Chiral Thioureas Promote Enantioselective Pictet-Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction

Article abstract of DOI:10.1021/jacs.7b06811

An investigation of the mechanism of benzoic acid/thiourea co-catalysis in the asymmetric Pictet-Spengler reaction is reported. Kinetic, computational, and structure-activity relationship studies provide evidence that rearomatization via deprotonation of

Full text of DOI:10.1021/jacs.7b06811

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Article
Chiral Thioureas Promote Enantioselective Pictet–
Spengler Cyclization by Stabilizing Every Intermediate and
Transition State in the Carboxylic Acid-Catalyzed Reaction
Rebekka S. Klausen, C. Rose Kennedy, Alan M. Hyde, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Aug 2017
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Journal of the American Chemical Society
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Chiral Thioureas Promote Enantioselective Pictet–Spengler Cycliza-
tion by Stabilizing Every Intermediate and Transition State in the
Carboxylic Acid-Catalyzed Reaction
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‡
Rebekka S. Klausen†, C. Rose Kennedy, Alan M. Hyde , Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Brønsted acid co-catalysis, anion-binding catalysis, kinetic isotope effects, reaction mechanism, tetrahydro-β-carboline
ABSTRACT: An investigation of the mechanism of benzoic acid/thiourea co-catalysis in the asymmetric Pictet−Spengler reaction is re-
ported. Kinetic, computational, and structure−activity relationship studies provide evidence that rearomatization via deprotonation of the
pentahydro-β-carbolinium ion intermediate by a chiral thiourea•carboxylate complex is both rate- and enantioselectivity-determining. The
thiourea catalyst induces rate acceleration over the background reaction mediated by benzoic acid alone by stabilizing every intermediate and
transition state leading to up to and including the final selectivity-determining step. Distortion–interaction analyses of the transition struc-
tures for deprotonation predicted using density functional theory indicate that differential π–π and C–H⋯π interactions within a scaffold
organized by multiple hydrogen-bonds dictate stereoselectivity. The principles underlying rate acceleration and enantiocontrol described
herein are expected to have general implications for the design of selective transformations involving deprotonation of high-energy interme-
diates.
C–C bond formation notwithstanding, kinetic isotope effect (KIE)
and pH–rate dependence studies of the biosynthesis of stric-
INTRODUCTION
The intramolecular Friedel–Crafts alkylation of β-arylethylimines
has attracted intense research interest since it was first reported by
Pictet and Spengler over a century ago.1,2 Synthetic chemists and
biological systems routinely employ this transformation for the
efficient construction of bioactive heterocycles including tetrahy-
dro-β-carbolines and tetrahydroisoquinolines.3–15 The products
arising from Pictet–Spengler reactions of tryptamine derivatives
alone account for the cores of all monoterpene indole alkaloids16,17
and numerous other secondary metabolites (Figure 1A), and simi-
lar motifs are of continual interest as pharmaceutical candidates.18–
tosidine provide evidence that rearomatization, mediated by an
active site glutamate residue, is in fact rate-limiting (Figure 1C).21–
23,46
The analogous, nonenzymatic reaction in aqueous acetic acid
buffer displays similar behavior.21 However, little is known about
the rearomatization process in the nonpolar media commonly em-
ployed for stereoselective synthetic methods.
In 2009, we reported an enantioselective protocol for the Pictet–
Spengler reaction of substituted tryptamines based on the coopera-
tive action of chiral thiourea (1a) and benzoic acid co-catalysts
(Figure 1D).47 This method exhibits broad substrate scope: tryp-
tamine nucleophiles bearing diverse substitution (2) as well as both
aryl and aliphatic aldehyde electrophiles (3) undergo reaction to
afford chiral tetrahydro-β-carboline products (4) in high enanti-
oselectivity. The cooperative catalysis between weak achiral
Brønsted acids and chiral thioureas revealed in this work has subse-
quently proven to be broadly applicable to a variety of enantioselec-
tive transformations of interest.34,48–52 Motivated by the synthetic
utility of the Pictet–Spengler method and the generality of the cata-
lytic approach,53 we undertook a thorough analysis of this reaction
system with the goal of elucidating its mechanism.
20
The enzymes catalyzing these transformations have been scruti-
nized by the structural biology and enzymology communi-
ties,3,16,17,21–23 and parallel attention has been devoted to the devel-
opment of small molecule catalysts for stereocontrolled Pictet–
Spengler reactions.24–35
Interest in the synthetic applications of the Pictet–Spengler reac-
tion has long been intimately linked to speculation and investiga-
tion regarding the details of its molecular mechanism. Following
condensation of a β-arylethylamine with an aldehyde, addition of
the pendant arene to the resultant iminium ion and subsequent
rearomatization (via deprotonation) are necessary to generate the
final product. In the case of tryptamine derivatives, the C–C bond-
forming step may, in principle, occur by direct electrophilic aro-
matic substitution at the C2 position or by alkylation at the more
nucleophilic C3 position followed by C–C migration (Figure 1B).
System-dependent evidence has been provided for the viability of
both paths to the requisite pentahydro-β-carbolinium ion interme-
diate.36–45 The important questions surrounding the mechanism of
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A. The Protio-Pictet–Spengler Reaction of Tryptamines:
B. Mechanistic Questions in the Pictet–Spengler Reaction of Tryptamines
1
2
3
4
5
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8
A Tool for (Bio)Synthesis
– H+
H
NH
R
N
NH
3
*
"H+"
NH2
*
R
NH
R
*
2
rearomatization
C2 addition
R
N
H
*
N
H
N
H
H
RCHO
N
H
N
H
Which step(s) control turnover
and stereoinduction?
tryptamine
tetrahydro-β-carboline
• both C2- and C3-addition have
been demonstrated as viable
NH
*
OGlc
O
*
R
• rearomatization is rate-determining in
enzyme active sites and aqueous solution
NH
NH
C–C migration
C3 addition
N
9
Me
• mechanism in organic solvents is unknown
N
H
H
H
H
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HO
O
Strictosidine MeO2C
Me
N
H
C. Enzymatic Catalysis Relies on a Key Carboxylic Acid
Glu309
(+)-Isoelacolamine
His307
Glu309
H
N
O
O
H
N
OTMB
OMe
H
N
H
Phe226
MeO
NH2
H
H
MeO2C
H
OGlc
O
O
(–)-Reserpine
H
H
N
H
O
NH
151
Tyr
H
Strychnine
His277
CF3
O
MeO2C
D. A Small-Molecule-Catalyzed,Enantioselective Pictet–Spengler Reaction
Catalyst:
Catalyst (20 mol %)
Me iPr
N
S
15 examples
R = aryl, alkyl
NH2
BzOH (20 mol %)
NH
R
O
Ph
*
+
N
H
N
H
CF3
X
X
H
R
PhMe (0.05 M), rt
X = H, 4-OMe,5-OMe
N
H
N
H
O
1a
2
3 (1.1 equiv)
up to 90% yield,99% ee
4
Figure 1. The Pictet–Spengler Reaction of Tryptamines. Key catalytic residues (silver) in the enzyme active site of strictosidine synthase (B) depicted
in the overlay of structures bound to tryptamine (light pink, PDB 2FPB) and secolognin (slate blue, PDB 2FPC); see ref 46. Glc = glucose. Glu =
glutamic acid. His = histidine. Phe = phenylalanine. TMB = 3,4,5-trimethoxybenzoyl. Tyr = tyrosine.
Herein we describe experimental and computational studies to-
ward this aim. On the basis of kinetic characterization, kinetic iso-
tope effects, structure–enantioselectivity relationships, and compu-
tational analyses, we advance that the thiourea catalyst stabilizes
every intermediate and transition state leading to up to and includ-
ing the rate- and enantioselectivity-determining deprotonation of
the final pentahydro-β-carbolinium ion intermediate. The factors
controlling rate acceleration and enantioselectivity in this trans-
formation may guide the design of other stereoselective methods
requiring the deprotonation of high-energy intermediates.
Scheme 1. Reaction Conditions for Kinetic Analysis.
[1a ]tot = 0–10 mM
N
[BzOH]tot = 0–10 mM
NH
Ara
Ara
PhMe/DCE (1:1)
30 °C
N
H
N
H
MeO
MeO
5a
(R)-4a
88% ee where:
[1a ]tot =10 mM, [BzOH]tot = 5 mM
[5a]0 = 50 mM
Ara = 4-CN-C6H4
The kinetic order of each of the co-catalysts was also determined by
varying either [1a]tot or [BzOH]tot while holding the other con-
stant. A competitive racemic background reaction is observed when
[1a]tot << [BzOH]tot, but the rate is too slow to measure accurately
under the conditions used to probe the catalytic reaction. However,
the rate constant for this racemic, benzoic acid-mediated process
(krac) can be extrapolated from the non-zero y-intercept in Figure
2A. The kinetic dependence on [1a]tot is further complicated by the
propensity for amido-thioureas to aggregate in solution. Catalysts
similar to 1a are known to exist as resting-state inactive homodi-
RESULTS AND DISCUSSION
Thiourea and Benzoic Acid Both Contribute to Rate Acceleration
We initiated our investigation with the goal of identifying the rate-
and stereoselectivity-determining step(s) of the transformation.
The originally reported conditions (Figure 1D) produced hetero-
geneous reaction mixtures and long reaction times that were not
conducive to rigorous kinetic analysis. The use of pre-formed imine
5a as a substrate along with binary mixtures of toluene and 1,2-
dichloroethane (DCE) as solvent resulted in homogenous reaction
media and formation of tetrahydro-β-carboline 4a in good yield
and with only a modest reduction in observed enantioselectivity
(88% ee under homogeneous conditions compared with 94% ee
under those reported initially; Scheme 1).54 The distinctive absorp-
tion spectrum of cyano-substitued imine 5a enabled facile reaction
progress kinetic analysis by in situ attenuated total reflectance Fou-
rier-transform infrared (ATR FTIR) spectroscopy.55,56 Through
such an analysis, the reaction was observed to exhibit a first-order
dependence on substrate [5a].57
meric complexes in related anion-abstraction reactions,58–61 and H
1
NMR titration experiments in toluene-d8 and CD2Cl2 reveal that 1a
is partially aggregated at the concentrations used in the catalytic
reaction (see Supporting Information). Taking this behavior into
account, the non-linear dependence of reaction rate on [1a]tot can
be fit readily to a model involving a single molecule of 1a in the
transition state and a change in the stoichiometry of the resting-
state from a monomer at low [1a]tot to a dimer at high [1a]tot (Fig-
ure 2A).
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A.
B.
C.
1
2:1 1:1 1:2
1.6
1.2
0.8
0.4
0.0
3.2
2.4
1.6
0.8
0.0
0.15
0.12
0.09
0.06
0.03
0.0
2
3
4
5
6
7
8
9
10
11
12
13
14
with [BzOH]tot = 5 mM
with [1a]tot = 10 mM
NBu4OBz
Kdim = 5800 Mꢀ1 (fixed)
kobs = 6.2(7) ⇥ 10ꢀ3 sꢀ1
Kdim = 140 Mꢀ1 (fixed)
kobs = 13.4(4) ⇥ 10ꢀ3 sꢀ1
4-F-BzOH
krac = 2.9(9) ⇥ 10ꢀ6 M sꢀ1
0.0
2.0
4.0
6.0
8.0
10.0
0.0
2.0
4.0
6.0
8.0
10.0
0.0
0.2
0.4
0.6
0.8
1.0
[1a]tot ⇥ 103 (M)
[BzOH]tot ⇥ 103 (M)
ꢀ1a
Figure 2. Kinetic Evidence for Thiourea and Benzoic Acid Co-Catalysis. (A) The rate dependence for consumption of imine 5a (see Scheme 1) on
[1a]tot. (B) The rate dependence for consumption of imine 5a on [BzOH]tot. Rates determined at 20% conversion. Blue dashed lines represent the fit
to a model accounting for non-productive catalyst self-aggregation, using independently determined self-dimerization constants (Kdim). See Support-
ing Information for derivation. (C) Job plot of the association of thiourea 1a and a guest, either tetrabutylammonium benzoate (purple diamonds) or
4-fluorobenzoic acid (green squares), generated by monitoring the CF3 resonance in the 19F NMR spectrum of catalyst 1a in toluene-d8 at 25 °C. [1a
+ guest]tot = 0.01 M
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Similar analysis over a range of [BzOH]tot reveals that no product
formation occurs in the absence of the Brønsted acid. The reaction
exhibits a first-order dependence on [BzOH]tot over much of the
concentration range examined (Figure 2B), but a slight deviation
from linearity at high [BzOH]tot reflects ground-state aggregation
between two molecules of the carboxylic acid.62 While the propen-
sity for benzoic acid self-dimerization is weaker than that observed
with the amido-thiourea catalyst, the self-dimerization equilibrium
constant for 4-fluorobenzoic acid, measured independently
through 19F NMR titration experiments in toluene-d8 and CD2Cl2,
could be used to fit the kinetic data.
to mimic a reaction at partial conversion (Figure 3A, blue dots and
purple diamonds). This result provides unequivocal evidence that
product inhibition, rather than catalyst decomposition, is responsi-
ble for the significant catalyst deactivation occurring over the
course of the reaction.
Scheme 2. General Catalytic Cycle.a
S
4
5
R*
ArF
(IV)
(I)
N
H
N
H
product
release
imine
protonation
OBz
H
The combined kinetic data thus indicate that the rate-limiting tran-
sition state for the enantioselective Pictet–Spengler reaction in-
volves a ternary 1a•BzOH•5a complex. The cooperative associa-
tion of the two co-catalysts in the mechanism of catalysis is further
supported by the observation of 1:1 complexation between thiou-
rea 1a and 4-fluorobenzoic acid by 19F NMR analysis in toluene-d8
(Figure 2C).63,64 We hypothesize that the resulting complex exhibits
increased acidity relative to free benzoic acid and thus contributes
to substrate activation en route to product formation, as proposed
in the catalytic cycle outlined in Scheme 2. Consistent with this
analysis, added tetrabutylammonium benzoate (NBu4OBz), which
forms a much stronger complex with thiourea 1a (Figure 2C),
S
S
R*
ArF
R*
ArF
N
H
N
H
N
H
N
H
S
1
R*
ArF
OBz
m
N
N
H
OBz
H
m =1,2
X
H
N
R
X
H
1
NH
+
H
OBz
n =1,2
n
N
H
N
H
R
S
R*
ArF
(III)
(II)
N
H
N
H
deprotonation/
rearomatization
alkylation
(concerted or stepwise)
OBz
34,49,51,52,65–80
inhibits the reaction. This inhibition is also of signifi-
X
NH
(V)
product
inhibition
cance given that the secondary amine product of the Pictet–
Spengler reaction is substantially more basic than the imine sub-
strate,81,82 thereby introducing the potential for formation of a simi-
larly counterproductive ammonium benzoate complex during the
course of the reaction (Scheme 2, step V).34
N
H
R
H
S
R*
ArF
X
N
H
N
H
NH2
N
H
R
OBz
To probe whether product inhibition is operative, the absolute
rates of two reactions with the same catalyst concentrations, [1a]tot
and [BzOH]tot, but different initial imine concentrations, [5a]0,
were compared over the entire reaction course.83 The resultant rate
vs. concentration curves do not overlay (Figure 3A, blue dots and
green squares); this behavior is a signature of diminishing catalytic
activity during the course of the reaction as a result of either prod-
uct inhibition or catalyst decomposition. Much better overlay of
the rate vs. concentration plots is observed when the reaction is
conducted with initial imine and product concentrations selected
a ArF = 3,5-bis(trifluoromethyl)phenyl
This insight sheds light on a likely cause for the poor catalytic effi-
ciency observed under the conditions optimized originally, where
20 mol % loading of each of the two co-catalysts was required to
achieve good product yields within 1–5 day reaction times. To
overcome the deleterious effects of product inhibition on reaction
rate, modified conditions were devised to trap the product amine in
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situ (Figure 3B). With the addition of a slight excess of Boc2O,84 the
protonation were rate-determining (Scheme 2, step I), no signifi-
1
2
3
4
5
6
7
8
enantioselective Pictet–Spengler reaction can be conducted over
the same reaction period with a 10-fold reduction in the loading of
each co-catalyst. The lower catalyst concentrations carry the added
benefit of disfavoring nonproductive catalyst self-aggregation,
thereby amplifying the increase in catalytic efficiency. These modi-
fied conditions overcome an important limitation of the original
procedure, thereby enhancing the practical value of this method for
the preparation of enantioenriched tetrahydro-β-carbolines.
cant kinetic isotope effect (KIE) would be expected for either the
5a-d1(Cϕ) or 5a-d1(C2) isotopomers, since the deuterium-bearing
carbons are essentially unaffected in that step. If the alkylation step
(Scheme 2, step II), either via C2- or C3-addition, were rate-
limiting, deuteration of the Cφ position of imine 5a would be ex-
pected to result in an inverse, secondary kinetic isotope effect aris-
ing from an sp2 to sp3 hybridization change at the carbon bearing
the isotope. In contrast, the C2-labelled isotopomer would be ex-
pected to display an inverse, secondary KIE in the case of rate-
limiting C2-addition or C–C migration but not C3-addition. Final-
ly, only rate-limiting deprotonation/rearomatization (Scheme 2,
step III) should result in a relatively large primary KIE with 5a-
9
A. Kinetic Evidence for Product Inhibition
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[1a]tot = 5 mM
N
[BzOH]tot = 5 mM
NH
Ara
Ara
PhMe/DCE (1:1)
30 °C
N
H
N
H
d1(C2)
.
MeO
MeO
5a
(R)-4a
[5a]0 = 50 or 25 mM
[4a]0 = 0 or 25 mM
H/D
φ
1a (20 mol %)
NH
BzOH (20 mol %)
2.4
N
Ara
[5a]0 = 50 mM
[5a]0 = 25 mM
[5a]0 = 25 mM +
[4a]0 = 25 mM
H/D
H/D
Ara
PhMe/DCE
30 °C
N
H
2
MeO
N
H
MeO
5a
4a
1.8
1.2
0.6
0.0
predicted isotope effect:
5a-d
5a-d
1(C2)
1(C
)
φ
imine protonation
1.0
1.0
C2-addition
C3-addition
0.7–0.9
0.7–0.9
0.7–1.0
0.7–1.0
0.7–0.9
1.0
C–C migration
rearomatization
0.7–0.9
>1.3
observed isotope effect:
0.79(3)a
3.00(17)b
with 5a (no D)
with 5a-d
with 5a-d
1(C2)
0
10
20
30
40
50
1(C
)
φ
[5a] ⇥ 103 (M)
equilibrium [I] increased
TSrearomatization raised
∆G‡
B. Improved Catalyst Efficiency via Accelerated Product Release
AraCHO
arom,H
∆G‡
arom,D
I
∆Galk,H
PD
∆Galk,D
I
I
NH2
Boc
CH2Cl2, Na2SO4;
N
SM
SM
PD
SM
PD
karom,H
Ara
(R)-6a: 94% yield, 87% ee
then, 1a (2 mol %)
n
n
o
n
io
t
iza
N
H
N
H
Kalk,H
io
io
MeO
MeO
t
t
a
observed =
observed =
n
yla
BzOH (2 mol%)
Boc2O (1.1 equiv)
PhMe, 36 h, rt
o
t
t
lk
Kalk,D
karom,D
a
o
a
r
p
m
2a
r
ea
r
a
Figure 4. Isotope Effect Measurements. Competition isotope effect
10-fold reduction in thiourea catalyst loading • 10-fold reduction in BzOH loading
determined from the ratio of recovered 5a and 5a-d1(Cϕ) at low conver-
b
sion. Isotope effect determined from the relative first-order rate con-
Figure 3. Kinetic Evidence for Product Inhibition and New Reaction
Conditions for Minimizing Product Inhibition. See Scheme 1 for reac-
tion conditions used for kinetic analysis; results from multiple inde-
stants for formation of 4a measured independently with 5a and 5a-
d1(C2). Rates are uncorrected for incomplete deuterium incorporation
(94% D for 5a-d1(C2)). See ref 86. Ara = 4-cyanophenyl.
pendent runs are overlaid. Ara
butoxycarbonyl.
= 4-cyanophenyl. Boc = tert-
Competition experiments between imine isotopologues 5a and 5a-
d1(Cϕ) under standard catalytic conditions afforded a secondary
inverse isotope effect of 0.79(3) at the imine position. Independent
rate measurements with imine isotopologues 5a and 5a-d1(C2) re-
vealed a normal isotope effect of 3.0(2) at C2.85,86 These results are
consistent only with a scenario involving rate-limiting deprotona-
tion/rearomatization. The increased rate from Cφ-deuteration can
be attributed to an increased equilibrium concentration of the high-
energy pentahydro-β-carbolinium ion intermediate, I, (i.e. an equi-
librium isotope effect, EIE).87 Normal, primary KIEs of similar
magnitude to that observed with 5a-d1(C2) were measured through
intermolecular competition experiments with imines bearing dif-
ferent aryl substituents (see Supporting Information),85 providing
evidence that rate-limiting rearomatization is general for this cata-
lyst system. As noted in the introduction, rearomatization has also
been identified as the rate-determining step in Pictet–Spengler
reactions catalyzed by enzymes including strictosidine synthase21
Rate- and Enantiodetermining Rearomatization is Promoted
through the Cooperative Action of the Thiourea and Benzoic Acid
Co-Catalysts
As noted above, the kinetic data provide evidence that the rate-
determining step in the thiourea/benzoic acid co-catalyzed Pictet–
Spengler reaction involves a ternary 1a•BzOH•5a complex. How-
ever, the kinetic analysis is consistent with any of the three funda-
mental steps in the proposed mechanism (Scheme 2, steps I–III)
being rate- and enantioselectivity-determining, since they all in-
volve a complex with the same stoichiometry. In order to under-
stand the basis for catalysis and enantioselectivity, a set of isotope
effect experiments was designed to distinguish which step is rate-
limiting. Namely, analogs of 5a bearing deuterium at either the Cφ
or the C2 positions were prepared and their cyclizations under
standard catalytic conditions were analyzed (Figure 4). If imine
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In order to determine whether the thiourea S or amide O of catalyst
(Figure 1B) and norcoclaurine synthase,22 which play central roles
in alkaloid biosynthesis.88
1a may be responsible for deprotonation of the pentahydro-β-
carbolinium ion intermediate, the electronic properties of each of
the two motifs were varied systematically (Figure 5A). Ureas are
generally stronger Brønsted bases and H-bond acceptors than anal-
ogous thioureas by several orders of magnitude.91–93 On this basis,
urea 1b would be expected to demonstrate improved reactivity
and/or enantioselectivity if thiourea 1a serves as a Brønsted base in
the rate- and enantioselectivity-determining transition state. How-
ever, urea 1b is a slightly less active and enantioselective catalyst
than thiourea 1a. Likewise, a more electron-rich thiourea, 1c, also
exhibits reduced activity and enantioselectivity.94 Taken together,
these results provide evidence that the thiourea moiety of catalyst
1a does not serve as a base in the rate and selectivity-determining
step. Instead, the modestly reduced activity and enantioselectivity
observed with 1b and 1c most likely reflect their diminished H-
bonding ability.95,96
1
2
The observation that rearomatization is rate-determining in the
thiourea- and benzoic acid co-catalyzed Pictet–Spengler reaction
implies that the preceding protonation and alkylation steps are
reversible; therefore, rearomatization must also be enantioselectivi-
ty-determining.89 Thus, while two stereogenic centers are formed
during reversible C2- or C3-addition steps, only diastereomer-
selective deprotonation of the resultant chiral pentahydro-β-
carbolinium ion intermediate dictates the final stereochemistry
observed in the product.90 Given the non-intuitive nature of a rate-
and enantioselectivity-determining deprotonation event from such
a high-energy intermediate, we became interested in elucidating the
features of the reaction system responsible for substrate activation
and enantiocontrol. As a first step in this effort, we sought to de-
termine the identity of the active Brønsted base, given that the dual
catalyst system consists of multiple potentially basic sites.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reactivity and enantioselectivity are similarly insensitive to the
basicity of the amide moiety. Ester 1e,97 which is predicted to be at
least an order of magnitude less basic than an analogous amide,93 is
only slightly less enantioselective than 1b and a sterically similar
amido-thiourea, 1d, and it affords modestly improved reaction
rates. This relationship suggests that any interaction with the car-
bonyl O must, therefore, be similar in strength in the major and
minor transition structures and must lead to a net increase in the
activation barrier. Thus, while the amide moiety of catalyst 1a may
be involved in substrate binding, it must not be responsible for
deprotonation of the pentahydro-β-carbolinium ion intermediate
in the rate- and selectivity-determining step.
A. Activity and Enantioselectivity Depend on H-Bond Donor Strength
Catalyst (20 mol %)
NH2
NH
Arb
BzOH (20 mol %)
*
ArbCHO (1.1 equiv)
N
N
MeO
MeO
H
H
PhMe (0.05 M), rt
Arb = 4-Cl-C6H4
2a
4b
Catalyst:
Me iPr
S
Me iPr
N
O
Me iPr
S
N
ArF
ArF
N
Ph
Bn
N
H
N
Bn
S
N
H
N
H
Bn
N
H
N
H
H
O
O
O
1a : 93% ee
krel =1.0 (def)
1b : 91% ee
krel = 0.52(4)
1c : 84% ee
krel = 0.23(2)
Given the evidence that amido-thiourea 1a does not act as a
Brønsted base, we hypothesized that the conjugate base of the ben-
zoic acid co-catalyst may serve this role instead. A series of 4-
substituted benzoic acid co-catalysts spanning acidities over more
than an order of magnitude were therefore evaluated in the enanti-
oselective Pictet–Spengler reaction of imine 5b (Figure 5B).98 No
linear relationship is observed between the electronic properties of
the benzoic acid and the reaction rate (see Supporting Infor-
mation), but this may simply reflect the competing demands of
equilibrium imine protonation prior to the rate-determining step.
Nonetheless, the reaction exhibits a strong correlation between the
benzoic acid Hammett σp value and enantioselectivity, wherein the
most basic benzoates (or least acidic benzoic acids) afford tetrahy-
dro-β-carboline 4b with the highest level of enantioselectivity.99,100
However, despite the excellent correlation, the overall electronic
effect is in fact quite small (ρ = –0.33). Taken together, these ob-
servations implicate the benzoate as the Brønsted base responsible
for enantioselectivity-determining deprotonation but suggest that it
plays only a minor role in enantiodiscrimination.
Me iPr
iPr
O
N
ArF
O
ArF
Me
N
H
N
H
Me
N
H
N
H
O
O
1d : 91% ee
1e : 89% ee
krel = 0.89(7)
krel = 0.37(3)
B. Enantioselectivity Correlates with Benzoate Basicity
1a (20 mol %)
N
NH
Arb
4-X-C6H4CO2H (20 mol %)
*
Arb
PhMe (0.05 M), rt
N
H
N
MeO
MeO
H
5b
4b
1.6
⇢ = ꢀ0.33
X =
b = 1.34
Me
R2 = 0.96
1.4
H
OMe
Br
1.2
CN
CF3
The Thiourea Catalyst Influences Multiple Steps by Anion-Binding
The thiourea/benzoic acid co-catalyzed Pictet–Spengler reaction is
observed to be approximately four-fold faster than the process me-
diated by benzoic-acid alone.101 The basis for this rate acceleration
was probed through construction of a reaction coordinate energy
diagram based on computed models of energy-minimized interme-
diates and transition states using density functional theory
(DFT).102–107 To ascertain an appropriate starting point for this
analysis,108 the relative acidities of acetic acid and a model iminium
ion were assessed computationally using an implicit solvent mod-
el,109,110 and imine protonation by acetic acid was calculated to be
NO2
1.0
-0.5
0.0
0.5
1.0
ꢀp
Figure 5. Co-Catalyst Structure–Reactivity–Enantioselectivity Rela-
tionships. Enantiomeric excess reported for the formation of 4b under
the conditions shown. Relative rate constants (krel) determined from
the first-order rate constants for formation of 4a under the conditions
in Scheme 1. Arb
bis(trifluoromethyl)phenyl.
=
4-chlorophenyl. ArF
=
3,5-
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A.Thiourea Co-Catalysis Stabilizes Multiple Steps via Anion Binding
Catalyst:
1
2
3
(S,R)-TS3 • –OAc
S
(S,R)-TS2 • –OAc
(S,R)-I2 • –OAc
+18.7 (+20.8)
Me
N
Me
N
H
+16.8 (+20.8)
+16.4 (+20.4)
H
1f
4
5
(S,R)-TS3 • –OAc • 1f
6
7
8
+14.0 (+16.5)
(S,R)-TS2 • –OAc • 1f
(S,R)-I2 • –OAc • 1f
+10.7 (+14.1)
+9.7 (+13.1)
9
(E)-5b • HOAc
(S,R)-I3 • HOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–2.7 (+0.5)
(E)-5b • HOAc • 1f
(E)-I1• –OAc • 1f
0.0 kcal/mol (def.)
(R)-4b • HOAc
–1.7 (–0.9)
(S,R)-I3 • HOAc • 1f
–8.9 (–5.5)
–3.4 (–1.0)
(R)-4b • HOAc • 1f
–10.2 (–7.3)
H
H
H
N
NH
Arb
N
NH
Arb
H
N
OAc
OAc
– OAc
Arb
Arb
Arb
N
H
N
H
H
OAc
MeO
N
H
N
H
MeO
N
H
H
MeO
MeO
(E)-I1• –OAc
H
MeO
H
H
– OAc
(E)-5b • HOAc
(S,R)-I2 • –OAc
(S,R)-I3 • HOAc
(R)-4b • HOAc
B. C2-Addition to Either Imine Isomer Allows Access to Multiple Diastereomeric Intermediates
As Above:
Alternatives Examined:
Me
Me
Me
Me
N
Me
N
S
N
N
H
+
N
N
δ
+
δ
S
O
H
S
Me
S
O
H
H
N
H
Arb
H
O
H
Me
+
δ
N
+
δ
H
H
H
O
+
δ
Arb
N
N
H
Arb
H
O
+
N
δ
O
H
H
Me
H
H
H
Me
MeO
H
MeO
N
N
MeO
O
H
H
N
H
+
Me
Me
H
b Nδ
H
Me
+N
δ
Ar
O
MeO
from (E)-5a
from (Z)-5a
H
(S,R)-TS2,chair • –OAc • 1f
(R,R)-TS2,chair • –OAc • 1f
(R,R)-TSspiro • –OAc • 1f
(R,R)-TS2,boat • –OAc • 1f
+10.7 (+14.1)
+14.3 (+18.0)
+17.1 (+21.8)
+21.7 (+25.8)
Figure 6. Computational Evaluation of the Basis for Rate-Acceleration by Thiourea and Brønsted Acid Co-Catalysis. With the exception of
(R,R)-TS2,chair, only structures arising from the major, (E)-imine isomer are represented. Calculations performed with B3LYP-D3(BJ)/6-
31+G(d,p)/CPCM(toluene)//B3LYP/6-31G(d)/CPCM(toluene). Electronic energies reported in kcal/mol. Corrected free energies listed
in parentheses in kcal/mol. For additional information and discussion, including analyses of structures arising from the (Z)-imine isomer, see
Supporting Information. Arb = 4-chlorophenyl
highly unfavorable in the nonpolar medium relevant to this study.
The degree of interaction between model imine 7111 and benzoic
acid was assessed experimentally by 1H NMR spectroscopy
(Scheme 3). The chemical shift of an imine’s formyl hydrogen is
highly sensitive to electrostatic perturbation,112 and changes in
imine chemical shift have previously been taken as evidence of
imine protonation by stronger Brønsted acids.113 No change in the
signal was observed upon addition of a full equivalent of benzoic
acid, thus providing further support for the prediction that imine
protonation is highly endergonic in the reaction solvent. As such,
the neutral, H-bonded encounter complex between 5b and acetic
acid114 (rather than the free iminium ion) was employed as the
starting point for subsequent evaluation. Furthermore, while only
(E)-5b is detected under the standard conditions employed for the
imine preparation, interconversion with the (Z)-isomer may, in
principle, occur in situ. Accordingly, the full reaction coordinate en
route to (R)-5b accessed through either of the isomers was exam-
ined. In both cases, the results obtained with the inclusion of N,N’-
dimethylthiourea (1f) were compared with the background pro-
cess mediated by acetic acid alone.
Consistent with experimental observations, no discrete iminium
ion intermediate could be located in the reaction coordinate analy-
sis of the uncatalyzed reaction (Figure 5A, red). Instead, imine
protonation and C2-addition to form high-energy pentahydro-β-
carbolinium ion I2 occur in a single, highly asynchronous step. In
contrast, the inclusion of 1f results in a reduced penalty to imine
protonation such that the stationary point for the resultant ion pair
is slightly lower in energy than the neutral encounter complex
(Figure 6A, blue). These observations suggest that anion-binding
interactions between 1f and the conjugate base of acetic acid en-
hance the acidity of the weak Brønsted acid, thereby enabling for-
mation of the protioiminium ion intermediate under the non-polar
reaction conditions.
Scheme 3. Imine Protonation is Endergonic in Nonpo-
lar Media.
H
O
N
N
O
O
Ph
+
H
H
HO
Ph
CDCl3, 25 °C
monitored
CN
CN
not detected
[7] = 0.05 M
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From (E)-5b:
From (Z)-5b:
Catalyst:
1
2
3
R1
Me
N
S
R2
Me
N
H
N
H
O
4
5
6
1g: R1 = iPr, R2 = Ph
1h: R1 = iPr, R2 = H
1i: R1 = H, R2 = Ph
2.05
2.01
1.84
2.11
1.94
1.84
7
Conserved Features:
8
9
S
2.17
N
H
N
H
2.09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
(S,R)-TS3 • –OAc • 1g
(R,R)-TS3 • –OAc • 1g
Me
H
O
N
H
Arb
+0.0 (def.)
+5.7 (+5.9)
–
δ
OMe
O
H
+
δ
N
• chair-like conformation
• dual H-bonding interactions between
the thiourea and carboxylate anion
• H-bonding interaction between the
amine N–H and distal carboxylate O
2.19
1.84
1.80
2.05
1.92
2.06
• H-bonding interaction between
the indole N–H and amide O
2.13
• deprotonation by the proximal
carboxylate O
2.04
(R,S)-TS3 • –OAc • 1g
(S,S)-TS3 • –OAc • 1g
• highly symmetric breaking and
forming bond lengths
+5.1 (+6.6)
+3.1 (+3.0)
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7. Enantiodetermining Rearomatization Occurs within a Conserved Network of Cooperative Hydrogen-Bonding Interactions. Calcu-
lations performed with B3LYP-D3(BJ)/6-31+G(d,p)/CPCM(toluene)//B3LYP/6-31G(d)/CPCM(toluene). Electronic energies reported
in kcal/mol. Corrected free energies listed in parentheses in kcal/mol. Select bond lengths listed in Å. Dotted lines represent H-bonding or
C–H⋯π interactions; dashed lines represent breaking and forming bonds. H = white, C = silver, N = blue, O = red, S = yellow, Cl = magenta.
Table 1. Stereodiscrimination Arises from Stabilizing π–π and C–H⋯π Interactions
ΔΔE‡
ΔΔE‡
ΔΔE‡
ΔΔE‡int (kcal/mol) with:
Entry
Transition Structure
Imine
Product
tot
dist,1g
dist,5b•HOAc
(kcal/mol)
(kcal/mol)
(kcal/mol)
1g
1h
1i
1
2
3
4
(S,R)-TS3•–OAc•1g
(S,S)-TS3•–OAc•1g
(R,S)-TS3•–OAc•1g
(R,R)-TS3•–OAc•1g
(E)-5b
(Z)-5b
(E)-5b
(Z)-5b
(R)-4b
(S)-4b
(S)-4b
(R)-4b
+0.0
+3.1
+5.1
+5.7
+0.0
+0.3
–0.4
+0.1
+0.0
+0.5
+2.6
+0.8
+0.0
+2.3
+2.9
+4.8
+0.0
+2.0
+3.1
+3.5
+0.0
+0.2
+1.8
+3.5
While the impact of the H-bond donor on preequilbrium protona-
tion is pronounced, the calculations reveal that it is the persistence
of anion-binding interactions throughout subsequent steps involv-
ing cationic transition states and intermediates that results in a net
reduction of the energetic span of the reaction.115,116 Specifically, the
the presence of the thiourea co-catalyst, C2-addition through both
the (E)- and (Z)-imine isomers is energetically accessible. While
(R,R)-TS2,chair is higher in energy than (S,R)-TS2,chair, it is energeti-
cally comparable with (S,R)-TS3,chair and (R,R)-TS3,chair (see Sup-
porting Information). As such, the intermediacy of all possible
diastereomers of the pentahydro-β-carbolinium ion intermediate—
namely, (S,R)-I2 and (R,R)-I2 en route to the major enantiomer of
product, (R)-4b, as well as (R,S)-I2 and (S,S)-I2 en route to (S)-
4b—must be considered in examination the rate-determining
deprotonation event. Nonetheless, it is clear that the thiourea
serves as an anion-binding catalyst throughout the reaction. While
anion-binding interactions attenuate the kinetic basicity of the
benzoate and therefore decelerate the step with the highest overall
transition state energy (i.e. I2 → I3), reduction in the net energetic
span of the reaction arising from the stabilization of all charged
intermediates and transition states results in an overall rate-
acceleration.115,116
acetate anion engages in attractive C2–H⋯O interactions to guide
C2-addition (TS2) and facilitate deprotonation (TS3). While the
pentahydro-β-carbolinium ion I2 is stabilized to an even greater
extent than either of these transition states, the overall barrier to
initial addition (TS2) and subsequent deprotonation (TS3) are
reduced by 4–6 kcal/mol and ~3 kcal/mol, respectively, relative to
the lowest energy ground state.117 Furthermore, the significant
stabilization of the chair-like transition structure for C2-addition
(TS2,chair) renders it the only accessible path for cyclization en route
to pentahydro-β-carbolinium ion (I2). Alternative modes of cycliza-
tion, such as those involving a boat-like conformation (TS2,boat) or
C3-addition (TS2,spiro) are predicted to be at least 3 kcal/mol higher
in energy than either TS2,chair or TS3 (Figure 6B).118 Nonetheless, in
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tion structure (ΔΔE‡dist,1g), the relative energy required to distort
Enantiodetermination Arises from Attractive π–π and C–H⋯π
Interactions Enabled by a Cooperative Network of Conserved H-
Bonds
the (E)-5b•HOAc complex126 into the conformation assumed in
the catalyzed transition structure (ΔΔE‡dist,5b•HOAc), and the relative
interaction energy between the distorted 5b•HOAc complex and
catalyst 1g (ΔΔE‡int). These differential distortion and interaction
terms reveal that the degree of catalyst distortion has only a small
impact on enantioselectivity, consistent with the qualitative as-
sessment that its conformation changes little across the structures
examined. The degree of substrate distortion is modestly more
important, particularly in contributing to the destabilization of
(R,S)-TS3•–OAc•1g, but the overall, discrimination between the
diastereomeric complexes is overwhelmingly dictated by the inter-
actions between the catalyst and the reactive species.
1
2
3
4
5
6
7
8
In an effort to elucidate the specific interactions between the ami-
do-thiourea catalyst, the benzoic acid co-catalyst, and the reactive
pentahydro-β-carbolinium ion responsible for enantiodetermina-
tion, we focused subsequent computational work on the deproto-
nation step. Chiral thiourea 1g (Figure 7) was employed in this
analysis, as truncation of the amide benzyl substituent and aryl CF3
groups has only a modest impact on the enantioselectivity observed
experimentally (Figure 5B), but affords a substantial reduction in
the size of the system and therefore in the computational expense.
Through this analysis, several conserved catalyst–substrate interac-
tions were observed across the lowest energy transition structures
derived from each of the four possible diastereomers of the pen-
tahydro-β-carbolinium ion intermediate (Figure 7). These include:
(a) two N–H⋯O H-bonding interactions between the thiourea
and carboxylate base, (b) an H-bonding interaction between the
amine N–H and the distal O of the carboxylate, (c) an H-bonding
interaction between the amide O and the indole N–H, and (d)
highly symmetric breaking and forming C⋯H⋯O bonds (1.30–
1.36 Å), wherein the proximal O of the carboxylate base effects the
deprotonation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Numerous noncovalent interactions contribute to the total interac-
tion energy for each of the predicted transition structures. While
very little variation is observed in the H-bond lengths between
acetate and the pentahydro-β-carbolinium ion, we noted sizable
differences (up to 0.14 Å) in the lengths of the H-bonds between
acetate and the thiourea catalyst. These differences are consistent
with the observation that enantioselectivity is correlated to elec-
tronic properties of both the H-bond donor and the benzoate anion
(Figure 5). However, as noted above, even significant changes in
benzoate basicity have a relatively small net impact on the overall
enantioselectivity;98 we were thus compelled to consider other
interactions that could potentially contribute to stereodiscrimina-
tion to a greater degree.
These features account for the observation that decreasing the
amide Lewis basicity does not impact the observed enantioselectiv-
ity (Figure 5A), as the N–H⋯O lengths are comparable for all of
the structures examined. However the importance of this interac-
tion for enabling well-defined organization of the reactive complex
is underscored by the observation that masking the indole N–H
leads to a dramatic reduction in the enantioselectivity observed
experimentally (Scheme 4). Furthermore, while the conformations
of the amido-thiourea and carboxylate are predicted to be fairly
constant across the computed structures, the orientations of the
reacting pentahydro-β-carbolinium ion with respect to the catalyst
differ substantially, with the lowest-energy structure, (S,R)-TS3•–
OAc•1g, accurately predicting formation of the major enantiomer
of product, (R)-4b. Analogous transition structures optimized for
the full experimental system (i.e. catalyst 1d and substrate 5b) with
Visual inspection of the computed structures in Figure 7 reveals
that the catalyst isopropyl side-chain and phenyl thiourea moieties
are positioned in close proximity to other components of the cati-
onic assembly in the lowest energy transition state, (R,S)-TS3•–
OAc•1g. We hypothesized that these groups might be engaged in
stabilizing π⋯π and C–H⋯π interactions that are absent or dimin-
ished in the competing transition structures. To evaluate the rela-
tive contributions of these interactions, the differential interaction
energies were recomputed with truncated catalysts (1h and 1i;
Figure 7) that lack the substituents in question. Ablation of the
phenyl group (as in 1h) is predicted to have only modest impact
on enantioselectivity. The lowest-energy transition structure (R,S)-
TS3•–OAc•1 as well as the transition structures leading to the mi-
nor enantiomer of product all position either the substrate indole
or 4-chlorophenyl moieties directly over the ablated phenyl group
and are, thus, similarly impacted by the loss of a π⋯π interaction.
In contrast, ablation of the isopropyl group (as in 1i) has a sub-
stantial impact on the relative interaction energies of all four transi-
tion structures. Of particular note, the relative interaction energy of
(S,S)-TS3•–OAc•1 is decreased by 2.1 kcal/mol such that ΔΔE‡int is
almost identical for (S,R)-TS3•–OAc•1i and (S,S)-TS3•–OAc•1i.
Only (S,R)-TS3•–OAc•1g exhibits a C–H⋯π interaction with the
isopropyl group of the catalyst, and this pronounced change in the
relative interaction energies indicates that, along with the H-
bonding interactions between the thiourea and benzoate anion, this
attractive interaction is a major controlling feature in the observed
enantioselectivity.
a
functional designed to account for dispersive interactions
(M062X/6-31+g(d,p)/SMD(toluene)) are qualitatively similar to
those depicted in Figure 7,104,107,119–121 and the predicted enantiose-
‡
lectivity (ΔΔG = 1.6 kcal/mol) is in excellent agreement with
experimental values.122
Scheme 4. The Indole N–H is Necessary for Enantio-
control.
1a (20 mol %)
NH2
NH
BzOH (20 mol %)
*
Ara
AraCHO (1.1 equiv)
N
N
MeO
MeO
R
PhMe (0.05 M), rt
Ara = 4-CN-C6H4
R
2a: R = H
8: R = Me
4a: 93% ee
9:12% ee
To better understand the factors contributing to stereochemical
discrimination, a modified distortion–interaction analysis of each
of the four energetically accessible, diastereomeric transition struc-
tures was conducted (Table 1).123–125 Through this analysis, the
differential electronic energy of activation was decomposed into
terms describing the relative energy required to distort amido-
thiourea catalyst 1g into the conformation assumed in the transi-
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Ara
=
4-cyanophenyl; Arb
=
4-chlorophenyl; ArF
=
3,5-
CONCLUSION
1
bis(trifluoromethyl)phenyl; Boc = tert-butoxycarbonyl; DCE = 1,2-
The experimental and computational analyses described herein
provide insight into the cooperative mechanism of thiourea and
Brønsted acid co-catalysis in the enantioselective protio-Pictet–
Spengler reaction. The combined application of kinetic studies,
isotope effects, structure-enantioselectivity relationships, and com-
putational analyses enable identification of rearomatization as the
rate- and enantioselectivity-determining step, wherein the co-
catalysts play key roles in multiple steps leading up to and including
the rate-determining deprotonation event. Acidification of the
weak benzoic acid co-catalyst upon coordination with the thiourea
promotes pre-equilibrium substrate protonation, and anion-
binding interactions with the conjugate base further stabilize the
pentahydro-β-carbolinium ion intermediate. These interactions
increase the concentrations of high-energy intermediates en route
to the rate-determining step and thereby contribute to rate acceler-
2
3
4
5
6
7
8
9
dichloroethane; Glc = glucose; TMB = 3,4,5-trimethoxybenzoyl
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Complete experimental procedures, characterization data, kinetic data,
derivation of the rate law, 1H NMR titration data, further computation-
al data, geometries and energies of all calculated stationary points
(PDF)
AUTHOR INFORMATION
Corresponding Author
* jacobsen@chemistry.harvard.edu.
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Present Addresses
† Department of Chemistry, The Johns Hopkins University, Baltimore,
MD 21218, USA
‡ Process Research and Development, Merck & Co., Inc., Rahway, NJ
07065, USA
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This paper is dedicated to Professor Robert Bergman on the occasion
of his 75th birthday. This work was supported by the NIH (GM-
43214). The authors thank Stephan Zuend and Chris Uyeda for help-
ful suggestions and Professor Theodore Betley and Evan King for ac-
cess to UV/Vis instrumentation. The computations in this paper were
run on the Odyssey cluster supported by the FAS Sciences Division
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(87) The isotope effect data are also consistent with a mechanism in-
volving concerted C2-addition and rearomatization. These two
possibilities cannot be distinguished on the basis of isotope effects
alone, but computational predictions favor a stepwise process, vide
infra.
(88) The isotope effect observed with 5a-d1(C2) for the racemic, benzoic
acid-mediated reaction in CHCl3 (1.8 ± 0.2) is also consistent with
rate-limiting rearomatization.
(89) The product-determining step or selectivity-determining step is
“[t]he step of a stepwise reaction in which the product distribution
is determined. The product-determining step may be identical to,
or occur later than, the rate-controlling step on the reaction coor-
dinate.” See: IUPAC. Compendium of Chemical Terminology,
2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A.
Wilkinson. Blackwell Scientific Publications: Oxford, 1997. XML
on-line corrected version: http://goldbook.iupac.org (2006-) cre-
ated by M. Nic, J. Jirat, B. Kosata; updates compiled by A. Jenkins.
ISBN 0-9678550-9-8. DOI:10.1351/goldbook.P04862. Last up-
date: 2014-02-24; version: 2.3.3.
(103) For a discussion of methods in the computational analysis of cata-
lytic, enantioselective reactions: Lam, Y.-h.; Grayson, M. N.; Hol-
land, M. C.; Simon, A.; Houk, K. N. Acc. Chem. Res. 2016, 49,
750–762. DOI: 10.1021/acs.accounts.6b00006
(104) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. DOI:
(90) Isotopic substitution has only a small effect on the enantiomeric
10.1063/1.464913
excess of product 4a or 4a-d1 (83% ee with 5a; 85% ee with 5a-
(105) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Ma-
ter. Phys. 1988, 37, 785–789. DOI: 10.1103/PhysRevB.37.785
(106) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett.
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(107) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010,
132, 154104. DOI: 10.1063/1.3382344
d1(C ); 81% ee with 5a-d1(C2)) indicating that the isotope effects for
ϕ
the formation of the major and minor enantiomer of product are
similar in magnitude. As such, deprotonation/rearomatization can
be assigned definitively as the rate- and selectivity-determining
step following rapid and reversible cyclization.
(91) Lequestel, J. Y.; Laurence, C.; Lachkar, A.; Helbert, M.; Berthelot,
M. J. Chem. Soc., Perkin Trans. 2, 1992, 2091–2094. DOI:
10.1039/P29920002091
(108) Computational studies reported previously begin with a fully pro-
tonated iminium ion intermediate, which should form readily in
(92) Laurence, C.; Berthelot, M.; Lequestel, J. Y.; Elghomari, M. J. J.
aqueous media. (See refs. 21 and 44.). However, the iminium car-
boxylate protonation state is expected to be substantially less fa-
vored in a nonpolar medium.
Chem. Soc., Perkin Trans.
2 1995, 2075–2079. DOI:
10.1039/P29950002075
(93) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault,
E. J. Med. Chem. 2009, 52, 4073–4086. DOI:
10.1021/jm801331y
(109) Calculations were performed using the CPCM implicit solvent
model for toluene. See Supporting Information for details.
(110) Scalmani, G.; Frisch, M. J. J. Chem. Phys. 2010, 132, 114110.
DOI: 10.1063/1.3359469
(94) A related N-phenylthiourea catalyst was found to be superior to
the analogous N-(3,5-bis(trifluoromethyl)phenyl)thiourea for a
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(111) Imine 7 was employed to avoid the potential for confounding
(120) Zhao, Y. ; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241.
1
cyclization during the analysis.
DOI:10.1007/s00214-007-0310-x
(112) Mayr, H.; Ofial, A. R.; Würthwein, E.-U.; Aust, N. C. J. Am. Chem.
Soc. 1997, 119, 12727–12733. DOI: 10.1021/ja972860u
(113) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science,
2010, 327, 986–990. DOI: 10.1126/science.1182826
(114) Under the conditions shown in Figure 1D, use of the benzoic acid
co-catalyst affords tetrahydro-β-carboline 4b in 94% ee. Use of
acetic acid instead affords 4b in 92% ee with modestly reduced
yield. The minimal change in enantioselectivity lends credence to
the assumption that the features of the path en route to the major
enantiomer of product are highly conserved even upon this simpli-
fication.
(115) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101–110. DOI:
10.1021/ar1000956
(116) Kozuch, S. WIREs Comput. Mol. Sci. 2012, 2, 795–815. DOI:
10.1002/wcms.1100
(117) Consistent with experimental observations, the turnover-limiting
intermediate is predicted to be the product-bound complex (R)-
4b•HOAc•1f.
(118) A strong energetic preference for C2 addition over C3 addition
was also predicted in other computational studies. See refs. 21, 44,
and 45.
(121) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B,
2009, 113, 6378–6396. DOI:10.1021/jp810292npmid:19366259
(122) The free energies predicted at this high level of theory provide a
superior quantitative description of the degree of enantioselectivity
but little additional qualitative information relative to the calcula-
2
3
4
5
6
7
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tions
performed
with
B3LYP-D3(BJ)/6-
31+G(d,p)/CPCM(toluene)//B3LYP/6-
31G(d)/CPCM(toluene). Given the significant additional com-
putational expense with little added benefit, the bulk of the calcula-
tions described here were performed at the lower level of theory.
See Supporting Information.
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(123) Wheeler and coworkers have employed this strategy in the analysis
of transformations catalyzed by chiral phosphoric acids; see: Se-
guin, T. J.; Lu, T.; Wheeler, S. E. Org. Lett. 2015, 17, 3066–3069.
DOI: 10.1021/acs.orglett.5b01349
(124) Seguin, T. J.; Wheeler, S. E. ACS Catal. 2016, 6, 2681–2688. DOI:
10.1021/acscatal.6b00538
(125) Seguin, T. J.; Wheeler, S. E. Angew. Chem. Int. Ed. 2016, 55,
15889–15893. DOI: 10.1002/anie.201609095
(126) For this analysis, we assume that E/Z isomerization is rapid under
the reaction conditions. The (E)-5b•HOAc complex is 3.6
kcal/mol lower in energy than (Z)-5b•HOAc and thus represents
the minimum starting point for this analysis.
(119) While the relative energies of TS2,chair and TS2,spiro varied across the
functionals evaluated, the transition state for rearomatization
(TS3) was predicted to be higher in energy than that for cyclization
in all cases.
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Journal of the American Chemical Society
SYNOPSIS: Mechanistic study of a small-molecule catalyst system for the Pictet–Spengler reaction reveals an unusual enantioselectiv-
ity-determining step for the classic transformation.
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