An Atropisomerically Enforced Phosphoric Acid for Organocatalytic Asymmetric Reactions

Article abstract of DOI:10.1002/ejoc.201600296

Three BINOL-derived phosphoric acids exhibiting atropisomerism in the 3,3′-positions were obtained by Suzuki coupling reaction. The diastereomeric mixture was resolved by HPLC. Structural assignment was achieved by NOE-NMR analysis and by TD-DFT simulatio

Full text of DOI:10.1002/ejoc.201600296

DOI: 10.1002/ejoc.201600296
Full Paper
Organocatalysis
An Atropisomerically Enforced Phosphoric Acid for
Organocatalytic Asymmetric Reactions
Luca Bernardi,[a] Giada Bolzoni,[a] Mariafrancesca Fochi,[a] Michele Mancinelli,[a] and
Andrea Mazzanti*[a]
Dedicated to Professor Achille Umani Ronchi on the occasion of his 80th birthday
Abstract: Three BINOL-derived phosphoric acids exhibiting acid structures. All three catalysts were competent in promoting
atropisomerism in the 3,3′-positions were obtained by Suzuki the reactions, rendering excellent enantioselectivity (98 % ee) in
coupling reaction. The diastereomeric mixture was resolved by one case. The atropisomeric features at the 3,3′-position were
HPLC. Structural assignment was achieved by NOE-NMR analysis indeed found to influence the outcome of the reaction, demon-
and by TD-DFT simulation of the electronic circular dichroism strating the potential of atropisomeric conformational control
(ECD) spectra. The three atropisomeric catalysts were tested in at the 3,3′-position of the BINOL core in the rationalization of
three enantioselective reactions, comparing their ability to in- catalyst performances and in the design of new efficient struc-
duce enantioselectivity with related, well-known, phosphoric tures.
Introduction
phoric acid catalyst 4 features flat aromatic rings at the 3,3′-
positions, reminiscent of the 1-naphthyl derivative 3. However,
the arrangement of these rings and of the methyl substituents
The search for new atropisomeric systems and the related con-
formational analysis is still a broad field of research. On the
other hand, the development of new chiral Brønsted acids, and
in particular phosphoric acids,[1] is an area of great interest for
organocatalysis. Combining these two spheres of research, we
speculated on the preparation of a chiral Brønsted acid catalyst
with additional atropisomeric features. Many of the phosphoric
acids synthesized and applied so far derive from structural
modifications of BINOL featuring aryl substituents at the 3- and
3′-positions. The well-known and high-performing derivatives
1[2] and 2[3] are highly congested systems. Although the rota-
tion around the aryl–aryl bond is sterically hindered, it does not
produce additional chiral axes because of the local C2v symme-
try of tris-2,4,6-(isopropyl)phenyl and 9-anthracenyl moieties
(Figure 1). Dissymmetric but less hindered substituents such as
1-naphthyl in catalyst 3[4] give instead rapid interconversion at
ambient temperature, precluding the isolation of the single
atropisomers. Consequently, to develop atropisomerism, the
substituents linked to positions 3 and 3′ of the BINOL scaffold
should be both non-C2-symmetric at their point of insertion
and sufficiently hindered to prevent free rotation.[5] Our atten-
tion fell on 2-methylnaphthalene, which can be introduced by
using a standard Suzuki–Miyaura reaction. The resulting phos-
[a] Department of Industrial Chemistry “Toso Montanari”, University of
Bologna,
Viale Risorgimento 4, 40136 Bologna, Italy
E-mail: andrea.mazzanti@unibo.it
https://www.unibo.it/sitoweb/andrea.mazzanti
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600296.
Figure 1. Atropisomerically enforced chiral phosphoric acid catalysts 4.
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in phosphoric acid 4 is “frozen”; catalysts featuring these groups
pointing inwards and outwards relative to the catalophoric
phosphoric acid can be isolated and tested for catalytic per-
formance.
Table 1. Summary of the relative conformational energies of the three dia-
stereoisomers of 4 (relative energies in kcal/mol), calculated at the B3LYP/6-
31G(d) level of theory.
Diastereoisomer
Conf. 1
Conf. 2
Conf. 3
The local symmetry of the 2-methylnaphthyl moiety adds
two additional stereogenic axes to the BINOL scaffold when
the aryl–aryl rotation is frozen. The steric constrains of the 2-
methylnaphthyl ring mean that the rotational barrier should be
sufficiently high to produce atropisomers that are stable at and
above room temperature. From the point of view of aryl–aryl
rotation, the system is indeed a trisubstituted biaryl system,
and, compared with the BINOL scaffold (a tetrasubstituted bi-
aryl system), the rotational barrier of 2-methylnaphthyl should
be smaller, thus making the thermal interconversion of the at-
ropisomers through 2-methylnaphthyl rotation conceivable,
leaving unchanged the conformational chirality of BINOL.
From a stereochemical point of view, the presence of two
additional stereogenic axes should produce four diastereoiso-
mers. However, the two stereogenic axes between BINOL and
2-methylnaphthalene are mutually related by the C2 axis of the
BINOL, thus only three diastereoisomers are generated (Fig-
ure 2). They can be conveniently described by using the M/
P terminology[6] as (1) M,M,M, (2) M,P,P, and (3) M,P,M≡ M,M,P
(hereafter the bold descriptor is related to the stereogenic axis
of enantiopure M-BINOL).
M,P,P
M,M,P
M,M,M
0.83
0.70
0.71
1.10
0.88
0.68
0.06
0.00
0.01
to be the most stable, the relative energies are very similar and
a reliable prediction cannot be inferred. On the other hand, the
very similar energies forecast an equilibrium population in
which all three diastereoisomers should be populated with a
similar ratio.
Given the symmetry of the system, the rotational path of the
2-methylnaphthyl moieties may be modeled for only one of
them, the other being related by symmetry. Two different tran-
sition states have to be considered for the interconversion be-
tween the three atropisomeric structures. The first transition
state (TS) corresponds to the crossing of the 2-methyl group
over the OH (TS1, Figure 3, left), whereas the second TS corre-
sponds to a rotation of the 2-methyl over the hydrogen in posi-
tion 4 of the BINOL (TS2, Figure 3, right). DFT calculations run
at the B3LYP/6-31G(d) level suggest that TS1 has a lower energy
with respect to TS2 (29.4 and 31.0 kcal/mol, respectively). In
both cases, however, the suggested energy values should be
sufficiently high to develop stable atropisomers at and above
room temperature.
Figure 2. The three available diastereoisomers of the binaphthol precursor
6, optimized at the B3LYP/6-31G(d) level. Hydrogen atoms are omitted for
clarity.
Figure 3. The two available transition states for diasteromerization due to the
2-methylnaphthyl rotation.
Results and Discussion
Preparation
Before undertaking the synthetic preparation, computational
studies were performed to understand the relative stability of Compound 5 was obtained by using two different approaches
the conformers outlined in Figure 2, and to evaluate the theo- (Scheme 1), both based on the Suzuki–Miyaura coupling reac-
retical rotational barrier to assess a priori whether the condi- tion starting from (M)-2,2′-dimethoxy-1,1′-binaphthalene, which
tions for atropisomerism can be met. Binaphthol 6 (i.e., the pre- was treated with nBuli/TMEDA and then converted into (M)-
cursor of the target phosphoric acid 4, see Figure 2) was se- (2,2′-dimethoxy-[1,1′-binaphthalene]-3,3′-diyl)diboronic acid or
lected for computational analysis. The ground states for the (M)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthalene by reaction
three conformational diastereoisomers of 6 were optimized at with trimethylborate or iodine. The two intermediates were
the B3LYP/6-31G(d) level. The presence of the two OH groups then reacted with 2-bromo-1-methylnaphthalene (route A) or
in close proximity meant that more than one energy minimum 2-methylnaphthylboronic acid (route B) by using Pd(PPh3)4 as
was found for each diastereoisomer because of the different catalyst and Ba(OH)2 as the base in a dioxane/water (3:1) mix-
disposition of the two hydroxyl groups. These may assume ture.
three available dispositions (see the Supporting Information for
details), the energies of which are summarized in Table 1.
Good conversion by using the first procedure required the
use a large excess of the aromatic halide (10 equiv.) to reduce
Within each diastereoisomer, the most stable geometry cor- the amount of byproducts deriving from monocoupling fol-
responds to the same disposition of the OH pointing towards lowed by dehalogenation of the intermediate. The coupling re-
each other. Although the M,M,P diastereoisomer is calculated action occurred in about 18 h at 70 °C with 50–55 % yield. As
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peaks with the same molecular weight, corresponding to the
three diastereoisomers of 6. The HPLC traces reported in Fig-
ure 5 are relative to the pre-purified crude material of the de-
protected binaphthols 6a–c. The different ratio observed for the
two traces (54:38:8 vs. 46:42:12) suggests either that partial
equilibration occurred during the coupling reaction at higher
temperatures, or a different stereochemical outcome of the Suz-
uki coupling depending on the reagents combination.
Scheme 1.
a variation of the previous method, the coupling reaction be-
tween (M)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthalene and 2-
methylnaphthyl-boronic acid (4 equiv.) was conducted at reflux
(ca. 105 °C) for 6 h while maintaining a constant flow of nitro-
gen, with a 45–50 % yield in compound 5.
Figure 5. HPLC chromatograms of compound 6. Right: route A. Left: route B
(C18 column, see Exp. Sect. for details).
The 1H NMR spectrum of the crude material from the first
reaction showed four singlet signals in the methyl region, as
well as for the OMe signals (see Figure 4). Within each set of
signals, two had the same intensity whereas the remaining two
signals had different intensities (54:19:19:8 ratio). This is in
agreement with the presence of the three diastereoisomers 5a–
c. The two C2-symmetric diastereoisomers (M,M,M and M,P,P)
To gain more information about the thermal stability of the
two stereogenic axes, the first chromatographic peak was col-
lected from a semipreparative C18 column and the compound
was dissolved in C2D2Cl4 and kept at 100 °C in an oil bath. NMR
spectra were then collected at defined times to monitor the
conversion of the single diastereoisomer to the thermodynamic
mixture. NMR spectra confirmed that the first eluted peak corre-
sponds to one of the two C2-symmetric atropisomers (see next
section for the assignment), and a thermodynamic ratio of
25:50:25 was reached after 10 d at 100 °C (see the Supporting
Information).
1
display half of the signals both in the H and 13C NMR spectra.
In contrast, the asymmetric diastereoisomer exhibits different
signals for all hydrogen atoms because of its C1 symmetry. It
was therefore straightforward to assign the M,M,P diastereoiso-
mer 5b to the diastereoisomer showing two methyl signals with
the very same intensity.
Degradation byproducts were not observed during any of
the procedures. Given the complexity of the full kinetic treat-
ment of an equilibrium reaction with three exchanging species,
the reaction rate for interconversion of the pure compound into
the thermodynamic mixture was derived by using the kinetic
data at the beginning of the reaction with the simpler initial
rate approach. This method yielded
a rate constant of
2.7 × 10–6 s–1 at 100 °C, corresponding to ΔG≠ = 31.5 kcal/mol.
This barrier corresponds to a lifetime of more than 400 years at
ambient temperature, and it confirms the reliability of prelimi-
nary calculations. At the same time, the barrier is much lower
than that of BINOL (37 kcal/mol),[7] so the central stereogenic
axis can be preserved during thermal diastereoisomerization.
The ratio observed after thermal equilibration is rather differ-
ent from that observed in the crude reaction product. This sug-
Figure 4. 1H NMR spectrum of the diastereomeric mixture of 5 (25 °C,
600 MHz in CDCl3). The red dots indicate the C1-symmetric diastereoisomer
(M,M,P), whereas blue and green dots mark the two C2-symmetric diastereo-
isomers.
Several separation tests using reverse-phase C18 columns on gests that enantiopure M-BINOL drives both the first and the
HPLC apparatus showed that the separation of the atropiso- second coupling reactions mainly towards one of the three
meric mixture 5 was not achievable under such conditions. The diastereoisomers,[8] and the coupling conditions (6 h at 105 °C)
protecting OMe groups were therefore removed at this stage cannot bring the system to the thermodynamic equilibrium.
to increase the polarity of the compounds. The reaction with This phenomenon can be confirmed by the more unbalanced
BBr3 was conducted below 60 °C to avoid thermal equilibration ratio obtained when lower temperatures (70 °C, see first syn-
due to 2-methylnaphthyl rotation. Under these conditions, thetic route) were used during the cross-coupling reaction. The
good conversion in binaphthols 6a–c was obtained. HPLC anal- reaction can therefore provide a larger amount of the first
ysis on C18 stationary phase now showed three well-separated eluted diastereoisomer if the separation is carried out just after
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the reaction, or a larger amount of the second eluted atropiso-
mer if the purification is performed after thermal equilibration.
Structural Assignment
Whereas the assignment of the C1-symmetric M,M,P was
straightforward, NOE experiments were performed on the two
C2-symmetric diastereoisomers to assign their configuration. In
both compounds, some NOE effects can act as control signals
while additional NOEs can be used for diagnostic purposes.
On saturation of the 2-methyl signal, the H-4 on BINOL and
H-3′ on naphthalene must experience NOE enhancement due
to their proximity with the 2-methyl group in both diastereoiso-
mers. In contrast, in the case of the M,P,P diastereoisomer (for
which the two methyl groups point outward), an additional en-
hancement should also be observed for H-8; that is, the peri
hydrogen of the second ring of BINOL. Although both methyl
signals are simultaneously saturated because of their chemical
shift equivalence, the enhancement on H-8 remains diagnostic
because this hydrogen is far from the 2-methyl within the same
naphthol ring, but it is only 3.6 Å apart from the methyl bound
to the naphthalene of the other naphthol ring of BINOL (red
arrow in Figure 6).
Figure 7. DPFGSE-NOE spectra of the two C2 symmetric diastereoisomers of
6 on saturation of the 2-methyl signal.
Figure 6. 3D structures of the two C2-symmetric diastereoisomers of 6. Blue
arrows indicate control NOE, whereas the red arrow indicates the diagnostic
NOE.
The experimental NOE spectra[9] shown in Figure 7 con-
firmed that only in one case was the signal of H-8 observed on
saturation of the methyl signals, thus confirming the validity of
the theoretical approach.
Figure 8. ECD spectra of M-BINOL and of the three diastereoisomers of 6,
taken in acetonitrile.
In the most simple case of the M,P,M/M,M,P atropisomer 6b,
the two 2-methylnaphthalenes have opposite dihedral angle
with each naphthol ring of M-BINOL, and their exciton cou-
plings mainly compensate themselves. The resulting ECD spec-
trum is therefore due to the M-BINOL exciton coupling, yielding
an ECD trace very similar in terms of shape and intensity to that
of M-BINOL itself (red line in Figure 8).
These results allowed the assignment of the M,M,M configu-
ration to the first eluted diastereoisomer 6a, and the M,P,P con-
figuration to the third eluted diastereoisomer 6c, with the
M,P,M/M,M,P diastereoisomer 6b being the second eluted com-
pound. Electronic circular dichroism (ECD) spectra of the three
diastereoisomers were acquired in acetonitrile to further sup-
port the assignment based on NOE spectra (see Figure 8). For
the comprehension of the ECD spectra it should be taken into
When the two C2-symmetric diastereoisomers are consid-
account that they are dominated by the exciton couplings aris- ered, the exciton coupling of two external stereogenic axes are
ing from any pair of bonded naphthalenes. As a second note, governed by the C9Naph–C1Naph–C3BINOL–C2BINOL dihedral angle,
the exciton couplings are generated by the two dipoles on the whereas the central stereogenic axis of BINOL is defined by the
long axis of the naphthalenes; thus, they are related to the sign C2′–C1′–C1–C2 dihedral angle. As a consequence, when the
of the dihedral angle starting from the quaternary carbon in two naphthol rings have negative dihedral angle (M-BINOL con-
position 9 of the naphthalene, independent of whether this has figuration), the corresponding disposition of each naphthol ring
higher or lower CIP priority with respect to the carbon in posi- with 2-methylnaphthalene switches to a P configuration. The
tion 2.
ECD spectra of the two symmetric atropisomers should be con-
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sidered within this framework. In the case of the M,M,M dia- dure,[18] compounds 6a–c were treated with a concentrated so-
stereoisomer 6a, the two exciton couplings due to the external lution of POCl3 in anhydrous pyridine under nitrogen flow. The
stereogenic axes are positive and opposite to that of the central reaction was carried out at 60 °C until disappearance of the
axis, thus the ECD spectrum yields a positive exciton coupling starting compounds (16–20 h). The final phosphoric acids 4a–c
due to the subtraction of the negative M-BINOL exciton from were acidified with concentrated HCl at ambient temperature
1
the two positive excitons of 2-methylnaphthalene (blue trace in to remove all the salts, and fully characterized by means of H,
Figure 8). When the M,P,P atropisomer 6c is considered, the 13C, and 13P NMR spectroscopy.
three dihedral angles are all negative and the excitons sum up,
yielding a strong negative coupling.
Catalytic Tests
Given that the three stereogenic axes are not exactly equiva-
lent and the external dihedral angles could be different from Having at hand the three atropisomeric forms of the phosphoric
that of M-BINOL, the previous considerations could be thwarted acids 4a–c, we were eager to test their performances in promot-
by the different dipole disposition and absorption wavelength. ing catalytic enantioselective reactions. Catalyst 4a features a
To confirm the assignment, we performed TD-DFT simulations C2-symmetry with the methyl groups pointing towards the cata-
of the ECD spectra.[10] In the present case, the molecules are lytic center, which is reminiscent of the steric hindrance offered
very rigid and only one conformation must be considered.[11] by the large 2,6-isopropyl groups of catalyst 1 (Figure 1). In
The electronic excitation energies and rotational strengths were catalyst 4c, which is also C2-symmetric, the methyl groups point
calculated in the gas phase by using the geometries optimized outwards; the active center is thus closer to the flat aromatic
at the B3LYP/6-31G(d) level and using TD-DFT with four differ- rings of the naphthalene units. Such arrangement looks more
ent functionals to explore whether different theoretical models related to the 9-anthracenyl-substituted catalyst 2 (Figure 1).
provide different shapes of the simulated spectra. Simulations Catalyst 4b is not C2-symmetric; one methyl group points in-
were performed by using the hybrid functionals BH&HLYP[12] wards, the second one outwards. Based on our experience in
and M06-2X,[13] the long-range correlated ωB97XD,[14] which in- phosphoric acid catalysis[19] and considering these structural
cludes dispersion, and CAM-B3LYP,[15] which includes long- features, we initially selected two known asymmetric transfor-
range correction. All the simulations employed the 6- mations wherein catalysts 1 and 2 show contrasting behaviors,
311+G(d,p) basis set (Figure 9). In all cases, the ECD simulations and which we thought useful to compare the catalytic perform-
reproduce well the experimental spectra, thus confirming the ances of 4a–c with these phosphoric acid catalysts. We also
assignment made based on NMR spectroscopy.
included the “non-frozen” 1-naphthyl-substituted catalyst 3 for
this comparison.
We first studied the Povarov reaction[20] between the N-4-
methoxyphenyl aldimine 7 and 2-vinylindole 8 (Table 2).[19a] In
this reaction, the highly hindered catalyst 1 affords very good
enantioselectivity (entry 1), whereas the 9-anthracenyl deriva-
tive 2, bearing flat substituents, is less efficient (entry 2). The 1-
naphthyl-substituted catalyst 3 affords intermediate results (en-
try 3).
Table 2. Povarov reaction between imine 7 and 2-vinylindole 8 catalyzed by
4a–c, and comparison with catalysts 1–3.[a]
Figure 9. ECD spectra and TD-DFT simulations for M-BINOL and of the three
diastereoisomers of compound 6. The black trace corresponds to the experi-
mental spectrum in acetonitrile. The four colored lines are the TD-DFT simula-
tions obtained with four different functionals and the 6-311++G(2d,p) basis
set.
Entry
Catalyst
Conversion[b] [%]
ee[c] [%]
1[d]
2[d,e]
3
4
5
ent-1
ent-2
3
4a
4b
>90
88
65
72
68
61
98
66
81
91
77
84
Once separated and identified, compounds 6a–c needed to
be converted into phosphoric acids 4a–c to determine whether
they could be successfully applied in asymmetric synthesis with
good performance. Reported synthetic routes to obtain cata-
lysts 1[16] and 2[17] employ too drastic reaction temperatures
(ca. 100 °C for more than 24 h), at which the thermal stability
of the two stereogenic axes is not complete. It was therefore
necessary to use a synthetic method that operates at a temper-
ature not exceeding 60 °C. By following a reported proce-
6
4c
[a] Reaction conditions: imine 7 (0.025 mmol), catalyst 4 (0.0025 mmol,
10 mol-%), vinylindole 8 (0.0275 mmol), 3 Å MS, toluene, 45 °C, 3 h. [b] Deter-
mined by 1H NMR spectroscopic analysis after a plug on silica gel and evapo-
ration of the solvents. [c] Determined by CSP-HPLC analysis. [d] Refers to ent-
9. Data taken from ref.[19a] [e] Reaction performed at room temp. for 72 h, in
the absence of MS.
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We were very pleased to find that the three new catalysts improved to a more satisfactory 78 % ee by cooling the reaction
4a–c could all be used to promote this Povarov reaction, deliv- to 0 °C (entry 7).
ering the corresponding 1,2,3,4-tetrahydroquinoline 9 as a sin-
gle cis-diastereoisomer with moderate to good enantioselectivi-
ties (entries 4–6). All three catalysts derived from (M)-BINOL
yielded the (2S,4S)-9 as the major isomer. Given that the catalyst
ent-1 gave (2R,4R)-9 as the major product, this result indicates
that it is mainly the absolute configuration of the BINOL core
that controls the stereochemistry of the reaction, as expected.
The same holds true for the other catalytic reactions studied
(see below). More in detail, the C2-symmetric catalyst 4a, with
the methyl substituents pointing towards the phosphoric acid,
was found to be the most efficient; its superior behavior com-
pared with the 9-anthracenyl and 1-naphthyl derivatives 2 and
3 (entries 2 and 3) is remarkable, highlighting the importance
of the steric hindrance furnished by these methyl substituents.
However, even the other C2-symmetric catalyst 4c, with the
methyl groups pointing outwards, was found to be superior to
both 4b (one methyl inwards, one methyl outwards) and the 9-
anthracenyl catalyst 2.
We then moved to study the related vinylogous Povarov
reaction of the same aldimine 7 with 1-amidodiene 10
(Table 3).[17] According to our previous studies, this reaction is
somehow complementary to the previous one in terms of cata-
lyst requirements; catalyst 2 gives good enantioselectivity,
whereas both the more hindered phosphoric acid 1 and the
less substituted 3 afford very poor results (entries 1–3). The
results reported in Table 3 with the new catalysts 4a–c (en-
tries 4–6) show that all these three structures performed much
better than 1 and 3, although the results obtained were lower
than with the optimal 2.
Finally, we decided to test catalysts 4a–c in the Friedel–Crafts
addition of indole 13 to N-tosyl imine 12.[21] In this reaction,
unsubstituted 1-naphthyl groups at the 3,3′-positions of the
BINOL core were reported to be optimal, catalyst 3 giving better
results compared with 1 and 2 (Table 4, entries 1–3). Catalyst 3
has the same conformational features of 4a–c, but the three
diastereoisomers rapidly interconvert at ambient temperature,
so the observed enantioselectivity is the result of a weighted
average of the enantioselectivity of the three conformational
diastereoisomers. Nevertheless, also for this reaction, catalysts
4a–c performed rather well (entries 4–6), with the non-C2-sym-
metric catalyst 4b giving slightly better results than the two C2-
symmetric structures. Remarkably, all three catalysts furnished
the product with respectable ee values of >80 %; furthermore,
a reaction performed with catalyst 4a at lower temperatures
(–60 °C) showed that outstanding enantioselectivity in product
14 can be achieved (entry 7).
Table 4. Friedel–Crafts addition of indole 13 to N-tosylimine 12 catalyzed by
4a–c, and comparison with catalysts 1–3.[a]
Entry
Catalyst
Conversion[b] [%]
ee[c] [%]
1
2
1
2
ent-3
4a
4b
4c
4a
83
89
80
91
89
89
76
52
30
95
80
86
80
98
3[d]
4
5
Table 3. Povarov reaction between imine 7 and 1-amidodiene 10 catalyzed
by 4a–c, and comparison with catalysts 1–3.[a]
6
7[e]
[a] Reaction conditions: imine 12 (0.025 mmol), catalyst 4 (0.0025 mmol,
10 mol-%), indole 13 (0.125 mmol), toluene, 0 °C, 30–60 min. [b] Determined
by 1H NMR spectroscopic analysis after a plug on silica gel and evaporation
of the solvents. [c] Determined by CSP-HPLC analysis. [d] Refers to ent-14.
Data taken from ref.[21a] [e] Reaction performed at –60 °C.
Conclusions
Entry
Catalyst
Conversion [%][b]
ee [%][c]
1[d]
2[d]
3
4
5
1
2
3
4a
4b
4c
4b
72
59
60
79
83
56
80
13
92
32
55
67
60
78
Three BINOL-derived phosphoric acids exhibiting atropisomer-
ism in the 3,3′-positions were obtained by Suzuki coupling reac-
tion of BINOL intermediates with 2-methylnaphthylboronic acid
or 1-bromo-2-methylnaphthalene. The diastereomeric mixture
was resolved by HPLC and the results of kinetic studies demon-
strated that the coupling was stereoselective towards a C2-sym-
metric diastereoisomer 4a, whereas the equilibrium is shifted
towards the C1-symmetric diastereoisomer 4b. Structural as-
signment was achieved by NOE-NMR spectroscopic analysis and
by TD-DFT simulation of the ECD spectra.
6
7[e]
[a] Reaction conditions: imine 7 (0.025 mmol), catalyst 4 (0.00125 mmol,
5 mol-%), 1-amidodiene 10 (0.0375 mmol), 4 Å MS, toluene, room temp., 16–
24 h. [b] Determined by 1H NMR spectroscopic analysis after a plug on silica
gel and evaporation of the solvents. [c] Determined by CSP-HPLC analysis.
[d] Data taken from ref.[17] [e] Reaction performed at 0 °C.
The three atropisomeric phosphoric acids 4a–c were tested
As expected, catalyst 4c, with the planar rings pointing in- in three enantioselective reactions (two Povarov cycloaddition
wards, gave better enantioselectivity than 4a (methyl inwards). reactions and a Friedel–Crafts addition of indole), comparing
Somewhat surprisingly, in this case, the non-C2-symmetric 4b their ability to induce enantioselectivity with the related well-
gave the best enantioselection among the set of catalysts 4. known structures 1–3 (Figure 1). The results obtained can be
The enantioinduction offered by this catalyst could be readily summarized as follows:
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with a 36000 Hz spectral width, 5.5 μs (60° tip angle) pulse width,
1 s acquisition time, and 5 s delay time. A line broadening function
of 1–2 Hz was applied before the Fourier transformation. The as-
signment of the 13C NMR signals was achieved based on DEPT se-
quences. NOE spectra were obtained at 600 MHz by using the
DPFGSE sequence[9] and a 50 Hz selective pulse with a R-SNOB
shape.[28]
(1) All three catalysts 4a–c of the set can be used to promote
typical phosphoric acid catalyzed reactions of imines with mod-
erate to good enantioselectivities; in one case, 4b was found to
be extremely efficient (98 % ee).
(2) A moderate influence of atropisomerism at the 3- and 3′-
positions on the enantioinduction was observed. As expected,
catalyst 4a, featuring methyl groups pointing towards the ac-
tive phosphoric acid, performed better in a reaction in which
the highly hindered catalyst 1 had been previously found to
be optimal. Instead, rather surprisingly, the non-C2-symmetric
structure 4b (one methyl inward and one methyl outward) gave
better results both in a reaction usually performed with 9-an-
thracenyl-substituted catalyst 2, and in another transformation
in which the 1-naphthyl derivative 3 was the most enantio-
selective structure.
(3) Whereas the results obtained with the previous optimal cat-
alysts 1–3 in these reactions could not be reached by the new
structures 4a–c, it should be recognized that these new cata-
lysts feature some intermediate properties, rendering them
more “general” than structures 1–3. In other words, they were
able to afford moderately good results in all three reaction stud-
ied, whereas catalysts 1–3 were only competent in a single
transformation.
ECD spectra were recorded at 25 °C in far-UV HPLC-grade aceto-
nitrile solutions. The concentrations of the samples (ca. 10–4
M) were
tuned by dilution of a mother solution (1 × 10–3
M) to obtain a
maximum absorbance of approximately 0.8–0.9 in the UV spectrum
using a 0.2 cm path length. The spectra were recorded in the 190–
400 nm interval as the sum of 16 spectra. Reported Δε values are
expressed as L mol–1 cm–1
.
Ground-state optimizations and transition states were obtained by
DFT computations performed by the Gaussian 09 rev. D.01 series of
programs[29] using standard parameters. The calculations for
ground states and transition states employed the B3LYP hybrid HF-
DFT functional[30] and the 6-31G(d) basis set. The analysis of the
vibrational frequencies for the optimized structures showed the ab-
sence of imaginary frequencies for the ground states, and the pres-
ence of one imaginary frequency for each transition state. Visual
inspection of the corresponding normal mode validated the identi-
fication of the transition states. If not stated otherwise, the energy
values presented in the results and discussion section derive from
total electronic energies. The ECD spectra of M-BINOL and com-
pounds 6a–c were calculated by using TD-DFT with BH&HLYP, M06-
2X, ωB97XD, CAM-B3LYP and the 6-311++G(2d,p) basis set. 70 dis-
crete transitions were calculated for each conformation and the ECD
spectrum was obtained by convolution of Gaussian shaped lines
(0.5 eV line width). The simulated spectra resulting from the Boltz-
mann averaged sum of the conformations were redshifted by 6–
12 nm to get the best simulations of the experimental spectra.
Overall, the results demonstrate well the potential of atrop-
isomeric conformational control at the 3,3′-position of the BI-
NOL core in the rationalization of catalyst performances and in
the design of new efficient structures.
Experimental Section
General Methods and Materials: M-2,2′-Dimethoxy-1,1′-binaphth-
alene
and
M-(2,2′-dimethoxy-[1,1′-binaphthalene]-3,3′-diyl)di-
M-2,2′-Dimethoxy-3,3-di(2-methylnaphthyl)-1,1′-binaphthalene
(5a–5c). Route A: A mixture of M-(2,2′-dimethoxy-[1,1′-binaphthal-
ene]-3,3′-diyl)-diboronic acid (0.5 g, 1.25 mmol), under nitrogen
flux, were dissolved in a 3:1 mixture of dioxane/H2O. Then
Ba(OH)2·8H2O (2 g, 6.33 mmol), 1-bromo-2-metilnaphthalene
(2.84 g mL, 12.83 mmol) and Pd(PPh3)4 (0.057 g, 4 % mol/mol) were
added and the stirred solution was kept at 70 °C for 18–20 h. H2O
was then added and the solution was extracted three times with
boronic acid,[22] M-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthalene[23]
and 2-methylnaphthyl-boronic acid[24] were prepared as described
previously. Silica gel 60 Å F254 (Merck) for the TLC and silica gel
60 Å (230–400 mesh, Sigma Aldrich) for atmospheric pressure chro-
matography were employed as stationary phases for the chroma-
tography. Reactions that required anhydrous conditions were per-
formed under a dry nitrogen flow. The glassware used in these
reactions was placed in an oven at 100 °C for at least 3 h immedi-
ately before use. Semipreparative HPLC columns (Phenomenex C18
Kinetex® 250 × 20 mm, 5 μm) were used to purify the three dia-
stereoisomers of 6. Toluene was distilled from Na before use. N-4-
Methoxyphenyl imine 7 was obtained by heating to reflux an equi-
molar mixture of 4-methoxyaniline and benzaldehyde in EtOH for
1–2h,andcollectedbyfiltration.2-Vinyl-1H-indole8,[25]N-Cbz1-amino-
butadiene 10,[26] and N-tosylimine 12[27] were prepared according
to reported procedures. Racemic samples were prepared by using
diphenylphosphoric acid as catalyst. The absolute configuration of
the catalytic products 9, 11, and 14 was assigned by comparing
their elution order on CSP-HPLC by using the same stationary
phases and eluents as reported previously. The same enantiomer
was obtained in the three tested reactions when using 4a, 4b, or
4c as catalyst.
CH2Cl2. The organic layer was washed with 3
M HCl, dried (Na2SO4),
filtered through silica gel and concentrated under reduced pressure.
A pre-purification was achieved by chromatography on silica gel (n-
hexane/ethyl acetate, 9:1), yielding 0.4 g (54 %) of a mixture of the
three diastereoisomers 5a–c, that was used in the following step.
Route B: A mixture of M-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphth-
alene (0.56 g, 1.0 mmol) and 2-methylnaphthylboronic acid (0.74 g
4.0 mmol), were dissolved in a 3:1 mixture of dioxane/H2O under
nitrogen flux. Then Ba(OH)2·8H2O (2 g, 6.33 mmol), and Pd(PPh3)4
(0.046 g, 4 % mol/mol) were added and the stirred solution was
heated at 105 °C for 6 h. H2O was then added and the solution was
extracted three times with CH2Cl2. The organic layer was washed
with 3
M HCl, dried (Na2SO4), filtered through silica gel and concen-
trated under reduced pressure. A pre-purification was achieved by
chromatography on silica gel (n-hexane/ethyl acetate, 9:1), yielding
0.4 g (50 %) of a mixture of the three diastereoisomers 5a–c, that
was used in the following step.
NMR spectra were recorded with a spectrometer operating at a field
of 14.4 T (600 MHz for 1H, 150.8 for 13C) and at a field of 9.4 T
(161.9 MHz for 31P). Chemical shifts are given in ppm relative to the
internal standard tetramethylsilane (1H and 13C). 31P chemical shifts
are given relative to the external standard 85 % H3PO4. The 13C
NMR spectra were acquired under proton decoupling conditions
M-3,3-Bis(2-methylnaphthyl)-1,1′-binaphthalene-2,2-diol (6a–
c): Prepared from M-2,2′-dimethoxy-3,3-di(2-methylnaphthyl)-1,1′-
binaphthalene (5a–c) by following the procedure described previ-
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ously.[22] The crude reaction mixture was pre-purified on silica gel
126.6 (2CH), 127.4 (2CH), 127.7 (2CH), 127.8 (2CH), 128.3 (2CH),
(n-hexane/ethyl acetate, 8:2) yielding 304 mg of the diastereomeric 129.15 (2CH), 131.4 (2Cq), 131.6 (2Cq), 131.7 (d3J13C–31P = 3.3 Hz, 2Cq,
mixture of 6a–c (yield 80 %). The three diastereoisomers were than ), 132.3 (2Cq), 132.35 (2Cq), 132.6 (2Cq), 132.7 (2CH), 135.3 (2Cq),
2
isolated by semipreparative HPLC on Phenomenex® Kinetex C18 col-
145.9 (d, 2Cq, J13C–31P = 9.6 Hz) ppm. 31P NMR (161.9 MHz, CDCl3,
umn (250 × 20 mm, 5 μm; 20 mL/min; 254 nm UV detection; aceto- 25 °C): δ = 2.40 (bs) ppm.
nitrile/H2O, 85:15 v/v as eluent).
1
Compound 4b: H NMR (600 MHz, CDCl3, 25 °C): δ = 1.95 (s, 3 H),
Compound 6a: Retention time: 16.25 min. 1H NMR (600 MHz,
CD3CN, 25 °C): δ = 2.36 (s, 6 H), 6.19 (s, 2 H), 7.36–7.39 (m, 2 H),
7.39–7.45 (m, 4 H), 7.45–7.51 (m, 4 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.57–
7.61 (m, 2 H), 7.87 (s, 1 H), 7.92 (d, J = 8.3 Hz, 2 H), 7.93–7.96 (m, 4
H) ppm. 13C NMR (150.8 MHz, CD3CN, 25 °C): δ = 20.0 (2C3), 114.1
(2Cq), 123.8 (2CH), 124.2 (2CH), 125.1 (2CH), 125.6 (2CH), 126.35
(2CH), 126.9 (2CH), 127.9 (2CH), 128.0 (2CH), 128.2 (2CH), 128.8
(2CH), 128.9 (2Cq), 129.6 (2Cq), 131.5 (2CH), 132.3 (2Cq), 133.3 (2Cq),
133.8 (2Cq), 134.2 (2Cq), 135.0 (2Cq), 151.8 (2Cq) ppm. HRMS (ESI-
Orbitrap M-H): m/z calcd. for C42H29O2: 565.2173; found 565.2171.
2.18 (s, 3 H), 6.93 (d, J = 8.3 Hz, 1 HAr), 7.08 (d, J = 8.4 Hz, 1 HAr),
7.17 (t, J = 7.8 Hz, 1 HAr), 7.22 (t, J = 7.3 Hz, 2 HAr), 7.27 (d, J =
8.5 Hz, 1 HAr), 7.31 (t, J = 7.3 Hz, 1 HAr), 7.37 (d, J = 8.4 Hz, 1 HAr),
7.41 (d, J = 8.5 Hz, 1 HAr), 7.42–7.48 (m, 3 HAr), 7.53–7.61 (m, 5 HAr),
7.68 (d, J = 8.2 Hz, 1 HAr), 7.86 (s, 1 HAr), 7.90 (s, 1 HAr), 7.94 (d, J =
7.8 Hz, 1 HAr), 7.99 (d, J = 8.3 Hz, 1 HAr) ppm. 13C NMR (150.8 MHz,
3
CDCl3, 25 °C): δ = 21.15 (1CH3), 29.7 (1CH3), 122.2 (d, J13C–31P
=
2.23 Hz, 1Cq), 122.3 (d, 3J13C–31P = 2.2 Hz, 1Cq), 124.25, 124.5, 125.3,
125.4, 125.85, 125.9, 126.1, 126.35, 126.56, 126.61, 127.2, 127.3, 127.4,
127.74, 127.79, 127.86, 127.95, 128.3, 128.5, 128.9, 131.34, 131.46,
131.54, 131.56, 131.65, 131.87, 131.91, 131.93, 132.18, 132.22, 132.3,
Compound 6b: Retention time: 17.05 min. 1H NMR (600 MHz,
CD3CN, 25 °C): δ = 2.33 (s, 3 H), 2.40 (s, 3 H), 6.23 (s, 1 H), 6.25 (s, 1
H), 7.27–7.30 (m, 1 H), 7.34–7.43 (m, 6 H), 7.43–7.47 (m, 1 H), 7.47–
7.50 (m, 2 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.58–
7.61 (m, 1 H), 7.67 (d, J = 8.6 Hz, 1 H), 7.87 (s, 2 H), 7.90–7.96 (m, 6
H) ppm. 13C NMR (150.8 MHz, CD3CN, 25 °C): δ = 20.0 (1C3), 30.0
(1C3), 114.0 (1Cq), 114.1 (1Cq), 123.8 (1CH), 123.8 (1CH), 124.1 (1CH),
124.2 (1CH), 125.1 (2CH), 125.65 (1CH), 125.9 (1CH), 126.1 (1CH),
126.35 (1CH), 126.9 (1CH), 127.0 (1CH), 127.8 (1CH), 127.9 (1CH),
127.9 (1CH), 128.0 (1CH), 128.25 (1CH), 128.3 (1CH), 128.8 (1CH),
128.8 (1CH), 128.9 (1Cq), 128.9 (1Cq), 129.6 (1Cq), 129.6 (1Cq), 131.5
(1CH), 131.5 (1CH), 132.3 (1Cq), 132.3 (1Cq), 133.3 (2Cq), 133.9 (2Cq),
134.15 (1Cq), 134.2 (1Cq), 134.9 (1Cq), 135.0 (1Cq), 151.8 (1Cq), 151.9
(1Cq) ppm. HRMS (ESI-Orbitrap, M-H): m/z calcd. for C42H29O2:
565.2173; found 565.2170.
2
132.5, 132.75, 132.95, 134.5, 135.1, 145.7 (d, J13C–31P = 8.9 Hz, 1Cq),
145.9 (d, J13C–31P = 8.9 Hz, 1Cq) ppm. 31P NMR (161.9 MHz, CDCl3,
2
25 °C): δ = 2.20 (bs) ppm.
1
Compound 4c: H NMR (600 MHz, CDCl3, 25 °C): δ = 2.09 (s, 6 H),
7.14 (t, J = 7.5 Hz, 2 HAr), 7.19 (d, J = 8.5 Hz, 2 HAr), 7.41–7.28 (m,
6 HAr), 7.51–7.59 (m, 8 HAr), 7.88 (s, 2 HAr), 7.97 (d, J = 8.1 Hz, 2
HAr) ppm. 13C NMR (150.8 MHz, CDCl3, +25 °C): δ = 20.5 (2C3), 122.4
3
(d, J13C–31P = 2.2 Hz, 2Cq), 124.4 (2CH), 125.35 (2CH), 125.8 (2CH),
126.6 (2CH), 126.8 (2CH), 127.1 (2CH), 127.2 (2CH), 127.65 (2CH),
128.3 (2CH), 128.4 (2CH), 131.35 (2Cq), 131.7 (d3J13C–31P = 2.7 Hz,
2Cq, ), 131.8 (2Cq), 132.1 (2Cq), 132.3 (2Cq), 132.7 (2CH), 132.9 (2Cq),
2
134.65 (2Cq), 145.95 (d, J13C–31P = 9.1 Hz, 2Cq) ppm. 31P NMR
(161.9 MHz, CDCl3, 25 °C): δ = 2.07 (bs) ppm.
(2S,4S)-4-(1H-Indol-2-yl)-6-methoxy-2-phenyl-1,2,3,4-tetra-
hydroquinoline (9):[19a] To a flame-dried Schlenk tube equipped
with a magnetic stirring bar, 3 Å spherical-shaped molecular sieves
(ca. 70 mg) were added under a N2 atmosphere. The molecular
sieves were thermally activated under vacuum for 10 min and then
cooled to room temp. The Schlenk tube was backfilled with N2, then
aldimine 7 (5.3 mg, 0.025 mmol) was added, followed by catalyst 4
(1.5 mg, 0.0025 mmol, 10 mol-%) and anhydrous toluene (0.5 mL).
After heating to 45 °C, 2-vinylindole 8 (3.9 mg, 0.0275 mmol) was
added. The mixture was then stirred at the same temperature under
a N2 atmosphere. After 3 h, the reaction mixture was diluted with
CH2Cl2 and filtered through a plug of silica gel, and the plug was
washed with EtOAc (4 ×). After concentration of the solvents, the
residue was analyzed by 1H NMR spectroscopy to determine the
conversion of the reaction and the diastereomeric ratio of the cy-
cloadduct 9 (>9:1 in all cases). 1H NMR (300 MHz, CDCl3, 25 °C): δ =
2.31 (br. q, J = 11.7 Hz, 1 H), 2.41 (ddd, J = 13.2, 6.2, 2.7 Hz, 1 H),
3.59 (s, 3 H), 6.59 (br. s, 1 H), 6.67–6.72 (m, 1 H), 7.07–7.16 (m, 2 H),
7.22–7.26 (m, 1 H), 7.28–7.35 (m 1 H), 7.35–7.41 (m, 2 H), 7.44–7.49
(m, 2 H), 7.55–7.60 (m, 1 H), 7.89 (br. s, 1 H) ppm. CSP-HPLC (Daicel
Chiralcel® OD; n-hexane/isopropane, 80:20 v/v; 1 mL/min; room
temp.): tR = 15.9 (major), 18.9 (minor) min.
Compound 6c: Retention time: 17.75 min. 1H NMR (600 MHz,
CD3CN, 25 °C): δ = 2.41 (s, 6 H), 6.26 (s, 2 H), 7.27–7.34 (m, 4 H),
7.37–7.45 (m, 6 H), 7.57 (d, J = 8.4 Hz, 2 HAr), 7.64 (d, J = 8.4 Hz, 2
H), 7.87 (s, 2 H), 7.90–7.96 (m, 6 H) ppm. 13C NMR (150.8 MHz,
CD3CN, 25 °C): δ = 20.0 (2CH3), 114.0 (2Cq), 123.8 (2CH), 124.0 (2CH),
125.05 (2CH), 125.9 (2CH), 126.1 (2CH), 127.0 (2CH), 127.85 (2CH),
127.9 (2CH), 128.3 (2CH), 128.8 (2CH), 128.95 (2Cq), 129.6 (2Cq), 131.5
(2CH), 132.3 (2Cq), 133.3 (2Cq), 134.0 (2Cq), 134.1 (2Cq), 134.9 (2Cq),
151.9 (2Cq) ppm. HRMS (ESI-Orbitrap, M-H): m/z calcd. for C42H29O2:
565.2173; found 565.2169.
General Procedure for the Preparation of 4a–c:[18] To compound
6a–c ( 20 mg, 1 equiv., 0.035 mmol) dissolved in anhydrous pyr-
idine, POCl3 (3.4
M in pyridine, 0.16 mL, 0.54 mmol, 15 equiv.) was
slowly added under a positive nitrogen flux. The stirred mixture was
kept at 60 °C until disappearance of the starting compound (16–
20 h), then H2O (1 mL) was added and the mixture was stirred and
heated at 60 °C for an additional 3 h. HCl (3
added to the cooled solution and stirring was continued for 3 h.
The mixture was diluted with CH2Cl2, washed with HCl (3 , 3 ×
M, 1 mL) was then
M
20 mL) and then dried on Na2SO4. The crude material was purified
on silica gel (CH2Cl2 then gradient to CH2Cl2/CH3OH, 9:1) to give
compound 4a–c (yields 70–80 %). Spectroscopic characterization
Benzyl {(E)-2-[(2S,4R)-6-Methoxy-2-phenyl-1,2,3,4-tetrahydro-
quinolin-4-yl]vinyl}carbamate (11):[17] To a flame-dried Schlenk
tube equipped with a magnetic stirring bar, 4 Å powdered molec-
ular sieves (ca. 20 mg) were added under a N2 atmosphere. The
molecular sieves were thermally activated under vacuum for 5 min
was performed after stirring the pure compound in 3
M HCl for 1 h
followed by extraction with CH2Cl2 and drying on Na2SO4.
1
Compound 4a: H NMR (600 MHz, CDCl3, 25 °C): δ = 2.11 (s, 6 H),
6.96 (d, J = 7.9 Hz, 2 HAr), 7.22–7.29 (m, 4 HAr), 7.31–7.38 (m, 4 HAr), and then cooled to room temp. After backfilling the Schlenk tube
7.41–7.45 (m, 2 HAr), 7.53–7.60 (m, 4 HAr), 7.75 (d, J = 8.0 Hz, 2 HAr), with N2, aldimine 7 (5.3 mg, 0.025 mmol), catalyst 8 (0.8 mg,
7.87 (s, 2 HAr), 7.94 (d, J = 8.2 Hz, 2 HAr) ppm. 13C NMR (150.8 MHz, 0.00125 mmol, 5 mol-%), and toluene (100 μL) were added. The
3
CDCl3, 25 °C): δ = 21.0 (1CH3), 29.7 (1CH3), 122.2 (d, J13C–31P
=
mixture was stirred for 5 min, then diene 10 (7.6 mg, 0.0375 mmol)
2.3 Hz, 2Cq), 124.6 (2CH), 125.45 (2CH), 125.9 (2CH), 126.1 (2CH), was added. The mixture was stirred at room temp. under a N2 at-
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[7] E. P. Kyba, G. W. Gokel, F. De Jong, K. Koga, L. R. Sousa, M. G. Siegel, L.
Kaplan, D. Y. Sogah, D. J. Cram, J. Org. Chem. 1977, 42, 4173.
[8] For a review, see: P. Lloyd-Williams, E. Giralt, Chem. Soc. Rev. 2001, 30,
145.
[9] J. Stonehouse, P. Adell, J. Keeler, A. J. Shaka, J. Am. Chem. Soc. 1994, 116,
6037–6038.
[10] For reviews, see: a) G. Bringmann, T. Bruhn, K. Maksimenka, Y. Hember-
ger, Eur. J. Org. Chem. 2009, 2717; b) G. Pescitelli, L. Di Bari, N. Berova,
Chem. Soc. Rev. 2011, 40, 4603; c) A. Mazzanti, D. Casarini, WIREs Comput.
Mol. Sci. 2012, 2, 613.
mosphere. After 16–24 h, the reaction mixture was diluted with
CH2Cl2, filtered through a plug of silica gel, and the plug was
washed with Et2O (4 ×). After concentration of solvents, the residue
was analyzed by 1H NMR spectroscopy to determine the conversion
of the reaction and diastereomeric ratio of the cycloadduct 11 (>9:1
in all cases). Finally, the product 11 was purified by chromatography
on silica gel (petroleum ether/EtOAc, 9:1). 1H NMR (600 MHz, CDCl3,
25 °C): δ = 1.86 (q, J = 14.1 Hz, 1 H), 2.14–2.04 (m, 1 H), 3.68–3.59
(m, 1 H), 3.73 (s, 3 H), 3.80 (br. s, 1 H), 4.41 (d, J = 11.4 Hz,1 H), 4.90
(dd, J = 14.6, 10.3 Hz, 1 H), 5.15 (d, J = 12.8 Hz, 1 H), 5.18 (d, J =
12.8 Hz, 1 H), 6.50 (d, J = 9.1 Hz, 1 H), 6.54 (d, J = 10.1 Hz, 1 H), 6.65
(dd, J = 8.4, 2.9 Hz, 1 H), 6.76–6.68 (m, 2 H), 7.44–7.28 (m, 10 H) ppm.
CSP-HPLC (Phenomenex Lux® Cellulose-1; n-hexane/iPrOH, 70:30;
0.75 mL/min; room temp.): tR = 19.4 (major), 45.1 (minor) min.
[11] Being non-chromophoric, different disposition of the OH groups do not
modify the simulations to a large extent.
HF
[12] In Gaussian 09 the BH&HLYP functional has the form: 0.5*EX
+
LSDA
Becke88
LYP
0.5*EX
+ 0.5*ΔEX
+ EC .
[13] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215.
[14] J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10, 6615.
[15] T. Yanai, D. Tew, N. Handy, Chem. Phys. Lett. 2004, 393, 51.
[16] M. Klussmann, L. Ratjen, S. Hoffmann, V. Wakchaure, R. Goddard, B. List,
Synlett 2010, 14, 2189.
(S)-N-[(1H-Indol-3-yl)(phenyl)methyl]-4-methylbenzenesulfon-
amide (14):[21] In a flame-dried Schlenk tube equipped with a mag-
netic stirring bar, imine 12 (6.5 mg, 0.025 mmol) and catalyst 4
(1.5 mg, 0.0025 mmol, 10 mol-%) were dissolved in anhydrous tolu-
ene (100 μL) under a N2 atmosphere. After cooling the solution to
0 °C, indole 13 (15.0 mg, 0.125 mmol) was added. The reaction
mixture was stirred for 30–60 min at the same temperature under
N2, then diluted with CH2Cl2, and filtered through a plug of silica
gel. The plug was washed with EtOAc, and the solvent evaporated.
The residue was analyzed by 1H NMR spectroscopy to determine
the conversion of the reaction. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
2.34 (s, 3 H), 5.24 (d, J = 7.2 Hz, 1 H), 5.82 (d, J = 6.9 Hz, 1 H), 6.61
(d, J = 2.4 Hz, 1 H), 6.97 (t, J = 7.8 Hz, 1 H), 7.06 (d, J = 7.8 Hz, 2 H),
7.11–7.27 (m, 8 H), 7.53 (d, J = 8.4 Hz, 2 H), 8.02 (br., 1 H) ppm. CSP-
HPLC (Daicel Chiralcel® OD; n-hexane/2-propanol, 80:20 v/v; 1 mL/
min; λ = 254 nm; room temp.): tR = 27 (major), 16 (minor) min.
[17] L. Caruana, M. Fochi, S. Ranieri, A. Mazzanti, L. Bernardi, Chem. Commun.
2013, 49, 880.
[18] K. Shen, X. Liu, Y. Cai, L. Lin, X. Feng, Chem. Eur. J. 2009, 15, 6008–6014.
[19] a) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi, A. Ricci,
Chem. Commun. 2010, 46, 327; b) L. Bernardi, M. Comes-Franchini, M.
Fochi, V. Leo, A. Mazzanti, A. Ricci, Adv. Synth. Catal. 2010, 352, 3399; c)
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Received: March 11, 2016
Published Online: ■
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Organocatalysis
L. Bernardi, G. Bolzoni, M. Fochi,
M. Mancinelli, A. Mazzanti* ......... 1–10
An
Atropisomerically
Enforced
Phosphoric Acid for Organocatalytic
Asymmetric Reactions
Three atropisomeric phosphoric acids lent enantioselectivity (98 % ee), con-
for organocatalysis were obtained by firming the potential of atropisomeric
a single Suzuki coupling reaction, and conformational control at the 3,3′-po-
resolved by HPLC. All three catalysts sition of the BINOL core to infuence
could be used to promote organocata- catalyst performance.
lytic reactions, rendering up to excel-
DOI: 10.1002/ejoc.201600296
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim