Anion-π Catalysts with Axial Chirality

Article abstract of DOI:10.1002/chem.201702672

The idea of anion-π catalysis is to stabilize anionic transition states by anion-π interactions on aromatic surfaces. For asymmetric anion-π catalysis, π-acidic surfaces have been surrounded with stereogenic centers. This manuscript introduces the first anion-π catalysts that operate with axial chirality. Bifunctional catalysts with tertiary amine bases next to π-acidic naphthalenediimide planes are equipped with a bulky aromatic substituent in the imide position to produce separable atropisomers. The addition of malonic acid half thioesters to enolate acceptors is used for evaluation. In the presence of a chiral axis, the selective acceleration of the disfavored but relevant enolate addition was much better than with point chirality, and enantioselectivity could be observed for the first time for this reaction with small-molecule anion-π catalysts. Enantioselectivity increased with the π acidity of the π surface, whereas the addition of stereogenic centers around the aromatic plane did not cause further improvements. These results identify axial chirality of the active aromatic plane generated by atropisomerism as an attractive strategy for asymmetric anion-π catalysis.

Full text of DOI:10.1002/chem.201702672

DOI: 10.1002/chem.201702672
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Supramolecular Chemistry |Hot Paper|
Anion-p Catalysts with Axial Chirality
[a]
Chao Wang and Stefan Matile*
Abstract: The idea of anion-p catalysis is to stabilize anionic
transition states by anion-p interactions on aromatic surfa-
ces. For asymmetric anion-p catalysis, p-acidic surfaces have
been surrounded with stereogenic centers. This manuscript
introduces the first anion-p catalysts that operate with axial
chirality. Bifunctional catalysts with tertiary amine bases next
to p-acidic naphthalenediimide planes are equipped with a
bulky aromatic substituent in the imide position to produce
separable atropisomers. The addition of malonic acid half
thioesters to enolate acceptors is used for evaluation. In the
presence of a chiral axis, the selective acceleration of the dis-
favored but relevant enolate addition was much better than
with point chirality, and enantioselectivity could be observed
for the first time for this reaction with small-molecule anion-
p catalysts. Enantioselectivity increased with the p acidity of
the p surface, whereas the addition of stereogenic centers
around the aromatic plane did not cause further improve-
ments. These results identify axial chirality of the active aro-
matic plane generated by atropisomerism as an attractive
strategy for asymmetric anion-p catalysis.
Introduction
Anion-p catalysis; that is, the stabilization of anionic transition
states and reactive intermediates on aromatic surfaces, was in-
[
1]
troduced explicitly in 2013. Since then, contributions from
[
2]
[3–8]
[9,10]
[11]
anion-p interactions to enolate,
enamine,
iminium,
[
12]
transamination and oxocarbenium chemistry have been re-
[
13]
ported. The delocalized nature of anion-p interactions has
2
Figure 1. Anion-p catalyst 2 with axial chirality (P enantiomer, R=SO -octyl),
been confirmed as particularly attractive to stabilize long-dis-
compared to previously reported anion-p catalyst 1 with point chirality.
[
11,13]
tance charge displacements in cascade processes,
the first
[
6,13]
anion-p enzymes have been prepared
sisted anion-p catalysis has been explored.
and electric-field-as-
7]
reogenic centers in the Leonard turn between aromatic surface
and amine base. The introduction of chiral sulfoxides as p-ac-
cepting substituents R in the core of the NDI at the edge of
the aromatic plane has failed so far because separation of the
[
For asymmetric anion-p catalysis, p-acidic aromatic surfaces
have been surrounded by stereogenic centers (Figure 1). Exam-
ples range from chiral sulfoxides right at the edge of the aro-
[4]
diastereomers by chiral HPLC was unsuccessful.
[
9,10]
matic plane
to fusion catalysts with classical motifs in orga-
However, chirality within rather than around aromatic planes
originates from chiral axes rather than from chiral points. This
axial chirality of aromatic planes is generated with atropisom-
ers. Atropisomerism results from hindered rotation around a
single bond of highly substituted biaryls and related com-
[
13]
nocatalysis from cinchona alkaloids. In 1, one of the most
studied anion-p catalysts, the p-acidic aromatic plane is provid-
[
14–16]
ed by a naphthalenediimide (NDI).
A tertiary amine base is
positioned in closest possible proximity to turn on anion-p in-
[15–22]
teractions as soon as proton transfer injects the negative
pounds.
Atropisomers with high enough barriers generate
[
4]
charge into the substrate (Figure 1). For asymmetric anion-p
catalysis, point chirality from stereogenic centers has been in-
stalled around the site of the reaction in 1, that is, the p-acidic
surface of the NDI. This includes the a carbon of the leucine
solubilizer on the imide opposite to the amine base and ste-
stable axial chirality and can be separated as enantiomers.
They are ubiquitous throughout chemistry. In medicinal
chemistry, atropisomers show different activity and selectivity,
[17]
and atropisomerism is exploited to improve drug efficiency.
Atropisomeric scaffolds are also widely distributed in natural
[18]
products and used in organic materials, molecular machines,
[
15,16,19]
models, probes, and so on.
As a result, atroposelective
[a] Dr. C. Wang, Prof. S. Matile
[20]
Department of Organic Chemistry
University of Geneva, Geneva (Switzerland)
E-mail: stefan.matile@unige.ch
synthesis has recently attracted much interest.
Moreover,
atropisomerism has been utilized in privileged chiral ligands
and catalyst structures such as BINAP or chiral phosphoric
Homepage: www.unige.ch/sciences/chiorg/matile
[21,22]
acids.
To achieve asymmetric catalysis on aromatic planes,
Supporting information, which includes full experimental details, and the
ORCID number(s) for the author(s) of this article can be found under
https://doi.org/10.1002/chem.201702672.
the introduction of this intrinsic axial chirality was thus most
promising. Axially chiral NDIs have been prepared previously in
Chem. Eur. J. 2017, 23, 1 – 7
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[
15,16]
several variations for different purposes.
Here, we report
design, synthesis, and evaluation of the first axially chiral
anion-p catalysts.
Results and Discussion
To introduce axial chirality to asymmetric anion-p catalysis, we
decided to replace the leucine solubilizer in bifunctional cata-
lyst 1 with the ortho substituted phenyl group in 2 (Figure 1).
The axial chirality in anion-p catalyst 2 is created by the sub-
stituents R in the core of the NDI as well as the hindered rota-
tion around the single bond that connects the NDI plane, the
site of the reaction, with the phenyl substituent in the imide
opposite to the amine base (Figure 1). This rotation is blocked
by the bulky pivaloyl (Piv) substituent in ortho position of this
phenyl group. The atropisomer shown in Figure 1 introduces
axial chirality with the absolute configuration P.
The substitution of the leucine in 1 with the ortho substitut-
ed phenyl in 2 turns the solubilizing alkyl group to reside
below the aromatic plane rather than at the periphery. This
central position of the bulky pivaloyl group was expected to
direct the other substituents to the other side of the aromatic
plane and thus structure the chiral space around at the site of
action on the p-acidic NDI surface somehow by remote con-
Scheme 1. [a] Separation on chiral HPLC (CHIRALPAK ID, 250ꢁ10 mm,
À1
Daicel, 4 mLmin and detection at labs =300 nm; (f )-3a: R =6–9 min, (f )-
1
t
2
3a: R
=17.5–20 min (CH
SiH, CH Cl , 86–90%.
t
=16–24 min (CH
2
Cl
2
/EtOAc 9:1); (f
1
)-3b: R
t
=16–17.5 min, (f
2
)-3b:
R
Et
t
2
Cl
2
/EtOAc 99:1). [b] 1. TFA, CH
2
Cl ; 2. CH O (aq), TFA,
2
2
3
2
2
[
4]
trol. Although better turns are available, the p surface and
the amine catalyst in 2 were connected with a simple achiral
[
4]
Leonard turn to isolate contributions from axial chirality from
any interference from point chirality.
Synthetic access to axially chiral anion-p catalysts has been
hindered so far by the failure to separate stereoisomers by
[
4]
chiral HPLC in the presence of a tertiary amine base. To solve
this problem, the stereoisomers should be separated before
the introduction of the tertiary amine. In NDIs 3, the tertiary
amine needed in the final catalyst 2 is kept on the level of a
Boc-protected primary amine (Scheme 1). NDIs 3a and 3b
with aryl or alkyl sulfides in the core were readily available by
adapting established synthetic routes (see Schemes S1 and S2
in the Supporting Information). Details on preparation and
characterization of all new compounds can be found in the
Supporting Information. The two enantiomers of 3a and 3b
appeared as very well separated peaks in the chiral HPLC
(Figure 2).
The circular dichroism (CD) spectra of the separated enantio-
mers were exact mirror images (Figure 2b). The maximum of
their first CD Cotton effect at lmax =505 nm coincided with the
absorption maximum. From this induced CD, it was not possi-
ble to assign their absolute configuration. The obtained pair of
enantiomers is thus described in the following as (f )-3 and (f )-
Figure 2. a) Analytical chiral HPLC of the mixture of (f
1
)-3a (R
=12.7 min, top), and the purified enantiomers (f )-3a (middle) and
)-3a (bottom). b) CD spectra of (f )-3a (solid) and (f )-3a (dashed). c) CD
)-4a (solid) and (f )-4a (dashed).
t
=4.4 min) and
(
(
f
f
2
)-3a (R
t
1
2
1
2
1
2
spectra of (f
1
2
3
, referring to fraction 1 and fraction 2 eluted from the chiral
HPLC under the specified conditions. They were stable at room
temperature. Racemization in DMF at 383 K occurred with t =
nation of the liberated primary amines with formaldehyde. The
50
2
.0 h (Figure S6 in the Supporting Information). The corre-
CD spectra of the obtained catalysts (f )-4 and (f )-4 remained
1
2
À5 À1
°
sponding k =9.5ꢁ10
s
calculated to a barrier of DG =
mirror images (Figure 2c). Preserved CD Cotton effects demon-
strated that the axial chirality remained intact during the intro-
duction of the tertiary amine. Further support of this conclu-
sion was obtained with sulfoxide instead of sulfide substitu-
ents in the NDI core (see below).
rac
À1
1
05 kJmol (Figure S7).
The pure enantiomers (f )-3 and (f )-3 were transformed into
1
2
the active catalysts (f )-4 and (f )-4 by removing the Boc pro-
tecting groups with TFA in CH Cl , followed by reductive ami-
1
2
2
2
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[
23]
The redox switch in the NDI core was turned on only for
(
f1)-3 because the preparation of the complementary set of
enantiomers from (f )-3 was considered redundant. Controlled
2
oxidation under routine conditions with ꢀ1 equivalent of
meta-chloroperbenzoic acid (mCPBA) per sulfide at À208C af-
forded sulfoxides 5 as a mixture of four diastereomers. The
four diastereomers were separable by chiral HPLC (Figures S1
and S2). With octylsulfoxides 5b, the circular dichroism (CD)
spectra of the fractions eluting second and third (i.e., (f )-5b
12
and (f )-5b) were almost perfect mirror images with strong
13
broad CD Cotton effects also at long wavelength, maximizing
around 450 nm (Figure 3b). Previous comparison with crystal
structures of other NDIs with two sulfoxides in the core have
shown that CD active isomers can be assigned to syn configu-
[
16]
ration.
With the SÀO bond oriented in plane toward the
naphthalene core, syn isomers have both alkyl tails on the
same side of the aromatic plane (Scheme 2). The nearly CD
silent anti isomers eluted as (f )-5b and (f )-5b (Scheme 2,
1
1
14
Figure 3b). The order of elution was the same also with aryl
substituents. The first and the last eluting diastereomers (f )-
11
5
a and (f )-5a were almost CD silent and therefore anti,
14
whereas (f )-5a and (f )-5a were CD active, that is, syn (Fig-
12
13
Figure 3. a) CD spectra of 5a in CH
2
Cl
2
separated into HPLC fractions f11 (red,
ure 3a). As already described for (f )-4, deprotection and reduc-
tive amination of both sets of diastereomeric pre-catalysts af-
1
anti), f12 (blue, syn), f13 (green, syn) and f14 (black, anti). b) CD spectra of f11
2
(red, anti), f12 (blue, syn), f13 (green, syn) and f14 (black, anti) for 5b in CH Cl .
2
forded complementary collection of catalysts (f )-6. The ab-
1
sence of detectable diastereomeric products provided compel-
ling evidence for the lack of axial epimerization during these
two steps.
The addition of malonic acid half thioester 8 to enolate ac-
ceptor 9 was selected to elaborate on asymmetric anion-p cat-
alysis on axially chiral p surfaces (Figure 4). This reaction is
emerging as a useful model to probe for anion-p catalysis. So
far, enantioselectivity has been achieved with conventional or-
Complete oxidation of precatalyst (f )-3 with excess mCPBA
1
gave precatalyst (f )-7 with two achiral sulfone acceptors in the
1
core (Scheme 2). Conversion into catalyst (f )-2 followed the
1
[24]
[6]
procedure introduced above.
ganocatalysts and anion-p enzymes but neither with small-
Scheme 2. [a] 1. 2.4 equiv mCPBA, CH
2
Cl
2
, À20 to À108C, 78%; 2. Separation on silica gel: (f11,12,14)-5b: R
f
(CH
2
Cl
2
/EtOAc 4:1): 0.20; (f13)-5b: R
=6.4–8.6 min, (f12)-
Cl , RT, 90%.
, 85–92%. Note, absolute configurations are unknown, stereoisomers are differentiated from their elution
f 2 2
(CH Cl /EtOAc
À1
4
:1): 0.10; and chiral HPLC: CHIRALPAK ID, 250ꢁ10 mm, Daicel, CH
2
Cl
2
/EtOAc 9:1, 4 mLmin and detection at labs =300 nm; (f11)-5b: R
t
5
b: R
t
=8.8–11.6 min, (f14)-5b: R
t
=15–24 min. Syn and anti configurations were assigned according to CD (Figure 3). [b] 10 equiv mCPBA, CH
SiH, CH Cl
2
2
[c] 1. TFA, CH
2
Cl ; 2. CH O (aq), TFA, Et
2
2
3
2
2
from HPLC.
Chem. Eur. J. 2017, 23, 1 – 7
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[
a]
Table 1. Catalyst characterization.
[
b]
[c]
[d]
[e]
Entry
Catalyst
Conditions
A/D
e.r.
1
2
3
4
5
6
7
8
9
(f
(f
1
)-4a (S)
)-4b (S)
CDCl
CDCl
CDCl
CDCl
CDCl
CDCl
CDCl
3
3
3
3
3
3
3
/[D
/[D
/[D
/[D
/[D
/[D
/[D
8
8
8
8
8
8
8
]THF 1:1
]THF 1:1
]THF 1:1
]THF 1:1
]THF 1:1
]THF 1:1
]THF 1:1
3.9
4.2
6.1
5.9
2.9
4.0
4.3
7.2
11.5
4.1
4.7
7.8
3.5
4.8
3.5
7.1
3.4
5.6
7.0
12.1
50:50
50:50
54:46
56:44
52:48
52:48
57:43
57:43
57:43
59:41
58:42
57:43
60:40
50:50
56:44
61:39
47:53
55:45
60:40
59:41
50:50
61:39
61:39
1
(f11)-6b (SO)
(f12)-6b (SO)
(f13)-6b (SO)
(f14)-6b (SO)
1 2
(f )-2b (SO )
Figure 4. Anion-p catalysts accelerate the addition (A) of 8 to 9, yielding 10,
and decelerate the intrinsically favored decarboxylation (D) of 8, yielding 11,
presumably by discriminating the planar reactive intermediate RI-A and tran-
sition state TS-A from the twisted TS-D on their p-acidic aromatic surface.
(f12)-6b (SO)
(f12)-6b (SO)
(f12)-6b (SO)
(f12)-6b (SO)
(f12)-6b (SO)
(f12)-6b (SO)
CD
2
Cl
2
TBME
C D
6 6
10
1
1
[D
8
]Toluene
/CDCl 1:1
1,3-DMB
1
1
2
3
C
6
F
6
3
[
3]
[4]
molecule anion-p catalysts, including NDI tweezers, NDIs,
[
5]
14
(f
1
)-4b (S)
1,3-DMB, 08C
1,3-DMB, 08C
1,3-DMB, 08C
1,3-DMB, 08C
1,3-DMB, 08C
1,3-DMB, 08C
TBME, 08C
TBME/CDCl
TBME/CDCl 1:1, 08C
3
TBME/CDCl 1:1, 08C
and PDIs with rigidified chiral Leonard turns, nor with elec-
1
1
5
6
(f11)-6b (SO)
(f12)-6b (SO)
(f )-6b (SO)
tric-field-assisted anion-p catalysis with NDIs on conducting
[
7]
solid surfaces. This failure contrasts sharply with excellent re-
sults reported for other reactions in asymmetric anion-p cata-
lysts, which overall proved competitive with conventional cata-
17
1
3
18
19
20
21
(f14)-6b (SO)
(f )-2b (SO
(f12)-6b (SO)
(f )-4b (S)
1
2
)
[
9–13]
lysts.
Moreover, this reaction is of central importance in
1
3
1:1, 08C
16.4
17.7
20.4
chemistry and biology. However, without enzymes, the forma-
22
2
(f )-6b (SO)
1
2
3
3
(f
1
)-2b (SO
2
)
tion of the chiral enolate addition product 10 (or A) is disfa-
[3–7]
vored, decarboxylation product 11 (or D) dominates instead.
[a] Reactions were conducted with 200 mm 8, 20 mol% catalyst and 2m
acceptor 9 at 208C if not indicated otherwise, and monitored by H NMR
spectroscopy. Total conversion (A+D) was always almost quantitative (>
9
refer to the oxidation level of the redox switch in the NDI core). [c] Differ-
ent conditions tested (TBME: tert-butyl methyl ether). [d] Chemoselectivi-
ty: yield of addition (10)/yield of decarboxylation (11). [e] Enantiomeric
ratio.
1
Under routine conditions, the intrinsic selectivity observed in
the presence of TEA and related base catalyst is A/D=0.7. Cat-
alyst 1 with a Leonard turn as in 2 and ethyl sulfides in the
0%). [b] Catalysts, see Schemes 1 and 2 for structures (S, SO, and SO
2
[
4]
core inverts this selectivity to A/D=1.9. Oxidation of the sul-
fide donor to sulfoxide and sulfone acceptors further increases
the selective acceleration of the disfavored but useful enolate
[
4]
addition to A/D=2.5 and A/D=2.8, respectively.
The axially chiral catalyst (f )-4a with phenylsulfide substitu-
1
ents in the core was evaluated first (Scheme 1). The obtained
A/D=3.9 (Table 1, entry 1) revealed that already at lowest p
acidity produced by sulfide donors, anion-p catalysts with axial
chirality selectively accelerate the disfavored but relevant eno-
late addition to an extent that has never been reached with
point chirality.
decrease in selectivity also under these highly optimized condi-
tions (Table 1, entries 21–23). Overall, these results indicated
that for anion-p catalysts with axial chirality, increasing p acidi-
ty is more important than additional point chirality at the edge
[4]
of the p surface, at least for “tortoise-and-hare” catalysis, that
is, the selective acceleration of the intrinsically disfavored reac-
tion.
In the aryl series, oxidation of sulfides 4a to sulfoxides 6a
and sulfones produced catalysts of increasingly poor solubility.
Replacement of the aryl sulfides with alkyl sulfides solved this
problem. The diastereomeric catalysts 6b with sulfoxides in
the core gave selectivities ranging from A/D=2.9 to A/D=6.1
With regard to enantioselectivity under routine conditions,
the sulfide catalyst (f )-4a afforded racemic product 10
1
(Figure 4, Table 1, entry 1). However, among the diastereomers
6b, the emergence of enantioselectivity could be observed
(Table 1, entries 3–6). Best enantiomeric ratios e.r.=56:44 for
sulfoxide diastereomer (f )-6b coincided with high A/D=5.9
(Table 1, entries 3–6). These significant differences, ranging
from the best to the worst, confirmed that the point chirality
at the edge of the p surface retains high importance also in
the presence of axial chirality in the catalysts. Further increase
of p acidity in catalyst 2b with sulfones did not improve the
selectivity (A/D=4.3) compared to that with sulfides 4b (A/
D=4.2, Table 1, entries 2, 7).
12
(Table 1, entry 4). Interestingly, further oxidized sulfone (f )-2b
1
without sulfur point chirality gave preserved e.r.=57:43
(Table 1, entry 7). Thus, the axial chirality is apparently domi-
nant in determining the enantioselectivity under these condi-
tions. Solvent screening afforded the highest enantioselectivity
e.r.=60:40 for sulfoxide (f )-6b in 1,3-dimethoxybenzene (1,3-
Modification of reaction conditions allowed us to increase
selectivities significantly. For instance, sulfoxide (f )-6b
12
DMB), albeit with low A/D=3.5 (Table 1, entry 13). Although
this chemoselectivity could be improved by using more p-
12
reached A/D=7.8 in C F /CDCl 1:1 and A/D=11.5 in tert-butyl
6
6
3
methyl ether (TBME) at 208C (Table 1, entries 12, 9). Best results
were obtained at low temperature. The highest selectivity A/
D=20.4 was observed for sulfone (f )-2b in TBME/CDCl 1:1 at
acidic sulfone catalyst (f )-2b under optimized conditions up
1
to A/D=20.4 (Table 1, entry 23), the enantioselectivity was
found difficult to surpass. Nevertheless, the most important
finding here is that the highest chemo- and enantioselectivities
1
3
0
8C (Table 1, entry 23). Reduction of the p acidity in the best
sulfoxide (f )-6b and in sulfide (f )-4b caused the respective
were obtained with sulfone catalyst (f )-2b without point chir-
12
1
1
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ality. These results supported the conclusion that, for asymmet-
ric anion-p catalysis, axial chirality is more important than
point chirality.
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[
5
8
Conclusion
Anion-p catalysis occurs on aromatic planes. To break the sym-
metry of these planes, axial chirality is required. For asymmet-
ric anion-p catalysis, axial chirality should thus be more effec-
tive than point chirality installed around the active aromatic
plane. This study, introducing the first anion-p catalysts with
axial chirality, provides direct experimental support for these
predictions. The synthetic strategy developed to realize axial
chirality also in the presence of tertiary amine catalysts is par-
ticularly valuable because it opens new perspectives to inte-
grate anion-p catalysts into more complex systems. Current in-
terest focuses on remote control of such advanced anion-p
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Manuscript received: June 9, 2017
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Version of record online: && &&, 0000
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ÝÝ These are not the final page numbers!

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FULL PAPER
Chiral planes: To stabilize anionic transi-
tion states by anion-p interactions on
aromatic surfaces stereoselectively, sym-
metry breaking of this active plane with
axial chirality is more powerful than the
accumulation of point chirality around
the same active plane.
&
Supramolecular Chemistry
C. Wang, S. Matile*
& – &&
&
Anion-p Catalysts with Axial Chirality
Chem. Eur. J. 2017, 23, 1 – 7
www.chemeurj.org
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ