Unified Mechanistic Understandings of Pictet-Spengler Reactions

Article abstract of DOI:10.1016/j.chempr.2018.06.006

Pictet-Spengler reactions are extensively utilized in the synthesis of various indole alkaloids. However, their mechanisms have been a controversial research topic. The role of spiroindolenine, the generally proposed key intermediate in catalytic asymmetric Pictet-Spengler reactions, remains elusive. Herein, combined density functional theory calculations and direct molecular dynamics simulations reveal that the role of this intermediate is divergent. The spiroindolenine acts as either a productive or a non-productive intermediate depending on the shape of the potential energy surface. In the former case, dynamic effects play an important role in the rearrangement of spiroindolenine, which can occur without passing through the intervening transition states along the reaction coordinates. In the latter case, the formation of spiroindolenine is only an off-cycle equilibrium. These theoretical predictions were verified experimentally. Furthermore, these insights were applied to seven reported catalytic asymmetric Pictet-Spengler reactions, leading to unified mechanistic understandings of this synthetically enabling reaction. The unique charm of synthetic chemistry stems from its room for creativity in breaking and constructing chemical bonds. Developing novel synthetic methodologies is the central task of fundamental organic chemistry, which can facilitate or enable access to valuable classes of compounds or materials. The Pictet-Spengler reaction is a key method for the synthesis of indole-derived natural products, an important class of compounds in drug discovery. Rational design of new chemical reactivity largely relies on deep mechanistic understandings. However, because of the inherent complexity of systems on the molecular level, usually a reaction mechanism can be perturbed by subtle changes of single reaction parameters. Hence, pursuing unified mechanistic understandings of synthetically enabling reactions is of great significance academically and can pave the way for crucial industrial synthetic applications in various fields. Pictet-Spengler reactions have widely been employed in the synthesis of polycyclic-indole-derived natural products. However, the mechanism of this reaction has remained as a controversial research topic. In this article, You and co-workers performed combined density functional theory calculations and direct molecular dynamics simulations to provide unified mechanistic understandings of Pictet-Spengler reactions with an emphasis on the divergent role played by spiroindolenine intermediates. The key theoretical predictions are well supported by further experiments.

Full text of DOI:10.1016/j.chempr.2018.06.006

Article
Unified Mechanistic Understandings of Pictet-
Spengler Reactions
Chao Zheng, Zi-Lei Xia, Shu-Li
You
zhengchao@sioc.ac.cn (C.Z.)
slyou@sioc.ac.cn (S.-L.Y.)
HIGHLIGHTS
Dynamics effects might be
involved in Pictet-Spengler
reactions
Spiroindolenine can be either a
productive or a non-productive
intermediate
DFT calculations and direct
molecular dynamics simulations
have been utilized
Pictet-Spengler reactions have widely been employed in the synthesis of
polycyclic-indole-derived natural products. However, the mechanism of this
reaction has remained as a controversial research topic. In this article, You and co-
workers performed combined density functional theory calculations and direct
molecular dynamics simulations to provide unified mechanistic understandings of
Pictet-Spengler reactions with an emphasis on the divergent role played by
spiroindolenine intermediates. The key theoretical predictions are well supported
by further experiments.
Zheng et al., Chem 4, 1–15
August 9, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.06.006

Please cite this article in press as: Zheng et al., Unified Mechanistic Understandings of Pictet-Spengler Reactions, Chem (2018), https://doi.org/
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Article
Unified Mechanistic Understandings
of Pictet-Spengler Reactions
1
1,2,
Chao Zheng,1, Zi-Lei Xia, and Shu-Li You
*
*
SUMMARY
The Bigger Picture
The unique charm of synthetic
chemistry stems from its room for
creativity in breaking and
Pictet-Spengler reactions are extensively utilized in the synthesis of various
indole alkaloids. However, their mechanisms have been a controversial research
topic. The role of spiroindolenine, the generally proposed key intermediate
in catalytic asymmetric Pictet-Spengler reactions, remains elusive. Herein,
combined density functional theory calculations and direct molecular dynamics
simulations reveal that the role of this intermediate is divergent. The spiroindo-
lenine acts as either a productive or a non-productive intermediate depending
on the shape of the potential energy surface. In the former case, dynamic effects
play an important role in the rearrangement of spiroindolenine, which can occur
without passing through the intervening transition states along the reaction
coordinates. In the latter case, the formation of spiroindolenine is only an off-
cycle equilibrium. These theoretical predictions were verified experimentally.
Furthermore, these insights were applied to seven reported catalytic asym-
metric Pictet-Spengler reactions, leading to unified mechanistic understandings
of this synthetically enabling reaction.
constructing chemical bonds.
Developing novel synthetic
methodologies is the central task
of fundamental organic chemistry,
which can facilitate or enable
access to valuable classes of
compounds or materials. The
Pictet-Spengler reaction is a key
method for the synthesis of
indole-derived natural products,
an important class of compounds
in drug discovery. Rational design
of new chemical reactivity largely
relies on deep mechanistic
understandings. However,
INTRODUCTION
because of the inherent
Capturing and characterizing reactive intermediates in homogeneous catalytic reac-
tions undoubtedly holds a significant position in modern organic chemistry, since it
can provide first-hand information about the details of the reaction mechanism.
Thanks to the exponentially increasing computational capability and constantly
emerging novel theoretical methods, computational chemistry has evolved as a
powerful tool for mechanistic studies.1–4 It is complementary to the direct isolation
of reactive intermediates or the in situ observation of them by sophisticated spec-
troscopies, and especially useful when those intermediates are too unstable to be
isolated or their lifetimes are considerably shorter than the timescales of the spectro-
scopic methods. Conventionally, density functional theory (DFT) calculations
are widely employed to reveal informative structural and energetic properties of
key transition states and intermediates. Notably in recent years, direct molecular
dynamics simulations5–11 have found broad applications in interpreting unusual
profiles of organic reactions whose product distribution and stereochemistry are
determined by the shape of the potential energy surface (PES) or non-statistical
dynamics effects, rather than by the relative heights of energetic barriers, and there-
fore cannot be well described by classic transition state theory (TST).12–29
complexity of systems on the
molecular level, usually a reaction
mechanism can be perturbed by
subtle changes of single reaction
parameters. Hence, pursuing
unified mechanistic
understandings of synthetically
enabling reactions is of great
significance academically and can
pave the way for crucial industrial
synthetic applications in various
fields.
Pictet-Spengler reactions are among the most extensively utilized methods in the
synthesis of various indole alkaloids.30–34 Moreover, their mechanistic aspect is
intriguing and has been a topic of intensive research for quite a long time.35–42 In gen-
eral, two reaction paths are proposed (Scheme 1): the initial iminium ion I generated
from the condensation between the corresponding tryptamine and aldehyde might
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cyclize directly at the C2 position of the indole ring, delivering protonated tetrahy-
dro-b-carboline II (path a). Alternatively, I might first undergo spiroindolization,
giving five-membered-ring aza-spiroindolenine III (step 1, path b), then the migration
of the iminium moiety yielding the same intermediate II (step 2, path b). From inter-
mediate II, no matter by which reaction path it is generated, a proton abstraction pro-
cess delivers final Pictet-Spengler product IV. A key issue that still remains elusive
is the role played by intermediate III herein. Although it is well known that related
spiroindolenine compounds can be synthesized independently,43 to the best of
our knowledge direct evidence supporting the validity of path b under catalytic asym-
metric Pictet-Spengler conditions is not available. Therefore, providing a thorough
and unified mechanistic picture of Pictet-Spengler reactions is of great importance.
In the past few years, we have looked into the mechanism of Pictet-Spengler-type
reactions with Ir-catalyzed asymmetric allylic dearomatization reaction as a probe
(Scheme 2).44–51 On the basis of our mechanistic understandings, we have synthe-
sized a series of enantioenriched five-membered-ring carbo- and aza-spiroindole-
nines, and have shown the possibility that their stereoselective migration can be
achieved in a highly controllable fashion. DFT calculations (PBE1PBE/6-311+G**)
demonstrated that the close interaction between the electron-rich indole ring and
the positively charged migratory group is critical for the chirality maintenance during
the migration process.52 However, a major drawback of these studies is that they did
not prove the necessity of the involvement of the five-membered-ring aza-spiroindo-
lenine intermediates as well as their stereoselective migration in real Pictet-Spengler
reactions. To address this issue, we recently performed combined DFT calculations
and direct molecular dynamics simulations of Pictet-Spengler reactions and re-
vealed that the formation of spiroindolenine intermediate can be a kinetically
competitive pathway compared with the direct C2 cyclization. The roles played by
spiroindolenine intermediates are highly dependent on the shape of the PES. In
particular, significant dynamics effects are observed for the prototype substrate
having an electron-withdrawing group on the iminium nitrogen. In this case, spiroin-
dolenine acts as a productive intermediate and its stereochemical information can
be transferred to the final product very effectively. On the other hand, in the reaction
of the prototype substrate with an electron-donating group on the iminium nitrogen,
the formation of spiroindolenine is only an off-cycle equilibrium. The theoretical pre-
dictions were further supported experimentally. On the basis of these results, unified
mechanistic understandings of Pictet-Spengler reactions were postulated. Herein,
we report the details of this study.
RESULTS
DFT Calculations on the Prototype Pictet-Spengler Reactions
In this study, tosylic acid-catalyzed Pictet-Spengler reactions of two prototype sub-
strates containing either a N–Bn (series A) or a N–Tf (series B) iminium moiety were
first investigated by DFT calculations at the PBE1PBE/6-311+G** level of theory
(Figure 1). In both cases, the reaction starts from an E-iminium precursor (I-A,
1State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
0.0 kcal/mol; or I-B, 0.0 kcal/mol) generated from the condensation between the cor-
responding tryptamine and an aldehyde. Structurally, I-A and I-B are quite different
from each other in terms of the distances between their corresponding iminium
1
moiety and the indole ring (defined as l =
/
[B(C2–C8) + B(C3–C8)]) (Figure 2).
2
˚
A small l value of about 2.5 A in I-B indicates some interactions between the
positively charged N–Tf iminium moiety and the electron-rich indole ring of this spe-
cies. Atoms in molecules (AIM) topological analysis53 revealed the existence of bond
path and bond critical point between these two moieties. Wiberg bond indices54
2Lead Contact
*Correspondence: zhengchao@sioc.ac.cn (C.Z.),
slyou@sioc.ac.cn (S.-L.Y.)
https://doi.org/10.1016/j.chempr.2018.06.006
2
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N
N
PG
PG
Path a
N
N
H
H
H
R
R
H
I
II
PG
N
N
Path b
spiroindolization
Path b
PG
R
N
migration
H
R
N
H
III
IV
Scheme 1. General Mechanistic Proposal of Pictet-Spengler Reaction
between C2 and C8 (0.19) and C3 and C8 (0.16) also confirm some weak bonding
interaction between these atom pairs. On the other hand, A large l value of about
˚
3.2 A was observed in I-A. Accordingly, the interaction between the N–Bn iminium
moiety and the indole ring can be safely ignored.
The energetic barriers of nucleophilic attacks at the C2 or C3 positions of the indole
ring (TS1 and TS2) are of undoubted importance in understanding the mechanism of
Pictet-Spengler reactions. We employed two parameters, d (the energy difference
between TS1 and TS2, defined as d = DG(TS2) À DG(TS1)) and h (the average barrier
height of TS1 and TS2, defined as h = 1/2[DG(TS1) + DG(TS2)]), to characterize these
nucleophilic attacks. In both cases, the nucleophilic attacks at the C2 or C3 positions
are almost equally accessible. A small or even negligible d value was observed for
series A (dA = 1.2 kcal/mol) and B (dB = 0.0 kcal/mol), respectively, which indicates
that the formation of spiroindolenines (III-A, 3.5 kcal/mol and III-B, À17.5 kcal/mol) is
a kinetically competitive pathway compared with direct C2 cyclization in their corre-
sponding reactions. However, the average barrier heights of the two transition states
are rather different. Considerable energetic barriers should be overcome for both
spiroindolization and C2 cyclization in series A (hA = 13.5 kcal/mol), whereas such
barriers are very small in series B (hB = 0.4 kcal/mol). Notably, benchmark calcula-
tions on d and h values with various density functionals, including M06-2X,
uB97X-D, and B3LYP-D3(BJ), gave qualitatively consistent results (see Tables S1
and S2 for details). It should be noted that the differences between the two systems
in terms of general energetics of the spiroindolization and C2 cyclization processes,
as well as structural parameters of iminium precursors, will result in significantly
varied mechanistic scenarios, especially regarding whether or not dynamics effects
play a role in the migration of spiroindolenine intermediate (vide infra).
Although both III-A and III-B can be formed effectively, neither of them is the
global minimum of the corresponding PES. In fact, direct C2 cyclization leads to pro-
tonated tetrahydro-b-carbolines II-A (9.4 kcal/mol) and II-B (À12.0 kcal/mol), from
which the irreversible proton abstraction by tosylate anion (TS3-A, 15.7 kcal/mol;
TS3-B, À10.6 kcal/mol) furnishes tetrahydro-b-carboline as the thermodynamically
most stable species in each system (IV-A, À4.2 kcal/mol; IV-B, À27.7 kcal/mol).
Notably, the deprotonation is the rate-determining step in series A,39,41 whereas
on the other hand it is kinetically trivial in series B.
GiventhatIII-AandIII-Bcanbeaffordedeffectivelyandatthe sametimearenotthether-
modynamically most stable species in each series, their downstream transformations
become quite intriguing. This is also the most elusive part of the mechanistic puzzle of
Pictet-Spengler reactions. On the basis of the knowledge of d and h values in both sys-
tems, we envisioned that the downstream transformations of III-A or III-B should be
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CO2Me
CO2Me
CO2Me
MeO2C CO2Me
MeO2C
[Ir]
acid
N
H
(ref. 47)
concerted
allyl migration
N
H
N
OCO2Me
Ph
Ts
N
Ts
N
[Ir]
acid
N
H
(ref. 50)
N
Ts
stepwise
iminium migration
Ph
N
H
Ph
N
(±)
OCO2Me
Scheme 2. The Synthesis and Migration of Spiroindolenines
highly dependent on the shape of the corresponding PES. A better description of this
issue comes from the calculated two-dimensional PESs of the two series (electronic en-
ergies at the PBE1PBE/6-31G** level of theory) with respect to the distances of C2–C8
and C3–C8 bonds (Figure 3). First, the retro-process of the spiroindolization in series A
was considered (Figure 3A). A particle coming from III-A via TS2-A (2.53, 2.02) will most
likely be trapped in the deep potential well around local minimum I-A (3.22, 3.21), which
indicates that the direct transformation from III-A to II-A might be interrupted. On the
other hand, as shown in Figure 3B, a typical caldera-shaped PES55–60 was observed
for series B. There is only minor geometric distortion and hence a small energetic in-
crease (<1 kcal/mol) from I-B (2.53, 2.63) to TS1-B (2.26, 2.56) or TS2-B (2.50, 2.30).
The existence of a flat region around these three species might introduce significant
dynamics effects into the reaction, making the downstream transformation of III-B a
non-trivial event in the whole mechanistic scenario.61 In other words, a particle coming
from III-B via TS2-B might traverse this caldera-shaped area without interruption, head-
ing for II-B. This means that although two transition states and one intermediate are
located along the reaction pathway from III-B to II-B, this transformation might proceed
like a concerted process to some extent.62–65
Direct Molecular Dynamics Simulations of the Migration Processes
To evaluate the dynamics effects in series B, we applied quasi-classical Born-Oppen-
heimer molecular dynamics simulations66 to investigate the migration of spiroindo-
lenine III-B. First, based on TS2-B, an ensemble of initial coordinates and momenta
for all the atoms of the system was sampled, which reflects how the particles traverse
the nearby region of this transition state (see Figures S3 and S4 for details). Then,
starting from each set of initial coordinates and momenta, a trajectory was propa-
gated in both forward and reverse directions until either C2–C8 or C3–C8 bond
was fully constructed or a total time of 2 ps was reached. Detailed analyses of
100 trajectories revealed some intriguing mechanistic information about the migra-
tion process of spiroindolenine III-B from the perspective of dynamics (Figure 4). The
calculated trajectories can be grouped into five categories: (1) ‘‘reactive’’ trajectories
that proceed from III-B to II-B (44 cases), (2) ‘‘recrossing’’ trajectories that re-form
III-B after complete breaking of C3–C8 bond (44 cases), (3) ‘‘staying’’ trajectories
that bounce back and forth in the nearby region of I-B for over 2 ps (eight cases),
(4) ‘‘reversed recrossing’’ trajectories that pass from II-B to the area around TS2-B
and then re-form II-B (three cases), and (5) a ‘‘collapsed’’ trajectory that eventually
leaves the caldera region (one case). Of particular interest is the observation of quite
a few ‘‘reactive’’ trajectories (see Figures S5 and S6 and Video S1 for the details of a
typical reactive trajectory). Their duration ranges from 41 to 1,993 fs, with an average
value of 755 fs, which is just one order of magnitude larger than the lifetime of a
4
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A
B
Figure 1. The Calculated Reaction Pathways of the TsOH-Catalyzed Pictet-Spengler Reactions
The reaction pathways with (A) N–Bn and (B) N–Tf protecting groups. Relative Gibbs free energies (in kcal/mol) were calculated at the PBE1PBE/
6-311+G** level of theory. The optimized structures of all stationary points can be found in Figures S1 and S2.
typical concerted transition state.67 The overlay of these ‘‘reactive’’ trajectories (Fig-
ure 4A) perfectly matches the shape of the low-energy area in the corresponding PES
(Figure 3B), which confirms a valley channel that allows direct transformation of spi-
roindolenine intermediate III-B to protonated tetrahydro-b-carboline II-B. Mean-
while, the dynamics effects also contribute significantly to the stereochemistry of
the reaction. In most cases, wandering of the particle in the caldera region lasts
for several hundred femtoseconds no matter where a trajectory finally ends.
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Figure 2. The Structures of I-A and I-B
(A and C) The optimized structures of (A) I-A and (C) I-B calculated at the PBE1PBE/6-311+G** level
of theory.
(B and D) The contour maps of the Laplacian of the electron density (V2r) of (B) I-A and (D) I-B in the
plane defined by C2, C3, and C8. Bold values (in black) and italic values (in purple) are bond
distances (in angstroms) and Wiberg bond indices, respectively, for B(C2–C3), B(C2–C8), and
B(C3–C8). Blue dots indicate bond critical points. Gray lines indicate bond paths.
However, during this journey the maximum value of the average bond distance of
˚
C2–C8 and C3–C8 is roughly less than 3.5 A, suggesting the existence of the inter-
action between the iminium moiety and the indole ring, which lends some stability to
this ‘‘bent’’ conformation in which the side chain at the C3 position of the substrate is
bent so that the iminium moiety is an approximation to the indole ring (Figures 4F
and 4G). As a consequence, only one pro-chiral face of the iminium carbon
(Si-face in this model) is oriented toward the indole ring, which guarantees the con-
servation of the configuration of the C8 position in the migration event. Notably, it is
observed only in one case (the ‘‘collapsed’’ trajectory) where the distance between
˚
the iminium moiety and indole ring is elongated to over 4 A. Hence, the racemization
at the C8 position becomes possible because the ‘‘bent’’ conformation is completely
unlocked, and, therefore, both pro-chiral faces of the free iminium carbon will be
available for subsequent spiroindolization or C2 cyclization.
To make a comparison, we also performed similar direct molecular dynamics simu-
lations for series A. Starting from initial geometries sampled on the basis of TS2-A,
six trajectories were propagated for 2 ps. As expected, all the trajectories were
finally trapped in the deep potential well in the nearby region of I-A and thus cate-
gorized as ‘‘staying’’ (see Figures S7–S9 for details). These results are in agreement
with the energy profile obtained by DFT calculations (Figure 1). The attack at the C3
position of the indole ring in series A can be regarded as a simple reversible process,
and there is no direct channel connecting III-A and II-A.
Two Limiting Types of Mechanism of Pictet-Spengler Reactions
According to the results presented above, two types of mechanistic scenarios can be
drawn for Pictet-Spengler reactions (Scheme 3). In both cases, the spiroindolization
at the C3 position and direct cyclization at the C2 position are kinetically
6
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Figure 3. The Two-Dimensional PESs of the TsOH-Catalyzed Pictet-Spengler Reactions
The two-dimensional PESs with (A) N–Bn and (B) N–Tf protecting groups. Relative electronic
energies (in kcal/mol, scaled by the colored bars) were calculated at the PBE1PBE/6-31G** level of
theory. The positions of selected stationary points are marked with crosses or short arrows. The
schematic reaction coordinates of the migration of the corresponding spiroindolenines are shown
by curved arrows.
competitive. This suggests that the formation of spiroindolenine intermediate is a
common reaction pathway. However, the role of the spiroindolenine intermediate
is divergent and highly depends on the shape of the PES. For the prototype sub-
strate bearing an electron-withdrawing group (Tf) on the iminium nitrogen atom
(type I), the spiroindolenine is a productive intermediate that can be transformed
to protonated tetrahydro-b-carboline, the direct precursor of the final product, via
dynamics effects over the caldera-shaped PES. This corresponds to the scenario in
which the migration of spiroindolenine intermediate is in operation. Moreover, in
this scenario the spiroindolenine intermediate is important in terms of stereochem-
istry. The configuration of the iminium carbon is very likely reserved during the
migration, indicating that significant chirality transfer from spiroindolenine to the
final Pictet-Spengler product can be expected. On the other hand, for the prototype
substrate bearing an electron-donating group (Bn) on the iminium nitrogen atom
(type II), the spiroindolization process is an off-cycle equilibrium, making spiroindo-
lenine a non-productive intermediate. There is no direct migration that connects spi-
roindolenine and protonated tetrahydro-b-carboline. In addition, the configuration
of the iminium carbon established in the spiroindolization process will be irrelevant
to the stereochemistry of the final product. Notably, in the type II scenario the final
deprotonation is the rate-determining step, whereas in the type I scenario, it is not.
Experimental Verifications
To test the aforementioned theoretical predictions experimentally, we prepared spi-
roindolines 1a (N–Ts) and 1b (N–Bn) in enantioenriched form and subjected them to
a sequential oxidation and migration reaction (Scheme 4). With manganese dioxide
(MnO2) or iodosobenzene (PhIO) as the oxidant, the secondary amine moieties of 1a
and 1b could be converted to imines. The in-situ-formed spiroindolenines under-
went iminium migration in the presence of racemic phosphoric acid (rac-PA), deliv-
ering their corresponding tetrahydro-b-carbolines 2a and 2b in moderate yields.
Notably, compound 2a was afforded in 95% enantiomeric excess (ee), and 2b was
afforded in completely racemic form. These results serve as solid evidence support-
ing the two limiting mechanistic scenarios proposed in the previous section.
Applications in Selected Known Pictet-Spengler Reactions
Our next aim was to investigate how the two limiting mechanistic scenarios can be
applied in more realistic situations. In this regard, seven representative examples
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Figure 4. The Results of BOMD Calculations
(A–E) The overlays of the plots of ‘‘reactive’’ (A, blue), ‘‘recrossing’’ (B, orange), ‘‘staying’’ (C, red), ‘‘reversed recrossing’’ (D, purple), and ‘‘collapsed’’
(E, black) trajectories of series B with respect to the distances of C2–C8 and C3–C8 bonds. Black crosses show the stationary points (I-B (2.53, 2.63),
TS1-B (2.26, 2.56), II-B (1.58, 2.55), TS2-B (2.50, 2.30), and III-B (2.54, 1.57)) of the PES.
(F) Summary of maximum average distance of C2–C8 and C3–C8 bonds during a trajectory.
(G) Distribution of the duration of each trajectory in the time scales of 0–300, 300–600, 600–900, 900–1,200, 1,200–2,000, and >2,000 fs.
of known catalytic asymmetric Pictet-Spengler reactions68–74 were considered
(Scheme 5). These reactions were catalyzed by either a chiral phosphoric acid or a
chiral thiourea. A wide range of iminium precursors with diverse steric and electronic
properties of the side chains were covered. The key intermediates and transition
states of each system (series C–I) with a truncated catalyst were optimized at the
PBE1PBE/6-311+G** level of theory (see Table S3 for details). Interestingly, the en-
ergy profiles of these ‘‘real’’ Pictet-Spengler reactions varied significantly from each
other. To accomplish unified understandings of the mechanism of Pictet-Spengler
reactions, we developed a mechanistic diagram on the basis of the two parameters
(d and h) that we employed to characterize the shape of the PES of the reaction (Fig-
ure 5). All the series studied herein can be scattered into this diagram according to
their own d and h values. Each series is represented as either a black cross or a red
circle depending on whether the deprotonation is the rate-determining step or not.
As discussed in previous sections, d and h values are two key parameters that char-
acterize the shape of the PES of a Pictet-Spengler reaction. A smaller d value indi-
cates a larger possibility that a spiroindolenine intermediate can be formed in the
reaction. On the other hand, a smaller h value indicates a more typical caldera-
shaped PES, and hence larger possibility that a productive migration of spiroindole-
nine intermediate is involved via dynamics effects. In our mechanistic diagram, the
two prototype reactions, series A (13.5, 1.2) and B (0.4, 0.0), are located in the right
side and the lower-left corner, respectively, as two references. The detailed knowl-
edge about these two series obtained in this study will help interpretation of the
mechanistic aspects of other enantioselective Pictet-Spengler reactions. In cases
8
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Type I
Productive intermediate
Spiroindolenine
protonated tetrahydrocarboline
Pictet-Spengler product
Iminium precursor
2
C3 attack
C2 attack
deprotonation
fast
N
N
N
3
N
Tf
8
N
Tf
N
H
8
2
Ph
3
N
H
H
TsO
N
H
H
Tf
Ph
Ph
TsO
Ph
8
Tf
H
TsO
TsOH
H
weak interaction between
indole ring & N-Tf iminium
Dynamics effects & Chirality transfer
Type II
Non-productive intermediate
Pictet-Spengler product
Spiroindolenine
protonated tetrahydrocarboline
Iminium precursor
2
deprotonation
r.d.s.
C3 attack
C2 attack
N
N
N
3
N
N
Bn
8
Bn
N
H
8
2
Ph
3
N
H
H
TsO
N
H
H
Bn
Ph
Ph
TsO
Ph
8
Bn
H
H
TsO
TsOH
no interaction between
indole ring & N-Bn iminium
Off-cycle equilibrium & irrelevant to
overall stereochemical outcomes
Scheme 3. Two Limiting Types of Mechanism of Pictet-Spengler Reactions
where a relatively small d value is observed—series C (2.8, 1.3), D (13.1, 0.8),
and I (6.8, 1.7)—the spiroindolenine intermediates might be formed in a non-negli-
gible proportion.75 Among these cases, series D resembles series A the most in that
the spiroindolenine serves as non-productive intermediate. Although with a rela-
tively less typical caldera-shaped PES, we believe that series C behaves like
series B to some extent. The spiroindolenine intermediates formed in this reaction
can migrate without significant interruption. The stereochemistry established during
the spiroindolization process will contribute to that of the final Pictet-Spengler
product. With a medium-level h value, series I resides in the somewhat borderline
region of the mechanistic spectrum. In this case, we believe that both types of
limiting mechanisms of Pictet-Spengler reactions might be in operation at the
same time. For the cases with a larger d value such as series E (4.3, 3.4),
F (5.4, 3.7), G (10.0, 2.3), and H (9.8, 3.5), a much higher energetic barrier is required
to be overcome for the spiroindolization than that for the direct C2 cyclization.
Therefore, the spiroindolization becomes a minor process in the whole reaction,
and the downstream transformation of spiroindolenine species is of less importance.
In series A and F, the final deprotonation was identified as the rate-determining step.
Thus, the stereochemistry of the reaction might be irrelevant to both spiroindoliza-
tion and C2 cyclization processes.41 This mechanistic spectrum shows that, although
the structural perturbation of substrate and the switch of catalyst will alter the profile
of Pictet-Spengler reactions significantly, a quick but insightful interpretation of
the mechanism of a given Pictet-Spengler reaction can be drawn on the basis of
two simple parameters (d and h) in energetics.
Conclusion
In this study, we performed detailed computational studies on the mechanism of
Pictet-Spengler reactions. Combined DFT calculations and direct molecular dy-
namics simulations were carried out on two prototype reactions, from which two
types of limiting mechanistic scenarios have been proposed. The divergent roles
played by spiroindolenines, key intermediates commonly proposed in previous
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PG
PG
N
oxidant
rac-PA
N
migration
N
PG
O
O
O
Ph
rt
N
H
Ph
P
N
H
Ph
N
OH
1a (PG = Ts)
99% ee
1b (PG = Bn)
97% ee
oxidant = MnO2
oxidant = PhIO
2a (PG = Ts)
37% yield, 95% ee
2b (PG = Bn)
rac-PA
41% yield, 0% ee
Scheme 4. The Experimental Verifications of the Mechanistic Proposals
mechanisms, have been demonstrated. These theoretical predictions were sup-
ported by experimental investigations. In addition, the current work serves as a vivid
example showing the possibility that the stereochemical outcomes of a synthetically
useful reaction might be complexed by dynamics effects, a term beyond traditional
TST.76,77 On the basis of the two limiting scenarios, a comprehensive mechanistic
spectrum was developed and applied to several representative examples of known
catalytic asymmetric Pictet-Spengler reactions. We believe that these results can be
utilized as a practical guide in exploring novel reactivity of spiroindolenine species
and related chemistry.
EXPERIMENTAL PROCEDURES
Computational Part
All the calculations in this study were performed with the Gaussian09 package.78
During the exploration of the reaction profile, the DFT method was employed
with the PBE1PBE functional. The standard 6-311+G** basis sets were applied for
all atoms. Optimizations were conducted without any constraint according to the im-
plicit solvation model (SMD) in THF ( 3 = 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). Ultrafine grid was specified for numerical inte-
grations. Benchmark calculations with PBE1PPBE, M06-2X, uB97XD, and B3LYP-
D3(BJ) functionals were performed with 6-31G** or 6-311+G** basis sets and the
same solvation model. Two-dimensional relaxed PES scans were carried out at the
PBE1PBE/6-31G** level of theory. Quasi-classical Born-Oppenheimer molecular dy-
namics simulations were performed with the ‘‘BOMD’’ keyword implemented in
Gaussian09 package. The initial coordinates and momenta of all the trajectories
were generated from the normal mode sampling (at 300 K) from the transition
state TS2-B or TS2-A optimized at the PBE1PBE/6-31G** level of theory. From
each set of initial coordinates and momenta, a trajectory was propagated with the
classical equations of motion with energies and forces computed with PBE1PBE/6-
31G** in THF (SMD). Trajectory propagation was performed in both forward and
reverse directions until either C2–C8 or C3–C8 bond was fully constructed or a total
time of 2 ps was reached. AIM topological analysis and Wiberg bond index analysis
were performed with Multiwfn.79 All calculated structures were visualized with
CYLview80 or VMD.81
Experimental Part
The Procedure of Sequential Oxidation and Migration Reaction of 1a
Anhydrous dichloroethane (2 mL) and MnO2 (284.0 mg, 3 mmol, 92% w/w) were
added to a mixture of 1a (41.0 mg, 0.1 mmol, 99% ee), rac-PA (7.0 mg,
˚
0.02 mmol), and 3 A MS (100 mg) under argon. The reaction mixture was stirred at
25ꢀC and monitored by thin-layer chromatography (TLC). Upon its completion,
the reaction was quenched with saturated NaHCO3 and extracted with dichlorome-
thane (33). The combined organic layer was washed with brine, dried over Na2SO4,
and filtrated. After the solvent was removed under reduced pressure, the residue
10
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Series C68
Series D69
CO2Et
CO2Et
CO2Et
(S)-CPA-1
(20 mol %)
Na2SO4
NH2
N
Ac
CO2Et
NH2
1) 3 Å MS or Na2SO4
NH
N
H
N
H
N
N
H
C5H11
H
+
2) AcCl (1.0 equiv)
2,6-lutidine
(1.0 equiv)
TU-1 (10 mol %)
Et2O, -78 ~ -60 °C
toluene, -30 °C
Et
+
65% yield
95% ee
O
O
76% yield
88% ee
Et
C5H11
Series E70
Series F71
1) (R)-CPA-2
(5 mol %)
toluene, 0 °C
3 Å MS, BHT
O
NH
NH
TU-2 (10 mol %)
O
N
S
N
TMSCl
N
N
H
N
H
H
Ph
Ph
C5H11
H
H
N
H
2) HCl, PhSH
TBME, -55 °C
Ph
HO
87% yield
84% ee
+
80% yield
97% ee
O
C5H11
BHT = 3,5-(tBu)2-4-hydroxytoluene
Series G72
Series H73
HN
O
R
HN
(R)-CPA-3
(10 mol %)
Au-1
O
O
N
N
(R)-CPA-3
(10 mol %)
(0.5~1 mol %)
S
O
HN
S
N
N
N
R
N
Me
H
O
H
Me
H
toluene/CH2Cl2
(21:1)
O
toluene
110 °C
N
+
O
H
74% yield
83% ee
85% yield
88% ee
60 °C
Me
R = p-FC6H4
Series I74
(R)-CPA-4
(10 mol %)
N
N
Me
O
Me
O
N
N
CCl4
3 Å MS, rt
H
H
90% yield
91% ee
R
R2
N
tBu
S
R
tBu
tBu
Au
O
O
O
SbF6
P
P
O
O
O
R1
N
N
H
OH
H
P
O
N
Me
Ph
OH
Me
R
R
TU-1 (R1 = R2 = iBu)
TU-2 (R1
nC5H11 R2 = Me)
CPA-1 R = 2,4,6-(iPr)3-C6H2
CPA-2 R = 3,5-(CF3)2-C6H3
CPA-3 R = SiPh3
Au-1
CPA-4 R = 2,4,6-(iPr)3-C6H2
=
Scheme 5. Representative Examples of Known Catalytic Asymmetric Pictet-Spengler Reactions Considered in This Study
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Figure 5. The Two-Dimensional Mechanistic Spectrum of Pictet-Spengler Reactions
The spectrum was established on the basis of parameters d (the energy difference between
transition states of spiroindolization and C2 cyclization processes) and h (the average barrier height
of spiroindolization and C2 cyclization processes) values. Each series is represented by a black
cross (deprotonation is the rate-determining step) or a red circle (deprotonation is not the rate-
determining step).
was purified by preparative TLC (ethyl acetate/petroleum ether = 1/4) to afford 2a
(15.0 mg, 37% yield, 95% ee).
The Procedure of Sequential Oxidation and Migration Reaction of 1b
Anhydrous dichloroethane (4 mL) and PhIO (53.0 mg, 0.24 mmol) were added to a
˚
mixture of 1b (68.0 mg, 0.2 mmol, 97% ee), rac-PA (7.0 mg, 0.02 mmol), and 3 A
MS (200 mg) under argon. The reaction mixture was stirred at 25ꢀC and monitored
by TLC. Upon its completion, the reaction was quenched with saturated NaHCO3
and extracted with dichloromethane (33). The combined organic layer was washed
with brine, dried over Na2SO4, and filtrated. After the solvent was removed under
reduced pressure, the residue was purified by preparative TLC (ethyl acetate/
petroleum ether = 1/9) to afford 2b (26.0 mg, 41% yield, 0% ee).
More detailed information can be found in the Supplemental Information (Scheme
S1, Figures S10–S25, and associated text).
DATA AND SOFTWARE AVAILABILITY
The structure of compound 4 (reported in the Supplemental Information) has been
deposited in the Cambridge Crystallographic Data Centre under accession number
CCDC: 1811798.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 25 fig-
ures, 1 scheme, 3 tables, 1 video, and 1 data file and can be found with this article
online at https://doi.org/10.1016/j.chempr.2018.06.006.
ACKNOWLEDGMENTS
We thank the National Key R&D Program of China (2016YFA0202900), the National
Basic Research Program of China (973 Program 2015CB856600), the National
12
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Natural Science Foundation of China (21332009 and 21772219), the Science and
Technology Commission of Shanghai Municipality (16XD1404300 and
18QA1404900), and the Strategic Priority Research Program (XDB20000000), Key
Research Program of Frontier Sciences (QYZDYSSWSLH012), and Youth Innovation
Promotion Association (2017302) of the Chinese Academy of Sciences for generous
financial support.
AUTHOR CONTRIBUTIONS
C.Z. contributed the concepts and ideas, performed the computations, analyzed
data, and drafted and revised the manuscript. Z.-L.X. performed the experimental
studies. C.Z., Z.-L.X., and S.-L.Y. commented on the results. S.-L.Y. conceived the
project and served as the principal investigator.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: April 1, 2018
Revised: May 9, 2018
Accepted: June 12, 2018
Published: July 12, 2018
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