the ee’s of the products
as well as the absolute configuration of the chiral center at the
allylic position conserved. To the best of our knowledge, this is
the first observation of highly stereoselective migration of
optically active chiral spiroindolenines. In addition, it also
provides a unique opportunity for the mechanistic research of
intramolecular C2 alkylation of indoles, especially for the details
of the migration process. Herein, we present our theoretical
investigation into this highly stereoselective migration of
spiroindolenines which suggests that the “three-center-two-
electron”-type transition state is crucial for the maintenance of
chirality at the allylic position. Further studies on other related
models showed that the electronic property of the migratory
group and the ring size of the spiroindolenines have pronouced
effects on the reaction pathway as well as the stereochemistry of
the migration process. Some predictions based on the
computational results were supported by additional experi-
ments.
tetrahydrocarbazole products. These results verified the
migration process is highly favored thermodynamically.
The migration reaction was conducted in the presence of a
catalytic amount of acid. Therefore, the complex of the indol-3-
yl allylic carbonate and tosylate acid (5a) was set as the
reference for the migration process (Figure 1). The transition
state for the allyl migration (TS-1a) was located with an
energetic barrier of 19.5 kcal/mol. The intrinsic reaction
coordinate (IRC) calculation indicated that the migration
process is concerted (see the Supporting Information for
details). TS-1a connects directly to 5a and the corresponding
tosylate-bound protonated tetrahydrocarbazole 6a (4.6 kcal/
mol). Both the bond formation of C2−C8 and the bond
cleavage of C3−C8 are involved in one single step (B(C2···C8)
= 2.141 Å, B(C3···C8) = 2.280 Å in TS-1a). The geometric
feature of TS-1a reveals a “three-center-two-electron”-type
structure. The HOMO of TS-1a (E = −6.7 eV) clearly showed
the electronic interaction between the indole ring and the
migratory allyl group. One p orbital of C8 bridges over the π
orbital of the C2−C3 bond (Figure 2), which is similar to the
structure of the corner-protonated cyclopropane or nonclassical
carbocations10 that are often involved in the pinacol and
Wagner−Meerwein rearrangement.11 We believe the “three-
center-two-electron”-type transition state is the critical reason
that accounts for the highly stereoselective phenomenon. The
allyl group keeps interacting with the C2−C3 bond of the
indole ring, and no “free” allyl carbocation is formed during the
migration process. Therefore, the chirality of C8 can be
reserved and no racemization happens. Subsequently, the
proton at the C2 position of intermediate 6a is readily
abstracted by the tosylate anion (TS-2a, 7.7 kcal/mol) to afford
the complex of the chiral tetrahydrocarbazole and tosylate acid
(7a, −9.2 kcal/mol). In addition, all efforts aimed at locating an
intermediate possessing a free allyl carbocation (8a′), which is
an analogue of 8d′ and 8e′ (vide infra), failed. Instead, we
obtained a multisubstituted 2H-furanium intermediate 8a (22.6
kcal/mol) that is formed via nucleophilic attack of one carbonyl
oxygen atom of the ester group to the allyl moiety. The energy
of the transition state leading to this intermediate (TS-5a, 35.0
RESULTS AND DISCUSSION
■
Reaction Mechanisms. We started our study by
comparing the thermodynamic stabilities of spiroindolenine
and tetrahydrocarbazole products (Scheme 2). There are two
chiral centers in the spiroindolenine 2a; thus, two pairs of
diastereomers exist. In this paper, we only present the reaction
profile of the (3S,8R) isomer according to the experimental
results. As expected, both the allyl migration product 4a (−23.0
kcal/mol) and the product of methylene migration 4b (−21.2
kcal/mol), which is not observed experimentally, are
significantly more stabilized than 2a (0.0 kcal/mol), probably
due to the recovery of the aromaticity of the indole ring in the
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Figure 1. Reaction profile of TsOH-catalyzed allyl/methylene migration of spiroindolenine 2a and the optimized structures of TS-1a, TS-1b, TS-5a,
and TS-5b. Calculated at PBE1PBE/6-311+G(d,p) level of theory. ΔGTHF and ΔETHF (in parentheses) are in kcal/mol. Bond distances are in
angstroms.
not observed in the current system. We studied the methylene
migration of complex 5a (Figure 1), and TS-1b (26.8 kcal/
mol) was found for this methylene migration. The energetic
barrier of TS-1b is substantially higher than that of TS-1a by
7.3 kcal/mol, which is in accord with the experimental
observations. Although TS-1b also features a “three-center-
two-electron”-type structure, the distances between the
migratory carbon (C9) and indole C2−C3 bond (B(C2···C9)
= 1.907 Å, B(C3···C9) = 1.985 Å) are somewhat shorter
compared to the corresponding values in TS-1a. We reasoned
that the energetic difference and the structural deviation
between TS-1a and TS-1b are the reflection of different
abilities of allyl and methylene in stabilizing the positive charge.
NBO charge analyses indicated the sum of positive charge that
distributes over the allyl moiety in TS-1a is +0.325 while the
positive charge possessed by the migratory methylene group in
TS-1b is only +0.263.14 Since the methylene group is a poorer
electron-donating group than the allyl group, a stronger
interaction between it and indole ring should be required to
Figure 2. Calculated HOMO of TS-1a.
kcal/mol) is quite high. These results further support that the
allyl migration is concerted and no free allyl carbocation is
likely to be involved in this process.12
Although the alkyl migration of 3,3-disubstituted indolenines
is known in the literature,13 the methylene migration of C9 was
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Figure 3. Reaction profile of TsOH-catalyzed benzyl migration and the optimized structures of TS-1c and TS-5c. Calculated at PBE1PBE/6-
311+G(d,p) level of theory. ΔGTHF and ΔETHF (in parentheses) are in kcal/mol. Bond distances are in angstroms.
Figure 4. Reaction profile of TsOH-catalyzed rearrangement of N-Bn aza-spiroindolenine and the optimized structure of intermediate 8d. Calculated
at PBE1PBE/6-311+G(d,p) level of theory. ΔGTHF and ΔETHF (in parentheses) are in kcal/mol. Bond distances are in angstroms.
stabilize the positive charge during the migration process. The
electron-rich indole ring interacts with the methylene group
more significantly than with the allyl group, which makes the
NBO charge on methylene in TS-1b less positive. Meanwhile,
the strong interaction brings the migratory methylene and
indole moiety closer in TS-1b and raises its energy as well. Like
the case of allyl migration mentioned above, the intermediate
with a free terminal methylene carbocation (8b′) does not exist.
Instead, this methylene carbocation can be stabilized by the
allyl moiety to form a cyclohexanylium intermediate (8b, 23.3
kcal/mol). However, the transition state that connects 8b and
the starting complex (TS-5b, 65.1 kcal/mol) is energetically
inaccessible.
Influence of the Electronic Property of the Migratory
Group. The above results implicate the importance of the
electronic property of the migratory group on the transition
state of migration process. Thus, we decided to test the
migration processes with other migratory groups computation-
ally. As depicted in Figure 3, the TsOH-catalyzed rearrange-
ment of phenyl-substituted spiroindolenine was considered.15
The relative energy and the structural characters of the
transition state for the benzyl migration (TS-1c, 16.3 kcal/
mol) are rather similar to those of the allyl migration. The
benzyl migration is still concerted with the migratory carbon
(C8) keeping interaction with the indole moiety in TS-1c
(B(C2···C8) = 2.231 Å, B(C3···C8) = 2.383 Å). The NBO
charge on the benzyl group (+0.328) is only slightly more
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Figure 5. Reaction profile of TsOH-catalyzed rearrangement of N-Tf aza-spiroindolenine and the optimized structure of intermediate 8e. Calculated
at PBE1PBE/6-311+G(d,p) level of theory. ΔGTHF and ΔETHF (in parentheses) are in kcal/mol. Bond distances are in angstroms.
positive than the allyl group in TS-1a. On the other hand, the
intermediate with a free benzyl carbocation (8c′, 27.1 kcal/
mol), an analogue of 8d′ and 8e′ (vide infra), is rather unstable,
and its formation is also kinetically unfavorable (TS-5c, 31.5
kcal/mol). These calculations suggest the benzyl migration in
achiral acidic media may also be a highly stereoselective process
if enantioenriched phenyl-substituted spiroindolenine could be
prepared.
rotation about C9−C10 bond (TS-5d) is only 3.8 kcal/mol,
making the linear form of the N-Bn aryl iminium intermediate
8d′ (−2.6 kcal/mol) readily accessible. The NBO charges
distributed over the PhCH segments of 8d (+0.610) and 8d′
(+0.631) are similar in value, which may imply that no
remarkable charge transfer exists between the indole ring and
the N-Bn aryl iminium moiety in 8d and the positive charge can
be stabilized well by the N-Bn group itself due to its electron-
donating nature.17 These results suggest the fast racemization at
the C8 position must happen during this rearrangement
process and no enantioenriched product can be obtained if the
enantioenriched N-Bn aza-spiroindolenine is exposed in an
achiral acidic environment.18
On the contrary, the reaction profile of the TsOH-catalyzed
rearrangement of N-Tf aza-spiroindolenine is noteworthy
(Figure 5). The energetic barrier of C3−C8 bond cleavage
(TS-3e) is 18.1 kcal/mol, which is much higher than its N-Bn
counterpart and comparable to that of the allyl and benzyl
migration. The N-Tf iminium intermediate 8e (17.1 kcal/mol)
is then attacked by the C2 position of indole (TS-4e, 18.1 kcal/
mol) to generate the protonated N-Tf tetrahydro-β-carboline
(6e, 3.3 kcal/mol). The potential energy surface is quite flat
from TS-3e to TS-4e, and only minor structural shifts can be
observed for these two transition states and the key
intermediate 8e. More importantly, the distances of C2···C8
and C3···C8 in 8e are 2.497 and 2.579 Å, respectively, much
shorter than that observed in the N-Bn analogue 8d and only
slightly longer than the distances of C2···C8 and C3···C8 in
TS-1a for allyl migration. This structural character implicates
that there must be some interaction between the N-Tf aryl
iminium motif and indole ring in 8e. Indeed, the second-order
perturbation theory analysis on the basis of NBOs suggests a
significant donor−acceptor interaction between these two
moieties. The stabilization energy E(2) from the “filled”
What if the migratory group has a much stronger ability to
stabilize the positive charge than allyl and benzyl groups? We
regarded the aza-spiroindolenines with aryl iminium as the
latent migratory group to be proper models. The rearrange-
ment of this type of substrates may be closely related to the
mechanism of the Pictet−Spengler reaction. Since the
protecting group on the nitrogen could also affect the electronic
property of the imine group significantly, we considered two
additional model systems with either a benzyl (5d) or a triflate
(5e) group attached on the imine nitrogen atom.16 Different
from the concerted migrations of the allyl, methylene, and
benzyl groups mentioned above, the rearrangements of these
two aza-spiroindolenines to their corresponding tetrahydro-β-
carbolines are stepwise. The bond cleavage of C3−C8 of 5d is
quite facile (TS-3d), and its energetic barrier is only 8.9 kcal/
mol (Figure 4). The N-Bn iminium intermediate 8d generated
is rather stable (−4.1 kcal/mol). Subsequently, the iminium
carbon (C8) is easily attacked by the C2 position of indole ring
(TS-4d, 6.4 kcal/mol), affording the protonated N-Bn
tetrahydro-β-carboline intermediate (6d, 2.6 kcal/mol). The
final TsOH-bound product 7d (−4.1 kcal/mol) is obtained
after the deprotonation step (TS-2d, 10.3 kcal/mol). However,
the optimized structure of the key intermediate 8d reveals that
the N-Bn aryl iminium motif has little interaction with the
indole ring. The distances of C2···C8 and C3···C8 in 8d are
3.287 and 3.228 Å, respectively. The energetic barrier of
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π(C2−C3) orbital to the “empty” p*(C8) orbital is estimated
to be 74.38 kcal/mol for 8e.19 As a result, the rotation about
C9−C10 bond (TS-5e, 25.4 kcal/mol) breaking such
interaction is energetically highly unfavorable. The linear
form of the N-Tf aryl iminium 8e′ (21.3 kcal/mol) is also
unstable relative to 8e. Analysis of the NBO charges that are
distributed over the PhCH segments of 8e (+0.574) and 8e′
(+0.827) led to a similar conclusion. The much less positive
charge possessed by the PhCH segment of 8e could be
explained by some charge transfer from the electron-rich indole
ring to the electron-deficient N-Tf aryl iminium moiety.
However, this type of stabilization effect cannot exist in 8e′,
and the charge-separate nature raises its energy as well.20 Since
the formation of “free” N-Tf aryl iminium species from 8e is
much higher in energy compared with the nucleophilic attack of
the C2 position of the indole ring, it suggests that the
rearrangement of N-Tf aza-spiroindolenine, although stepwise,
might also be a highly stereoselective process.
Table 1. Calculated Energy of the Spiroindolenines, the
Migration Products, and the Corresponding Transition
a
States with Different Ring Sizes
The influence of the electronic properties of the migratory
groups on the reaction profiles of the rearrangements of five-
membered spiroindolenines is described in Figure 6. In general,
a
Calculated at PBE1PBE/6-311+G(d,p) level of theory. ΔGTHF and
b
ΔETHF (in parentheses) are in kcal/mol. Energetic barrier relative to
the complexes of the corresponding spiroindolenines and tosylate acid.
indicating the energy cost due to the fact that formation of the
strained cyclobutene motif cannot be compensated with the
recovery of aromaticity of the indole ring.
The possibility of the TsOH-catalyzed allyl migration of
these three spiroindolenines was also investigated. The allyl
[1,2]-shift of 2f and 2g can occur through related “three-center-
two-electron”-type transition states TS-1f and TS-1g. There-
fore, the retention of configuration at the allylic position is
expected. The energetic barrier of TS-1f (24.0 kcal/mol) is 4.5
kcal/mol higher than that of TS-1a, which suggests the allyl
migration affording a seven-membered-ring product requires
much harsher reaction conditions. The energetic barrier of TS-
1g (11.7 kcal/mol), on the other hand, is quite low, an apparent
outcome for the formation of energetically favored five-
membered ring. It also implies the spiroindolenine 2g cannot
be easily separated and has a strong tendency to migrate.21
After several attempts, we could not locate the transition state
of acid-catalyzed allyl migration that connects 2h and 4h.
Further relaxed scan of the potential energy surface (PES)
reveals that the energy is increasing monotonously along the
conversion from the TsOH-bound 2h to the “TsOH-bound
4h” and the latter one is not a stationary point on PES (see the
Supporting Information for details). Thus, we might conclude
the three-membered spiroindolenine may be stable to some
extent and the direct conversion to the cyclobut[b]indole ring
system is not likely to operate under mild conditions.
Experimental Validation. Further experimental investiga-
tion was carried out to verify the prediction based on the above
calculations (Scheme 3). The ethyl-substituted spiroindolenine
2I (7:1 dr) was synthesized and subjected to the standard
conditions of the migration reaction (in this section, we use
capital letters to denote the corresponding compounds
synthesized experimentally). Not surprisingly, no migration
product was observed even with elongated reaction time. This
result indicates that the alkyl migration is less effective
compared with the allyl migration. In addition, the phenyl-
substituted five-membered spiroindolenine 2C-epi was synthe-
sized. Its relative configuration was established as (3S*,8S*) by
NOE analysis. In the presence of 30 mol % of TsOH, the
Figure 6. Schematic description for the rearrangements of five-
membered spiroindolenines with various migratory groups.
as the ability for the migratory group to stabilize positive charge
increases from methylene to N-Bn aryl iminium, the trans-
formation from the spiroindolenines to their corresponding
tetrahydrocarbazole or tetrahydro-β-carboline derivatives be-
comes easier and the reaction shifts from concerted to stepwise.
Besides, the rearrangements of methylene, allyl, benzyl, and N-
Tf aryl iminium moieties might be highly stereoselective
processes because of the “three-center-two-electron”-type
transition states or a related key intermediate with close
interaction between the migratory group and the indole ring.
Influence of the Ring Size. Next, we explored the
influence of the ring size to the reaction profile of the allyl
migration. In order to keep consistence with the previous
calculations, we only present the results on the allyl migration
of the (3S,8R)-isomers of the six-, four-, and three-membered
spiroindolenines 2f−h (Table 1). Thermodynamically, the
seven- and five-membered ring-expansion products 4f and 4g
are more stabilized than the corresponding starting materials by
18.3 and 29.1 kcal/mol, respectively, whereas the rearrange-
ment of the three-membered-ring analog 2h is not favored. The
Gibbs free energy of 4h is 8.1 kcal/mol higher than that of 2h,
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THF including zero-point energy corrections (ΔETHF) are also given
in parentheses for reference. All figures of the calculated 3D structures
were prepared using CYLview.28
Scheme 3. Experimental Validation
Procedure for Converting Spiroindolenine into Tetrahydro-
carbazole. Synthesis of 2I. A flame-dried Schlenk tube was cooled to
room temperature and filled with argon. To this flask were added
[Ir(cod)Cl]2 (5.4 mg, 0.008 mmol, 2 mol %), phosphoramidite ligand
(S,S,Sa)-L1 (8.4 mg, 0.016 mmol, 4 mol %), THF (1.0 mL), and n-
propylamine (1.0 mL). The reaction mixture was heated at 50 °C for
30 min, and then the volatile solvents were removed in vacuo to give a
pale yellow solid. After that, allylic carbonate 1a (155.6 mg, 0.4 mmol),
cesium carbonate (260.3 mg, 0.8 mmol, 200 mol %), and THF (4.0
mL) were added. The reaction mixture was refluxed for 2 h. After the
reaction was complete (monitored by TLC), the crude reaction
mixture was filtrated with Celite and washed with EtOAc. The solvents
were removed under reduced pressure. The product 2a was used for
the next step without further purification.
enantiopure 2C-epi was converted smoothly to the correspond-
ing phenyl-substituted tetrahydrocarbazole 4C in 4 h in 86%
yield and 97% ee. This result demonstrated that no
racemization at the benzylic position occurs during the benzyl
migration process, which is in well accord with the above
calculations.
To a solution of 2a in anhydrous MeOH (4 mL) was added Pd/C
(40.0 mg, 0.04 mol, 0.1 equiv). The reaction mixture was stirred under
H2 atmosphere (1 atm) at rt for 4 h. After the reaction was complete
(monitored by TLC), the crude reaction mixture was filtrated with
Celite and washed with EtOAc. The solvents were removed under
reduced pressure. Then the residue was purified by silica gel column
chromatography (PE/EA = 2/1) to afford the desired product 2I.
SUMMARY
■
1
2I: white solid (81.9 mg, 65% yield for two steps); H NMR (400
In this work, we performed computational studies on the
reaction mechanism of the experimentally observed acid-
catalyzed highly stereoselective migration of spiroindolenines.
The calculated results suggest that the allyl migration of the
five-membered spiroindolenine is a concerted reaction through
a “three-center-two-electron”-type transition state. This feature
also accounts for the highly stereoselective phenomenon
because no free carbocation can be formed during the
migration process and thus no racemization can occur at the
allylic position. The electronic property of the migratory group
has pronounced effect on the reaction profile. In general, the
acid-catalyzed rearrangement of the spiroindolenine species
becomes easier as the ability for migratory group to stabilize
positive charge increases. Our calculations suggest that the
methylene, benzyl, and even N-Tf aryl iminium migration
might be stereoselective processes if the enantioenriched
precursors could be synthesized. In addition, the influence of
the ring size (n = 3−6) to the allyl migration has also been
investigated, revealing the migration aptitude as 4 > 5 > 6 > 3.
In addition, some predictions based on the computations have
been supported by additional experiments. We believe this
detailed mechanistic study will be helpful for deep under-
standing of the mechanism of the indole C2 functionalization
reactions.22 Further exploration to expand the reaction scope
based on the present investigation is currently underway in this
laboratory.
MHz, CDCl3) δ 0.65 (t, J = 7.6 Hz, 3H), 0.70−0.78 (m, 1H), 0.83−
0.90 (m, 1H), 2.37 (d, J = 14.8 Hz, 1H), 2.48−2.52 (m, 2H), 2.72 (d, J
= 7.2 Hz, 1H), 3.11 (d, J = 15.2 Hz, 1H), 3.77 (s, 3H), 3.83 (s, 3H),
7.23 (dd, J = 7.6, 6.4 Hz, 1H), 7.32 (s, 1H), 7.34 (s, 1H), 7.60 (d, J =
7.6 Hz, 1H), 8.01 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 12.4, 22.5,
39.0, 40.4, 45.9, 52.9, 53.1, 59.0, 66.2, 121.1, 123.1, 125.9, 127.8, 140.9,
155.3, 171.9, 172.7, 177.6; IR (thin film) νmax (cm−1) = 2957, 1729,
1558, 1437, 1251, 1197, 1173, 1127, 1098, 940, 858, 753; MS (EI-
quadrupole, m/z, rel intensity) 247 ([M]+, 95), 218 (100); HRMS
(ESI-TOF) calcd for C18H22NO4 [M + H]+ 316.1549, found
316.1537; mp = 72.3−73.0 °C.
Migration of 2I. To a solution of spiroindolenine 2I (63.1 mg, 0.2
mmol, 1.0 equiv) in anhydrous THF (4 mL) was added p-
toluenesulfonic acid (11.4 mg, 0.06 mmol, 0.3 equiv). The reaction
1
mixture was stirred at rt and monitored by TLC and H NMR. The
starting material was recovered after 12 h.
Migration of 2C-epi. To a solution of spiroindolenine 2C-epi (49.4
mg, 0.2 mmol, 1.0 equiv) in anhydrous THF (4 mL) was added p-
toluenesulfonic acid (11.4 mg, 0.06 mmol, 0.3 equiv). The reaction
mixture was stirred at rt for 4 h. After the reaction was complete
(monitored by TLC), the reaction mixture was quenched with
saturated aqueous NaHCO3 and then diluted with water and EtOAc.
The organic layer was separated, washed sequentially with water and
brine, and dried over Na2SO4. The solvents were removed under
reduced pressure. Then the residue was purified by silica gel column
chromatography (PE/EA = 10/1) to afford the desired product 4C as
a pale yellow oil.
4C: viscous yellow oil (42.4 mg, 86% yield), 97% ee [Daicel
Chiralcel OD-H, hexane/2-propanol = 40/1, v = 0.4 mL·min−1, λ =
254 nm, t(minor) = 30.30 min, t(major) = 31.56 min]; [α]20D = +6.0
(c = 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.78−1.92 (m, 2H),
1.99−2.07 (m, 1H), 2.25−2.31 (m, 1H), 2.81−2.84 (m, 2H), 4.13 (dd,
J = 8.0, 5.6 Hz, 1H), 7.06−7.12 (m, 2H), 7.14−7.17 (m, 3H), 7.22−
7.32 (m, 3H), 7.40 (brs, 1H), 7.52 (dd, J = 6.0, 2.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.0, 22.0, 34.1, 41.5, 110.6, 111.7, 118.1, 119.1,
121.3, 126.7, 127.5, 128.3, 128.6, 135.5, 135.8, 144.2; IR (thin film)
νmax (cm−1) = 3057, 2970, 1679, 1619, 1490, 1321, 1081, 1044, 936,
878, 742, 699; MS (EI-quadrupole, m/z, rel intensity) 247 ([M]+, 95),
218 (100); HRMS (EI-TOF) calcd for C18H17N [M]+ 247.1361,
found 247.1363.
EXPERIMENTAL SECTION
■
Computational Methods. All calculations in this paper were
performed with the Gaussian09 package.23 The density functional
theory (DFT) method was employed using the PBE1PBE functional.24
The standard 6-311+G(d,p) basis sets were applied for all atoms.
Optimizations were conducted without any constraint using SMD
model25 in THF (ε = 7.4257). Frequency analyses were carried out to
confirm each structure being a minimum (no imaginary frequency) or
a transition state (only one imaginary frequency). Single-point
calculations of some key structures using the M06-2X functional26
were also performed, the results of which are consistent with that
obtained using PBE1PBE functional.27 The natural bond orbital
(NBO) analyses were performed using NBO 3.1 implemented in
Gaussin09. Throughout this paper, we mainly discuss the Gibbs free
energies in THF (ΔGTHF), unless specified. The electronic energies in
The synthetic procedure and characterization of 2C-epi are given in
the Supporting Information.
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Article
2853. (ab) Edwankar, C. R.; Edwankar, R. V.; Deschamps, J. R.; Cook,
J. M. Angew. Chem., Int. Ed. 2012, 51, 11762. (ac) Huang, D.; Xu, F.;
Lin, X.; Wang, Y. Chem.−Eur. J 2012, 18, 3148. (ad) Cai, Q.; Liang, X.-
W.; Wang, S.-G.; You, S.-L. Org. Biomol. Chem. 2013, 11, 1602.
(2) For recent reviews: (a) Edwankar, C. R.; Edwankar, R. V.;
Namjoshi, O. A.; Rallapalli, S. K.; Yang, J.; Cook, J. M. Curr. Opin.
Drug Discovery Dev. 2009, 12, 752. (b) Pulka, K. Curr. Opin. Drug
Discovery Dev. 2010, 13, 669.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete citation of ref 23, calculation details including the
figures and tables not presented in the text, 3D structures and
Cartesian coordinates for all calculated stationary points,
synthetic procedure and characterization of 2C-epi, and copies
1
of the H, 13C NMR and HPLC spectra. This material is
(3) (a) Williams, J. R.; Unger, L. R. Chem. Commun. 1970, 1605.
(b) Ungemach, F.; Cook, J. M. Hetrocycles 1978, 9, 1089. (c) Bailey, P.
D. J. Chem. Res., Synop. 1987, 202. (d) Kawate, T.; Nakagawa, M.;
Ogata, K.; Hino, T. Hetrocycles 1992, 33, 801. (e) Edwankar, R. V.;
Edwankar, C. R.; Namjoshi, O. A.; Deschamps, J. R.; Cook, J. M. J.
Nat. Prod. 2012, 75, 181.
(4) (a) Jackson, A. H.; Smith, A. E. Tetrahedron 1965, 21, 989.
(b) Jackson, A. H.; Smith, A. E. Tetrahedron 1968, 24, 403. (c) Jackson,
A. H.; Smith, P. Tetrahedron 1968, 24, 2227. (d) Jackson, A. H.;
Naidoo, B.; Smith, P. Tetrahedron 1968, 24, 6119. (e) Ibaceta-Lizana,
J. S. L.; Jackson, A. H.; Prasitpan, N.; R. Shannon, P. V. J. Chem. Soc.,
Perkin Trans. 2 1987, 1221.
(5) It was also found that direct attack at the C2 position could occur
under certain circumstances and the selectivity was affected by many
reaction parameters. Casnati, G.; Dossena, A.; Pochini, A. Tetrahedron
Lett. 1972, 52, 5277.
(6) For theoretical studies that supported direct attack mechanism
using the MNDO approach, see: (a) Kowalski, P.; Bojarski, A. J.;
Mokrosz, J. L. Tetrahedron 1995, 51, 2737. (b) Kowalski, P.; Mokrosz,
J. L. Bull. Soc. Chim. Belg. 1997, 106, 147.
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: (+86) 21-5492-5085. Fax: (+86) 21-5492-5087. E-mail:
zhengchao@sioc.ac.cn, slyou@sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Basic Research Program of China (973 Program
2010CB833300) and the National Natural Science Foundation
(20923005, 21025209, 21121062) of China are acknowledged
for generous financial support. We are also grateful to Prof. Yu-
Xue Li at SIOC for helpful discussions.
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̈
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