Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions

Article abstract of DOI:10.1021/acs.joc.9b01980

Four distinct folding patterns are identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns are characterize

Full text of DOI:10.1021/acs.joc.9b01980

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Featured Article
Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions
Antti J. Neuvonen, Dimitris Noutsias, Filip Topi#, Kari
Rissanen, Tamás Földes, Imre Pápai, and Petri M. Pihko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01980 • Publication Date (Web): 19 Sep 2019
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Dynamic Refolding of Ion‐Pair Catalysts in Response to Different An‐
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ions
Antti J. Neuvonen,‡¶ Dimitris Noutsias,‡¶ Filip Topic,¶ Kari Rissanen,¶ Tamás Földes,† Imre Pápai,† Petri M.
Pihko*¶
¶ Department of Chemistry and NanoScience Center, University of Jyväskylä, FI-40014 JYU, Finland
† Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Magyar
tudósok körútja 2, Hungary
Petri.Pihko@jyu.fi
‡ These authors contributed equally.
KEYWORDS catalysis, folding, anion binding, X-ray, solution structures, conformational change
ABSTRACT: Four distinct folding patterns are identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit
by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns characterized by
different intramolecular hydrogen bonding schemes that arise largely from different thiourea conformers. The free base forms of the catalysts
are characterized by folds where the intramolecular hydrogen bonds between the urea and the thiourea units remain intact. In contrast, the
catalytically relevant salt forms of the catalyst, where the catalyst forms an ion pair with the substrate or substrate analogues, appear in two
entirely different folding patterns. With larger anions that mimic the dialkyl malonate substrates, the catalysts maintain its native fold both in
the solid state and in solution, but with smaller halide anions (fluoride, chloride and bromide), the catalysts fold around the halide anion
(anion receptor fold) and the intramolecular hydrogen bonds are disrupted. Titration of catalyst hexafluoroacetylacetonate salt with tetra-n-
butylammonium chloride results in dynamic refolding of the catalyst from the native fold to the anion receptor fold.
importance of conformational adaptability is well recognized in the
INTRODUCTION
realm of enzymes, conformational flexibility of synthetic catalysts
has gained recognition only relatively recently.6 In particular,
synthetic peptides, in the same fashion as larger enzyme proteins,
provide an important exception to the typical rigidity of synthetic
catalysts. 6c-e
The prevailing tenet in designing enantioselective catalysts is
that the catalyst must be able to efficiently differentiate between
two competing diastereomeric transition states leading to different
enantiomers of the product.1 To this end, catalyst structures often
include relatively bulky side chains to increase steric constraints2
and to restrain conformational flexibility.
Herein we describe a pair of highly enantioselective synthetic
catalysts displaying significant conformational flexibility, with a
native, active folded state and at least three alternative folded states.
In contrast to the rigid design of synthetic catalysts, recent
research has unearthed evidence that enzyme catalysis is highly
tolerant of conformational flexibility in the structure of the protein.3
In some cases, the binding of the substrate helps in preorganizing
the active site of the enzyme.4 It also appears that even after long
periods of evolutionary optimization, enzymes often possess
significant conformational flexibility that enables them to adapt to
different substrates.5 These properties are crucial for evolution of
new functions and also for allosteric regulation. While the
The catalysts that are the subject of the current study (1-3, see
Scheme 1) are capable of highly enantioselective catalysis of
Mannich reaction between malonate esters, or β-keto esters, and
imines.7,8 The intramolecular urea-thiourea hydrogen bond motif in
these catalysts was originally designed by the Smith group as a β-
turn mimic,9 connecting the design our catalysts to the realm of
peptides. Mechanistically, an initial proton transfer event, the
malonate or β-keto ester anions are proposed to be tightly bound
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to the catalytic pocket via hydrogen bonds (Scheme 1 a).7a While
all catalysts gave reasonable enantioselectivities in the catalytic
Mannich reaction (Scheme 1 b), catalyst 1 was superior to catalyst
2 in both selectivity as well as reactivity (Scheme 1 b),7d and catalyst
3 was even more selective than either catalysts 1 or 2. We have
earlier reported7a how important the catalytic pocket and the
overall fold, including the rigid indane ring7c (rings C and D), are
for catalysis with this catalyst family (Scheme 1 c).
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Figure 1. Two examples of previously characterized folding patterns of
catalyst 2 (CCDC codes YEKPEL and YEKPIP) in their active, salt
form.7c
The presence of several different folds in catalysts is well
established in the realm of enzymes, where it is possible to
distinguish between the native, catalytically competent state, and
other, improperly folded or even denatured states.5 Our foldamer-
like catalysts, are complex enough that different folding patterns
may similarly emerge. These folding patterns, or folds, arise as a
combination of four possible conformations for the thiourea unit
(Figure 2 a)10 and the presence of hydrogen bond acceptors and
donors within the catalyst, giving rise to additional conformational
possibilities. Some of the possible folding patterns are shown in
Figure 2 b. Fold A is the fold that we have previously associated
with catalytic activity,7a,7c exhibiting the anti-anti thiourea unit and
intramolecular urea-thiourea hydrogen bonds. Given its potential
role in catalysis, fold A is herein called the “native fold”, whereas the
chloride-disrupted fold D is called “anion receptor fold”.11
Scheme 1. a) The catalytic Mannich reaction via ion-pair intermediate,
b) structures of catalysts 1-3 and their relative performance in a test
reaction (10 mol% catalyst, toluene, 0 °C for catalysts 1 and 3, –40 °C
for 2, see ref. 7a and 7c) and c) transition state (TS) structure(DFT)
showing catalyst 3 and the test substrates, showing the folding of the
catalyst in the TS (left) and the surface of the active site cleft (right)7a.
However, evidence for alternative folds with these catalysts was
evident even in our first X-ray studies. For example, a completely
different type of fold was characterized by X-ray when the counter
anion was a small chloride ion (Figure 1). In this case, the
intramolecular hydrogen bonded fold and the catalytic cleft was
completely disrupted and the catalyst instead folded around the
chloride ion.
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Scheme 2. Improved synthesis of catalysts 1 and 2 directly from dia-
mine 5.
Solid-state Structures of Free Catalysts 1 and 2. The X-ray
structures of the free catalysts 1 and 2 were published previously.7c
For comparison, the salient features of the structures are discussed
herein.
Catalyst 1 exhibits the native folded conformation 1A in the X-
ray structure (Figures 3 and 4). In this structure, the thiourea sulfur
atom is hydrogen bonded to the urea HN5. The distance from the
thiourea sulfur to N5 was 3.29 Å (HN5…S distance 2.48 Å)12. In turn,
the hydrogen bond from thiourea sulfur to the second urea HN4 was
weaker, with S…N4 distance of 3.51 Å (HN4…S 2.68 Å). The
differentiation between the two urea H-bond donors is mainly
caused by geometrical restraints from the aminoindanol linker and
limited rotation around the ether bonds due to 1,5-interaction. In
this structure, the angle between least squares planes of the urea
and thiourea is 75.8°. The thiourea unit is in the catalytically active
(anti-anti) conformation, with the N2-H and N3-H bonds parallel,
facing outwards and open for coordination by hydrogen bond
acceptors. The HN2–N2–CB1–HB1 and HN3–N3–CC1–HC1 dihedral
angles on both sides of the thiourea are governed by allylic strain by
minimizing the interaction between sulfur and the neighboring
alkyl groups. This conformation is analogous to highly preferred
120° or 180° φ-angle clusters in peptides.13 In fact, in catalyst 1,
torsion angle of HN2–N2–CB1–HB1 is close to 120° (133°) and the
torsion angle of HN3–N3–CC1–HC1 is close to 180° (169°) (Figure
3). The thiourea hydrogens HN2 and HN3 form intermolecular
hydrogen bonds to urea oxygen of the adjacent catalyst molecule
with hydrogen bond lengths 3.00 Å (N2…O’) and 2.99 Å (N3…O’)
(H…O’ distance being 2.17 Å for both hydrogen bonds).
Figure 2. a) Different thiourea conformations with unsymmetrical
thioureas and b) possible folding patterns in catalyst 1.
Our early studies, however, did not establish to what extent the
native fold of these catalysts was maintained in solution.
Furthermore, why did the chloride anion give rise to the anion
receptor folding pattern, while the hexafluoroacetylacetonate
(hfacac) anions maintained the native fold of the catalyst? In order
to study the behavior of the catalysts in a more systematic manner,
we decided to examine the original catalysts 1 and 2, and their salts
with different anions, both in solution and in the solid state. The
free catalysts were examined first, followed by a more systematic
variation of different anions, from small halides to larger organic
anions mimicking possible pronucleophiles.
RESULTS AND DISCUSSION
Improved Synthesis of Catalysts 1 and 2. We have found that the
precursor 4 (Scheme 2) is hindered enough to enable
straightforward and highly selective monothiourea formation
between 4 and 5 (via a isothiocyanate derived from 4). In this
manner, catalysts 1 and 2 can be obtained very easily from
precursor 4 after reductive amination of intermediate 6 or 7.
a
Figure 3: φ-angle torsions in (anti-anti) conformer of solid-state
structure of catalyst 1.
In contrast to the free catalyst 1, the X-ray structure of catalyst 2
shows two crystallographically independent conformations, 2B and
2C (Figure 4). Fold 2A was not observed in the solid state. In both
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conformations (2B and 2C), the catalyst backbone stays relatively
unchanged, highlighting its rigidity. However, the folding of the
rest of the catalyst is different from the fold 1A observed for 1
(Figure 4). In both 2B and 2C, the thiourea is the syn-anti
conformer, and the intramolecular hydrogen bonds between the
urea and thiourea units are retained. The difference between 2B
and 2C lies in the orientation of cyclohexyl ring B. In 2B, the
dimethylamino group (N1) can form one more intramolecular
hydrogen bond with the thiourea HN2 (N2…N1 distance 2.70 Å and
HN2…N1 distance 2.37 Å), but in 2C, a similar contact is not
possible. A weaker hydrogen bond between N1 and HN3 is feasible
based on the N3…N1 distance, 3.03 Å and HN3…N1 distance of 2.56
Å.
used
DFT
calculations
at
the
M06-2X/6-
311++G(3df,3pd)//M06-2X/6-311G(d,p) level to compute the
structure and the relative stability of various catalyst conformers
(for details, see Supporting Information).
The most stable computed structures are shown in Figure 5 b
and d. For catalyst 1, three conformers with very similar relative
stabilities were identified. Conformer 1A displays the conformation
observed in the X-ray structure of 1, with the anti-anti thiourea.
The conformers 1B and 1C, in contrast, possess a syn-anti thiourea
unit, but still involving intramolecular H-bonding interactions
between the thiourea S atom and the urea NH groups. Neither of
these folds were observed in the X-ray studies of 1, but the 1B fold
is similar to the fold 2B of catalyst 2. For catalyst 2, the most stable
form corresponds to conformer 2B displaying a syn-anti thiourea
unit, whereas the anti-anti-thiourea conformation (2A) is predicted
to be 1.5 kcal/mol less favored in free energy. The overall fold of 2B
in the X-ray structure is almost identical with the DFT structure
(see Figure 5b). Interestingly, although fold 2C was present in the
X-ray structure (see above), it turned out to be 3.0 kcal/mol less
stable than 2B, even after optimization of the structure. The
existence of fold 2C in the X-ray crystal structure (Figure 4) may be
attributed to intermolecular hydrogen bonds between the
structures 2B and 2C in the X-ray structure (Figure 5 f). These
hydrogen bonds could stabilize 2C in the solid state.
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N4
N5
E
C
F
F
N4
N5
E
2.79
2.42
N1
2.37
2.48
2.68
N2
C
N2
2.49
B
D
D
N1
Diastereomer 1, fold A (1A)
Diastereomer 2, fold B (2B)
In solution, the most diagnostic NOESY cross-peaks in catalyst 1
were those observed between N1-Me↔HC2, HB1↔HN5 and
N4
N5
F
E
HB1↔HN4. The observed N1-Me↔HC2 interaction is consistent
with the structures 1C (computed distance 2.3 Å) and possibly also
with 1A (5.1Å), but appears inconsistent with the most stable
conformer 1B (6.1Å). The HB1↔HN5 interaction can be also
supported by conformers 1A (2.5 Å) and 1C (3.5 Å), but the
distance in 1B is longer (4.8 Å). Last, the interaction between
HB1↔HN4 is expected on the basis of structure 1A (computed
distance 3.8 Å) and 1C (3.1 Å), but appears less likely for
conformer 1B (5.0 Å). Taken together, these results suggest that
catalyst 1 is mostly populated by conformers 1A and 1C in the
solution state, but we cannot rule out the contribution of
conformer 1B to the solution structure. The G‡ for the rotation
around the thiourea C–N bond is 13.5-14.4 kcal/mol,14 and as such
NMR experiments at 303 K probe temperature used herein are well
above the coalescence temperature.14a
2.78
2.53
N3
D
C
2.56
N1
B
D
Diastereomer 2, fold C (2C)
Diastereomer 2, fold C (2C), back view
Figure 4. The X-ray structures of diastereomers 1 (CSD: YEKQEM)
and 2 (YEKPAH) showing three distinct folds for the catalysts. All
except NH hydrogens are omitted for clarity.
Solution Structures of Free Catalysts 1 and 2. The observation of
three distinct folds in these X-ray structures supported the notion
that these catalysts can adopt a variety of conformations in the solid
state. The catalytic reactions, however, take place in solution. To
assess the solution conformations, NOESY NMR spectra of the
catalysts 1 and 2 were recorded in CD2Cl2. Different conformations
of the catalysts 1 and 2 were also examined computationally. We
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Catalyst 1
5
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b
DFT
a
NMR
CF3
CF3
O
E
4
1
F
E
5
N
E
B
E
F
N
H2
F
F
CF3
Me
1
1
6
H
H
H
9
C2
Ha
O
Me
N1
H
3
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S
H
H
Hb
3.1 Å
C
C
B
3
N
Me
B
2
N
C1
C
B1
2.3 Å
1
B
C
D
D
H
H
D
D
1A
1A (0.1)
1B (0.0)
1C (0.4)
Catalyst 2
d
c
DFT
NMR
F6
2.9 Å
F3C
CF3
O
F
F
4
N
F
1
5
N
E
E
F2
E
F2
2
H
E
CF3
3.2 Å
1
6
H
H
H
Me
Ha
3
B6
O
1
H
Hb
S
C2
H
2
H
B
Me
1
B
C
D
C
3
N
2
N
6
F
C
B
C
D
1
B
N
2
D
H
H
Me
D
2B (0.0)
2C (3.0)
2A
2A (1.5)
e
f
F3C
CF3
O
H
F
F
4
N
1
5
E
E
N
6
Ha
H2
CF3
1
H
H
H
O
H
3
2C
Hb
S
H
3
N
Me
2B
2
C
1
2 H
C
Me
1
N
N
D
2
B
H
1
D
B
2B
2B (X-ray + DFT overlay)
2B + 2C in the X-ray structure
Figure 5. a-d) Key NOESY correlations (NMR) and the most stable DFT structures of free catalysts 1 and 2. To rationalize the NMR results for
catalyst 2, two different folds (2A and 2B) are presented to account for the observed NOESY cross-peaks (see text). e) Overlay of the X-ray of fold 2B
(gold) with the DFT structure (blue). f) Packing of structures 2B and 2B in the X-ray structure of 2 (CSD: YEKPAH). The computed relative stabili-
ties shown in parenthesis (in kcal/mol) refer to solution phase Gibbs free energies with respect to the most stable forms of catalysts 1 and 2.
and hydrobromic acid salts of both catalysts 1 and 2. Salts of
hydroiodic acid, however, did not afford crystalline material with
either catalyst diastereomer.
In catalyst 2, the key diagnostic NOESY cross-peaks correspond
to the correlations between N1-Me↔HC2, HB6eq↔HF2/F6 and the
N1-Me↔HF2/F6. The most stable DFT structures, 2A and 2B, are
consistent with most of the observed NOESY cross-peaks. The N1-
Me↔HC2 correlation is readily explained by fold 2B (computed
distance 4.5 Å), but not by 2A (MeN1 HC2 distance 6.7 Å).
Likewise, the correlation N1-Me↔HF2/F6 is expected for 2B (2.9 Å)
but the corresponding computed distance in 2A is 5.4 Å. In
The X-ray structures (Figure 6) show that the structures of the
hydrohalide salts are remarkably similar with different anions. In all
structures, the halide anions are bound to the catalyst 1 via the urea
HN4 and HN5 hydrogens and via one of the thiourea NH, the HN2.
The thiourea is in the anti-syn conformation.15 The protonated
ammonium HN1 forms a weaker hydrogen bond to the halide with a
longer H…N distance. For example, in 1∙HF the HN1…F distance is
2.54 Å (N1…F 3.10 Å), while the contacts to the thiourea and urea
protons are shorter (HN2…F 1.93 Å, HN4…F 2.08 Å, HN5…F 1.87 Å).
In addition, the fluoride ion also contacts the thiourea HN3 of the
adjacent catalyst molecule in the solid state structure (see the SI).16
…
contrast, the correlation
HB6eq↔HF2/F6 cannot be readily
rationalized by fold 2B (distance 7.3 Å) but it is well consistent
with 2A (distance 2.9 Å). These data suggest that in solution, both
folds, 2A and 2B, may contribute to the averaged NMR structure
since neither of these structures alone can fully rationalize the
observed NOEs.
All catalyst 1 halide salts show a similar bonding pattern, and the
catalyst molecules overlap almost perfectly. Although the binding
of the halide causes a small distortion in the upper CDEF urea
segment of the catalyst molecule, the overlaid structures of the free
catalyst 1 and 1∙HCl show remarkable degree of similarity (Figure 6
e).
Structures of the Halide Salts in the Solid State and in Solution.
We decided to probe the effect of anion size by generating a series
of structures from two available catalyst diastereomers with
hydrohalic acids. Indeed, we could successfully form salts and
isolate good quality single crystals of hydrofluoric, hydrochloric
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The X-ray crystal structures of the hydrohalide salts of catalyst 2
It is evident from these solid state structures that the halides do
are also remarkably similar to the HX salts of catalyst 1. The only
major change in the folding pattern is that the dimethylammonium
group in this diastereomer is better able to contact the halide ion,
even in the case of the smallest, fluoride anion (see Figure 6 b). In
contrast, the thiourea HN2 is not ideally pointed towards the halide
ion, and forms only a weak contact with the anion, with a HN2…F
distance of 2.96 Å in 2·HF (Figure 6 b).
not fit the pocket perfectly and thus allow the formation of
intermolecular hydrogen bonds on the exposed face of the anion. In
particular, the bromide ion is large enough that it is bound only
from one side of the sphere by one catalyst molecule, as exemplified
by the spacefill structure of 1∙HBr (Figure 6 f).
Structures of Catalyst Hydrochloride salts: Solution State
Structures. The NOESY spectrum of the HCl salt of catalysts ent-
117 and 2 confirms most of the expected interactions that are
observed in the X-ray structure (Figure 7). Many of the NOESY
correlations observed in the free catalysts remained similar in the
HCl salts. However, the correlation between HN2 and HC1 indicates
a conformational change in the thiourea moiety to the anti-syn
conformation. Furthermore, the cross-peaks between MeN1 and HF2
in both structures as well as HN5 and HB2 in ent-1·HCl were
indicative of a folded, compact conformation where the catalyst
wraps around the chloride ion.
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b
a
N5
N4
N4
N5
2.05
1.59
2.96
2.08
2.08
1.93
1.87
N1
N2
N2
Diastereomer 2.HF
Diastereomer 1.HF
c
Overlay of 1.HX (X = F, Cl, Br)
Overlay of 1.HX (X= F, Cl, Br),
backside view
d
Figure 7. Structures of HCl salts of catalysts ent‐1 and 2 in a) CD3CN
(with diagnostic NOESY cross-peaks indicated by arrows) and b) in
the solid state (X-ray). For the structure of ent-1·HCl, the mirror
image of the X-ray of 1·HCl is shown for clarity.
Overlay of 2.HX (X = F, Cl, Br)
Overlay of 2.HX (X= F, Cl, Br),
backside view
f
e
Structures of Catalyst with Organic Acids. In contrast to the salts
of hydrohalic acids, we had already previously recorded examples
where catalysts 1-3 exhibited the native fold A in the presence of
organic acids.7c We therefore examined a series of acids with
catalysts 1 and 2 to obtain further insight how the size and the
shape of the anions affect the overall fold of the catalyst.
Although it would have been desirable to obtain X-ray structures
for a complete series of anions, in practice these studies had to be
limited to scattered cases where the crystal properties were
satisfactory. In many cases, even if proper size crystals were
obtained, they were often soft or brittle making the experiments
hard to conduct. Nevertheless, in addition to the previously
characterized 2·hfacac (Figure 1), we could also obtain the
Overlay of 1.HCl with free base 1
1.HBr, spacefill model
Figure 6. a-d: Solid state structures of the HX salts of catalysts 1 and 2.
e) Overlay of the X-ray structures of 1∙HCl (blue, except for the urea
and thiourea units) and free catalyst 1 (YEKQEM, gold) showing the
similar folding of the CDEF region of the catalyst. f) Spacefill model of
1∙HBr showing how the bromide ion protrudes out from the binding
pocket.
corresponding
trifluoroacetate
(TFA,
Figure
8
a),
diphenylphosphate (DPP, Figure
8
b) and bis(2,6-
trifluoromethyl)benzoate (BTB, see SI) salts, all of which exhibited
the expected native fold A. The intermolecular hydrogen bonding
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patterns observed in these structures are, however, dependent on
Interestingly, the lower reactivity and selectivity of catalyst 2
relative to 1 may be related to its relatively lower preference for the
active anti-anti conformer (fold A). Catalyst 2 will need to adopt
the active fold 2A instead of the preferred folds 2B or 2C (with a
syn-anti thiourea unit) upon binding to the malonate ion.7a,7c In
contrast, catalyst 1 appears to populate the native fold 1A with
greater occupancy in solution (see Figure 4a). If fold A is the fold
required for catalysis, this difference may explain the higher
reactivity and selectivity of catayst 1 compared to 2.
the hydrogen bond acceptor properties of the anion. For example,
in the DPP salt, the ammonium HN1 contacts a neighboring
diphenylphosphate anion in the solid state (see the SI) instead of
forming a third hydrogen bond to the anion that is bound by the
urea. For these reasons, these X-ray structures may not always offer
a realistic insight into the conformers populated in solution.
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a
b
Addition of Chloride Ion Source Dynamically Switches the
Catalyst Conformation in Solution. We also hypothesized that the
refolding of the catalyst in the presence of different anions might be
sufficiently rapid so that the event could be monitored by NMR. To
this end, we selected n-Bu4NCl as the chloride anion source that
could potentially replace the hfacac anion in solution (Scheme 3).
F
F
E
E
C
C
B
B
D
D
Diastereomer 2, TFA salt
Diastereomer 2, DPP salt
Figure 8. Solid state structures of catalyst 2 as the a) TFA salt and b)
DPP salt.
Structures of Catalyst -hfacac Salts: Solution State Structures.
The solution state structures of the hfacac salts of catalysts 1 and 2
were obtained by recording NOESY spectra in CD2Cl2 and analysis
of the key correlations. The results (Figure 9) support the notion
that these catalysts primarily populate fold A in solution with larger
anions such as hfacac and the enolate of dimethyl malonate.7a For
example, the HN3↔HC2 NOESY cross-peak observed in 1·hfacac
shows that the thiourea moiety is likely to adopt an anti-anti
configuration. Most diagnostically, the cross-peaks between HF2
and HB2 and HB4ax (1·hfacac) or HF2 and H5ax (2·hfacac) are
consistent with fold A (Figure 9).
Scheme 3. Dynamic switching between the A and D folds of the cata-
lyst with addition of n-Bu4NCl as the chloride source.
Thus, a solution of 2∙hfacac in CD3CN was titrated with a
solution of n-Bu4NCl (0.5 M in CD3CN). During the titration, the
1H NMR of the mixture slowly began to resemble the spectrum of
pure 2·HCl (compare Figures 10a and 10b), and only very little
change was detectable beyond 1.2 equiv of n-Bu4NCl (Figure 10 c).
These data suggest that during the titration, catalyst 2 had almost
exclusively switched from the fold 2A to the anion receptor fold 2D.
Similar results were obtained with catalyst 1 and n-Bu4NCl (see the
SI for details). The titration results with n-Bu4NCl point indicate
that the equilibrium in this case lies on the side of the chloride
complexes (D fold). However, titration of a solution of 2∙hfacac
with n-Bu4NBr (a source of bromide ion) yielded a more complex
NMR spectrum, suggesting that in this case the switch was either
not complete or that other conformations were also populated.
Figure 9. Solution state structures of hfacac salts of catalysts 1 and 2.
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Figure 10. a) 1H NMR spectrum of 2·HCl. b) 1H NMR spectrum of 2·hfacac after addition of 1.2 equiv of n-Bu4NCl. c)1H NMR titration of 2·hfacac
with 0.5 M solution of n-Bu4NCl. All spectra were recorded in CD3CN.
where the catalytic pocket is intact, was maintained in the free base
SUMMARY AND CONCLUSIONS
form of the catalyst as well as in its hfacac or TFA salts. However,
In conclusion, the folding patterns of our foldamer-type catalysts,
the thiourea unit of the catalyst does not uniformly adopt the
capable of highly enantioselective Mannich reactions have been
desired anti-anti conformation, and it turned out that the less-
characterized. The patterns that emerge from the solid-state XRD
reactive catalyst 2 favoured the undesired syn-anti thiourea
studies appear to be preserved in solution in high fidelity. Thus, the
intramolecular hydrogen bonds in the native fold of the catalyst,
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were refined with anisotropic thermal parameters. Hydrogen atoms
conformer in solution, as established by a combination of NMR
studies and computational conformational analysis.
were introduced in proper positions with isotopic thermal parameters
using the ‘riding model’. ORTEP figure was plotted and structure was
analyzed with Mercury v 3.10.
In contrast, the salts with simple hydrohalic acids adopt a
different, anion-receptor type fold, where the intramolecular
hydrogen bonding is completely disrupted, and the catalyst
conformation changes to allow multiple hydrogen bond contacts
with the small halide counteranion. This fold is made possible by
the alternative anti-syn conformation of the thiourea unit, instead
of the syn-anti conformation observed for catalyst 2. These folding
patterns were identified by X-ray structures in the solid state for
both catalyst diastereomers, and for different anions (F–, Cl–, and
Br–) and the hydrochloride salts of two catalyst diastereomers were
found to populate similar conformations in solution according to
NOE studies.
Synthesis of Catalysts. CAUTION: CSCl2 (thiophosgene) is a toxic
and corrosive reagent that must be used in an efficient fume cupboard.
1-(2-(((1R,2R)-1-(3-((1R,2R)-2-aminocyclohexyl)thioureido)-2,3-
dihydro-1H-inden-2-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(3,5-
bis(trifluoromethyl)phenyl)urea (6). Amine 4 (430 mg, 0.76 mmol,
100 mol-%) was dissolved in a stirred biphasic mixture of DCM, THF
and saturated aqueous NaHCO3 (10:1:10, total volume 21 mL) at 0
°C. The stirring was stopped and thiophosgene (117 μL, 1.52 mmol,
200 mol-%) was added via syringe to the organic layer. Stirring was
started and continued for 4 h at 0 °C after which the layers were sepa-
rated and the aqueous layers extracted with DCM (3 × 20 mL). The
combined organic extracts were dried over Na2SO4 and concentrated.
The crude isothiocyanate was dissolved in a mixture of dry DCM, THF
(5:1, total volume 12 mL) under argon and diamine (R,R)-5 (174 mg,
1.52 mmol, 200 mol-%) was added in one portion at 0 °C. The reaction
mixture was stirred at rt for 3 h after which most of the solvents were
removed under reduced pressure (2 mL of solvent left in the flask).
Purification of the residue by flash chromatography (100:1:1
DCM:MeOH:Triethylamine) afforded the desired product 6 as off-
white solid (535 mg, 98%). Rf (4% 7N NH3/MeOH in DCM) = 0.35;
mp 141−142 °C; ꢀαꢁꢃꢂꢄ °ꢅ = −50.7 (c 1.0, CH2Cl2); IR (film, cm¬1):
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The choice of the fold could also be modulated by addition of
chloride ions. Titration of the hfacac salts of the catalysts 1 and 2,
possessing the native fold in solution, with a chloride source (n-
Bu4NCl), resulted in a switch to the anion receptor mode as
1
observed by H NMR. The fact that different anions can affect the
shapes of the catalysts suggests that anions could also be used to
modulate the selectivities and activities of synthetic catalysts.
Studies towards these goals are ongoing.
EXPERIMENTAL SECTION
1
3259, 3083, 2934, 2860, 1709, 1543, 1385, 1276, 1170, 1121, 681; H
General Information. All reactions were carried out under an argon
atmosphere in flame-dried glassware, unless otherwise noted. When
needed, nonaqueous reagents were transferred under argon via syringe
or cannula and dried prior to use. THF and CH2Cl2 were obtained by
passing deoxygenated solvents through activated alumina columns
(MBraun SPS-800 Series solvent purification system). Other solvents
and reagents were used as obtained from supplier, unless otherwise
noted. Analytical TLC was performed using Merck silica gel F254 (230-
400 mesh) plates and analyzed by UV light or by staining upon heating
with anisaldehyde solution (2.8 mL anisaldehyde, 2 mL conc. H2SO4,
1.2 mL conc. CH3COOH, 100 mL EtOH), vanillin solution (6 g
vanillin, 5 mL conc. H2SO4, 3 mL glacial acetic acid, 250 mL EtOH) or
KMnO4 solution (1 g KMnO4, 6.7 g K2CO3, 1.7 mL 1M NaOH, 100
mL H2O). For silica gel chromatography, the flash chromatography
technique was used, with Merck silica gel 60 (230-400 mesh) and p.a.
grade solvents unless otherwise noted.
NMR (500 MHz, CD2Cl2): δ 10.25 (s, 1H), 9.21 (s, 1H), 8.69 (s, 1H),
8.67 (brs, 1H), 8.17 (s, 2H), 7.53 (s, 1H), 7.34 – 7.30 (m, 4H), 7.25 (d,
J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.64 (brs, 1H), 6.13 (brs,
1H), 4.61 (app q, J = 8.2 Hz, 1H), 3.66 (dd, J = 14.9, 7.2 Hz, 1H), 3.25
(app. dd, J = 14.9, 9.1 Hz, 1H), 2.51 (app. td, J = 10.1, 3.7 Hz, 1H),
2.04 (m, 1H), 1.78 – 1.13 (m, 9H); 13C{1H} NMR (125 MHz,
CD2Cl2): δ 184.1, 152.6, 150.0, 141.7, 138.9, 138.0, 132.3 (q, J = 33.1
Hz), 131.1, 129.1, 128.1, 125.7, 124.7 (q, J = 32.6), 123.9 (q, J = 272.6
Hz), 123.4, 122.7 (q, J = 271.1 Hz), 119.5, 118.5, 115.9 (quint, J = 3.8
Hz), 115.4, 113.7, 90.1, 66.1, 63.5, 56.4, 37.3, 35.2, 32.8, 25.0, 24.9;
HRMS (ESI+, TOF): m/z calcd for [C32H31F9N5O2S]+ 720.2049,
found 720.2045, Δ = 0.6 ppm.
1-(2-(((1R,2R)-1-(3-((1S,2S)-2-aminocyclohexyl)thioureido)-2,3-
dihydro-1H-inden-2-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(3,5-
bis(trifluoromethyl)phenyl)urea (7). The reaction performed using 4
(300 mg, 0.53 mmol, 100 mol-%) and (S,S)-5 (121 mg, 1.06 mmol,
200 mol-%) using the procedure used for the preparation of 6. The
product was purified by flash chromatography (100:1:1
DCM:MeOH:Triethylamine) to afford 7 as off-white solid (290 mg,
76%). Rf (4% 7N NH3/MeOH in DCM) = 0.45; mp 142−143 °C;
ꢀαꢁꢃꢂꢄ °ꢅ = −183.0 (c 1.0, DCM); IR (film, cm¬1): 3273, 2932, 2859,
1
The H NMR and 13C NMR spectra were recorded in CD2Cl2 or
CD3CN on Bruker Avance 500, 400 or 250 spectrometers. The
chemical shifts are reported in ppm relative to CHD2CN (δ 1.94) or
1
CHDCl2 (δ 5.32) for H NMR. For the 13C NMR spectra, the residual
CD3CN (δ 118.26) or CD2Cl2 (δ 53.84) were used as the internal
standards. The enantiomeric excesses (ee) of the products were
determined by HPLC in comparison to the corresponding racemic
samples using Waters 501 pump and Waters 486 detector. Melting
points (mp) were determined in open capillaries using Gallenkamp
melting point apparatus. IR spectra were recorded on a Tensor27 FT-
IR spectrometer. Optical rotations were obtained with a Perkin-Elmer
343 polarimeter. High resolution mass spectrometric data were
measured using MicroMass LCT Premier Spectrometer.
Single crystal X-ray diffraction analyses were performed at indicated
measuring temperature on an Agilent Super-Nova diffractometer using
mirror monochromatized Mo-Kα (λ = 0.71073 Å) or Cu-Kα (λ =
1.54184 Å) radiation. CrysAlisPro program was used for the data
collection and processing. The intensities were corrected for absorp-
tion using the Analytical face index absorption correction method. The
structure was solved by charge flipping method with SUPERFLIP5 and
refined by full-matrix least-squares methods using the OLEX2-1.2
software, which utilizes the SHELXL module. All non-hydrogen atoms
1
1710, 1542, 1442, 1384, 1276, 1122, 681; H NMR (500 MHz,
CD2Cl2): δ 10.23 (s, 1H), 9.51 (s, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.53
(s, 1H), 8.19 (s, 2H), 7.52 (s, 1H), 7.31 – 7-24 (m, 5H), 7.08 (d, J =
8.4 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.07 (br s, 1H), 4.59 (q, J = 8.2
Hz, 1H), 3.67 (dd, J = 15.2, 7.4 Hz, 1H), 3.25 (dd, J = 15.1, 8.9 Hz,
1H), 3.08 (brs, 1H), 2.62 (td, J = 10.3, 3.5 Hz, 1H), 1.81 (app. d, J =
12.5 Hz, 1H), 1.75 – 1.63 (m, 5H), 1.21 – 1.07 (m, 4H); 13C{1H}
NMR (125 MHz, CD2Cl2): δ 183.7, 152.5, 150.0, 141.7, 138.4, 137.9,
132.2 (q, J = 33.0 Hz), 131.1, 129.1, 127.9, 125.7, 124.8 (q, J = 271.6
Hz), 124.6 (q, J = 33.7 Hz), 123.9 (q, J = 272.7), 123.5, 119.4, 118.4,
115.7, 115.4, 113.9, 91.4, 66.3, 63.1, 56.4, 37.4, 35.1, 32.6, 24.9; HRMS
+
(ESI+, TOF): m/z calcd for [C32H31F9N5O2S] 720.2049, found
720.2062, Δ = −1.8 ppm.
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(((1R,2R)-1-(3-((1R,2R)-
2-(dimethylamino)cyclohexyl)thioureido)-2,3-dihydro-1H-inden-2-
yl)oxy)-5-(trifluoromethyl)phenyl)urea (2). To
a solution of
compound 6 (200 mg, 0.28 mmol, 100 mol-%) in DCE (6 mL) was
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added formaldehyde (38% CH2O in water, 61 μL, 0.84 mmol, 300 mol-
1H), 7.57 (s, 1H), 7.32 – 7.24 (m, 5H), 7.17 (app. d, J = 8.3 Hz, 2H),
%) at rt. The reaction mixture was stirred at rt for 15 min after which
NaBH(OAc)3 (237 mg, 1.12 mmol, 400 mol-%) was added in one
portion. The reaction mixture was stirred at rt for 4 h before sat. aq.
NaHCO3 (18 mL) was added. The mixture was allowed to stir for 15
min, and then the layers were separated. The aqueous layer was washed
with DCM (3 × 18 mL). The combined organic extracts were dried
over Na2SO4 and concentrated. Purification of the residue by flash
chromatography (4% 7N NH3/MeOH in DCM) afforded the desired
product 2 as a pale crystalline solid (133 mg, 64%). Characterization
data are in full agreement with our previous publication.7c 1H NMR
(500 MHz, CD2Cl2): δ 9.40 (b rs, 1H), 8.71 (s, 1H), 8.61 (s, 1H), 8.20
(s, 2H), 7.53 (s, 1H), 7.33 – 7-28 (m, 4H), 7.26 (dd, J = 8.4, 1.4 Hz,
1H ), 7.09 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H), 6.34 (brs, 1H), 4.46 (app.
q, J = 8.1 Hz, 1H), 3.65 (dd, J = 14.6, 6.9 Hz, 1H), 3.49 (brs, 1H), 3.29
(dd, J = 14.6, 9.1 Hz, 1H), 2.31 (m, 1H), 2.21 (m, 1H), 1.93 (brs, 6H),
1.79 (m, 1H), 1.75 (m, 1H), 1.64 (brs, 1H), 1.27 (m, 1H), 1.16 – 1.12
(m, 3H); 13C{1H} NMR (75 MHz, CD2Cl2): δ 183.5, 152.6, 150.0,
141.8, 138.5, 138.1, 132.3 (q, J = 33.1 Hz), 129.2, 128.2, 125.8, 124.9
(q, J = 271.5 Hz), 124.9 (q, J = 31.7 Hz), 123.9 (q, J = 272.7 Hz),
119.5, 118.4, 115.7 (sept, J = 4.0 Hz), 115.4, 114.2, 90.9, 67.8, 65.6,
57.0, 40.1, 37.4, 33.8, 24.8 (2C), 22.6.
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(((1R,2R)-1-(3-((1S,2S)-
2-(dimethylamino)cyclohexyl)thioureido)-2,3-dihydro-1H-inden-2-
yl)oxy)-5-(trifluoromethyl)phenyl)urea (1). The reaction was
performed using 7 (187 mg, 0.28 mmol, 100 mol-%) utilizing the
procedure used for the preparation of 2. The product was purified by
flash chromatography (4% 7N NH3/MeOH in DCM) to afford 1 as a
pale crystalline solid (145 mg, 75%). Characterization data are in full
agreement with our previous publication.7c 1H NMR (500 MHz,
CD2Cl2): δ 9.61 (br s, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 8.21 (s, 2H),
7.53 (s, 1H), 7.34 (m, 3H), 7.27 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.4
Hz, 1H), 6.65 (brs, 1H), 6.00 (brs, 1H), 4.47 (app. q, J = 7.5 Hz, 1H),
3.65 (dd, J = 15.3, 7.6 Hz, 1H), 3.27 (app. dd, J = 15.3, 8.8 Hz, 2H),
2.34 (app. td, J = 10.5, 3.5 Hz, 1H), 2.02 (s, 6H), 1.79 (app. d, J = 11.2
Hz, 1H), 1.69 (m, 2H), 1.62 (m, 1H), 1.17 (m, 1H), 1.09 – 1.01 (m,
3H); 13C{1H} NMR (125 MHz, CD2Cl2): δ 184.3, 152.5, 150.0, 141.7,
138.4, 138.1, 132.3 (q, J = 33.1 Hz), 131.4, 129.2, 128.0, 125.8, 124.8
(q, J = 271.6 Hz), 124.8 (q, J = 32.4 Hz), 123.9 (q, J = 272.6 Hz),
123.3, 119.4 (app. q, J = 4.0 Hz), 118.4 (app. d, J = 3.0 Hz), 115.8
(quint, J = 3.9 Hz), 115.5, 114.7, 91.8, 68.3, 65.9, 57.2, 40.2, 37.5, 33.8,
24.8, 24.7, 22.5.
Typical Procedure for the Preparation of HCl Salts of Catalysts 1
and 2. To a solution of catalyst (10 mg, 0.013 mmol, 100 mol-%) in
DCM (2 mL) was added aq. HCl (conc., 53 μL, 0.65 mmol, 5000 mol-
%) at 0 °C. A white precipitate was immediately formed and the
mixture was stirred for 5 min at rt. The solvent and the excess of HCl
were removed carefully under reduced pressure.
All other Catalyst HX salts were prepared in an analogous manner
except that for non-volatile acids, 110 mol-% of the corresponding acid
was used. The crystalline salts were grown using diffusion method from
a binary solvent mixture consisting of either cyclopentane, benzene or
toluene (1st component) and dichloromethane (2nd component).
Note: The 2D NOESY spectrum of both HCl salts were measured
with 500 MHz spectrometer at 30 °C (303 K). Both salts show some
instability after 24 hours in CD3CN. ent-1·HCl salt is only sparingly
soluble in CD3CN and as such the NMR sample was warmed up to 70
°C before the start of the measurement and then recooled to the probe
temperature (303 K).
6.48 (t, J = 8.2 Hz, 1H), 5.29 (brs, 1H), 4.93 (brs, 1H), 3.63 (m, 2H),
2.83 (m, 1H), 2.78 (s, 3H), 2.77 (s, 3H), 2.24 (m, 1H), 2.08 (m, 1H),
1.90 (m, 1H), 1.80 (m, 1H), 1.59 – 1.49 (m, 2H), 1.41 – 1.26 (m, 2H);
13C{1H} NMR (125 MHz, CD3CN): 182.8, 153.7, 149.3, 143.1, 140.1,
138.6, 132.4 (q, J = 32.9 Hz), 131.0, 129.6, 128.9, 128.7, 128.5, 128.4,
125.7 (q, J = 271.9), 126.3, 124.6, 124.5 (q, J = 272.0 Hz), 123.4 (q, J =
33.9 Hz) 119.9, 115.6, 112.6, 110.9, 84.2, 67.2, 63.2, 56.2, 42.9, 37.4,
36.2, 32.8, 25.1, 24.7, 23.3.
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(1R,2R)-2-(3-((1S,2S)-2-(2-(3-(3,5-
bis(trifluoromethyl)phenyl)ureido)-4-(trifluoromethyl)phenoxy)-2,3-
dihydro-1H-inden-1-yl)thioureido)-N,N-dimethylcyclohexan-1-
aminium chloride (ent-1 HCl)
1H NMR (500 MHz, CD3CN): 11.20 (s, 1H), 9.39 (s, 1H), 8.68 (s,
1H), 8.20 (s, 3H), 7.90 (br s, 1H), 7.59 (s, 1H), 7.38 – 7.28 (m, 4H),
7.24 (m, 1H), 6.78 (br s, 1H), 5.24 (m, 1H), 4.80 (m, 1H), 3.98 (m,
1H), 3.60 (dd, J1 = 15.5, 7.1 Hz, 1H), 2.90 (d, J = 3.7 Hz, 3H), 2.83 (m,
1H), 2.79 (d, J = 4.3 Hz, 3H), 1.88 (m, 1H), 1.65 (app. d, J = 11.9 Hz,
1H), 1.47 (m, 1H), 1.42 (m, 1H), 1.26 – 1.12 (m, 3H), 0.75 (m, 1H);
13C{1H} NMR (125 MHz, CD3CN): 183.1, 153.7, 149.0, 143.0, 139.5,
139.0, 132.6 (q, J = 32.9 Hz), 131.0, 129.9, 128.5, 126.2, 125.6 (q, J =
270.2 Hz), 125.1, 124.5 (q, J = 271.9 Hz,), 123.7 (q, J = 32.2 Hz),
120.1, 116.0, 115.7, 113.1, 110.9, 87.5, 67.4, 63.2, 56.1, 42.8, 37.8, 36.5,
32.9, 24.9, 24.7, 23.1.
Catalyst Solution Structure Elucidation. Catalyst 1 solution struc-
ture: The sample was prepared by dissolving catalyst 1 (10 mg, 0.0134
mmol, 100 mol %) in 0.6 mL DCM-d2. The 2D NOESY spectrum was
measured with 500 MHz spectrometer at 303 K. Catalyst 2 solution
structure: The sample was prepared by dissolving catalyst 2 (10 mg,
0.0134 mmol, 100 mol %) in 0.6 mL DCM-d2. The 2D NOESY spec-
trum was measured with 500 MHz spectrometer at 303 K.
Solution Structures of Catalysts Hexafluoroacetylacetonate salts.
The sample of catalyst 1 hfacac salt was prepared by dissolving catalyst
1 (10 mg, 0.0134 mmol, 100 mol %) in 0.6 mL DCM-d2 and hfacac
(1.9 μL, 0.0134 mmol, 100 mol %) was subsequently added. The 2D
NOESY spectrum was measured with 500 MHz spectrometer at 303 K.
The sample of catalyst 2 hfacac salt was prepared by using the
procedure used for the 1·hfacac salt. The 2D NOESY spectrum was
measured with 300 MHz spectrometer at 303 K.
Titration experiments. Titration of catalyst 1·hfacac with tetra-n-
butylammonium chloride (n-Bu4NCl): Catalyst 1 (11.2 mg, 0.015
mmol, 100 mol %) was dissolved in CD3CN (0.6 mL), hfacac (2.1 μL,
0.015 mmol, 100 mol %) was subsequently added and transferred to
NMR tube. This solution was titrated with 0.5M solution of n-Bu4NCl
1
in CD3CN. H NMR (300 MHz) measurement was performed every
30 minutes after the addition of n-Bu4NCl, insertion of the sample into
the magnet, and initial shimming and receiver gain adjustment. All
measurements were carried out at a probe temperature 303 K.
ASSOCIATED CONTENT
Supporting Information: Details of the X-ray structural
characterization, and computational details: total energies and
Cartesian coordinates for the considered stationary points. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Petri.Pihko@jyu.fi
(1R,2R)-2-(3-((1R,2R)-2-(2-(3-(3,5-
bis(trifluoromethyl)phenyl)ureido)-4-(trifluoromethyl)phenoxy)-2,3-
dihydro-1H-inden-1-yl)thioureido)-N,N-dimethylcyclohexan-1-
aminium chloride (2 HCl). 1H NMR (500 MHz, CD3CN): δ 11.10 (s,
1H), 9.28 (brs, 1H), 9.15 (s, 1H), 8.74 (s, 1H), 8.21 (s, 2H), 7.61 (br s,
ACKNOWLEDGMENT
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(d) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic
Financial support for this work was provided by the Academy of
Enantioselective Formation of C−C Bonds by Addition to Imines and
Hydrazones: A Ten-Year Update. Chem. Rev. 2011, 111, 2626–2704.
(9) Jones, C. R.; Pantoş, G. D.; Morrison, A. J.; Smith, M. D.
Plagiarizing Proteins: Enhancing Efficiency in Asymmetric Hydrogen-
Bonding Catalysis through Positive Cooperativity. Angew. Chem. Int. Ed.
2009, 48, 7391–7394.
Finland (grants 297874 and 307624) and the Hungarian Scientific
Research Fund (OTKA, grant K-112028). We thank Dr. Nicolas
Probst for earlier synthetic and mechanistic efforts.
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