Asymmetric anion-π catalysis of iminium/nitroaldol cascades to form cyclohexane rings with five stereogenic centers directly on π-acidic surfaces

Article abstract of DOI:10.1021/jacs.6b04936

Anion-π interactions have been introduced to catalysis only recently, and evidence for their significance is so far limited to one classical model reaction in enolate and enamine chemistry. In this report, asymmetric anion-π catalysis is achieved for the first time for a more demanding cascade process. The selected example affords six-membered carbocycles with five stereogenic centers in a single step from achiral and acyclic substrates. Rates, yields, turnover, diastereo- and enantioselectivity are comparable with conventional catalysts. Rates and stereoselectivity increase with the π-acidity of the new anion-π catalysts. Further support for operational anion-π interactions in catalysis is obtained from inhibition with nitrate. As part of the stereogenic cascade reaction, iminium chemistry and conjugate additions are added to the emerging repertoire of asymmetric anion-π catalysis.

Full text of DOI:10.1021/jacs.6b04936

Communication
pubs.acs.org/JACS
Asymmetric Anion−π Catalysis of Iminium/Nitroaldol Cascades To
Form Cyclohexane Rings with Five Stereogenic Centers Directly on
π‑Acidic Surfaces
Le Liu,† Yoann Cotelle,† Alyssa-Jennifer Avestro,†,‡,§ Naomi Sakai,† and Stefan Matile*,†
†Department of Organic Chemistry, University of Geneva, Geneva, Switzerland
‡Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
S
* Supporting Information
The reaction between enal 1 and dinitropropane 2 was
ABSTRACT: Anion−π interactions have been introduced
to catalysis only recently, and evidence for their
significance is so far limited to one classical model reaction
in enolate and enamine chemistry. In this report,
asymmetric anion−π catalysis is achieved for the first
time for a more demanding cascade process. The selected
example affords six-membered carbocycles with five
stereogenic centers in a single step from achiral and
acyclic substrates. Rates, yields, turnover, diastereo- and
enantioselectivity are comparable with conventional
catalysts. Rates and stereoselectivity increase with the π-
acidity of the new anion−π catalysts. Further support for
operational anion−π interactions in catalysis is obtained
from inhibition with nitrate. As part of the stereogenic
cascade reaction, iminium chemistry and conjugate
additions are added to the emerging repertoire of
asymmetric anion−π catalysis.
selected because it affords cyclohexane rings 3 with five
consecutive stereocenters in a cascade that covers iminium
chemistry, conjugate additions, and Henry reactions (Figure
1a).13 To catalyze this process on π-acidic surfaces, trifunctional
systems 4−9 and bifunctional controls 10 and 11 were
designed and synthesized (Figure 1b). They all contain a
trans-cyclohexyldiamine as a rigidified Leonard turn14 that
places a tertiary amine13 next to the π-acidic surface of a
naphthalenediimide15 (NDI). These turns have been intro-
he integration of unorthodox noncovalent interactions
1
Tinto functional systems is of fundamental importance.
Current interest focuses on anion−π interactions1−4 and σ−
hole interactions2 such as halogen bonds,5 the underrecognized
counterparts of cation−π interactions6 and hydrogen bonds,
respectively. With regard to catalysis, halogen bonds receive
much attention,1,7 whereas the formal introduction of anion−π
interactions has been only as recent as 2013.8 Explicitly realized
examples, with evidence for increasing activity with increasing
π-acidity, reach from the initial Kemp elimination8 to more
relevant model reactions for enolate9 and asymmetric enamine
chemistry.10 Contributions from anion−π interactions have also
been suggested to operate in catalysts for asymmetric Henry
reactions11 and anion-binding catalysis.12 The general idea with
anion−π catalysis is to stabilize anionic reactive intermediates
and transition states on the π-acidic surface of electron-deficient
aromatic systems with positive quadrupole moments.8−10 This
concept is complementary to the conventional stabilization of
cationic intermediates on π-basic surfaces, known from
biosynthesis and increasingly implemented in organocataly-
sis.1,6 In this report, the scope of anion−π catalysis is expanded
to more demanding cascade processes that include also
reactions that are new to the topic (iminium chemistry, etc.),
stereoselectivities beyond the limits of conventional catalysts,
and selective anion−π inhibition.
Figure 1. (a) Cascade reaction catalyzed by (b) anion−π systems 4−
11, with notional transition states TS1 (in schematic side view (c) and
full structure (d)) and TS2 (e). Blue areas highlight π-acidic surfaces
and possible contributions of anion−π interactions to TS stabilization
(and iminium cations, c). Compound 6 is a mixture of sulfoxide
stereo- and regioisomers concerning the position of R. In 9, (S,S)-
instead of (R,R)-cyclohexyldiamine was used to attach the proline (the
stereochemistry of trans-cyclohexyldiamine did not influence the
catalytic activity significantly19).
Received: May 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b04936
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
duced as powerful tools to run reactions on aromatic surfaces
and enable also weak aromatic interactions to contribute to
catalysis.14
reactive intermediates.21,22 Performances in benzene were
indeed slightly better than in toluene (Table 1, entry 5 vs 6).
Clearly lower enantioselectivity obtained in the π-basic 1,3-
DMB compared to benzene indicated that the eventual
formation of aromatic donor−acceptor complexes23 with the
central π-surface hinders rather than helps asymmetric anion−π
catalysis (Table 1, entry 7). Although still slightly π-basic, π−π
stacking with complementary, electron-deficient nitrobenzene
could further increase the electron deficiency of the central π-
surface and thus enhance anion−π catalysis. The highest yield,
diastereoselectivity, and enantioselectivity obtained with
catalyst 7 in nitrobenzene were in agreement with these
expectations (Table 1, entry 9). Because of poor solubility of
the catalysts, the π-acidic hexafluorobenzene22 could only be
tested with chloroform as a cosolvent. Nevertheless, the
obtained results, comparable to those in nitrobenzene, could
be considered as further support of the above-mentioned
hypothesis (Table 1, entry 8).
Substitution of the phenyl sulfides in the NDI core of catalyst
7 by ethyl sulfides in catalyst 4 clearly reduced activity in
nitrobenzene, particularly with regard to enantioselectivity (Δee
= −18%, Figure 1, Table 1, entry 9 vs 10). The same trends
were observed in other solvents. These changes suggested that
peripheral crowding at the edge of the π-surface contributes to
stereoselectivity of the anion−π catalyst. The slight increase in
π-acidity by −40 meV of LUMO energy level20 from ethyl
sulfides in 4 to phenyl sulfides in 7 was too small to account for
Δee = +18%. More significant increases in π-acidity in catalyst 5
without core substituents (−90 meV vs 4)20 and catalyst 6 with
one ethyl sulfide and one ethyl sulfoxide in the core (−170
meV vs 4)20 caused less significant increases in enantiose-
lectivity (Δee = +3%, +13%, Table 1, entries 13, 14 vs 10,
Figures 1, 2b). With increasing π-acidity in this series 4−6, the
rate of the reaction increased as well. An almost linear
correlation was found between the half-life of the substrate and
the LUMO energy of the NDI in catalysts 4−6 (Figure 2a).
The coincidence of increasing π-acidity, rate (Figure 2a), and
enantioselectivity (Figure 2b) provided compelling1,6,8−10,14
Contrary to enamine chemistry,16 cationic iminium chem-
istry13,17 should be destabilized rather than stabilized on π-
acidic surfaces. In 4−10, a proline is positioned quite far from
the π-acidic surface to avoid such cation−π repulsion. Within
this electron-deficient “LUMO space,” substrate 2 should
become deprotonated, producing a π-acid-stabilized nitronate
intermediate that is ready to undergo a conjugate addition to
the iminium cation (Figure 1d). The resulting electron
acceptor−donor−acceptor triad in transition state 1 (TS1) is
a possibly general motif obtained by intriguing “LUMO
tweezers” (Figure 1c). Conjugate addition is followed by the
hydrolysis of the enamine and the formation of another π-
stabilized nitronate anion before the intramolecular Henry
reaction11,18 outlined in TS2 takes place (Figure 1e). This
cyclization, perhaps stabilized by oxyanion−π interactions and
possible hydrogen bonding to the amide hydrogen, affords
product 3.
Catalysts 4−11 were accessible in a few steps from
commercially available starting materials. Details of their
syntheses can be found in the Supporting Information (SI).19
The initial evaluation was performed with catalyst 7. This
catalyst carries two phenylsulfide substituents in the NDI core
to increase π-acidity relative to ethylsulfides20 and maximize
stereoselectivity by peripheral crowding at the edge of the
central π-surface.21
In the presence of 7, the reaction between enal 1 and
dinitropropane 2 afforded cyclohexane 3 in good yield and
stereoselectivity in all solvents except the more polar mixtures
of CDCl3 and CD3OD (Table 1, entries 1−9). Aromatic
solvents were particularly interesting because of eventual
interactions with the π-acidic surface in catalyst 7 and the
a
Table 1. Screening of Catalysts and Solvents
b
c
d
e
f
cat.
solvents
CD2Cl2
CD3CN
η (%)
dr
ee (%)
1
7
7
7
7
7
7
7
7
7
4
4
4
5
6
8
9
80
72
0
61:21:18
50:20:30
−
50
39
−
2
3
CDCl3/CD3OD 1:1
CDCl3
4
78
60
74
81
86
90
84
84
82
87
83
88
91
0
57:27:16
59:18:23
59:15:26
61:18:21
62:25:13
63:19:18
56:20:24
56:20:24
53:25:22
61:18:21
56:15:29
69:12:19
65:14:21
−
50
47
50
37
48
58
40
48
30
43
53
67
70
−
5
Toluene
6
Benzene
7
1,3-DMB
8
C6F6/CDCl3 1:1
Nitrobenzene
Nitrobenzene
C6F6/CDCl3 1:1
Benzene
9
10
11
12
13
14
15
16
17
18
Nitrobenzene
Nitrobenzene
Nitrobenzene
Nitrobenzene
Nitrobenzene
Nitrobenzene
g
10
12 + 13
81
60:21:19
−46
a
b
With 1.0 M 1, 0.5 M 2, 20 mol % catalyst. Catalysts (Figures 1, 2).
c
d
Solvents: DMB = Dimethoxybenzene. Total yield of 3 determined
by NMR after consumption of 2 (48−60 h (4−10), 96 h (12 + 13)).
Figure 2. Dependence of (a) substrate half-life time (t50) and (b) ee on
the π-acidity of catalysts 4−6 (indicated as LUMO energy of the
NDIs20). (c) Total yield η after 48 h (7) or 96 h (12 + 13) and (d) ee
of 3A obtained with 7 (left) and 12 + 13 (right) as a function of the
concentration of Bu4NNO3 (− = 0 M, + = 2.5 M, + + = 5.0 M). (e)
Structure of controls 12, 13 and intermediate RI1.
e
Diastereomeric ratio of three major isomers 3A/3B/3C (Figure 1).
f
Enantiomeric excess for 3A; negative ee’s indicate preference for the
g
opposite enantiomer of 3A. Mixture of sulfoxide stereo- and
regioisomers concerning the position of R.
B
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Communication
a
corroboration that anion−π interactions contribute to not only
catalysis but also enantioselectivity, i.e. asymmetric catalysis.
Further improvements in catalyst design could be achieved
by replacing the acyclic amine in 7 with a cyclic one in 8
(Figure 1). An ee = 67% was the result, together with the
highest diastereoselectivity observed for this reaction (Table 1,
entry 15). Maximized peripheral crowding in three dimensions
with adamantyl sulfides at the edge of the π-surface in 9 gave ee
= 70%, the best enantioselectivity of the series (Table 1, entry
16). These trends are particularly important because they
provide clear guidelines toward further improving asymmetric
anion−π catalysis.
The bifunctional catalyst 10 without tertiary amine was
inactive (Table 1, entry 17). This control was also important to
confirm that the cascade reaction occurs between the proline
and the tertiary amine in the trifunctional catalysts 4−9, that is
on the π-acidic surface.
The original mix of Jørgensen−Hayashi catalyst 12 and
DABCO (13) as an additional amine base has been reported to
give, at best, 90% ee and dr = 57:29:14 in CH2Cl2.13 However,
under conditions optimized for anion−π catalyst 7, this
noncovalent system 12 + 13 did not perform equally well
(Figure 2e, Table 1, entry 18). In nitrobenzene, the best ee =
70% obtained with anion−π catalysts, i.e., the overcrowded
adamantylsulfides 9, was Δee = +24% better than the
conventional system 12 + 13 with ee = −46% (Table 1, entry
16 vs 18). Interestingly, the absolute configuration of the main
diastereomer 3A obtained with anion−π catalysts 4−9 and
Jørgensen’s system 12 + 13 was opposite. Thus, with anion−π
catalysts the stereodetermining nitronate addition occurs from
the more hindered side of the proline fragment due to the
stabilization of the nitronate by the π-acidic surface (Figure 1d).
In the conventional system 12, this more hindered side of the
pyrrolidine ring is shielded in intermediate RI1, and the
conjugate addition occurs from the less hindered side of the
heterocycle (Figure 2e). The diastereoselectivity of anion−π
catalysts, best with dr = 69:12:19 for 8, is clearly beyond the
values reported for the conventional system 12 + 13 (Table 1,
entry 15 vs 18).
Table 2. Catalyst Inhibition and Comparative Evaluation
b
c
d
e
f
g
cat.
mol %
additive
η (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
7
7
7
7
20
5
90
89
10
46
81
74
77
79
80
63:19:18
63:13:24
53:23:24
nd
58
58
−
20
20
20
5
NO3
44
−
PF6
nd
12 + 13
12 + 13
12 + 13
12 + 11
10 + 13
60:21:19
58:24:18
62:16:22
48:25:27
53:24:23
−46
−39
−3
−54
38
−
20
20
20
NO3
a
Standard conditions: 1.0 M 1, 0.5 M 2, catalyst, nitrobenzene, 20 °C.
Catalysts (Figures 1, 2). Mol % of pyrrolidine containing catalyst (7,
12, and 10). Noncovalent amines were used equimolar. Additives.
NO3 : 5.0 M Bu4NNO3. PF6 : 5.0 M Bu4NPF6. Total yield of 3
determined by NMR after consumption of 2 (48−60 h (7, 10 + 13),
80 h (12 + 11), 96 h (12 + 13)). Diastereomeric ratio of three major
b
c
d
e
−
−
f
g
isomers 3A:3B:3C (Figure 1). Enantiomeric excess for 3A; negative
ee’s indicate opposite enantiomer.
presence of nitrate (Figure 2d; Table 2, entry 7). This finding
suggested that ion pairing with the iminium cation governs the
enantioselectivity of the noncovalent original 12 + 13 and
confirmed that anion−π catalyst 7 operates differently.
In summary, anion−π catalysts are introduced for cascade
processes that afford cyclohexane rings with five stereocenters
in one step. The observed dependence of rate and selectivity on
π-acidity, and inhibition with nitrate provide experimental
support for the contribution of anion−π interactions to the
stereoselective stabilization of the anionic transition states.
Under conditions optimized in their favor, anion−π catalysts
operate with yields, rates, and enantioselectivities that exceed
those of conventional catalysts, and the diastereoselectivity
reaches a new absolute maximum.
ASSOCIATED CONTENT
* Supporting Information
■
S
As confirmed for the MacMillan catalyst,24 it is conceivable
that the conventional catalyst 12 stabilizes the Leonard-
turned14 iminium intermediate with cation−π interactions
(RI1, Figure 2e). Noncovalent hybrid systems with additional
π-acidic surfaces, either 12 + 11 or 10 + 13, did not improve
performance (Table, 2, entries 8, 9). The change from 20 to 5
mol % catalyst did not affect the results with the covalent
anion−π catalyst 7 (89%, ee = 58%, Table 2, entry 2). With the
conventional catalyst 12 + 13, the same lowering in catalyst
loading reduced yield and enantioselectivity (74%, ee = −39%
(Table 2, entry 6).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b04936.
Detailed experimental procedures (PDF)
AUTHOR INFORMATION
Corresponding Author
*stefan.matile@unige.ch
■
Present Address
§Department of Chemistry, Durham University, Durham,
United Kingdom.
In the presence of nitrate, the yield obtained with catalyst 7
decreased with IC50 ≈ 2.5 M and reach almost full inhibition
with 5.0 M Bu4NNO3 (Figure 2c; Table 2, entry 3). The ee of
product 3A was not strongly affected by nitrate inhibition
(Figure 2d; Table 2, entry 3). In contrast, the yield dropped
only to 46% with 5.0 M Bu4NPF6 (Table 2, entry 4). These
findings were consistent with the selective inhibition of catalyst
7 by nitrate−π interactions,25 that is the existence and
functional significance of asymmetric anion−π catalysis. This
important conclusion was supported by the inability of 5.0 M
Bu4NNO3 to inhibit the original noncovalent system 12 + 13
(Figure 2c; Table 2, entry 7). However, the enantioselectivity of
the original mixture 12 + 13 completely vanished in the
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NMR and the Sciences Mass Spectrometry
(SMS) platforms for services, and the University of Geneva, the
European Research Council (ERC Advanced Investigator), the
Swiss National Centre of Competence in Research (NCCR)
Chemical Biology, the NCCR Molecular Systems Engineering,
and the Swiss NSF for financial support. A.-J.A. thanks the US
NSF for a GROW Fellowship and the Swiss SERI/FCS for a
Government Excellence Scholarship.
C
DOI: 10.1021/jacs.6b04936
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Journal of the American Chemical Society
Communication
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