Highly Enantioselective Kinetic Resolution of Michael Adducts through N-Heterocyclic Carbene Catalysis: An Efficient Asymmetric Route to Cyclohexenes

Article abstract of DOI:10.1002/chem.201802420

A highly efficient strategy for the kinetic resolution of Michael adducts was realized using a chiral N-heterocyclic carbene catalyst. The kinetic resolution provides a new convenient route to single diastereomers of cyclohexenes and Michael adducts in good yields with high enantiomeric excesses (up to 99 % ee with a selectivity factor of up to 458). This “two flies with one swat” concept allows the synthesis of these two synthetically valuable compound classes at the same time by a single transformation.

Full text of DOI:10.1002/chem.201802420

A Journal of
Accepted Article
Title: Highly Enantioselective Kinetic Resolution of Michael Adducts
through N-Heterocyclic Carbene Catalysis: An Efficient
Asymmetric Route to Cyclohexenes
Authors: Dieter Enders, Xiang-Yu Chen, Sun Li, Qiang Liu, Mukesh
Kumar, Anssi Peuronen, and Kari Rissanen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201802420
Link to VoR: http://dx.doi.org/10.1002/chem.201802420
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10.1002/chem.201802420
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COMMUNICATION
Highly Enantioselective Kinetic Resolution of Michael Adducts
through N-Heterocyclic Carbene Catalysis: An Efficient
Asymmetric Route to Cyclohexenes
Xiang-Yu Chen+, Sun Li+, Qiang Liu+, Mukesh Kumar, Anssi Peuronen, Kari Rissanen,
and Dieter Enders*
Dedicated to Professor Elias James Corey on the occasion of his 90th birthday
Abstract: A highly efficient strategy for the kinetic resolution of
Michael adducts was realized using a chiral N-heterocyclic carbene
catalyst. The kinetic resolution provides a new convenient route to
single diastereomers of cyclohexenes and Michael adducts in good
yields with high enantiomeric excesses (up to 99% ee with a
selectivity factor of up to 458). This “catch two flies with one stroke”
concept allows the synthesis of these two synthetically valuable
compound classes at the same time by a single transformation.
carried out early studies on the kinetic resolution of alcohols by
using NHC catalysis.[7] Very recently, significant progress has
been achieved in NHC-catalyzed kinetic resolution of alcohols
and amino compounds through (-unsaturated) acyl azolium
intermediates by the research groups of Zhao,[ 8 ] Yamada,[ 9 ]
Bolm[ 10] and Bode[ 11 ] (Scheme 1a). The kinetic resolution of
oxaziridines and azomethine imines via azolium enolate and
dienolate intermediates have also been developed by Ye[12] and
Chi,[13] respectively. These developments greatly extended the
potential of NHC catalysis. Inspired by the synthetic importance
of the cyclohexenes and Michael adducts, we herein disclose an
NHC-catalyzed enantioselective kinetic resolution of racemic
Michael adducts. The protocol allows the preparation of these
two highly enantiomerically enriched products by a single
transformation (Scheme 1b).
The value of cyclohexenes lies in their utility as building blocks
for a wide variety of biologically active molecules and natural
products.[1] Existing synthetic means to access them rely heavily
on the Diels–Alder reactions,[2] which is the method of choice to
prepare multisubstituted cyclohexenes. There have only been a
few alternative asymmetric routes to multisubstituted
cyclohexenes including organocatalytic cascade reactions[3] and
[4+2] annulations.[4] However, these strategies are not always
appropriate for the construction of an envisaged multisubstituted
cyclohexene product. Thus, the development of new asymmetric
approaches allowing flexible and various substitution patterns
remains of great importance and highly desirable.
The kinetic resolution is a reliable and powerful method for the
preparation of a wide range of enantioenriched compounds,[5]
which serves as an alternative and complementary approach to
asymmetric synthesis, even on large scale. Despite the synthetic
utility of multisubstituted cyclohexenes, their production by
kinetic resolution remains an elusive task. Additionally, the
obtained mixture of the product and recovered starting material
is a possible demerit to this protocol. However, if both of these
compounds are potentially valuable building blocks and obtained
in high enantiopurity, such as Michael adducts, this approach
would become more attractive. Interestingly, the catalytic kinetic
resolution of Michael adducts is surprisingly underdeveloped
and there is no efficient method to achieve this transformation.
We envisioned that these issues could be accomplished by N-
heterocyclic carbene (NHC) catalysis. NHCs hold a prominent
position among versatile organocatalysts for asymmetric C-C
bond formations.[6] Suzuki, Rovis, Maruoka, Scheidt and Studer
Scheme 1. Motivation and synthetic strategy.
To validate the feasibility of the proposed process, the model
reaction of the Michael adduct 1a[14] and the α-bromoenal 2a
was investigated under NHC catalysis (Table 1). It was found
that in the presence of A as the pre-catalyst and CsOAc as the
base, the reaction proceeded smoothly and afforded the desired
product 3a as a single diastereomer with 97% ee at 37%
conversion, albeit with only moderate ee (56%) of the recovered
starting material 1a. A selectivity factor (s) of 66 was obtained
(entry 1). Encouraged by this promising result, a variety of bases
were then screened. It should be noted that the ee of product 3a
was always excellent with different bases, while the ee of the
recovered 1a varied (entries 2-5). Gratifyingly, the employment
of NEt3 as the base significantly improved the ee of the
recovered 1a and gave the best conversion of 52% as well as a
high s factor of 24 (entry 6). Further improvement was achieved
when 4 Å molecular sieves were used as the additive (entry 7).
Notably, the gram-scale reaction proceeded smoothly under the
standard conditions (entry 8).
[*]
Dr. X.-Y. Chen, S. Li, Q. Liu, Dr. M. Kumar, Prof. Dr. D. Enders
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: enders@rwth-aachen.de
Dr. A. Peuronen, Prof. Dr. K. Rissanen
Department of Chemistry, Nanoscience Center,
University of Jyvaskyla, 40014 JYU (Finland)
+
X.-Y. Chen, S. Li and Q. Liu contributed equally
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201802420
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Table 1. Optimization of reaction conditions.
investigations into the effect of substituents at both aromatic
rings R1 and R2 revealed that the reactions were efficient,
affording the desired products 3s-v with good selectivities (89-
93% ee, s = 90-145; entries 19-22). Notably, all these starting
materials were recovered in 99% ee when the conversion was
slightly above 50%. For example, (S)-1s was recovered in 99%
ee at 51% conversion (entry 19). We next attempted the reaction
with various -bromoenals. The groups R3 on α-bromoenals,
such as 4-methylphenyl, 4-fluorophenyl, 4-phenylphenyl, 3-
chlorophenyl and 2-furyl groups, were well-tolerated giving the
corresponding cyclohexenes 3w-a’ with good selectivities (90-
98% ee, s = 47-170; entries 23-27). Additionally, the Michael
adduct of nitromethane to chalcone 1w was also tolerable with a
synthetically useful selectivity factor of 30 (entry 28).
Unfortunately, -alkyl substituted Michael adducts and α-
bromoenals as well as dimethyl- and diethylmalonate gave only
Entry
1
Base
ee3a [%][a]
ee1a [%][a]
Conv. [%][b]
s[b]
56
79
23
28
66
99
99
98
--
CsOAc
NaOAc
TMEDA
DABCO
DBU
97
97
91
98
97
92
95
97
--
37
45
20
22
40
52
51
50
--
116
159
26
2
3
a
trace amount of the products under different reaction
conditions.[16]
4
130
130
126
206
304
--
The absolute configuration of the cyclohexene 3a
was determined by the X-ray structure analysis[ 17 ] and the
configurations of all other products were assigned accordingly.
5
6
NEt3
7[c]
8[d]
9[e]
NEt3
A plausible catalytic cycle is depicted in Figure 1. The addition of
the NHC catalyst to the -bromoenal 2a leads to the formation of
the Breslow intermediate I, which tautomerizes to the
intermediate II. The α,β-unsaturated acyl azolium intermediate III
is then formed via bromide elimination.[18] The Michael addition
of the Michael adduct rac-1a to the α,β-unsaturated acyl azolium
III from the opposite side of the catalyst chiral backbone forms
the C−C bond[ 19 ] and generates the azolium enolate IV.[ 20 ]
Subsequently, an intramolecular aldol lactonization leads to the
unstable -lactone V and regenerates the NHC catalyst. A final
decarboxylation [21] affords the desired cyclohexene 3a.
NEt3
NEt3
[a] The ee was determined by chiral HPLC analysis of the purified products on
a chiral stationary phase. [b] Conversions and s factor values were calculated
by the methods of Kagan: Conv. = ee1/(ee1+ee3), s = ln[(1-Conv.)(1-ee1)]/ln[(1-
Conv.)(1+ee1)].[15] [c] 4Å MS were added. [d] The reaction was performed on a
4 mmol scale. [e] The reaction of R-1a with 2a gave only a trace amount of 3a
and the R-1a was recovered in 99% yield.
With the optimized conditions in hand, the scope of the kinetic
resolution of the Michael adducts with α-bromoenals was studied
(Table 2). A series of 2-(3-oxo-1,3-diarylpropyl)malononitriles 1
reacted smoothly. The electronic properties of the substituents
at the aromatic ring R2 had limited effect on the yields and
enantioselectivities. The corresponding cyclohexenes 3a-f were
obtained with good enantioselectivities of 87-97% ee. The 2-(3-
oxo-1,3-diarylpropyl)malononitriles 1a-f were then recovered
with excellent enantiopurities, which corresponded to s factors of
75-348 (entries 1-6). Substituents at the meta or ortho-position
(3-MeO, 3-Cl and 2-Cl) 1g-i were also well tolerated (entries 7-
9). The reaction of more challenging ortho, para-disubstituted
(2,4-Cl2) substrate also worked well under the optimized reaction
conditions giving the corresponding product 3j in good yield and
the highest s factor of 458 (entry 10). The reaction of a substrate
with
a 2-thienyl group showed good selectivity and the
cycohexene 3k was obtained in 90% ee and 41% yield, while 1k
was recovered in 99% ee and 57% yield (s = 99; entry 11). The
reaction of more electron-donating substrate 1l reacted as well
to give the s factor of 111 (entry 12). The R1 substituents can
also be broadly varied including electron-withdrawing aryl,
electron-donating aryl and heteroaryl groups. The desired
cyclohexenes 3m-r were obtained with good to high
enantioselectivities (87-95% ee). Unreacted 1m−r were
recovered in the yields of 42-51% with 84-99% ee and with s
factors ranging from 51 to 111 (entries 13-18). Furthermore,
Figure 1. Plausible catalytic cycle.
To demonstrate the synthetic usefulness of the present catalytic
strategy, an one-pot protocol for the asymmetric synthesis of
multisubstituted cyclohexenes was developed. Good yields for a
five-step transformation (22–38%) were observed with excellent
stereoselectivities (Table 3).
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Table 2. Substrate scope for the kinetic resolution of Michael adducts with α-bromoenals.
Entry
R1
R2
R3
Yield of 3 [%][a]
ee of 3 [%][b]
Yield of 1 [%][a]
ee of 1 [%][b]
Conv.[%]
s
Ph
1
Ph
Ph
54 (3a)
51 (3b)
49 (3c)
51 (3d)
51 (3e)
56 (3f)
55 (3g)
43 (3h)
46 (3i)
50 (3j)
41 (3k)
40 (3l)
45 (3m)
55 (3n)
53 (3o)
56 (3p)
49 (3q)
53 (3r)
45 (3s)
38 (3t)
38 (3u)
38 (3v)
50 (3w)
42 (3x)
30 (3y)
44 (3z)
52 (3a’)
20 (3b’)
95
87
93
90
92
97
95
88
97
98
90
91
95
91
87
87
88
90
93
89
90
92
91
94
98
90
89
90
44 (1a)
48 (1b)
51 (1c)
44 (1d)
44 (1e)
43 (1f)
42 (1g)
55 (1h)
52 (1i)
47 (1j)
57 (1k)
59 (1l)
51 (1m)
44 (1n)
46 (1o)
42 (1p)
50 (1q)
-- (1r)[c]
52 (1s)
54 (1t)
61 (1u)
49 (1v)
45 (1a)
57 (1a)
49 (1a)
55 (1a)
47 (1a)
57 (1w)
99
99
99
99
97
99
99
97
99
98
99
99
84
99
99
99
92
--
51
53
52
52
51
51
51
52
51
50
52
52
47
52
53
53
51
--
206
75
Ph
2
Ph
4-MeOC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-MeOC6H4
3-ClC6H4
2-ClC6H4
2,4-Cl2C6H3
2-thienyl
3,4-O2CH2C6H3
Ph
Ph
3
Ph
145
99
4
Ph
Ph
5
Ph
Ph
101
348
205
65
6
Ph
Ph
7
Ph
Ph
8
Ph
Ph
9
Ph
Ph
348
458
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28[d]
Ph
Ph
Ph
Ph
Ph
Ph
111
104
111
75
4-MeOC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
2-thienyl
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
75
Ph
Ph
51
Ph
Ph
--
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
Ph
Ph
99
99
99
99
99
99
41
81
99
46
51
52
52
52
52
51
30
47
53
34
145
90
Ph
Ph
99
Ph
126
111
170
148
47
4-MeC6H4
4-FC6H4
4-PhC6H4
3-ClC6H4
2-furyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
90
Ph
Ph
30
[a] Yields of isolated products. [b] The ee was determined by chiral HPLC analysis of the purified product on a chiral stationary phase. [c] The unreacted 1r was
unstable under the current conditions and unisolable. [d] The Michael adduct of nitromethane to chalcone was used as substrate (rac-1w).
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In conclusion, we have developed a highly efficient and practical
strategy for the kinetic resolution of racemic Michael adducts.
This strategy allows not only the recovery of the Michael adducts
with high enantiomeric excess, but also the asymmetric
synthesis of multisubstituted cyclohexenes in good yields and
very high stereoselectivity in a single transformation. The
scalable procedure can be carried out under one-pot conditions
and constitutes a valuable alternative to existing asymmetric
protocols.
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Acknowledgements ((optional))
Support from the European Research Council (ERC Advanced
Grant 320493 “DOMINOCAT”) is gratefully acknowledged.
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Keywords: N-heterocyclic carbenes • kinetic resolution •
cyclohexenes • Michael adducts • asymmetric synthesis
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via
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10.1002/chem.201802420
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[20] For
selected
examples
involving
-unsaturated
acyl
azolium/ammonium-azolium/ammonium enolate activation modes, see:
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10.1002/chem.201802420
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
Two flies with one stroke: A
new efficient NHC-catalyzed
kinetic resolution of Michael
adducts and the access to the
multisubstituted cyclohexenes
by a single transformation has
been developed. These two
kinds of useful building blocks
can thus be obtained in good
yields and very high enantiomer
purity through a scalable one-
pot procedure.
Xiang-Yu Chen, Sun Li, Qiang
Liu, Mukesh Kumar, Anssi
Peuronen, Kari Rissanen, and
Dieter Enders*
Page No. – Page No.
Highly Enantioselective Kinetic
Resolution of Michael Adducts
through N-Heterocyclic
Carbene Catalysis: An Efficient
Asymmetric Route to
Cyclohexenes
This article is protected by copyright. All rights reserved.