Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers

Article abstract of DOI:10.1021/jacs.9b04902

Enzymes are Nature's polyfunctional catalysts tailor-made for specific biochemical synthetic transformations, which often proceed with almost perfect stereocontrol. From a synthetic point of view, artificial catalysts usually offer the advantage of much broader substrate scopes, but stereocontrol is often inferior to that possible with natural enzymes. A particularly difficult synthetic task in asymmetric catalysis is to overwrite a pronounced preference for the formation of an inherently favored diastereomer; this requires a high level of stereocontrol. In this Article, the development of a novel artificial polyfunctional catalyst type is described, in which an imidazolium-aryloxide betaine moiety cooperates with a Lewis acidic metal center (here Cu(II)) within a chiral catalyst framework. This strategy permits for the first time a general, highly enantioselective access to the otherwise rare diastereomer in the direct 1,4-addition of various 1,3-dicarbonyl substrates to β-substituted nitroolefins. The unique stereocontrol by the polyfunctional catalyst system is also demonstrated with the highly stereoselective formation of a third contiguous stereocenter making use of a diastereoselective nitronate protonation employing α,β-disubstituted nitroolefin substrates. Asymmetric 1,4-additions of β-ketoesters to α,β-disubstituted nitroolefins have never been reported before in literature. Combined mechanistic investigations including detailed spectroscopic and density functional theory (DFT) studies suggest that the aryloxide acts as a base to form a Cu(II)-bound enolate, whereas the nitroolefin is activated by H-bonds to the imidazolium unit and the phenolic OH generated during the proton transfer. Detailed kinetic analyses (RPKA, VTNA) suggest that (a) the catalyst is stable during the catalytic reaction, (b) not inhibited by product and (c) the rate-limiting step is most likely the C-C bond formation in agreement with the DFT calculations of the catalytic cycle. The robust catalyst is readily synthesized and recyclable and could also be applied to a cascade cyclization.

Full text of DOI:10.1021/jacs.9b04902

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Article
Polyfunctional Imidazolium Aryloxide Betaine / Lewis Acid Catalysts
as Tool for the Asymmetric Synthesis of Disfavored Diastereomers
Felix Willig, Johannes Lang, Andreas C. Hans, Mark R
Ringenberg, Daniel Pfeffer, Wolfgang Frey, and René Peters
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04902 • Publication Date (Web): 03 Jul 2019
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Journal of the American Chemical Society
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Polyfunctional Imidazolium Aryloxide Betaine / Lewis
Acid Catalysts as Tool for the Asymmetric Synthesis of
Disfavored Diastereomers
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Felix Willig,≠ Johannes Lang,*≠ Andreas C. Hans,≠ Mark R. Ringenberg,§ Daniel Pfeffer,≠
Wolfgang Frey,≠ and René Peters*≠
≠ Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany.
§ Institut für Anorganische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany.
KEYWORDS: cooperative catalysis; direct 1,4-additions; multifunctional catalysts; betaine; asymmetric
catalysis
ABSTRACT: Enzymes are Nature‘s polyfunctional catalysts tailor-made for specific biochemical synthetic
transformations, which often proceed with almost perfect stereocontrol. From a synthetic point of view, artificial catalysts
usually offer the advantage of much broader substrate scopes, but stereocontrol is often inferior to enzymes. A particularly
difficult synthetic task in asymmetric catalysis is to overwrite a pronounced preference for the formation of an inherently
favored diastereomer and thus requires a particularly high level of stereocontrol. In this article, the development of a
novel artificial polyfunctional catalyst type is described, in which an imidazolium-aryloxide betaine moiety cooperates
with a Lewis acidic metal center (here Cu(II)) within a chiral catalyst framework. This strategy permitted for the first time
a general, highly enantioselective access to the otherwise rare diastereomer in the direct 1,4-addition of various 1,3-
dicarbonyl substrates to β-substituted nitroolefins. The unique stereocontrol by the polyfunctional catalyst system is also
demonstrated with the highly stereoselective formation of a third contiguous stereocenter making use of a
diastereoselective nitronate protonation employing α,β-disubstituted nitroolefin substrates. Asymmetric 1,4-additions of
β-ketoesters and α,β-disubstituted nitroolefins have never been reported before. Combined mechanistic investigations
including detailed spectroscopic and DFT studies suggest that the aryloxide acts as a base to form a Cu(II)-bound enolate,
whereas the nitroolefin is activated by H-bonds to the imidazolium unit and the phenolic OH generated during the proton
transfer. Detailed kinetic analyses (RPKA, VTNA) suggest that (a) the catalyst is stable during the catalytic reaction, (b)
not inhibited by product and (c) the rate-limiting step is most likely the C-C bond formation in agreement with the DFT
calculations of the catalytic cycle. The robust catalyst is readily synthesized, recyclable and could also be applied to a
cascade cyclization.
enolate. The latter nucleophile attacks the aldehyde
substrate that is activated by hydrogen bond formation
INTRODUCTION
Enzymes, the highly sophisticated catalysts that Nature
has evolved over billions of years to regulate biochemical
processes, make use of polyfunctional active sites. Many
of them are capable of activating two substrates
simultaneously by various active site functionalities.1
Interaction of these enzyme functional groups with a
proper nucleophile and a proper electrophile enables a
precise spatial organization of both substrates within the
chiral environment of the active site thus allowing for
excellent stereoselectivities. Likewise, this cooperative
mode of action leads to strongly increased reaction rates
for the inherently favored substrates.1
with a tyrosine residue to form two stereocenters in this
event.2
Because stereoisomers usually differ in their physiological
properties,3 a selective complementary access to different
diastereomeric addition products is often desirable, in
particular
in
medicinal
chemistry.
Achieving
diastereodivergency in asymmetric catalysis is thus an
important, but still very challenging synthetic task.
Therefore various concepts, strategies and approaches
have recently been developed to accomplish an efficient
access to the otherwise rare diastereomers for various
reaction types.4,5
For instance, class-II-aldolases constitute one of Nature’s
important tools to create C,C-bonds.2 Scheme 1 (top)
illustrates the suggested simplified operation mode of the
polyfunctional active site of such a metal dependent
enzyme, in which the bidentate pronucleophile forms a
chelate complex with Zn(II).2 This coordination further
acidifies the α-C,H-bond, which can thus be deprotonated
by a Brønsted basic glutamate residue to generate a Zn-
Next to aldol additions, catalytic direct Michael-additions
have been developed as efficient tools to construct C,C-
bonds with adjacent stereocenters in an atom-economic
and highly enantio- and diastereoselective fashion.6,7
A
synthetically attractive version is the direct conjugate
addition of β-ketoesters to nitroolefins, because the
carbonyl moieties as well as the nitro group offer many
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Journal of the American Chemical Society
Page 2 of 17
options for further synthetic transformations.8,9 Value-
imidazolium aryloxide betaine moiety and a chiral Lewis
1
2
3
4
5
6
7
8
added 1,4-addition products to nitroolefins were applied
to construct densely functionalized chiral products8
including bioactive natural products and active
pharmaceutical ingredients.10
acid fragment within the same catalyst framework
(Scheme 1, bottom).12 This polyfunctional catalyst is also
shown to be capable of creating an additional stereocenter
by stereoselective nitronate pronation using α,β-
disubstituted nitroolefins.
Despite the large number of investigations dealing with
the asymmetric addition of α-substituted β-ketoesters 1 to
nitroolefins 2, the so far described catalysts have in
common that for the overwhelming majority of reported
substrate combinations –in particular for all cyclic α-
substituted β-ketoesters– the formation of the same
relative product configuration is inherently strongly
favored (Scheme 1, middle).8,11 There is no general route
yet toward the rare epimeric product series and hence
epimeric follow-up products were not efficiently
accessible so far.
Ooi et al. could previously demonstrate the high potential
of ammonium betaine organocatalysts in asymmetric
synthesis.13 We initially chose to study this polyfunctional
catalyst approach based on the hypothesis that it might
allow for a more or less independent spatial control over
both reactants in the stereoselectivity determining
transition state of the C-C bond formation in order to
overwrite an inherent diastereoselectivity preference.
Like in an aldolase, the pronucleophile should form a
chelate complex with the metal center thus acidifying the
α-C,H-bond, which is then deprotonated by the basic
naphtholate to form a metal enolate. On the other hand
the electrophile should be activated by hydrogen bond
formation with the generated naphthol/imidazolium
moiety to synergistically facilitate the C-C-bond
formation. Kinetic and computational investigations
suggest that the stereoselectivity determining C-C-bond
formation is also rate limiting.
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Scheme 1. Top: Operation Mode of the Active Site
of
a
Class-II-Aldolase; Middle: Inherent
Diastereoselectivity of the Title Reaction;
Bottom: Use of an Artificial Polyfunctional
Catalyst.
Nature
Tyr113
O
Stereoselective C,C- bond formation
by a class-II-aldolase
H-bond donor
H
2O
OPO3
Lewis acid
RESULTS AND DISCUSSION
Catalyst Development and Optimization
His
O
His Zn
His
R
H
O
H
H
Brønsted base
O
Glu73
O
Bisimidazolium units have recently been explored by our
group in cooperative asymmetric catalysis as H-bond
donors,5k and because they might allow for additional π-
or electrostatic interactions. The new precatalysts C1-M
presented herein make use of an axially chiral binaphthyl
unit carrying both an imidazolium and an acidic phenolic
OH group. C1a-Ni and C1b-Ni (5 mol%) possessing
different configurations of the iminotriflamide ligand
fragment showed low activities (Table 1, entries 1 and 2),
poor diastereo- but promising enantioselectivities. The
activity could be increased by catalytic amounts of
different bases (2.5 mol%). NEt3, Na(acac), and KOtBu all
led to significant improvements in product yield and
enantioselectivity (entries 3-5). With NEt3 as the weakest
base the smallest effect was found. For the other two bases
the catalytic performance was very similar to each other,
which pointed to the formation of the corresponding
naphtholate of C1b-Ni as the catalytically active species.
However, the preference for the otherwise rare
diastereomer maintained at a low level. For that reason
different metal centers M were installed and with
copper(II) improved diastereoselectivity was attained. In
the absence of base, only 13% of product was formed
(entry 6). In the presence of Na(acac) as base,
enantioselectivity and yield were again significantly
improved (entry 8). Albeit catalyst C1b-Cu is not
performing as rapid as its Ni-counterpart, the
diastereoselectivity favoring the otherwise rare
diastereomer 3aA-D2 was significantly higher.
Previous Work
1
Typical configurational outcome of catalytic asymmetric 1,4-additions of ketoesters
2
to nitroolefins
chiral
catalst
O
O
R
O
R
CO2R'
NO2
NO2
+
CO2R'
CO2R'
1
disfavored
diastereomer
3-D2
inherently favored
diastereomer
3-D1
+
NO2
R
2
This Work
Polyfunctional imidazolium betaine / Lewis acid catalyst approach to form the
3-D2
unnatural stereoisomer
O
Ph
N
Ph
N
CO2R'
NO2
+
R
SO2CF3
2
1
Lewis acid
Cu
tBu
O
polyfunctional
betaine / Lewis
L
C1b-Cu*
acid catalyst
H bond donor,
electrostatic
interactions
N
Brønsted base /
after protonation
H bond donor +
Brønsted acid
H
O
R
N
O
NO2
CO2R'
major product
C1b-Cu*
3-D2
otherwise rare diastereomer
In this article, an artificial polyfunctional catalyst type is
reported in which similar tools as in enzymes (Lewis acid,
Brønsted base, H-bond donors, ionic interactions), have
been exploited to allow for an efficient enantioselective
access toward the otherwise rare diastereomer in the
addition of ketoesters 1 to nitroolefins 2. In particular,
this article introduces a novel cooperative catalysis
strategy featuring the synergistic interplay between an
NEt3 was again a less efficient base in terms of product
yield and enantioselectivity, but also regarding the
diastereoselectivity (entry 7). Also with KOtBu the
diastereoselectivity was initially smaller (entry 9). In
general we found that the base amount is a critical factor.
Since 5 mol% of the polyfunctional catalyst were used, but
just 2.5 mol% of base, only half of it would be in the more
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Journal of the American Chemical Society
active and selective betaine form. On the other hand, necessary to increase the concentration (compare entries
1
2
3
4
5
6
7
8
increasing the base loadings led to reproducibility
problems, which were explained by unreacted free base
leading to background reactions. Switching to THF as
solvent (entry 10) had a positive effect on the base
solubility and reproducibility.
1 & 2). High yields with lower catalyst loadings were
accomplished under neat reaction conditions, in which
the ketoester (1.5-2 equiv) also acts as solvent (entries 3-
5). With 0.5 mol% of catalyst it was possible to form the
product in 89% yield with a dr of 94:6 favoring the
otherwise rare diastereomer D2 in almost enantiopure
form (99% ee, entry 5).
To avoid free unreacted base, the betaine catalyst C1b-
Cu* was then preformed by filtration of C1b-Cu over
basic silica gel with CH2Cl2/THF/NEt3 (66:33:1) as eluent.
This proceeding provided reproducible data (entry 11).
The diastereomeric catalyst C1a-Cu* provided the optical
antipode of the rare product diastereomer 3aA-D2 with
high selectivity (entry 12).
Table 2. Optimization of Reaction Conditions.
9
Ph
N
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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NTf
OH2
Cu
O
tBu
O
CO2Et
O
XFb-Cu
(x mol%),
Ph
Table 1. Development of a Catalyst to Form the
Otherwise Rare Diastereomer 3aA-D2.
THF, 20 °C, t
NO2
C1b-Cu*
1a
N
+
CO2Et
NO2
O
N
O
3aA-D2
Ph
C1-M
base (2.5 mol%),
solvent, 22 °C, 24 h
(5 mol%),
CO2Et
2A
O
O
Ph
Ph
NO2
NO2
+
1a
+
CO2Et
CO2Et
NO2
Ph
3aA-D1
3aA-D2
2A
inherently favored
otherwise rare
#
x
equiv.
1a
c
t (h) yld. D1:D2a ee
Ph
N
Ph
(X, mol/L)
0.2
(%)a
(%)b
NTf
OH2
Ph
NTf
M
1
5.0 1.1
5.0 1.1
1.0 1.5
0.5 2
24
24
24
24
72
73
5:95
4:96
6:94
6:94
6:94
96
97
98
99
99
Ph
tBu
O
=
2
3
4
5
0.5
92
N
M = Ni, Cu
Cl
neat
neat
neat
1
85
N
Ph
Ph
NTf
Ph
Ph
65
N
OH
NTf
N
N
0.5 2
89
b
a
a
Determined by H NMR analysis of the crude product
b
C1-M
using mesitylene as an internal standard. Enantiomeric
excess of 3aA-D2 determined by HPLC.
#
catalyst base
solvent yield D1:D2a ee
(%)a (%)b
CH2Cl2 11 40:60 -51
Catalyst Synthesis
The catalyst synthesis is based on the transformation of
1
C1a-Ni
C1b-Ni
-
-
commercially
available
BINAM
(5)
with
2
3
4
5
6
7
8
9
CH2Cl2 35
CH2Cl2 77
CH2Cl2 93
CH2Cl2 94
CH2Cl2 13
CH2Cl2 34
CH2Cl2 62
CH2Cl2 20
43:57
38:62
38:62
35:65
32:68
21:79
13:87
24:76
11:89
11:89
63
91
97
98
74
92
96
78
97
97
paraformaldehyde and glyoxal in the presence of
phosphoric acid, water and ammonium chloride into the
bifunctional naphthol/imidazole building block 6, which
was previously described by Crabtree et al.14 Further
optimization of this procedure provided 6 in useful yield
(Scheme 2).
C1b-Ni NEt3
C1b-Ni Na(acac)
C1b-Ni KOtBu
C1b-Cu
-
C1b-Cu NEt3
Subsequent alkylation of 6 with the known benzylic
chloride 715 under SN2 conditions and then imine
formation with amine 9b proceeded smoothly.16 The
yellow colored ligand L1b was then treated with Cu(acac)2
providing the olive-green Cu(II) complex C1b-Cu. The
active, red-brown colored betaine form was obtained by
filtration over basic silica gel as described above. The last
two steps proceeded in quasi-quantitative yield and
delivered paramagnetic C1b-Cu and C1b-Cu* in pure
form as judged by microanalysis, mass spectrometry and
UV-Vis spectroscopy. Overall the synthesis took 5 steps
and the overall yield was 45%. The catalyst synthesis
strategy is modular and applicable to various catalyst
derivatives, as exemplified for the synthesis of the control
catalyst systems C3-C8 (Supporting Information, for the
structures see below in Table 6).
C1b-Cu Na(acac)
C1b-Cu KOtBu
10 C1b-Cu KOtBu
THF
THF
78
88
11 C1b-
preactiv.c
Cu*c
12 C1a-
preactiv.c
THF
98
9:91
-87
Cu*c
a
1
Determined by H NMR analysis of the crude product
b
using mesitylene as an internal standard. Enantiomeric
excess of the major diastereomer 3aA-D2 determined by
HPLC. A minus sign indicates that the other enantiomer than
the one depicted was produced in excess. The catalyst was
preactivated forming betaine C1-Cu* by filtration over silica
gel using with CH2Cl2/THF/NEt3 (66:33:1) as eluent.
c
High diastereoselectivities were attained by performing
the reaction at 20 °C (Table 2). For high yields it was
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Journal of the American Chemical Society
Page 4 of 17
tolerated. The same can be stated for different kinds of
1
2
3
4
5
6
7
8
substituents in para (entries 2, 5, 8, 11, 14, 17), meta
(entries 3, 6, 9, 12, 15, 17) and ortho (entries 4, 7, 10, 13,
16) positions. In the latter case, the largest variation of the
dr value ranging from 10:90 (entry 4) to 1:99 (entry 10)
was noted, whereas in the case of meta and para
substitution dr values were close to 5:95. Moreover,
heteroaromatic residues R were well accommodated
(entries 18 and 19).
Scheme 2. Synthesis of Betaine Catalyst C1b-Cu*.
H3PO4, NH4Cl,
H2O, dioxane
O
O
N
80-100 °C, 5 h
55%
NH2
NH2
N
+
+
H
H
Table 3. Application to Different Nitroolefins.
O
9
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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42
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44
45
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50
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54
55
56
57
58
59
60
O
C1b-Cu*
THF, 20 °C
(5 mol%),
R
O
O
5
6
NO2
NO2
CO2Et
+
R
OH
Cl
CO2Et
quant.
Ph
N
Ph
2
3a-D2
1a
tBu
CH2Cl2, RT, 16 h
7
O
yield D1 : D2a ee
(%)a (%)b
HN Tf
#
R
3a
OH
Ph
Ph
tBu
OH
tBu
1
Ph
3aA 99
3aB 91
3aC 96
3aD 83
3aE 98
3aF 96
3aG 83
6 : 94
6 : 94
4 : 96
99
99
99
Cl
OH
H2N HN Tf
N
N
Cl
9b
N
2
3
4
5
6
7
8
9
p-Br-C6H4
m-Br-C6H4
o-Br-C6H4
p-Cl-C6H4
m-Cl-C6H4
o-Cl-C6H4
CH2Cl2, RT, 22 h
N
OH
83%
10 : 90 99
5 : 95
3 : 97
7 : 93
99
99
99
98
99
99
99
99
99
99
99
99
99
8
L1b
Cu(acac)2,
CH3CN, 60°C,
98%
p-O2N-C6H4
m-O2N-C6H4
3aH >99 6 : 94
3aI >99 3 : 97
Ph
N
Ph
N
Ph
N
Ph
N
Tf
Tf
10 o-O2N-C6H4
11 p-Me-C6H4
3aJ 97
3aK 92
3aL 97
3aM 85
3aN 90
3aO 95
3aP 79
3aQ 94
1 : 99
7 : 93
4 : 96
4 : 96
7 : 93
4 : 96
5 : 95
5 : 95
Cu
Cu
tBu
O
OH2
tBu
O
OH2
CH2Cl2/THF/NEt3
(66/33/1), silica gel
12 m-Me-C6H4
13 o-Me-C6H4
14 p-MeO-C6H4
Cl
quant.
N
N
overall yield:
45% (5 steps)
N
OH
N
O
15
m-MeO-C6H4
16 o-MeO-C6H4
C1b-Cu*
C1b-Cu
17
O
O
Scope
18 2-furyl
19 2-thiophenyl
20
3aR 90
3aS 97
3aT 85
10 : 90 99
The model reaction was also investigated on a gram scale
(eq. 1). With 0.5 mol% of preactivated catalyst C1b-Cu*
under solvent-free conditions 1.2 g of almost enantiopure
product was isolated (91% yield) with a dr of 95:5.
4 : 96
9 : 91
98
97
21 iPr
3aU 92
3aV 90
3aW 96
3aX 86
3aY 96
3aZ 56
2 : 98
3 : 97
99
99
22c cyclo-Hex
23c cyclo-Pr
24c iBu
O
C1b-Cu*
20 °C
(0.5 mol%),
Ph
O
NO2
NO2
CO2Et
(1)
+
Ph
12 : 88 98
10 : 90 99
13 : 87 98
26 : 74 96
91%
CO2Et
dr = 95:5
ee (D2) = 99%
2A
3aA-D2
(1.2 g)
1a
25c nPr
O
26
Bn
O
The title reaction could also be applied to a number of
different nitroolefins 2 providing similar results (Table 3).
In all cases, the otherwise rare diastereomer was formed
a Yield of isolated product as diastereomeric mixture after
column chromatography. Diastereomeric ratios were
in excess
-
usually with high diastereo- and
determined from the crude product by 1H-NMR.
b
enantioselectivity and high to excellent yields. On
aromatic residues R σ-acceptors like Br and Cl atoms
(entries 2-7), π-acceptors like a nitro group (entries 8-10),
σ-donors like a methyl group (entries 11-13), and π-
donors like a methoxy group (entries 14, 16) were all well
c
Enantiomeric excess of 3a-D2 determined by HPLC.
Reaction performed under neat conditions.
The reaction is also applicable to a γ,δ-unsaturated
nitroolefin, i.e. a conjugated diene, and proceeded with
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Journal of the American Chemical Society
O
O
good
yield,
diastereoselectivity,
excellent
10
3kA 98
17 : 83
98
1
2
3
4
5
6
7
8
enantioselectivity and complete regioselectivity (entry
20). A possible 1,6-addition product was not detected.
Me
OEt
N
O
The reaction is also attractive for nitroolefins carrying
alkyl substituents. With the α-branched isopropyl and
cyclohexyl residues the otherwise rare diastereomers
were formed with high diastereoselectivity, yield and
enantioselectivity (entries 21 and 22). Good
diastereoselectivity was also attained with substrates
bearing cyclopropyl and isobutyl substituents (entries 23
and 24). In addition, linear alkyl groups like n-propyl
residues are well tolerated despite the relatively high C-H
acidity at the γ-position (entry 25). For entry 26, R is an
ester moiety, leading to product 3aZ containing a
a Yield of isolated product after column chromatography as
b
diastereomeric mixture. Enantiomeric excess of 3a-D2
determined by HPLC. c The reaction was performed at 0 °C.
d The reaction was performed at 30 °C.
Variation of the ester substituent at the cyclopentanone
ring had no large impact on stereoselectivity and yield.
With the more bulky isopropyl ester group the preference
for the otherwise rare diastereomer became a bit higher
(compare entry 2 with entry 1 and Table 3, entry 1).
Nevertheless, all other examples in Table 4 made use of
Me or Et esters. An indanone derivative was also well
accommodated (entry 3). Six-, seven- and eight-
membered rings were also tolerated and high
enantioselectivity was attained in all cases (entries 4-6).
For the less reactive cyclohexanone and -octanone the
diastereoselectivity was moderate, but the otherwise rare
product diastereomers were still favored. With an acyclic
ketoester, the enantioselectivity was lower than with the
cyclic ones (entry 7).19 The experiment described by entry
8 using a simple malonate20 substrate was conducted as a
mechanistic control experiment in order to elucidate, if
the catalyst is capable of controlling the stereocenter
generated at the nitroolefin more or less independently
from the formation of a stereocenter at the nucleophile.
The configuration of the generated stereocenter is in fact
the same as in the other cases thus demonstrating an
efficient control over the electrophile trajectory and face
differentiation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
configurationally
potentially
labile
stereocenter.
Nevertheless, the rare diastereomer was still formed in
access with high enantioselectivity under the mild
reaction conditions.
Overall, in all 26 cases almost enantiopure product was
formed. Additionally, the reaction was applied to different
1,3-dicarbonyl substrates as pronucleophiles (Table 4).17,18
Table
4.
Application
to
Different
Pronucleophiles.
O
C1b-Cu*
20 °C, neat or THF
(5 mol%),
Ph
O
O
NO2
NO2
R3
+
R3
R1
Ph
R2
R1
O
R2
3A-D2
2A
1
O
O
#
3
yield D1 : D2a ee
(%)a (%)b
R3
R1
R2
O
O
1
3bA 92
3cA 92
3dA 89
5 : 95
3 : 97
7 : 93
99
99
99
The 1,4-addition is not limited to β-ketoesters and
malonates, but could also be applied to a γ-lactam and a
succinimide carrying an additional ester moiety (entries 9
& 10).
OMe
O
O
2
3
OiPr
Moreover, the catalyst was applied to ketoester 1l
containing an enone moiety which could be used for a
cascade Michael cyclization forming a bicyclic core, in
which four contiguous stereocenters have been created
(Scheme 3).
O
O
OEt
4c
3eA 96
20 : 80
97
O
O
Scheme 3. Application to a Cascade Cyclization.
OEt
OEt
O
O
C1b-Cu*
25 °C, THF,
then TBAF (0.3 equiv),
25 °C, THF
(5 mol%)
OEt
O2N
O
O
5
6
3fA
96
9 : 91
99
92
+
Ph
NO2
1l
CO2Et
O
O
CO2Et
+
Ph
92%
NO2
Ph
dr = 93:7
ee (D2) = 97%
4-D1
4-D2
O
O
3gA 54
3hA 82
31 : 69
usually disfavored
diastereomer
2A
OEt
via:
O
Ph
O
Ph
O
O
7
16 : 84
75
NO2
NO2
Me
OMe
+
CO2Et
CO2Et
Me
3lA-D2
3lA-D1
O
O
8
3iA
3jA
58
71
-
80
91
4 can also be considered as a formal [4+2]-cycloaddition
product. Whereas the synthesis of diastereomer 4-D1 has
already been described in literature,21 an efficient access
to 4-D2 was previously elusive. With 5 mol% of catalyst
C1b-Cu* product 4 was formed in high yield and with
high diastereopreference for nearly enantiopure 4-D2.
MeO
Me
OMe
9d
16 : 84
O
O
OEt
N
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The intramolecular cyclization of the intermediate enantioselectivity were low (entry 2). The bifunctional
1
2
3
4
5
6
7
8
Michael addition product 3lA took largely place during
the reaction time, but did not go to completion. For that
reason, TBAF was added as a base after all nitroolefin had
been consumed to finalize the formation of the bicyclic
product. Addition of the base at this stage of the reaction
did not have a negative influence on the stereoselectivity.
imidazolium in C4 carrying an aliphatic OH as protic
moiety allowed for a similar diastereoselectivity, but a
significantly better yield and enantioselectivity thus
suggesting that an OH group is beneficial by hydrogen
bond activation.23 However, the enantio- and
diastereoselectivity were considerably lower than with
our standard catalyst system carrying a naphthol unit. In
the absence of base C4 was almost inactive under these
conditions (8% yield, D1:D2 = 47:53, ee(D2) = 40%).
Placing a methyl substituent at the imidazolium-2-
position led to a loss in diastereoselectivity, whereas the
enantioselectivity and activity were on a high level (entry
4). Both H-bond activation through the imidazolium’s
C(2)-H bond,24-26 but also Coulomb interactions are thus
likely to be involved in the activation process and
stereocontrol.27
Catalyst Recycling
An important practical aspect is the high robustness of the
catalyst, which is neither particularly prone to air nor to
moisture and can be readily recovered from the reaction
mixture and reused for additional runs (Table 5). The
catalyst was simply separated from the reaction mixture
by filtration over silica gel. The zwitterionic catalyst is
protonated on silica gel as is visible by the characteristic
color change from red-brown to olive-green (see above
and in the mechanistic investigations below). By washing
with petroleum ether/ethylacetate (1:1) the product,
starting materials, etc. were eluted whereas the charged
precatalyst was sticking on the silica gel. Subsequent
treatment of the silica pad with THF/CH2Cl2/NEt3
(66:33:1) regenerated the betaine species, which was
eluted and recovered in pure form as confirmed by ESI-
MS and UV-Vis.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. Investigation of Control Catalyst
Systems.
O
catalyst (5 mol%),
CO2Et
O
Na(acac) (2.5 mol%),
O
Ph
Ph
CH2Cl2, 22 °C, 24 h
NO2
NO2
+
1a
+
CO2Et
CO2Et
NO2
Ph
(ent)-3aA-D2
(ent)-3aA-D1
2A
With reisolated catalyst the productivity maintained on a
high level over at least four runs in terms of yield,
diastereo- and enantioselectivity. After the 4th run 60% of
the original catalyst amount was reisolated for the small
reaction scale. In the 5th run yield and diastereoselectivity
were still high, but started to decrease.
Ph
Ph
catalysts
Cl
Cl
Cl
tBu
C2
R =
NTf
N
N
N
N
O
Cu
Me
OH
N
N
N
tBu
OH2
OH
R
C3
C4
C5
Table 5. Repetitive Use of Recycled Catalyst.
Cl
O
N
HO
O
N
CO2Et
O
O
Ph
Ph
C1b-Cu*
(5 mol%),
Cl
OH
N
THF, 20 °C, 24 h
NO2
NO2
N
1a
CO2Et
CO2Et
+
OH
NO2
3aA-D2
3aA-D1
Ph
2A
C6
C7
C8
run
yld.
(%)a
D1:D2a
ee
(%)b
#
catalyst
yield
(%)a
D1:D2a
ee
(%)b
1
99
6:94
6:94
6:94
5:95
7:93
99
1
C2
C3
C4
C5
C6
C7
C8
83
30
94
88
84
25
61
80:20
26:74
28:72
52:48
60:40
17:83
6:94
5
2
3
4
5
95
98
2
25
76
79
2
96
98
3
98
87
98
4
5 c,d
98
a Yield of isolated product after column chromatography. b
Enantiomeric excess of 3aA-D2 determined by HPLC.
6
7 c,d
95
97
Mechanistic Studies and Considerations
Control Systems
a Determined by 1H NMR analysis of the crude product using
mesitylene as an internal standard. b Enantiomeric excess of
(ent)-3aA-D2 determined by HPLC. Note that the
iminotriflamide group has the opposite configuration than
The results shown in Table 1 indicate a crucial role of the
catalyst’s betaine moiety. To further investigate its role, a
number of control ligands were prepared and examined,
which were lacking one or the other functional group in
the residue R (Table 6). The structurally simplest complex
C2 carried a tert-butyl substituent. In the presence of
base this complex is catalytically active (entry 1), but the
inherently favored diastereomer D1 was formed in excess
and in almost racemic form.22 Installation of an
imidazolium moiety in catalyst C3 caused a switch of the
c
for C1b-Cu used above. KOtBu (4.5 mol%) was used as a
base instead of Na(acac). d Reaction was performed in THF.
This conclusion is further substantiated by the use of an
ether linked naphthol catalyst system C6, which provided
the inherently favored diastereomer in excess.
Interestingly, in this case D2 was almost racemic. For very
high enantio- and diastereoselectivity both the
imidazolium and an aromatic alcohol unit were necessary.
diastereopreference,
but
the
activity
and
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Journal of the American Chemical Society
Cl
Cl
Next to our standard catalyst system also the structurally
more simple complexes C7 and C8 containing phenol
moieties provided the otherwise rare diastereomer with
high selectivity.
1
DBU (1.5 equiv),
CDCl3, rt, 30 min
2
3
4
5
6
7
8
9
O
O
1'S
(2)
1'S
1S
1S
NO2
2'R
NO2
2'
Me
E
E
Me
Formation
Stereocenter
of
a
Third
Contiguous
3aE-Me
E = CO2Et
dr: (1S,1'S,2'R) : (1S,1'S,2'S)
3aE-Me epi-3aE-Me
/
E = CO2Et
dr: (1S,1'S,2'R) : (1S,1'S,2'S)
= 36 : 64
Since the polyfunctional catalyst in its protonated form is
expected to protonate a putative nitronate intermediate –
formed in the C-C bond formation step– using its
> 99 : 1
In a further control experiment, the simplified catalyst C3
lacking the naphtholate moiety was used (eq. 3). In that
case the level of stereocontrol regarding the stereocenter
created in the protonation step is poor affirming the role
of the naphthol moiety in the protonation event. In
addition the yield was poor.
naphthol moiety, we were interested, if
a third
stereocenter could also be controlled when employing
α,β-disubstituted nitroolefins 2-Me. Such asymmetric
reactions between β-ketoesters and α,β-disubstituted
nitroolefins have never been reported before. Table 7
showcases that high stereoselectivity was indeed attained
in this task.28 One out of four possible diastereomers was
formed in large excess and in nearly enantiopure form in
all six examples. The absolute configuration of 3aA-Me
and 3aE-Me was determined by X-ray crystal structure
analysis.18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
Cl
O
CO2Et
C3
(5 mol%),
Na(acac)
(2.5 mol%),
THF, rt
O
O
1a
1'R
1'R
1R
D3
D4
+
+
1R
NO2
2'R
NO2
+
(3)
+
2'S
E = CO2Et
NO2
E
E
Me
Me
3aE-Me
(1R,1'R,2'S)
Me
2E-Me
epi-3aE-Me
(1R,1'R,2'R)
Cl
Table 7. Control of a Third Stereocenter Using
α,β-Disubstituted Nitroolefins.
Ph
N
Ph
yield = 12 %
dr (1R,1'R,2'S) : (1R,1'R,2'R) : D3 : D4 =
53 : 34 : 4 : 9
NTf
OH2
X
ee (1R,1'R,2'S) = 89%
ee (1R,1'R,2'R) = 90%
Cu
tBu
O
O
C1b-Cu*
THF, 0 °C
(5 mol%),
O
NO2
NO2
Me
Cl
N
CO2Et
+
Me
2-Me
E
X
N
C3
3-Me
(major diastereomer)
(E = CO2Et)
1a
The attained level of stereocontrol with the betaine
catalyst C1b-Cu* is unprecedented for a Michael addition
to α,β-disubstituted nitroolefins generating three
contiguous stereocenters.28
#
X
3-Me
yield drb
(%)a
ee
(%)b,c
1
H
3aA-
Me
91
94.3 : 3.0 : 2.0 : 0.7 >99
94.2 : 2.6 : 2.4 : 0.8 >99
96.6 : 1.9 : 1.3 : 0.2 99
93.8 : 2.9 : 2.9 : 0.4 >99
91.6 : 4.9 : 2.2 : 1.3 >99
93.4 : 4.2 : 2.3 : 0.1 98
Kinetic Studies and Investigation of
Possible Non-Linear Effect
a
2
3
4
5
6
p-Br
m-Br
p-Cl
3aB-
Me
92
86
99
88
74
The initial reaction rate kinetics were investigated by 1H-
NMR. Using the differential method29 the following
empirical rate law was found for the model reaction in
THF at room temperature (for details see the Supporting
Information):
3aC-
Me
3aE-
Me
퐫 = 퐤 ∗ 퐂ퟏ퐛-퐂퐮 ퟎ.ퟗퟑ ∗ [ퟏ퐚]ퟎ.ퟔퟕ ∗ [ퟐ퐀]ퟎ.ퟗퟔ
∗
[
]
m-NO2
p-Me
3aI-
Me
The initial rate r thus approximately shows a first-order
kinetic dependence for the catalyst and the Michael
acceptor. The observation of a ca. 2/3-order kinetic
dependence for the pronucleophile 1a might point to a
partial substrate saturation.30b
3aK-
Me
a Yield of isolated product after column chromatography. b
Determined by HPLC from the crude product. c Enantiomeric
excess for the major diastereomer.
Since the order in catalyst suggests that a single catalyst
molecule is involved in the acceleration of the turnover-
limiting step in the model reaction, the possibility of a
non-linear effect was also investigated to confirm this
interpretation.31 Like expected, we found a strictly linear
correlation between catalyst ee and product ee values (for
details see the Supporting Information). In addition
concentration dependent UV-Vis experiments have been
performed which show a strictly linear correlation
between concentration and absorbance (Beer’s plot).
These findings support the assumption that catalyst
aggregates do not play an important role under the
catalysis conditions.
To probe if the high diastereoselectivity might be a
thermodynamic effect forming the most stable
diastereomer, product 3aE-Me was treated with DBU at
room temperature (eq. 2). Rapid partial epimerization
was observed resulting in an equilibrium mixture of 3aE-
Me and epi-3aE-Me with a ratio of 36 : 64. This shows
that the stereocenter in α-position to the nitro group was
formed under kinetic control in the catalytic reaction.
Because analysis of the initial reaction rates is limited to
relatively low conversions, the reaction progress kinetic
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analysis (RPKA) method of Blackmond was also studied
K2
K3
K4
dif. [C1b-Cu*]
dif. [1a]
0.11
0.15
0.11
0.10
0.10
0.15
2.5
5.0
5.0
by 1H-NMR spectroscopy to receive information about the
progress over the complete course of the catalytic
1
2
3
4
dif. [2A]
reaction.30 By the “same excess” protocol (see also the
30
Supporting Information),
the same reaction is
investigated starting from different points. Compared to a
standard reference reaction (Figure 1, blue curve) the
initial concentrations of substrates 1a and 2A in a second
experiment (red curve) corresponded to those of the
reference reaction experiment when the latter had
reached 50% conversion.30 In case of no catalyst
decomposition or product inhibition, for both
experiments the reaction progress from this point onward
should be the same.30
5
6
7
8
Vertical shift of
profile K4 to
enable VTNA.
b)
a)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-kobs = 2.9 (L/mol)2.9 s-1
Time
Adjustment
Figure 2. a) Conversion profile of the nitroolefin 2A
with different initial concentrations in 1a, 2A and
C1b-Cu*(see Table 7 for the color code). b) VTNA-
profiles with x-axis normalization for [C1b-Cu*],
[1a] and [2A]. Unit of the x-axis in (mol/L)2.9 s.
Over the complete reaction course, the best overlay was
achieved when partial orders of 0.90 for C1b-Cu*, 0.85
for 1a and 1.15 for 2A were used in the normalization of
the time scale axis. Under the reaction conditions kobs was
found to be 2.9 (L/mol)2.9∙s-1 (see Figure 2, b)). The
following empirical rate law was thus found for the model
reaction in THF at room temperature:
Figure 1. Reaction profiles of 2A using Blackmond’s
“same excess” protocol30 for probing catalyst
stability and product influence (■: standard
reaction, ●: 0.5 equiv. 1a and 2A, ▲ 0.5 equiv. 1a, 2A
plus 0.5 equiv. product 3aA; ○ and △: corresponding
time adjusted profiles.)
Indeed, a good overlay of the “time-adjusted” curves of
the kinetic profiles was observed, which indicates that no
significant catalyst deactivation takes place and that the
active catalyst concentration remains constant during the
catalytic reaction. In a third “same-excess” experiment
(green curve), the same starting point was used as in the
second experiment (blue curve), but 50 mol% of product
3aA was directly added from the start to the analyzed
reaction mixture. Also in that case, a good overlay of the
reaction profiles was obtained thus confirming that the
product 3aA does not significantly influence the catalyst
during the product formation.
풓 = 풌풐풃풔 ∗ 퐂ퟏ퐛-퐂퐮 ퟎ.ퟗퟎ ∗ [ퟏ퐚]ퟎ.ퟖퟓ ∗ [ퟐ퐚]ퟏ.ퟏퟓ
∗
[
]
Over the complete course the reaction rate r thus
approximately shows a first-order kinetic dependence for
the catalyst C1b-Cu* and the Michael acceptor 2a, in
relatively good agreement with the empirical rate law
determined from the initial reaction rates. The overall
kinetic dependence for the pronucleophile 1a of 0.85 is
closer to 1 than for the initial reaction rate kinetics (0.67).
However, taking a closer look, the order gradually
changed during the course of the reaction from 0.7 at the
beginning with β approaching a value of approximately 1
at the end of the reaction. Similar to Blackmond’s work we
explain the initial order between 0 and 1 with a partial
substrate saturation.30b,33 At higher conversions with
decreasing ratios of substrate / catalyst, the substrate
saturation will become less and less important. This is
also in agreement with titration studies shown below. The
dependence of the concentration of the catalyst and both
substrates on the reaction rate could be explained with the
C-C-bond formation as the rate determining step.
The variable time normalization analysis method (VTNA)
described by Burés was used to elucidate the orders of the
model reaction in all reaction components.32
Kinetic analysis monitoring 2A made use of four reactions
with different initial concentrations of C1b-Cu*, 1a and
2A (see Table 8, Figure
2 and the Supporting
Information).
Table 8. Initial Concentrations of the Kinetic
Experiments for Determining the Partial Orders
of the Model Reaction.
Structural and Spectroscopic Studies
Unfortunately and despite extensive attempts an X-ray
crystal structure analysis could so far not been obtained
for the activated Cu(II) betaine catalysts like C1b-Cu*, or
its precursor C1b-Cu. On the other hand, the related
BINOL-based control system C6 formed suitable crystals
(Figure 3).34 The crystal structure analysis confirmed the
[C1b-
Cu*]
[1a]
[2A]
#
Experiment
standard
/ mol/L / mol/L
/ mmol/L
K1
0.11
0.10
5.0
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Journal of the American Chemical Society
assumed square planar coordination geometry, in which
H2O serves as an additional ligand.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Top: UV-Vis-NIR spectra of C1b-Cu* (red
line), C1b-Cu (green line) and the free ligand
(black line). Bottom: UV-Vis titration
experiments adding ketoester 1a to catalyst C1b-
Cu*.
Figure 3. X-Ray crystal structure analysis of C6
(solvent molecules and H atoms have been omitted
for clarity).
As mentioned above, the protonation state of the
binaphthol(ate) moiety of the Cu(II) catalysts is already
visible. Whereas the betaine C1b-Cu* is red-brown
colored, the naphthol precatalyst form C1b-Cu is dark
olive-green. UV-Vis-NIR spectra of both species and of
the free ligand are depicted in Figure 4/top.
To get more information about this Cu(II) species EPR
studies were conducted (Figure 5).
Titration experiments were conducted in which the
betaine form C1b-Cu* was treated with ketoester 1a
(Figure 4 /bottom). With an increasing excess of
ketoester, the amount of a new catalyst species was
getting more and more dominant. An equilibrium is
obviously formed, probably by Cu enolate formation
including a proton transfer to the naphtholate function.
Note that for technical reasons, the titrations needed to be
performed at much lower concentrations than the
catalytic reactions. The ketoester substrate and THF are
expected to compete for the catalyst binding site. For that
reason the dilution should have a strong influence on the
equilibrium.
Figure 5. X-band EPR spectrum of C1b-Cu* (blue),
C1b-Cu* plus 100 equiv of 1a (red), and C1b-Cu* plus
400 equiv 1a (yellow) in THF at 108 K.
C1b-Cu* and the unactivated form C1b-Cu both showed
a typical Cu(II) axial signal in the X-band EPR spectrum
at 108 K in THF under high dilution. The four lines in the
parallel region arise from the hyperfine coupling of S = ½
to copper nuclear spin I = 3/2. C1b-Cu showed gll = 2.13,
AII (63,65Cu) = 523 MHz and gI = 1.97, A I (63,65Cu) = 33
MHz (see ESI) while C1b-Cu* showed a shift in the gll =
2.26, AII (63,65Cu) = 526 MHz and gI = 2.06, AI (63,65Cu)
= 38 MHz (Figure 5). The increase in the g value is typical
for increased axial coordination around the Cu(II) center
and is due to the change in ligand field and rigidity of the
ligand.35 Addition of nitroolefin to C1b-Cu* did not cause
any significant change to the EPR spectrum (see ESI).
Addition of 100 equiv of 1a resulted in a new signal to
appear at gll = 2.24, AII (63,65Cu) = 590 MHz and gI =
2.04, AI (63,65Cu) = 46 MHz (Figure 5). After addition of
400 equiv of 1a only the new signal could be detected
(Figure 5). While the final spectrum shows better
resolution of the A(14N), this is due to dilution and
reduced exchange broadening.36 The EPR spectrum of
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C1b-Cu* plus 400 equiv. 1a shows that a new species is catalytic cycle (Scheme 4). The energies of all species
1
2
3
4
5
6
7
8
generated, which is not C1b-Cu. Instead a more axial
signal suggests the binding of 1a.
within the energy profile are given relative to the energy
sum of the free educts (nitroolefin and ketoester), H2O
and C1b-Cu*-THF.
Calculations
The reaction is initially triggered by the ketoester (in its
keto form) replacing the H2O ligand of C1b-Cu* by
coordinating to the copper center. This results in
minimum structure I(keto) which adopts a coordination
number of 5 at the copper(II) center. Both square
pyramidal and trigonal bipyramidal metal geometries
have been discussed in literature for Cu(II) catalysis
employing bidentate substrates.41 This pathway is
endergonic and consumes 68 kJ/mol.
The crystal structure of C6 (Figure 3) served as a starting
point to calculate optimized minimum energy structures
of C6 and the betaine catalyst in its naphthol form
C1b-Cu (Figure 6). Having identified these structures, we
explored the reaction mechanism of the catalytic cycle
(Scheme 4) by calculating stationary points along the
reaction pathway (minima as well as transition state
structures; Figures 7 and S28 (see the SI)). The density
functional theory (DFT) calculations were performed at
the B3LYP37 level of theory using the cc-pVDZ38 basis set
as implemented in the Gaussian 16 program package.39 All
structures were preoptimized in the gas phase and
confirmed to be either true minima or true transition state
structures by frequency calculations (zero or one
imaginary frequency, respectively). We searched for the
most stable conformers as a function of the binding motifs
and torsion angles of the ligand. The structures were
reoptimized using the IEF-PCM model40 to include the
self-consistent reaction field of the solvent (THF). We
extracted and compared relative free Gibbs energies at
250 K. The presented structures are neutral (except C1b-
Cu, which is a cation) and exhibit a multiplicity of 2. All
calculations were performed in the electronic ground
states.
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We also took into consideration that C1b-Cu* may lose
the H2O ligand resulting in an intermediate structure
C1b-Cu*(-H2O). The copper center stabilizes the
naphtholate moiety by binding the ligand forming a
distorted square planar coordination sphere. However,
C1b-Cu* is 23 kJ/mol more stable than C1b-Cu*(-H2O).
C1b-Cu* might serve as well as a starting point of the
catalysis.
An exchange of the H2O ligand with a THF ligand results
in C1b-Cu*-THF. It lacks any stabilizing intramolecular
hydrogen bonds resulting in a higher reactivity than C1b-
Cu*. However, the direct H2O / THF ligand exchange
requires 87 kJ/mol, i.e. more energy than is needed to
form I(keto) or C1b-Cu*(-H2O) from C1b-Cu*. It is
more likely, that C1b-Cu*-THF is formed after finishing
a catalytic cycle by dissociation of the product from IV,
facilitated by the solvent THF (to be discussed in the
following).
In contrast to the solid state structure, two hydrogen
bonds stabilize the molecular entities of C6 and C1b-Cu
(Figure 6) between (1) the naphthol OH and the water
ligand and (2) between the water ligand and the sulfonyl
moiety. These conformations were found to be more
stable than the minimum structures with crystal-like
conformations (stabilization of 6 and 14 kJ/mol for C6
and C1b-Cu; details in the Supporting Information).
The ketoester may then easily replace the THF ligand of
C1b-Cu*-THF coordinating to the copper center. This
also results in the minimum structure I(keto). This
pathway is exergonic releasing 19 kJ/mol of energy.
I(keto) facilitates the exergonic formation of the next
minimum structure along the pathway, Cu-enolate
structure II. II exhibits a neutral naphthol OH group as
well as the ketoester in its enolate form coordinated to the
copper center. A hydrogen bond between these groups
stabilizes this structure significantly. Consequently, it is
the most stable structure within the proposed catalytic
cycle (57 kJ/mol).
A rotation of the coordinated
bidentate enolate by ca. 180° destabilizes the complex
significantly (details in the Supporting Information). We
found
a transition state structure (TS I(keto)/II)
connecting I(keto) and II. The virtual frequency
vibration of TS I(keto)/II illustrates the proton
migration from the keto CH group to the naphtholate O-
group (cf. displacement vector in Figure S26, see
Supporting Information). The activation barrier for this
process is 19 kJ/mol.
Figure 6. Most stable conformations of the control
system C6 (left) and the precatalyst C1b-Cu (right):
optimized structures by DFT calculations at the
B3LYP/cc-pVDZ/IEF-PCM (THF) level of theory.
The dotted blue lines indicate hydrogen bonding.
Light gray: H; dark gray: C; dark blue: N; orange: Cu;
light blue: F; yellow: S.
A number of stationary points were identified along the
reaction path and established an energy profile (Figures 7
and S28 (see the SI)) corresponding to the proposed
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state structure (TS III / III.1, see Figures 7 & S28 in the
1
2
3
4
5
6
7
8
9
SI) connecting III and III.1. The virtual frequency
vibration of TS III / III.1 illustrates the C-C-bond
formation (cf. displacement vector in Figure S27 in the
Scheme 4. Simplified Plausible Catalytic
Mechanism. For structural details, transition
state structures and energetics refer to Figures 7
and S28 (see SI).
Supporting Information). TS III / III.1 exhibits
a
hydrogen bond between the imidazolium C(2)-H5k,25 42
and the nitro group (CH…O distance: 1.877 Å). The finely
tuned network of OH…O and CH…O hydrogen bonds as
well as conceivable Coulomb interactions24b spatially
preorganize the nitroolefin during the C-C-bond
formation. In consequence, the catalyst can accomplish
the otherwise rare relative product configuration of
3aA-D2. This is in accord with our experimental
observations as the presence of both the OH group and
the imidazolium were crucial for high stereoselectivity
(Table 6). The activation barrier for the C-C-bond
formation is 70 kJ/mol (relative to III), which is the
highest barrier of the catalytic cycle. The calculations thus
suggest the C-C-bond formation as the rate-limiting event
of the reaction, in agreement with the kinetic studies. This
step is practically irreversible under the reaction
conditions, because ee values and diastereoselectivities
did not change upon prolonged reaction times.
,
Ph
N
Ph
N
Ph
N
Ph
N
Tf
Tf
Cu
Cu
H
O
O
O
THF
O
H
C1b-Cu*-THF
10
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C1b-Cu*
CO2Et
N
N
O
O
N
N
1a
O
Ph
NO2
THF
H2O
CO2Et
3aA
Ph
Ph
3aA
N
O
N Tf
Cu
O
OEt
H
O
THF
1a
N
O
N
Ph
N
Ph
N
Ph
N
Ph
Tf
I(keto)
N
Tf
A proton transfer from the naphthol group to the
nitronate completes the product formation and results in
minimum structure IV. The proton transfer is also an
endergonic process consuming 28 kJ/mol (relative free
energy of IV: 24 kJ/mol). A THF molecule, e.g., could
then close the catalytic cycle by replacing and releasing
the product. This results in structure C1b-Cu*-THF as
discussed above. Just releasing the product would result
in the structure C1b-Cu*(-H2O) as discussed above.
Likewise, 1a might displace the product leading directly
to I(keto).
O
O
Cu
Cu
OEt
Ph
OEt
O
O
O
O
H
H
N
N
O
N
O
N
N
O
II
O
IV
NO2
Ph
Ph
N
Ph
N
Ph
N
Ph
2A
N
O
Tf
Tf
O
O
Cu
Cu
OEt
OEt
O
O
O
Ph
Ph
H
N
O
N
O
H
N
N
H
N
O
N
O
H
O
H
O
III.1
III
The naphthol OH group of II facilitates the barrierless
bonding and activation of one nitroolefin molecule by
OH / ONO hydrogen bonding (OH…O distance: 1.650 Å)
resulting in minimum structure III. This is an endergonic
process consuming 21 kJ/mol due to the entropic penalty
of III (free energy: 36 kJ/mol relative to the energy sum
of the free educts and C1b-Cu*).
It follows the endergonic C-C-bond formation between
the enolate and the activated nitroolefin resulting in
minimum structure III.1 (relative free energy of
III.1: 4 kJ/mol). An OH / ONO hydrogen bond (OH…O
distance: 1.555 Å) stabilizes III.1. We found a transition
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Figure 7. Free energy profile of the proposed catalytic cycle (cf. Scheme 4), which shows calculated stationary
points (minima- and transition state structures) along the reaction coordinate. Free Gibbs energies at 250 K
are relative to the energy sum of the free educts (nitroolefin and ketoester), H2O and the intermediate
structure C1b-Cu*-THF. The structures arise from DFT calculations at the B3LYP/cc-pVDZ/IEF-PCM (THF)
level of theory. For structural details refer to Figure S28, see Supporting Information.
Scheme 5. Examples for possible application of
3aA-D2 to Synthesize Valuable Chiral Synthetic
Building Blocks (in the Box: Solid State Structure
of 10).
Derivatization
To showcase the utility of the new diastereomeric product
series, some further synthetic transformations were
studied giving products that were previously not
efficiently available with the depicted relative
configurations (Scheme 5). In no case
epimerization was noticed. The chemoselective reduction
of the keto group proceeded nearly fully
Zn, AcOH,
CH2Cl2/MeOH,
5 h, rt
NaBH4 (4 equiv),
EtOH, 78 °C to rt
O
Ph
HO
Ph
N
a partial
NO2
NO2
CO2Et
10
48%
74%
Ph
CO2Et
CO2Et
12
3aA-D2
diastereoselectively giving 10. Its absolute configuration
was determined by X-ray crystallography. Chemoselective
reduction of the nitro moiety was then achieved with
NaBH4 in the presence of NiCl2*6H2O providing γ-amino
acid ester 11,18 which could be readily transformed into
spirolactam 15.
NiCl2*6H2O,
83% NaBH4,
MeOH, 0 °C
Zn, NH4Cl,
H2O/THF (3/10), rt, N2
62%
dimethyl
but-2-yne-
dioate,
toluene,
reflux
MeO2C
MeO2C
O
N
O
HO
Ph
N
NH2
CO2Et
43%
Ph
CO2Et
Ph
CO2Et
Chemoselective reduction of the NO2 group of 3aA-D2
with Zn/HOAc yielded the bicyclic imine 12. In contrast,
in the presence of NH4Cl nitrone 13 was obtained.43 The
latter was applied to a thermal [3+2]-cycloaddition with
an electron-poor dipolarophile to give the tricyclic spiro-
compound 14. The new tetrasubstituted stereocenter was
formed with full diastereocontrol. Its configuration was
determined by noesy (see SI).
11
14
13
aq. KOH (10%, 4 equiv)
MeOH, 0°C to rt
93%
Ph
HO
NH
O
10
15
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preparation of several nitroolefin substrates and Konstantin
Dorst for helpful discussions.
CONCLUSIONS
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2
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4
5
6
7
8
In conclusion, we have reported a new strategy for
cooperative asymmetric catalysis, in which a Lewis acid
works in concert with an imidazolium aryloxide betaine
moiety within a polyfunctional chiral catalyst system. This
system enabled for the first time an efficient general
access to the otherwise rare diastereomeric product series
for the direct 1,4-addition of various 1,3-dicarbonyl
Michael donors to nitroolefins. Due to the robust nature
of the catalyst and its peculiar zwitterionic nature, it can
be readily recycled and reused. Control experiments
revealed that both the imidazolium and the aryloxide are
crucial to form the otherwise rare diastereomer in high
yield and with high enantioselectivity. Kinetic studies
including RPKA according to Blackmond and VTNA
according to Burés, suggest that a single catalyst molecule
is involved, which is stable and not inhibited by product,
and that the C-C-bond formation is the turnover limiting
event. This conclusion is further substantiated by DFT
calculations of the catalytic cycle, which reveals the
balanced interplay of the Cu(II) Lewis acid on the one
ABBREVIATIONS
acac, acetylacetonate; BINAM, 1,1'-bi(2-naphthylamine);
B3LYP, Becke 3 coefficients Lee Yang Parr; cc-pVTZ,
correlation consistent split valence double zeta, DFT, density
functional theory; IEF-PCM, integral equation formalism -
polarizable continuum model; HPLC, high performance
liquid chromatography; NIR, near infrared; NMR, nuclear
magnetic resonance; TBAF, tetra-n-butylammonium
fluoride; THF, tetrahydrofuran; UV, ultraviolet; vis, visible.
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ø
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Selected recent reviews: a) Lin, L.; Feng, X. Catalytic
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Notably, a third stereocenter could also be efficiently
controlled in the 1,4-addition with α,β-disubstituted
nitroolefin substrates making use of
a
highly
diastereoselective protonation of the nitronate
intermediate. Asymmetric reactions between β-ketoesters
and α,β-disubstituted nitroolefins have not been reported
before. The reaction scope could also be extended to a
5
Selected leading examples: a) Wang, B.; Wu, F.; Wang, Y.;
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a
bicyclic densely
functionalized building block with four contiguous
stereocenters. Further applications of this novel catalyst
type will be reported in due course.
ASSOCIATED CONTENT
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental details, spectral data, copies of 1H and 13C NMR
spectra of all new compounds, and copies of HPLC traces
(pdf), cif files for compounds C6, 3aA-D2, 3aA-Me, 3aB-
D2, 3aC-D2, 3aE-D2, 3aE-Me, 3aF-D2, 3aH-D2, 3aJ-
D2, 3aK-D2, 3cA-D2, 3dA-D2, 3hA-D2, 10 and 11).
AUTHOR INFORMATION
Corresponding Author
* rene.peters@oc.uni-stuttgart.de
Author Contributions
All authors have given approval to the final version of the
manuscript.
Asymmetric Diastereodivergent Deracemization,
Angew.
Chem., Int. Ed. 2011, 50, 12631; h) McInturff, E. L.; Yamaguchi,
E.; Krische, M. J. Chiral-Anion-Dependent Inversion of
Diastereo- and Enantioselectivity in Carbonyl Crotylation via
Ruthenium-Catalyzed Butadiene Hydrohydroxyalkylation, J.
Am. Chem. Soc. 2012, 134, 20628; i) Eitel, S. H.; Jautze, S.; Frey,
W.; Peters, R. Asymmetric Michael Additions of α-Cyanoacetates
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
by Soft Lewis Acid
/ Hard Brønsted Acid Catalysis:
This work was financially supported by the Deutsche
Forschungsgemeinschaft (PE 818/7-1, project number
310990893). JL acknowledges support by the state of Baden-
Württemberg through bwHPC and the German Research
Foundation (DFG) through grant no INST 40/467-1 FUGG
(JUSTUS cluster). We thank Mike D. Herrmann for the
Stereodivergency With Bi- vs Monometallic Catalysts, Chem.
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quaternary-quaternary
stereocenters
and
bioactive
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hyperolactones, Nat. Commun. 2018, 9, 1968.
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Selected reviews about 1,4-additions: a) Kanai, M.;
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Enantio- and Diastereoselective Michael Reaction of 1,3-
11 Note that in ref. 8f the relative configuration depicted for the
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12
For pioneering work on the general concept of cooperative
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Hydrogen bonding mediated enantioselective organocatalysis in
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Selected examples for the use of addition reactions of
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Broghammer, F.; Meisner, J.; Klepp, J.; Garnier, D.; Frey, W.;
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Appended Ammonium Salt as an Exceptionally Active
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K.; Mechler, M.; Schamne, I.; Mack, D.; Frey, W.; Peters, R.
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g) Schmid, J.; Frey, W.; Peters, R. Polynuclear Enantiopure
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Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki,
1
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The relative and absolute configuration of products 3aA-
D2, 3aA-Me, 3aB-D2, 3aC-D2, 3aE-D2, 3aE-Me, 3aF-D2,
3aH-D2, 3aJ-D2, 3aK-D2, 3cA-D2, 3dA-D2, 3hA-D2, 10
and 11 were determined by X-ray single crystal structure
analysis. The absolute configuration of all other products 3A-D2
was assigned in analogy. Their relative configurations were
assigned by comparison to literature or, if no data were available,
in analogy (see the Supporting Information).
M.
A Heterobimetallic Pd/La/Schiff Base Complex for
anti-Selective Catalytic Asymmetric Nitroaldol Reactions and
Applications to Short Syntheses of β-Adrenoceptor Agonists,
Angew. Chem., Int. Ed. 2008, 47, 3230; t) Sohtome, Y.; Kato,
Y.; Handa, S.; Aoyama, N.; Nagawa, K.; Shibasaki, M.
Stereodivergent Catalytic Doubly Diastereoselective Nitroaldol
Reactions Using Heterobimetallic Complexes, Org. Lett. 2008,
18
Supplementary crystallographic data for 3aA-D2
10, 2231; u) Trost, B. M.; Ito, H.
A Direct Catalytic
(1872231), 3aA-Me (1908072), 3aB-D2 (1872225), 3aC-D2
(1872232), 3aE-D2 (1872234), 3aE-Me (1908073), 3aF-D2
(1872233), 3aH-D2 (1872227), 3aJ-D2 (1872224), 3aK-D2
(1872235), 3cA-D2 (1872236), 3dA-D2 (1872229) and 3hA-
D2 (1872230), 10 (1872237) and 11 (1908074) have been
deposited with the Cambridge Crystallographic Data Centre.
Their deposition numbers are given in brackets. This material is
available free of charge via the Internet at http://pubs.acs.org
and http://www.ccdc.cam.ac.uk/products/csd/request/.
Enantioselective Aldol Reaction via a Novel Catalyst Design, J.
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For pioneering research on ammonium phenolate betaine
catalysis by the Ooi research group, see: a) Uraguchi, D.;
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A
Bifunctional Organic Base Catalyst for Asymmetric Mannich-
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19
For few acyclic products, the preferred formation of
diastereomer D2 has already been reported to proceed with low
to moderate diastereoselectivity, but the preference for
diastereomer 3-D2 was not generally found in these studies. See
e.g.: a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.
Enantio- and Diastereoselective Michael Reaction of 1,3-
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14 Chianese, A. R.; Crabtree, R. H. Axially Chiral Bidentate N-
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15
a) Mechler, M.; Latendorf, K.; Frey, W.; Peters, R. Homo-
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21 Li, Y.; Wang, J.; Sun, W.; Shan, Y.; Sun, B.; Lin, G.; Zou, J.
16 For related ligand syntheses, see e.g.: a) Kull, T.; Peters, R.
Contact Ion Pair (CIP) Directed Lewis-Acid Catalysis:
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of
bicyclo[2.2.2]octane-1-
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22
The ee value of the major diastereomer D1 was 1% (not
shown in the Table 6).
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23 Overview of hydrogen bonds in cooperative catalysis: Lu, X.;
Deng, L. Hydrogen bonding-mediated cooperative
Supplementary crystallographic data for C6 have been
34
deposited with the Cambridge Crystallographic Data Centre as
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the Internet at http://pubs.acs.org and
http://www.ccdc.cam.ac.uk/products/csd/request/.
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