Molecular Recognition and Cocrystallization of Methylated and Halogenated Fragments of Danicalipin A by Enantiopure Alleno-Acetylenic Cage Receptors

Article abstract of DOI:10.1021/jacs.9b13217

Enantiopure (P)₄- and (M)₄-configured alleno-acetylenic cage (AAC) receptors offer a highly defined interior for the complexation and structure elucidation of small molecule fragments of the stereochemically complex chlorosulfolipid danicalipin A. Solution (NMR), solid state (X-ray), and theoretical investigations of the formed host-guest complexes provide insight into the conformational preferences of 14 achiral and chiral derivatives of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic environment, extending previously reported studies in polar solvents. The conserved binding mode of the guests permits deciphering the effect of functional group replacements on Gibbs binding energies ΔG. A strong contribution of conformational energies toward the binding affinities is revealed, which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association. Enantioselective binding of chiral guests, with energetic differences ΔΔG_{293 K} up to 0.7 kcal mol^-1 between diastereoisomeric complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy ΔH but at the cost of a larger entropic penalty TΔS stemming from tighter binding.

Full text of DOI:10.1021/jacs.9b13217

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Article
Molecular Recognition and Cocrystallization of Methylated and
Halogenated Fragments of Danicalipin A by Enantiopure Alleno-
Acetylenic Cage Receptors
Cornelius Gropp, Stefan Fischer, Tamara Husch, Nils Trapp, Erick M. Carreira,*
and Franco̧ is Diederich*
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Supporting Information
ACCESS
ABSTRACT: Enantiopure (P)4- and (M)4-configured alleno-
acetylenic cage (AAC) receptors offer a highly defined interior
for the complexation and structure elucidation of small molecule
fragments of the stereochemically complex chlorosulfolipid
danicalipin A. Solution (NMR), solid state (X-ray), and theoretical
investigations of the formed host−guest complexes provide insight
into the conformational preferences of 14 achiral and chiral
derivatives of the danicalipin A chlorohydrin core in a confined,
mostly hydrophobic environment, extending previously reported
studies in polar solvents. The conserved binding mode of the
guests permits deciphering the effect of functional group
replacements on Gibbs binding energies ΔG. A strong contribution
of conformational energies toward the binding affinities is revealed,
which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association.
Enantioselective binding of chiral guests, with energetic differences ΔΔG293 K up to 0.7 kcal mol−1 between diastereoisomeric
complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that
the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy ΔH but at the cost of a larger entropic
penalty TΔS stemming from tighter binding.
structural attributes of the interior of the receptor resemble the
characteristic hydrophilic and hydrophobic domains of lipid
structures.2b
INTRODUCTION
■
The complexation and crystallization of small molecules in the
interior of receptor systems not only allow structure
elucidation of target molecules with atomic resolution but
also enable the study of intermolecular interactions and
conformational preferences of guests in confined chemical
space.1
Chlorosulfolipids are a class of marine membrane lipids that
have drawn wide attention from a synthetic perspective
because of the complex stereochemistry originating from
their polychlorinated backbone.6 Although little is known
about their biological activity, cell-based studies have
demonstrated their ability to compromise cell membranes,
presumably as a result of their discrete conformation adopted
in the lipophilic environment of the membrane.7 NMR
spectroscopic studies on chlorohydrin fragments of these
natural products have allowed detailed analysis of their
conformation and configuration in polar solvents.8 However,
scarce solubility of the chlorosulfolipids in apolar solvents has
In our previous studies, we identified enantiopure alleno-
acetylenic cage (AAC) receptors (P)4- and (M)4-1 as
privileged receptor systems to investigate the molecular
recognition and cocrystallization of small molecules−cyclo-
alkanes and tropane derivatives−containing both polar and
apolar functionalities (Figure 1A).2 The tertiary hydroxy
groups of the homochiral alleno-acetylenic arms of the
receptor establish a 4-fold hydrogen-bonding array in the
closed cage conformation.2a,3 Upon encapsulation of short-
chain alcohols, the 4-fold H-bonding array of the host is
expanded to incorporate the hydroxy group of the guest in
pentagonal and 4-fold and docking as well as hexagonal H-
bonding networks that close the cage.4 The lean, all-carbon
acetylenic backbone of the receptor forms a highly confined,
rather lipophilic cavity that facilitates dispersion and halogen-
bonding interactions with apolar domains of the guest.5 These
Received: December 8, 2019
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Alleno-acetylenic cage receptors, (P)4- and (M)4-1, offer a
well-defined, mostly lipophilic environment for the complex-
ation and conformational analysis of lipid fragments, together
with a fast readout both in solution by nuclear magnetic
resonance (NMR) and electronic circular dichroism (ECD)
spectroscopy as well as isothermal titration calorimetry (ITC)
and in the solid state by X-ray cocrystal structure analysis.
Complexation studies of chlorohydrin fragments with our AAC
model system give insight into the adopted conformation of
small molecule fragments of chlorosulfolipids in a more
hydrophobic environment (for isosurface calculations on the
host, see ref 2b).
Isosteric replacements of the functional groups, a widely
used strategy to optimize the biological activity of lead
candidates, allow for studying the contribution of dispersion
interactions, halogen-bonding, and dense packing to their
binding affinities.9,10 We present a series of 14 target molecules
with up to two stereogenic centers (Figure 1B). Of particular
interest is the effect of the functional group replacements on
the binding affinities and preferred conformations of the
complexed guests.
METHODOLOGY
■
The chiral guest molecules were synthesized as racemates (see
Supporting Information, Experimental Section S2). Structures
designated with a red diamond in Figure 1B were separated
into their respective enantiomers. The binding affinities of the
guests toward the enantiopure receptors were quantified in
solution through ECD spectroscopy and ITC.11 The solution-
state host−guest complexes were characterized by 1D and 2D
NMR spectroscopic studies. n-Octane was chosen as a weakly
competitive solvent for both techniques. Single crystal X-ray
Figure 1. A) (P)4-configured alleno-acetylenic cage (AAC) receptor 1
and C14-desulfated danicalipin A as lead structure. B) Summary of
guest molecules 2−12; structures are shown as racemates in the
Fischer projection. Starred C atoms are stereogenic centers; chiral
guests were synthesized as racemates. Structures designated with a red
diamond were separated into their enantiomers.
prevented their conformational analysis in a more hydrophobic
environment.
Figure 2. A) Binding constants (Ka) by ECD spectroscopic and ITC titrations with AAC (P)4-1 and guests 2−12 in n-octane at 293 K; for details,
see Supporting Information, Sections S3−S7. The overall error in Ka is estimated to be 20% (ΔG293 K 0.2 kcal mol−1). B) Single crystal X-ray
cocrystal structures of AAC (P)4-1 with guests 5, 9, (R*,S*)-7, and (R*,R*)-10; only one enantiomer of the guest is shown. CCDC numbers:
1914838; 1914840; 1914858; 1914842. The nature of the expanded H-bonding networks closing the cages is indicated. Corresponding X-ray
cocrystal structures with (M)4-1 are shown in the Supporting Information, Section S11.
B
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structures of 14 host−guest complexes give insight into the
binding mode and the adopted conformation of the complexed
guests in the solid state.12 Details are provided in the
Experimental Section of the Supporting Information (S1−
S12).
Packing coefficients of the host−guest complexes were
calculated based on the obtained X-ray cocrystal structures and
are provided in Section S4 of the Theoretical Section of the
Supporting Information.
All guest structures were optimized with the Perdew−
Burke−Ernzerhof density functional (PBE)13 in combination
with empirical D3 dispersion corrections (PBE-D3).14 We
chose a def2-TZVPP basis set15 for the PBE-D3 calculations.
Details on the theoretical methodology are provided in the
Theoretical Section of the Supporting Information (S1−S3).
Figure 3. Host-bound conformations extracted from the X-ray
cocrystal structures of AAC (P)4-1 with guest 5 (A) and of AACs
(P)4-1 and (M)4-1 with 9 (B). Relative occupancies of the
enantiomeric conformations of guest 9 complexed to (P)4- and
(M)4-1 are shown. CCDC numbers: 1914838; 1914840; 1914836.
other. The higher occupancy of one conformational
enantiomer (60:40 for (P)4-1 and 42:58 for (M)4-1, Figure
3B) indicates the preferential binding of one conformational
enantiomer over the other and exemplifies the highly
asymmetric environment of the cavity.17
RESULTS AND DISCUSSION
■
Our initial focus was to study the influence of the degree of
methyl substitution of the unfunctionalized n-butanol core (2−
6, 9) of danicalipin A on the binding affinity to the host
(additional methyl groups are highlighted in blue, Figure 1B),
exploring whether denser packing and optimized dispersion
interactions lead to an increase in association strength.9
While unfunctionalized n-butanol 2 did not show quantifi-
able association with the receptor, the introduction of a single
methyl group to the backbone, such as in primary alcohols 3
and (R/S)-4, induced a large increase in binding affinities to
ΔG293 K = −4.3 and −4.8 kcal mol−1, respectively (Figure 2A).
The addition of a second methyl group in positions 2 or 3 of
the n-butanol chain only slightly enhanced the binding strength
by ΔΔG293 K = −0.6 and −1.0 kcal mol−1 (guests 5 and (R/S)-
6, Figure 2A). 2,2,3-Trimethylbutan-1-ol 9, decorated with
three methyl groups, did not show further increase in
association strength but bound with comparable binding
affinity to guests 3 and (R/S)-4 (ΔG293 K = −5.1 kcal
mol−1). The strong initial rise in binding strength with
placement of one methyl group is remarkable, considering the
smaller influence of additional methyl groups toward the
association energies, despite denser packing of the ensemble
(see Section S4 of the Theoretical Section of the Supporting
Information).9
Variable temperature (VT) NMR spectroscopic binding
studies substantiated the binding mode of the aliphatic
alcohols also in solution. At 277 K, the two singlet 1H
resonances corresponding to the methyl groups of the host-
bound guest 9 are broad and upfield shifted to +0.19 and +0.73
ppm, respectively, compared to the free guest, indicating
shielding of the methyl groups by the acetylenic moieties (see
Supporting Information, Figure S49). At 238 K (Figure S50),
the methyl groups of the complexed guest are shifted to +0.21
and −0.36 ppm, and the two terminal methyl groups become
differentiable in the asymmetric environment of the host (two
1
doublets at +0.21 ppm). The splitting of the H resonances is
only observed for the host-bound guest (see Supporting
Information, Figures S49 and S50). In comparison, the
terminal methyl group of guest (R/S)-6 is shifted upfield
(−1.9 ppm at 218 K, see Supporting Information, Figure S47),
indicating close contact to the aromatic rings of the
resorcin[4]arene core of the receptor and a binding mode
comparable to guest 5.18
The isosteric replacement of the methyl groups in (R/S)-6
and 9 with Cl and Br leads to two diastereoisomeric sets of
enantiomers, the (R*,S*) and (R*,R*) configured halohydrins,
which correspond to the anti- and syn-addition products.
Compared to the Me-analogues, the Cl- and Br-containing
structures are able to undergo halogen-bonding interactions
with the alleno-acetylenic arms of the receptor.2b With the
halogenated fragments, we aimed to study the effects of
halogen replacements of the methyl groups on the bound
conformation of the guests and their influence on the binding
affinities through stronger interactions.
While (R*,S*)-7 showed comparable binding affinities to its
Me-analog (R/S)-6, its diastereoisomer (R*,R*)-7 gave
enhanced association strength with ΔG293 K = −6.6 kcal
mol−1 (ΔΔG293 K = −1.2 kcal mol−1 (R/S)-6 → (R*,R*)-7,
Figure 2A). A similar difference in binding energies between
the (R*,S*)- and the (R*,R*)-diastereoisomers was also
observed for bromohydrins 8. Compound (R*,S*)-8 gave
binding affinities of ΔG293 K = −6.6 kcal mol−1, while (R*,R*)-
8 bound by ΔΔG293 K = −1.1 kcal mol−1 stronger with ΔG293 K
= −7.6 kcal mol−1 (Figure 2A). The addition of another
methyl group to the backbone to optimize shape comple-
mentary and dispersion interactions did not result in an
increase in binding strength. (R*,S*)-10 and (R*,R*)-10 gave
comparable binding affinities to the receptor as (R*,S*)-8 and
The X-ray cocrystal structures of AAC (P)4-1 with molecules
5 and 9 show two different binding modes of the aliphatic
alcohols in the interior of the host (Figure 2B). 2,2-
Dimethylbutan-1-ol 5 is engaged in a 4-fold and docking
topology with the host, with the terminal methyl group
pointing toward the aromatic resorcin[4]arene core of the
receptor (average C−H···π distances of 3.8 Å).16 In this
binding mode, the terminal methyl group is anti-periplanar
relative to the CH2OH-functionality (Figure 3A). In contrast,
2,2,3-trimethylbutan-1-ol 9 forms a puckered pentagonal 5-fold
H-bonding network with the host (Figure 2B). The two
terminal methyl groups point toward the acetylenic function-
ality rather than the aromatic core (C−H···||| distances of 3.5−
3.8 Å), adopting an anti-periplanar and a gauche conformation
relative to the CH2OH group (Figure 3B). The increased
packing density and optimized dispersion interactions of guest
9 compared to guest 5 are presumably compensated by the
conformational energy resulting from the additional methyl
group, which explains the overall decrease in binding affinity
despite denser packing (Figure S131 of the Supporting
Information). Remarkably, the achiral guest 9 is complexed
in two chiral conformations, which are enantiomers of each
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(R*,R*)-8. This trend was already observed for the Me-
isosteres in the series and can be attributed to the
conformational energy resulting from the additional methyl
group. The replacement of one terminal methyl group in
(R*,S*)-8 and (R*,S*)-10 with a CF3-group resulted in a loss
of binding strength by ≈ 1 kcal mol−1 (ΔG293 K = −5.7 kcal
mol−1 for (R*,S*)-11 and (R*,S*)-12), indicating unfavorable
interactions of the F atoms with the electron-rich aromatic
rings and the alleno-acetylenes.19
the guest necessary to adopt the host-bound conformation.
The theoretically calculated conformations of the free guests in
gas and condensed phases (acetonitrile) are given in the
Supporting Information, Theoretical Section S1−S3. Exem-
plary J-based conformational analysis of the free guests
(R*,S*)-, (R*,R*)-7 and (R*,S*), (R*,R*)-8 in acetonitrile
is given in the Supporting Information, Section S10, Figure
S77. The preferred conformations of the uncomplexed guests
are compared to the host-bound conformations of the guests.
The replacement of the methyl groups in alcohol (R/S)-6
with Cl groups does not improve binding strength for the anti-
product (R*,S*)-7, whereas the syn-product yields increase in
binding strength by ΔΔG293 K = −1.2 kcal mol−1. This trend is
observed in the series of guests 7, 8, and 10, where syn-
products bind by ΔΔG293 K ≈ 1 kcal mol−1 stronger compared
to anti-products (Figure 4). This observation can be
rationalized by preferred conformations of uncomplexed
guest structures. Solution and theoretical studies demonstrate
that uncomplexed (R*,S*)-configured guests 7, 8, and 10
preferentially adopt conformations in which the halogens are
placed anti-periplanar to each other (Boltzmann populations
based on density functional theory calculation of 0.93, 0.95,
and 0.99, respectively; see also Table S41 in the Supporting
Information). Upon complexation to host, guests have to
undergo conformational changes from anti-periplanar to
gauche. In contrast, for uncomplexed (R*,R*)-configured
alcohols 7, 8, and 10, the gauche conformation becomes
significantly populated (Boltzmann populations of 0.65, 0.80,
and 0.78, respectively). We conclude that (R*,S*)-configured
alcohols 7, 8, and 10 have to undergo conformational changes
upon encapsulation while (R*,R*)-configured alcohols do not.
This is then likely reflected in generally higher association
constants of syn-products compared to their anti-analogues.
The results also show that replacement of Cl groups with Br
groups with conserved configuration yields an increase in
binding affinity of ΔΔG293 K ≈ 1 kcal mol−1, demonstrating
more effective halogen-bonding interactions of the higher
halides (Figure 4).20 Interestingly, the additional Me group at
C2, such as in structures (R*,S*)-10 and (R*,R*)-10, does not
lead to enhanced binding, despite denser packing of guests in
the interior of the host.9,21
Single crystal X-ray structures of (P)4-1⊃(R*,S*)-7 and
(P)4-1⊃(R*,R*)-10 are shown as an example for the
halohydrin series in Figure 2B. The crystallographic data of
all complexes of (P)4-1 and (M)4-1 with halohydrin guests is
given in the Supporting Information, Section S11. Structures of
(P)4-1⊃(R*,S*)-7 and (P)4-1⊃(R*,R*)-10 display hydroxy
groups of guests engaged in puckered pentagonal H-bonding
networks with OH-groups of the receptor. The halogen atom
at C2 on the n-butanol core points toward the acetylenic
moiety, with distances of 3.2−3.3 Å (C−X···|||). The second
halogen at C3 forms favorable C−X···π interactions with the
host resorcin[4]arene core (average C−X···π distances of 4.2−
4.4 Å). Generally, the distances between the methyl/halogen
and aromatic/acetylenic counterparts decrease along the series
Me → Cl → Br, consistent with some of the increase in
association strength observed in solution binding studies.
Noteworthy is the highly retained binding mode of guest
structures 7−10 in the interior of the host, where all halogens
are gauche to each other. All guests are crystallized as their
racemates; the enantiomeric pairs of the guest structures
generally bind in their mirror image gauche conformation
(Figure 2B and Supporting Information, Section S11).
High retention of the binding mode of guests inside the host
(for an overlay of the X-ray cocrystal structures, see the
Supporting Information Figure S87) allows drawing con-
clusions on the contribution of functional group replacements
toward their binding affinity. Figure 4 gives a summary of the
differences in binding affinities of the guests toward (P)4-1 as
measured by ITC.
The increase in binding strength upon the introduction of
halogens, thereby establishing directional halogen-bonding
interactions and reducing conformational costs for binding, is
also expressed in 1D and 2D NMR spectroscopic studies. With
increasing binding affinities of guests toward the receptor, the
complexes show slow exchange on the NMR time scale, further
enabling characterization of guests in the interior of the host
(see Supporting Information, Sections S8 and S9).
At slow exchange on the NMR time scale, formation of
diastereoisomeric complexes of enantiopure hosts, (P)4-1 or
(M)4-1, with chiral racemic guests results in two diastereoiso-
meric NMR resonances. The diagnostic splitting of 1D NMR
Figure 4. Schematic representation of the influence of functional
group replacement in structures 6−10. Differences in binding
affinities are given in kcal mol−1 and are derived from their ITC
association constants at 293 K.
1
signals−observed in the H, 13C, and 19F NMR traces−is
comparable to effects observed with chiral shift reagents. They
allow identification of the enantioselectivity of enantiopure
hosts toward chiral guests in solution (see Supporting
Information, Sections S8 and S9). In particular, the splitting
of the OH-bonding array resonance of the host enables a fast
and reliable readout of the enantioselectivities. In addition, the
relative occupancy of enantiomers inside the receptor in X-ray
cocrystal structures gives insight into enantioselectivities in the
Generally, binding affinities increase with establishment of
halogen-bonding interactions of respective halogens with
aromatic/acetylenic counterparts along the series Me → Cl
→ Br. It should, however, be noted that association modes of
guests are not only the result of H-bonding, halogen-bonding,
and dispersion interactions with interior walls of the receptor
but also are influenced by the conformational energy cost of
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solid state. The enantioselectivities observed in solution match
well with the ones observed in the solid state.
In order to demonstrate reliability of the diastereoisomeric
readout of host−guest complexes in solution, we separated
three of the stronger binding guests, namely (R*,S*)-8,
(R*,R*)-8, and (R*,R*)-10, into their respective enantiomers
(see Supporting Information, Section S2).
Figure 5A gives a summary of the differences in binding
affinities of enantiopure guests with (P)4-configured host 1 and
compares those to the diastereoisomeric ratios observed in
NMR and X-ray crystallographic analysis.
While the difference in binding affinity of (S,R)-8 and (R,S)-
8 is negligible (ΔΔG293 K = −0.1 kcal mol−1), inversion of a
single stereocenter to (S,S)-8 and (R,R)-8 results in
substantially higher enantioselectivity of ΔΔG293 K = −0.7
kcal mol−1. ITC results further show that the stronger binding
of one enantiomer results in a gain in enthalpy ΔH (−12.3 →
−13.3 kcal mol−1), however at the cost of a larger entropic
term TΔS (+4.8 → +5.2 kcal mol−1; see Tables S32 and S33).
This trend is also observed for guest 10, where enantiose-
lectivities between (S,S)-10 and (R,R)-10 amount to ΔΔG293 K
= −0.7 kcal mol−1 (ΔH = −12.6 → −14.3 kcal mol−1; TΔS =
+5.0 → +6.0 kcal mol−1; see Tables S36 and S37). This
emphasizes that stronger binding, accompanied by gain in
enthalpy, comes with an entropic penalty. Figure 5B gives an
overlay of 1H NMR spectroscopic traces of (P)4-1 with
racemic (R*,R*)-8 and the stronger binding (R,R)-8
1
enantiomer. Diagnostic splitting of the diastereoisomeric H
NMR spectroscopic resonances is only observed for the
racemic guest compound, allowing for the full characterization
of both diastereoisomeric complexes in solution.
Single crystal X-ray structure of (P)4-1 with both
enantiomers of (R*,R*)-8 (Figure 5C) substantiates the
difference in binding strength of the enantiomeric pair. The
stronger binding (R,R)-8 forms a puckered 5-fold H-bonding
array with the host. The Br-substituent in the 2-position forms
favorable C−Br···π interactions with the aromatic resorcin[4]-
arene core (average distances of 4.3 Å), while the second Br is
in close contact with the acetylenic moiety (C−Br···||| of 3.3 Å;
αXB = 160°). In comparison, the hydroxy group of the weaker
binding (S,S)-8 forms an energetically less favorable 4-fold and
docking topology with the H-bonding array of the host.4 The
Br-substituent in position 2 now forms C−Br···||| contacts of
3.7 Å (αXB = 140°), and the second Br interacts with the
aromatic core of the receptor (average distances of C−Br···π of
4.1 Å). These subtle differences in geometry, mainly of the
OH-array,4 of the two enantiomeric complexes result in
substantial differences in binding energy between the two
enantiomers of ΔΔG293 K = 0.7 kcal mol−1.
Figure 5. A) Association constants (Ka) and Gibbs binding energies
(ΔG293 K) obtained by ITC for the encapsulation of the enantiopure
guests by (P)4-1; the overall error in Ka is estimated to be 20%
(ΔG293 K 0.2 kcal mol−1); diastereoisomeric ratios are given for the
1HOH resonance of the host (600 MHz, at 277 K); relative
occupancies of the enantiomeric pairs are derived from the single
crystal X-ray structures (error margin of 5%). B) Overlay of the 600
1
MHz H NMR spectroscopic traces of (P)4-1 with the enantiopure
(R,R)-8 (1.5 equiv guest with 1 equiv bound to the host and 0.5 equiv
free in solution, top) and the racemic (R*,R*)-8 (3 equiv with 1 equiv
bound to the host and 2 equiv free in solution, signals correspond to
two sets of diastereoisomers of the host-bound guests and free guest
signals, bottom) in n-octane-d18 at 277 K. C) X-ray cocrystal
structures of (P)4-1 with racemic (R*,R*)-8. Distances are given in Å.
CCDC 1914842.
CONCLUSION
■
Enantiopure alleno-acetylenic cage receptors (P)4- and (M)4-1
offer well-defined, mostly lipophilic environments for complex-
ation of fragments of the natural product danicalipin A. Fast
readout of complexation in solution and solid state is presented
and allows, for the first time, a study of their conformation in a
more hydrophobic environment. Functional group replace-
ments on the core chlorohydrin fragment led to a series of 14
molecules with up to two stereogenic centers. The highly
retained binding mode of guest structures 7−10 in the host
interior gives insight into the influence of functional group
replacements toward the Gibbs binding energies of the
ensemble. Generally, binding strength increases along the
series Me → Cl → Br with the establishment and
strengthening of halogen-bonding contacts and with reduced
conformational energy costs. The syn-products (R*,R*) bind
by ΔΔG293 K ≈ 1 kcal mol−1 stronger compared to the anti-
products (R*,S*), which is a result of the conformational
energies associated with adopting the preferred host-bound
gauche conformation. The strongest binding affinities are
observed for the Br-derivatives (R*,R*)-8 and -10 with Gibbs
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binding energies of ΔG293 K = −7.6 and −7.5 kcal mol−1 (Kd =
2.1 μM and 2.6 μM), respectively. Denser packing and
optimized dispersion interactions in inclusion complexes did
not lead to higher binding affinities. Remarkably, achiral guest
9 is complexed in two chiral conformations with higher
occupancy of one conformational enantiomer, exemplifying the
highly asymmetric environment of the interior of the receptor.
The enantioselectivities of the enantiopure receptor toward
chiral guests were assessed in solution and solid state. The
diagnostic splitting of the diastereoisomeric OH-bonding array
resonances of the host upon complexation of chiral racemic
guests enables fast readout of enantioselectivities. Separation of
stronger binding guests into their respective enantiomers
demonstrated the reliability of this readout. The X-ray
cocrystal structures of (P)4-1 with (R,R)-8 and (S,S)-8
(68:32 relative occupancies) reveal subtle differences in
hydrogen-bonding, halogen-bonding, and dispersion interac-
tions between the two enantiomers that result in a difference in
Gibbs binding energy of up to ΔΔG293 K = 0.7 kcal mol−1.
Calorimetric studies (ITC) further show that the stronger
binding of one enantiomer is accompanied by an increase in
enthalpy ΔH but at the cost of a larger entropic penalty
stemming from tighter binding.
AUTHOR INFORMATION
Corresponding Authors
■
Erick M. Carreira − Laboratorium fur Organische Chemie,
̈
ETH Zurich, CH-8093 Zurich, Switzerland; orcid.org/
0000-0003-1472-490X; Email: carreira@org.chem.ethz.ch
Franco̧ is Diederich − Laboratorium fur Organische Chemie,
̈
ETH Zurich, CH-8093 Zurich, Switzerland; orcid.org/
0000-0003-1947-6327; Email: diederich@org.chem.ethz.ch
Authors
Cornelius Gropp − Laboratorium fu
Zurich, CH-8093 Zurich, Switzerland
Stefan Fischer − Laboratorium fur Organische Chemie, ETH
Zurich, CH-8093 Zurich, Switzerland
̈
r Organische Chemie, ETH
̈
Tamara Husch − Laboratorium fur Physikalische Chemie, ETH
Zurich, CH-8093 Zurich, Switzerland; Division of Chemistry
and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125, United States; orcid.org/0000-
0002-2880-2481
̈
Nils Trapp − Laboratorium fur Organische Chemie, ETH
Zurich, CH-8093 Zurich, Switzerland
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b13217
Funding
This fragment-based complexation study gives first insight
into preferred conformations of methylated and halogenated
structures in a more hydrophobic environment2b and comple-
ments the extensive conformational analysis studies of the free
fragments in polar solvents. Importantly, the AAC model
system exposes the influence of conformational energies and
preorganization toward binding affinities and allows drawing
the conclusion that denser packing of apolar side chains in the
complex does not necessarily result in higher association.
Finally, we wish to point out that this is one of the first detailed
host−guest complexation studies with neutral receptors and
neutral small acyclic guests.
C.G. was supported by the Studienstiftung des Deutschen
Volkes. We are grateful for the support by the ETH Research
Council (ETH-01 13-2) and the Swiss National Science
Foundation (SNF 200020_159802).
Notes
The authors declare no competing financial interest.
CCDC data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
ACKNOWLEDGMENTS
■
́
We thank Rene Arnold and Rainer Frankenstein for recording
NMR spectra, Michael Solar for recording single-crystal X-ray
structures, and Dr. Anatol Schwab for valuable comments on
the manuscript.
ASSOCIATED CONTENT
■
sı
* Supporting Information
REFERENCES
■
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b13217.
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