Enantiodivergent [4+2] Cycloaddition of Dienolates by Polyfunctional Lewis Acid/Zwitterion Catalysis

Article abstract of DOI:10.1002/anie.202009093

Diels–Alder reactions have become established as one of the most effective ways to prepare stereochemically complex six-membered rings. Different catalysis concepts have been reported, including dienophile activation by Lewis acids or H-bond donors and diene activation by bases. Herein we report a new concept, in which an acidic prodiene is acidified by a Lewis acid to facilitate deprotonation by an imidazolium–aryloxide entity within a polyfunctional catalyst. A metal dienolate is thus formed, while an imidazolium–ArOH moiety probably forms hydrogen bonds with the dienophile. The catalyst type, readily prepared in few steps in high overall yield, was applied to 3-hydroxy-2-pyrone and 3-hydroxy-2-pyridone as well as cyclopentenone prodienes. Maleimide, maleic anhydride, and nitroolefin dienophiles were employed. Kinetic, spectroscopic, and control experiments support a cooperative mode of action. High enantioselectivity was observed even with unprecedented TONs of up to 3680.

Full text of DOI:10.1002/anie.202009093

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Enantiodivergent [4+2]-Cycloadditions of Dienolates by
Polyfunctional Lewis-Acid / Zwitterion Catalysis
Authors: Vukoslava Miskov-Pajic, Felix Willig, Daniel M. Wanner,
Wolfgang Frey, and René Peters
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009093
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Enantiodivergent [4+2]-Cycloadditions of Dienolates by
Polyfunctional Lewis-Acid / Zwitterion Catalysis
Vukoslava Miskov-Pajic,[a] Felix Willig,[a] Daniel M. Wanner,[a] Wolfgang Frey,[a] and René Peters*[a]
Abstract: Diels-Alder reactions are established as one of the most
effective ways to prepare stereochemically complex 6-membered
rings. Different catalysis concepts have been reported including
dienophile activation by Lewis acids or H-bond donors and diene
activation by bases. Here we report a new concept, in which an acidic
prodiene is acidified by a Lewis acid to facilitate deprotonation by an
imidazolium-aryloxide entity within a polyfunctional catalyst. A metal
dienolate is thus formed, while imidazolium-ArOH moieties probably
form hydrogen bonds with the dienophile. The catalyst type which is
readily prepared in few steps with high overall yields, was applied to
3-hydroxy-2-pyrone and -pyridone as well as cyclopentenone
prodienes. Maleimide, maleic anhydride, and nitroolefin dienophiles
were employed. Kinetic, spectroscopic and control experiments
support a cooperative mode of action. Unprecedented TONs up to
3680 were achieved still attaining high enantioselectivity.
lactones. Similar lactones have been described as valuable
building blocks for the synthesis of a number of structurally
complex, biologically active natural products such as taxol,[6b] and
others.[12,13] Pyrones 1 are usually quite reluctant to undergo
DAs,[14] unless the electron density is increased by formation of a
dienolate.[15] Consequently, chiral Brønsted bases –in particular
cinchona alkaloid derivatives– have been reported for highly
enantioselective activation.[16] Maleimides
2
were initially
investigated as dienophiles, because succinimides not only
represent an important structural motif in bioactive compounds,[17]
but also because the previously reported methods using a
combination of 1 and 2 suffered from moderate enantioselectivity
and very limited scope.[16a-c]
Asymmetric Diels-Alder reactions (DAs) provide a very important
tool to enantioselectively construct stereochemically complex 6-
membered carbocycles.[1] Attractive features of this reaction type
include stereospecificity regarding diene and dienophile
components, wide applicability of different substrate types and the
possibility to stereoselectively construct a number of stereogenic
centers within the formed cyclohexene ring, thus creating
structural complexity.[1] Various concepts for catalytic asymmetric
DAs have been reported[1] including the use of chiral Lewis acids
(LA),[2] primary or secondary amines/ammonium salts,[3] Brønsted
acids,[4] hydrogen bond donors,[5] and organic Brønsted bases.[4]
With the traditional LA catalysts the dienophile’s LUMO energy is
decreased (Scheme 1).[2] More rarely, metal centers have also
served as tethers to allow for quasi-intramolecular reaction
pathways.[6] In contrast, bases were described to increase the
HOMO energy of acidic (pro)dienes.[1,3,4]
In this article, we report the use of polyfunctional catalysts, in
which the cooperation of a LA[7] and an aprotic imidazolium
aryloxide moiety is utilized to generate the reactive diene.[8] The
prodiene is acidified by coordination to the LA and then
deprotonated by the aryloxide moiety.[9] The LA should stabilize
the generated dienolate. Besides, hydrogen bond activation is
crucial in this catalyst system, as control experiments show, most
likely for activation of the dienophile.[10,11]
Scheme 1. Previous Diels-Alder approaches compared to presented one.
For our initial investigations, 3-hydroxy-2-pyrones 1 were studied
as diene component to form densely functionalized bicyclic
Cu(II)-/imidazolium-/naphthoxide complex C1a (5 mol%)[13] was
found to catalyze the reaction of 1a and 2A at room temperature
with complete endo-, yet low enantioselectivity (entry 1). At 40 °C,
the ee could be significantly increased to 88%, while an excellent
yield was maintained (entry 2). Lower reaction temperatures gave
a decreased enantioselectivity (not shown). Formally replacing
the N-Me substituent by the synthetically useful N-benzyl
protecting group caused a slightly improved enantioselectivity
[a]
M.Sc. V. Miskov-Pajic, M.Sc. F. Willig, M.Sc. D. M. Wanner, Dr. W.
Frey, Prof. Dr. R. Peters
Universität Stuttgart, Institut für Organische Chemie
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
E-mail: rene.peters@oc.uni-stuttgart.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202009093
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COMMUNICATION
employing the same conditions (entry 3). Product 3aB has been
described as valuable precursor to antagonists of
neurotransmitter SP, but was previously only accessible with
moderate enantioselectivity.[18] A change in configuration of the
iminosulfonamide moiety from (1S,2S) to (1R,2R) resulted in the
formation of the opposite product enantiomer (ee = 91%, entry 4).
This shows that the configurational outcome is dominated by the
iminosulfonamide moiety, rather than the axially chiral part.
significantly decreased ee value (entry 6). We suggest that the
coordination of 1 at Cu might result in different coordination
geometries depending on the sulfonamide residues. Lower
loadings still resulted in good results (entries 7-8).
Different pyrones 1 were examined as prodienes under conditions
of Table 1, entry 9, using catalysts C1a and C1b (Table 2). Next
to 1a, also the 4-Me and 4-halo substituted substrates were
effective and only endo products were found (entries 4-6).
Table 1. Development and optimization of the title reaction.
Table 2. Investigation of various 3-hydroxy-2-pyrones as well as -pyridones.
#
1
2
C1
R
H
H
1 or 4
1a
3B or 5B
3aB
yield[a]
97
dr[b]
ee[c]
90
C1a
C1b
>98:2
>98:2
1a
ent-3aB
98
98
3[d]
4
C1b
H
1a
1b
1c
1d
4a
4b
4b
4c
4a
4a
ent-3aB
3bB
96
93
92
94
97
98
95
97
94
94
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
97
93
C1a Me
5
C1a
C1a
C1b
Cl
Br
H
3cB
95
6
3dB
93
7[e]
8[e]
9[e]
ent-5aB
ent-5bB
5bB
94
96
95
C1b allyl
C1a allyl
Entry
C1 (config.)
X
2
T /°C yield[a]
dr[b]
ee[c]
1
2
3
4
C1a (1S,2S)
C1a (1S,2S)
C1a (1S,2S)
C1a (1R,2R)
5
5
5
5
2A
2A
2B
2B
25
99
97
97
95
>98:2
>98:2
>98:2
>98:2
30
88
10[e] C1b
11[e,f] C1b
12[e,g] C1b
Cl
H
ent-5cB
ent-5aC[f]
ent-5aF[f]
79
94
95
40
40
40
90
H
91
[a] Yield of isolated product. [b] Endo/exo ratios determined by 1H NMR using
the crude product. [c] The enantiomeric excess was determined by 1H NMR
using saturated CDCl3 solutions of (R)-(+)-binaphthol.[16a] A minus sign indicates
that the antipode of the enantiomer depicted was generated in excess. [d]
Reaction was performed on 5 mmol scale. [e] Reaction was performed at 25 °C.
[f] 4-O2N-C6H4 was used for Bn in 2. [g] H was used for Bn in 2.
5
C1b (1S,2S)
C1b (1R,2R)
C1b (1S,2S)
C1b (1S,2S)
C1b (1S,2S)
5
5
2B
2B
2B
2B
2B
40
40
40
40
40
98
96
98
95
98
>98:2
>98:2
>98:2
>98:2
>98:2
96
40
96
90
98
6
7[d]
8[d]
9[e]
2.5
1
To showcase the practicality of this method, it was performed on
a 5 mmol scale and provided excellent results (entry 3). In addition,
catalyst recovery of C1b was successful by silica gel filtration.[8]
Employing the recovered catalyst provided ent-3aB in
diastereopure form in 92% yield and with 98% ee for the second
run and 92% yield and with 96% ee for the third run.
5
[a] Yield of isolated product. [b] Endo/exo ratios determined by 1H NMR using
the crude product. [c] The enantiomeric excess of the endo-isomer was
determined by 1H NMR using saturated CDCl3 solutions of (R)-(+)-
binaphthol.[16a] A minus sign indicates that the antipode of the enantiomer
depicted was generated in excess. [d] Reaction time 18 h. [e] 1a was added by
syringe pump.
Besides pyrones 1, we also examined pyridones 4 (entries 7-12)
which are valuable to prepare bioactive compounds like the
antiviral drug Oseltamivir.[19] For catalytic asymmetric DAs of
pyridones with 2, there is a single method available providing high
enantioselectivity, which is currently limited though to N-
mesitylsulfonyl substituted substrates.[20] In our study 2-nosyl (Ns)
protected substrates 4 worked fine as well (entries 7-12). Again,
only endo-isomers were found and different enantiomers were
available with catalysts C1a and C1b.[21] The 2-Ns protecting
group could be readily removed as shown for ent-5aB by PhSH /
DBU at 25 °C in THF (yield: 94%, ee 94%).
It was found that the choice of the sulfonamide unit heavily
influences the enantioselectivity. Most residues R1 (Me, p-tolyl,
C6F5, 2- and 4-nitrophenyl, 2-naphthyl) resulted in poor to
moderate enantioselectivity (for details see the SI). Nevertheless,
with R1 = 1-naphthyl in C1b, which is accessible in an overall yield
of 84% starting from (R)-BINAM (see SI), the enantiomeric excess
increased to 96% (entry 5). Adding 1a by syringe pump further
improved the ee to 98% (entry 9).
To our surprise, with C1b the optical antipode of 3 was formed,
although the (1S,2S) iminosulfonamide configuration was used
(compare entries 3 & 5). In contrast, the (1R,2R) configuration for
C1b resulted in no switch of the preferred enantiomer, but a
Different maleimides 2 were also well tolerated (Table 3). Next to
unbranched and branched N-alkyl (entries 1-2), a Boc group
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10.1002/anie.202009093
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(entry 3) was accepted which was removable from 3aD in 92%
yield (ee = 92%) using TFA at 25 °C. Moreover, product formation
was also achieved with unprotected maleimide (entry 4 and Table
2, entry 12). In addition, aromatic substituents with various
electronic properties were tolerated (entry 5 and SI). The reaction
could also be extended to maleic anhydride 6 providing product
7.[16j] All products were formed in high yields in diastereopure form
with high enantioselectivity.[21]
(2.5 mol%) in the absence of a Cu complex formed racemic
product 3aB in 95% yield as an endo / exo mixture (84:16).
Table 4. Experiments with control catalyst systems.
Table 3. Investigation of maleimide dienophiles 2 and maleic anhydride 6.
#
1
2
2 or 6
2A
R-N / O
Me-N
(ent-)3a or 7
ent-3aA
yield[a]
93
dr[b]
ee[c]
93
[a] Yield of isolated product. [b] Endo/exo ratios determined by 1H NMR using
the crude product. [c] The enantiomeric excess was determined by 1H NMR
using saturated CDCl3 solutions of (R)-(+)-binaphthol.[16a] [d] In the absence of
Cs2CO3.
>98:2
>98:2
2D
cyc-Hex-N
ent-3aD
92
96
3[d]
4[e]
5
2E
2F
2G
6
Boc-N
H-N
Ph-N
O
3aE
ent-3aF
ent-3aG
7
90
89
94
92
>98:2
>98:2
>98:2
>98:2
92
90
With control catalysts C2-C4 (5 mol%) bearing either an alkyl
moiety R, a simple imidazolium or one with an aliphatic alcohol
moiety, the reaction outcome was almost identical as with only
Cs2CO3. The experiments with C2 and C4 were also repeated in
the absence of base providing yields of 5% (ee n.d.) and 10%
(racemic), respectively. In contrast, using Cs2CO3 and C5
equipped with a neutral axially chiral residue bearing an aromatic
OH group stereoselectivity was considerably higher. However,
nearly complete diastereoselectivity was only attained with control
91
6[d,f]
84
[a] Yield of isolated product. [b] Endo/exo ratios determined by 1H NMR using
the crude product. [c] The enantiomeric excess was determined by 1H NMR
using saturated CDCl3 solutions of (R)-(+)-binaphthol.[16a] A minus sign indicates
that the antipode of the enantiomer depicted was generated in excess. [d] C1a
(1S, 2S) was used as catalyst. [e] The reaction was performed at 20 °C. [f] The
reaction was performed at 0 °C.
catalyst C6 containing
a zwitterionic imidazolium/aryloxide
moiety.[26] In agreement with the observation that the
configuration of the axially chiral binaphthol unit has a minor effect
on stereocontrol, enantioselectivity was high with C6. Overall,
these results demonstrate that the zwitterionic moiety is
necessary to attain high control.[27]
Other types of C-H acidic prodienes can be applied as well as
demonstrated for enone 8 (Scheme 2). With 2B catalyst C1a
produced bicycloheptane 9 exclusively as exo-diastereomer
featuring four contiguous stereocenters (98% ee).[22] Surprisingly,
this catalytic asymmetric DA is unknown, although compounds
closely related to 9 have been reported as modulators of nuclear
hormone receptor function.[23] The unexpected exo-selectivity
might possibly point to a stepwise process in that case.
Next to the control experiments, kinetic and spectroscopic
experiments were performed (for details see SI). Blackmond’s
reaction progress kinetic analysis (RPKA) was done using H-
1
NMR spectroscopy.[28] By the “same excess” protocol, catalyst
robustness and a possible product inhibition was assessed.[27]
These experiments show that no significant catalyst
decomposition and product inhibition occur in the model reaction.
The empirical rate law was determined by the variable time
normalization analysis (VTNA) method introduced by Burés.[29]
Again, the model reaction of 1a and 2B was examined at 20 °C
in THF-d8 using catalyst C1b (1S,2S). Four reactions with
different initial concentrations of C1b, 1a and 2B were used
monitoring product ent-3aB. The best fit for the normalization of
the time scale axis was achieved for the following rate law:
Scheme 2. Extension to different substrate types (C1a with (1S,2S)-
configuration).
In addition, with nitroolefin 10 the cycloaddition proceeded very
efficiently (TON 3680, 92% yield) with just 0.025 mol% C1a. The
previously not available endo-product was obtained with an ee of
98%. Prior to this study, only the exo-isomer of 11 was accessible
with moderate dr by chiral amine catalysis with TONs <20.[24,25]
To learn more about the role of the aprotic betaine, experiments
with several control catalysts were conducted (Table 4). Cs2CO3
1.95
0.07
1.00
[
]
[
]
[
]
r = k * C1b
* 1a
* 2B
The reaction rate thus follows a second order kinetic dependence
for C1b, a first order for 2B, and zero order for 1a. The latter might
be explained by substrate saturation for 1a. The second order
dependence for C1b indicates that two catalyst molecules are
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10.1002/anie.202009093
Angewandte Chemie International Edition
COMMUNICATION
involved in the turnover-limiting step.[30] There is also a significant
positive non-linear effect for the model reaction of 1a and 2B
catalyzed by C1b (5 mol%) in THF at 40 °C. We suggest that a
dimeric catalyst might be the active species, because a dimeric
structure was also found for C6 by X-ray analysis[31] (details are
in the SI).
Hwang, W.-M. Dai, R. K. Guy, J. Chem. Soc., Chem. Commun. 1992,
1118-1119; c) chiral stoichiometric LA: D. E. Ward, M. S. Souweha, Org.
Lett. 2005, 7, 3533-3536; d) catalytic asymmetric method: J. Ishihara, S.
Nakadachi, Y. Watanabe, S. Hatakeyama, J. Org. Chem. 2015, 80,
2037−2041.
[7]
Selected reviews on catalytic asymmetric DAs: a) S. Reymond, J. Cossy,
Chem. Rev. 2008, 108, 5359–5406; b) X. Liu, H. Zheng, Y. Xia, L. Lin, X.
Feng, Acc. Chem. Res. 2017, 50, 2621-2631; c) H. Du, K. Ding, in
Comprehensive Enantioselective Organocatalysis, Ed.: P. I. Dalko,
Wiley-VCH, Weinheim, 2013, Vol. 3, pp 1131-1162.
UV-Vis titrations were performed in which C1b was treated with
1a. Having added 1.0 equiv. of 1a, the resulting spectrum is very
similar to the one of the precatalyst, in which a neutral naphthol
unit is present. With larger amounts of up to 10 equiv. of 1a, the
spectra did not significantly change anymore. This suggests that
1a is deprotonated by the zwitterionic moiety. In combination with
the zero order kinetic dependence for 1a, we suggest that 1a
binds to the Cu center where it gets deprotonated resulting in
substrate saturation. A Cu-dienolate could indeed be found by ESI
HRMS (disodium salt: m/z = 1128.2563, calculated: 1128.2564).
The interpretation was validated by 1H-NMR titrations, which were
done in THF-d8 at 20 °C. Because the catalyst is paramagnetic,
no well resolved signals were detected. By addition of 1 equiv. of
1a, its signals almost disappeared caused by the paramagnetism.
However, with an excess of 1a the signals were appearing again,
thus suggesting that the catalyst is already saturated with 1 equiv.
In conclusion, we have reported an efficient way to catalyze [4+2]-
cycloadditions with acidic prodienes. They are activated by
coordination to a LA and deprotonation by a zwitterionic moiety
forming a metal dienolate. The acidic OH group generated during
this proton transfer and the imidazolium unit are crucial for
excellent diastereo- and enantioselectivity. In combination with
the first order kinetic dependence for maleimide 2B, it is likely that
the cycloaddition step is usually turnover-limiting. The reaction
was found to be applicable to different substrate types and TONs
of up to 3680 were achieved. Moreover, the catalyst can be
prepared in very high overall yield, is stable during catalysis and
can be readily recycled by a simple filtration protocol.
[8]
[9]
Michael additions: F. Willig, J. Lang, A. C. Hans, M. R. Ringenberg, D.
Pfeffer, W. Frey, R. Peters, J. Am. Chem. Soc. 2019, 141, 12029–12043.
Lewis acid / Brønsted base catalysis: M. Shibasaki, N. Kumagai, in
Cooperative Catalysis – Designing Efficient Catalysts for Synthesis; R.
Peters (Ed.), Wiley-VCH, Weinheim, 2015.
[10] For more cooperative polyfunctional LA / azolium / H bond catalysts
developed by our group, see: a) M. Mechler, R. Peters, Angew. Chem.
Int. Ed. 2015, 54, 10303–10307; b) J. Schmid, T. Junge, J. Lang, W. Frey,
R. Peters, Angew. Chem. Int. Ed. 2019, 58, 5447-5451.
[11] Related cooperative bi-/polyfunctional LA catalysts bearing cationic side
arms developed by our group: a) D. Brodbeck, S. Álvarez-Barcia, J.
Meisner, F. Broghammer, J. Klepp, D. Garnier, W. Frey, J. Kästner, R.
Peters, Chem. Eur. J., 2019, 25, 1515-1524; b) D. Brodbeck, F.
Broghammer, J. Meisner, J. Klepp, D. Garnier, W. Frey, J. Kästner, R.
Peters, Angew. Chem. Int. Ed. 2017, 56, 4056–4060; c) F. Broghammer,
D. Brodbeck, T. Junge, R. Peters, Chem. Commun. 2017, 53, 1156-
1159; d) P. Meier, F. Broghammer, K. Latendorf, G. Rauhut, R. Peters,
Molecules 2012, 17, 7121–7150; e) T. Kull, J. Cabrera, R. Peters, Chem.
Eur. J. 2010, 16, 9132–9139; f) T. Kull, R. Peters, Angew. Chem. Int. Ed.
2008, 47, 5461–5464; for related polymetallic catalysts, see e.g.: g) J.
Schmid, W. Frey, R. Peters, Organometallics 2017, 36, 4313–4324; h)
M. Mechler, W. Frey, R. Peters, Organometallics 2014, 33, 5492-5508;
i) M. Mechler, K. Latendorf, W. Frey, R. Peters, Organometallics 2013,
32, 112–130.
[12] T. Suzuki, S. Watanabe, S. Kobayashi, K. Tanino, Org. Lett. 2017, 19,
922−925.
[13] H. Shimizu, H. Okamura, N. Yamashita, T. Iwagawa, M. Nakatani,
Tetrahedron Lett. 2001, 42, 8649–8651.
[14] K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner, Tetrahedron 1992,
48, 9111–9171.
[15] H. Okamura, T. Iwagawa, M. Nakatani, Tetrahedron Lett. 1995, 36,
5939–5942.
Acknowledgements
[16] a) With maleimide: H. Okamura, Y. Nakamura, T. Iwagawa, M. Nakatani,
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Iwagawa, M. Nakatani, Tetrahedron Lett. 1998, 39, 1211-1214; e) use of
an α-chloroacrylate: see ref. 12, f) use of enones and α,β-unsaturated
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2017, 19, 4532−4535; i) use of nitroolefins: K. J. Bartelson, R. P. Singh,
B. M. Foxman, L. Deng, Chem. Sci. 2011, 2, 1940-1944; j) for a non-
enantioselective method with maleic anhydride, see: E. J. Corey, A. P.
Kozikowski, Tetrahedron Lett. 1975, 16, 2389-2392.
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG, project 310990893). VMP thanks
the Landesgraduiertenförderung BW for a Ph.D. scholarship.
Keywords: asymmetric catalysis • Diels-Alder • lactones •
lactams • polyfunctional catalyst
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determined
by
X-ray
crystal
structure
analysis,
see
www.ccdc.cam.ac.uk/data_request/cif.
[22] Absolute configuration of 9 (CCDC 2002396) and 11a (after reduction of
the keto group (see SI), CCDC 1998669) were determined by X-ray
analysis, see www.ccdc.cam.ac.uk/data_request/cif.
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[27] In experiments using Cu(II) complexes with common enantiopure ligands
only poor to low enantioselectivity was attained (see SI).
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Entry for the Table of Contents
COMMUNICATION
A very efficient way for catalytic
asymmetric [4+2] cycloadditions is
reported in which acidic prodienes
are deprotonated by a betaine moiety
to form a Cu dienolate, whereas the
dienophile is activated by hydrogen
bond formation.
Vukoslava Miskov-Pajic, Felix Willig,
Daniel M. Wanner, Wolfgang Frey, and
René Peters*
Page No. – Page No.
Enantiodivergent [4+2]-
Cycloadditions of Dienolates by
Polyfunctional Lewis-Acid /
Zwitterion Catalysts
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