Highly enantioselective intermolecular stetter reaction of simple acrylates: Synthesis of α-chiral γ-Ketoesters

Article abstract of DOI:10.1002/chem.201202432

Simple Stetter: A novel N-heterocyclic carbene (NHC) was designed by combining an electron-rich 2,6-dimethoxy substituent and an underestimated yet promising chiral motif. With this NHC in hand, a highly enantioselective intermolecular Stetter reaction of simple acrylates was developed, yielding versatile α-chiral γ-ketoesters. This represents the first catalytic asymmetric route towards these valuable compounds (see scheme).

Full text of DOI:10.1002/chem.201202432

COMMUNICATION
DOI: 10.1002/chem.201202432
Highly Enantioselective Intermolecular Stetter Reaction of Simple
Synthesis of a-Chiral g-Ketoesters
ACHTUNGTRENUNNG crylates:
AHCTUNGTRENNUNG
Nathalie E. Wurz, Constantin G. Daniliuc, and Frank Glorius*[a]
The concept of N-heterocyclic carbene (NHC)-catalyzed
Umpolung has enabled the development of a broad range of
carbon–carbon bond-forming reactions.[1] Besides the ben-
zoin condensation, the Stetter reaction is the most exten-
sively studied transformation in the realm of NHC organo-
catalysis, generally leading to versatile products with an un-
natural distance between the functional groups.[2] Whilst the
asymmetric intramolecular version has been thoroughly in-
vestigated,[2d] the intermolecular variant has only moved
into focus over the past few years.[3] A recent report was
published by the group of Enders in 2008;[3a] the addition of
aromatic aldehydes to chalcone derivatives proceeded with
up to 78% enantiomeric excess (ee; Scheme 1). Since then
tivity. Key contributions were again made by Rovis and co-
workers, who focused on the use of alkylidenemalonates
and ketoamides.[3b,d]
In 2011, we reported a protocol using methyl 2-acetami-
doacrylate for the highly enantioselective synthesis of a-
amino acid derivatives.[3f] This was the first example of an
asymmetric intermolecular Stetter reaction of b-unsubstitut-
ed Michael acceptors. A stereocenter is only formed by
highly selective protonation of the rather acidic a-position.[4]
Unfortunately this Michael acceptor could not be varied
successfully. The NHAc moiety was crucial for the success
of the reaction and small variations led to a complete loss of
reactivity.
To date, an asymmetric intermolecular Stetter reaction of
simple acrylates without a second activating group has not
been described. Indeed, these acceptors are not only intrins-
ically poor substrates for NHC organocatalysis, but are also
inefficient electrophiles in other organocatalyzed processes
including enamine catalysis.[5] In this paper, we report an
asymmetric intermolecular Stetter reaction of simple a,b-un-
saturated esters enabled by the development of a novel
NHC catalyst.
Recently our group has made significant contributions to
the field of NHC-catalyzed hydroacylations of electron-neu-
tral carbon–carbon double and triple bonds.[6] Whilst the in-
tramolecular hydroacylation of alkenes and alkynes could
be accomplished with standard NHCs, a new class of NHCs
had to be developed for the enantioselective intermolecular
hydroacylation of cyclopropenes.[6f,g] In contrast to previous-
ly reported triazolium carbenes which commonly bear a
phenyl, mesityl, or pentafluorophenyl substituent on one of
the nitrogen atoms, these novel NHCs possess a 2,6-dime-
thoxyphenyl moiety, which led to superior reactivity and se-
lectivity.
Under the conditions previously described for the enan-
tioselective synthesis of a-amino acid derivatives[3f] the Stet-
ter reaction between 4-chlorobenzaldehyde (1a) and butyl
methacrylate (2a) gave product 3a in ꢀ5% (NHC precursor
4a, Scheme 2). However, moving to the corresponding cata-
lyst precursor 4b bearing a dimethoxyphenyl substituent led
to product formation in 15% yield and an encouraging ee of
84% (Scheme 2). In addition, a broad range of NHCs were
screened as catalysts in this transformation. Indeed NHC 5a
catalyzed this reaction, yielding the desired product with
low conversion, but in excellent 98% ee. This chiral motif is
very uncommon in NHC organocatalysis even though it is
Scheme 1. Michael acceptors previously employed in the asymmetric in-
termolecular Stetter reaction.
considerable progress has been made, but the only other
monoactivated olefins that have been employed successfully
in the Stetter reaction are nitroolefins, a system studied in
depth by the Rovis group.[3e,h,i,l] Otherwise all Michael ac-
ceptors require a second activating group for adequate reac-
[a] N. E. Wurz, Dr. C. G. Daniliuc, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax : (+49)251-83-33202
E-mail: glorius@uni-muenster.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202432.
Chem. Eur. J. 2012, 18, 16297 – 16301
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
16297

Figure 1. Crystal structure of triazolium salt 5b. (Thermal ellipsoids are
shown with 30% probability).
prepared. Catalyst 6 highlights the importance of the dime-
thoxyphenyl moiety, as its replacement with the sterically
similar, but electronically different, 2,5-diethylphenyl sub-
stituent leads to a drastic decrease in reactivity.[11] When the
benzhydrylpyrrolidine moiety was replaced with the
common benzylpyrrolidine system, a significant reduction of
ee (91 to 82%) was observed. The use of the sterically more
encumbered derivatives 8, 9, 10, and 11 did not lead to an
improvement in the degree of enantioinduction.
With catalyst 5b in hand, we further optimized the reac-
tivity of this transformation.[12] K3PO4 was found to be the
best base for this reaction, whilst toluene remained superior
to more polar solvents such as THF or 1,4-dioxane. Decreas-
ing the temperature from room temperature to 08C led to a
complete loss of reactivity. Using 15 mol% of 5b finally
gave full conversion, whilst the variation of other reaction
parameters or the employment of the NHCs described
above did not lead to any further improvement.
Under these optimized reaction conditions, precatalyst 5a
still afforded the product in only 21% isolated yield. In-
trigued by this large reactivity difference, we conducted ki-
netic studies (Figure 2). In both cases, benzoin formation is
observed as a side reaction, but this is a reversible process.
With NHC 5b, benzoin condensation is very fast and almost
complete after 2 h. Product formation is slow at the begin-
ning (23% conversion after 4 h), but reaches completion
after 12 h. With the mesityl analogue 5a, a similar product
distribution is observed after 4 h. Then the catalyst loses its
activity and no further reaction is observed.[14] However, ad-
ditional experiments have shown that 5a is still active at this
point.[15] Therefore it may not be concluded whether the
lower yield observed with catalyst 5a is solely caused by its
less nucleophilic nature compared to 5b or by a faster deg-
radation or both.
Scheme 2. Screening of NHCs. General reaction conditions: 1a
(0.2 mmol, 1.0 equiv), 2a (0.4 mmol, 2.0 equiv), NHC·HX (10 mol%),
KOtBu (8 mol%), toluene (0.5m), room temperature, 24 h. Ar=4-chloro-
phenyl. Conversions are given as determined by 1H NMR analysis of the
crude reaction mixture using CH2Br2 as the internal standard. [a] The S-
enantiomer was obtained. [b] These very low conversions were even ob-
served under the conditions as optimized for catalyst 5b (NHC·HX
(10 mol%) and K3PO4 (0.5 equiv)).
readily synthesized from inexpensive (S)-pyroglutamic
acid.[7] Encouraged by this result, an extensive screening of
the reaction parameters, such as solvent, base, and tempera-
ture, was conducted, but the conversion could not be in-
creased above 20%.[8] As a large increase in reactivity was
observed with NHCs 4a and 4b, the 2,6-dimethoxyphenyl
analogue of 5a (5b) was synthesized. A crystal structure of
5b is shown in Figure 1.[9] Indeed with catalyst 5b the prod-
uct was obtained with 50% conversion, even though the ee
slightly decreased to 91%.[10] In order to study the influence
of the substituents on the effectiveness of the new catalyst
5b, the two structurally closely related NHCs 6 and 7 were
A broad range of aromatic aldehydes could be employed
in this transformation (Table 1). The use of halide-substitut-
ed aromatic aldehydes led to the formation of the corre-
sponding products in excellent yields and with ee values of
90% or above (3a–3d).[16] Even a fluorine substituent in the
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Stetter Reaction of Simple Acrylates
COMMUNICATION
however, a reduction of conversion was observed (3i–3k).[17]
Comparable yields were obtained when NHC precursors 5c
and 8 were used (not shown). Even though the reaction with
an aliphatic aldehyde proceeded with relatively poor conver-
sion, we were glad to see that the corresponding product
was still formed with high ee (3l).[18] Employing a heteroaro-
matic aldehyde in this Stetter reaction gave the desired ke-
toester in excellent yield and with high enantioselectivity
(3m).
With the scope of the aldehyde component established,
we turned our attention to the variation of the Michael ac-
ceptor (Scheme 3). Alkyl substituents on both the ester and
Figure 2. Kinetic measurements for catalysts 5a (top) and 5b (bottom).
Table 1. Substrate scope with respect to aldehyde variation.[a]
R
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
4-chlorophenyl
4-bromophenyl
3-chlorophenyl
3,4-dichlorophenyl
2-fluorophenyl
phenyl
4-trifluoromethylphenyl
4-carbomethoxyphenyl
3-methylphenyl
4-biphenyl
3a
3b
3c
3d
3e
3 f
3g
3h
3i
90
89
91
86
77
53
86
86
43
30
31
26
97
91
91
92
90
91
92
91
93
92
93
92
87
93
Scheme 3. General reaction conditions: 1a (0.4 mmol, 1.0 equiv),
2
(0.8 mmol, 2.0 equiv), 5b (15 mol%), K3PO4 (1.0 equiv), toluene (0.8 mL,
0.5m), room temperature, 24 h. Ar=4-chlorophenyl. Isolated yields are
given. [a] 5b (20 mol%) and KOtBu (16 mol%) were used instead.
[b] Starting from (Z)-methyloct-2-enoate.
3j
3k
3l
4-tert-butylphenyl
benzyl
2-furyl
the a-position were well tolerated in terms of both conver-
sion and enantioselectivity (3n–3r). The employment of the
isopropyl substituted variant rendered the corresponding
product 3r with good conversion and an excellent ee of
97%. Whilst the use of benzyl- or phenyl-substituted acryl-
ates led to a significant reduction in conversion and ee (3s
and 3u), a bulky phthalimido substituent was well tolerated
(3t). Amino acid derivative 3v was obtained in good yield,
but surprisingly poor enantioselectivity (75%, 46% ee, not
shown). We found this to be mainly caused by K3PO4-cata-
lyzed racemization.[19] Indeed the ee was improved dramati-
cally to 89% by a small change in the reaction conditions:
3m
[a] General reaction conditions: 1 (0.4 mmol, 1.0 equiv), 2a (0.8 mmol,
2.0 equiv), 5b (15 mol%), K3PO4 (1.0 equiv), toluene (0.8 mL, 0.5m),
room temperature, 24 h. Isolated yields are given.
ortho-position was not detrimental to the reaction; the ke-
toester was still obtained in a good yield (3e). Other elec-
tron-withdrawing substituents are also well tolerated (3g,
3h). The use of aldehydes with an electron-donating moiety
still led to product formation with high enantioselectivity;
Chem. Eur. J. 2012, 18, 16297 – 16301
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16299

F. Glorius et al.
0.40 mmol, 1.0 equiv) in a glove box. Toluene (0.8 mL, 0.5m) and acrylate
(0.80 mmol, 2.0 equiv) were added under a positive pressure of argon.
The reaction mixture was stirred at room temperature for 24 h. EtOAc
was added, and the reaction mixture was filtered through a short pad of
silica and concentrated in vacuo. Purification by flash column chromatog-
raphy yielded the isolated products.
5b (20 mol%), KOtBu (16 mol%) and aldehyde were stir-
red in toluene for 30 min before addition of the acrylate.
Under these conditions, which were also employed in our
previous work,[3f] no free base other than the free NHC is
present, and therefore racemization of the product is avoid-
ed. Whilst b-substituted acceptors with E-configuration were
unreactive, we were pleased to find that first attempts at
using Z-configured acrylates in this transformation proved
promising. The use of (Z)-methyloct-2-enoate led to the cor-
responding product with good conversion and 80% ee
(KOtBu conditions, 3w).[20] Unfortunately, (Z)-ethyl cinna-
mate is not a suitable substrate for this transformation, as
the ketoester was obtained as a racemic mixture, presuma-
bly because of the high acidity of the stereocenter, which is
flanked by a keto and an aryl group.
Acknowledgements
We are indebted to the Deutsche Telekom Stiftung for a predoctoral fel-
lowship (N.E.W., 2009–2012). The research of F.G. has been supported by
the Alfried Krupp Prize for Young University Teachers of the Alfried
Krupp von Bohlen und Halbach Foundation. We thank Michael Schedler
for crystallization of catalyst 5b, Karin Gottschalk and Johannes B. Ernst
for skillful technical assistance, and Michael Schedler, Dr. Isabel Piel, Dr.
Xavier Bugaut and Fan Liu for the preparation of some catalysts.
This protocol provides access to highly versatile com-
pounds with stereogenic centers bearing a small substituent,
such as methyl. Their stereoselective introduction is often
nontrivial. To the best of our knowledge, this is the first cat-
alytic asymmetric route to compounds 3a–3s.[21] Comparably
substituted g-ketoacids have shown promising biological ac-
tivity.[22] In addition, g-ketoester 3a could be readily con-
verted into the corresponding lactone 12 with high diaster-
eoselectivity (Scheme 4).[23] The lactone was isolated as a
Keywords: acrylates · asymmetric catalysis · N-heterocyclic
carbenes · organocatalysis · Stetter reaction · synthetic
methods
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Scheme 4. Synthesis of a g-butyrolactone.
single diastereomer and with 99% ee. Since the butyrolac-
tone framework is a common motif found in many natural
products and pharmacologically active molecules, modular
stereoselective routes towards these compounds, especially
towards ones bearing multiple stereogenic centers, are of
high interest.
In conclusion, we have developed a highly enantioselec-
tive intermolecular Stetter reaction of simple acrylates that
previously could not be employed in this transformation.
This led to the formation of valuable building blocks with
an unnatural distance between the functional groups. The
key to success was combining an electron-rich 2,6-dimethox-
yphenyl moiety and an underestimated, but very promising
chiral motif derived from inexpensive (S)-pyroglutamic acid
to design a novel NHC. In combination with the other novel
NHCs presented in this study, this catalyst will provide new
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Experimental Section
A
dried Schlenk flask was charged with the aldehyde (0.40 mmol,
1.0 equiv), 5b (30.0 mg, 0.060 mmol, 15 mol%), and K3PO4 (84.9 mg,
16300
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Stetter Reaction of Simple Acrylates
COMMUNICATION
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[12] For details on the optimization of the transformation, see the Sup-
porting Information.
[13] M. Wadamoto, E. M. Phillips, T. E. Reynolds, K. A. Scheidt, J. Am.
Chem. Soc. 2007, 129, 10098–10099.
[14] When the benzoin of 1a was employed as the starting material, 5a
still gave the product with 15% conversion. Therefore, 5a catalyzes
the retro-benzoin reaction.
[4] For an intermolecular asymmetric Stetter reaction with a diastereo-
selective protonation of the a-position, see Reference [3d].
[5] For a review on enamine catalysis, see: P. P. Pihko, I. Majander, A.
Erkkilꢀ, Top. Curr. Chem. 2009, 291, 29–75.
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4171.
[15] First attempts at isolating possible decomposition products of the
NHCs by carrying out stoichiometric variants of the reaction have
been unsuccessful. See Supporting Information for details on how
the activity of the NHC was tested.
[16] The absolute configuration was determined by transforming 3 f into
the free acid and comparing its optical rotation with known litera-
ture values, see Supporting Information for details and F. J. McEvoy,
F. M. Lai, J. D. Albright, J. Med. Chem. 1983, 26, 381–394.
[17] This is a trend we have observed previously. Additional experiments
showed that with 4-tert-butylbenzaldehyde benzoin formation is still
fast and nearly complete after two hours, nevertheless the Stetter
product could only be obtained in 31%. Therefore the low isolated
yield is caused by slower conversion of the benzoin into the final
product. We surmise that the decrease in conversion is caused by
disfavored attack on the less electrophilic benzoin intermediate by
the NHC. For a competition experiment, see the Supporting Infor-
mation.
[7] More surprisingly, in a first report by Enders and co-workers its em-
ployment in an intermolecular benzoin reaction gave the product in
only 5% ee; a) D. Enders, J. Han, Tetrahedron: Asymmetry 2008, 19,
1367–1383; very recently, its combination with a pyridinyl substitu-
ent was reported: b) T. Soeta, Y. Tabatake, K. Inomata, Y. Ukaji,
Tetrahedron 2012, 68, 894–899; chiral fused bicyclic triazolium salts
were first introduced by Knight and Leeper: c) R. L. Knight, F. J.
Leeper, J. Chem. Soc. Perkin Trans. 1 1998, 1891–1894.
[18] In a recent report focusing on the use of aliphatic aldehydes in an
asymmetric intermolecular Stetter reaction, Rovis and co-workers
state that the use of aliphatic aldehydes in this transformation is
generally unsuccessful, because of their lower electrophilicity (see
Reference [3l]).
À
[8] Also, when the BF4 variant of 5a was used, the isolated yield did
not exceed 21%.
[9] CCDC-881491 (5b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[10] This is surprising as for the hydroacylation of cyclopropenes, the em-
ployment of the 2,6-dimethoxyphenyl NHC variant led to higher
enantioselectivities than the mesityl-substituted analogue. This was
attributed to an enhanced selectivity in the E/Z geometry of the
Breslow intermediate. Racemization experiments show that the de-
crease in ee is not induced by base or NHC-catalyzed racemization.
See Supporting Information for details.
[11] For the use of 2,6-diethylphenyl-substituted NHCs, see: a) D. E. A.
Raup, B. Cardinal-David, D. Holte, K. A. Scheidt, Nat. Chem. 2010,
2, 766–771; b) B. Cardinal-David, D. E. A. Raup, K. A. Scheidt, J.
Am. Chem. Soc. 2010, 132, 5345–5347; c) D. T. Cohen, B. Cardinal-
David, K. A. Scheidt, Angew. Chem. 2011, 123, 1716–1720; Angew.
Chem. Int. Ed. 2011, 50, 1678–1682; d) J. Dugal-Tessier, E. A.
OꢆBryan, T. B. H. Schroeder, D. T. Cohen, K. A. Scheidt, Angew.
Chem. 2012, 124, 5047–5051; Angew. Chem. Int. Ed. 2012, 51, 4963–
4967; e) B. Maji, L. Ji, S. Wang, S. Vedachalam, R. Ganguly, X.-W.
[19] When the product 3v (89% ee) was stirred with K3PO4 (1.0 equiv)
in toluene (0.5m) the ee dropped to 44% after 20 h. See Supporting
Information for details. Comparing the absolute configuration of
products 3a and 3v strongly suggests that the NHAc moiety is not
solely responsible for the enantioinduction. Therefore it is astonish-
ing that this substituent has such a strong influence on the reactivity
as we observed in our previous work. For this and for the determi-
nation of the absolute configuration of 3v, see Reference [3f].
[20] 71% yield, 70% ee under standard conditions.
[21] For a synthetic route from enantiomerically enriched starting mate-
rials, see E. Nakamura, K. Sekiya, I. Kuwajima, Tetrahedron Lett.
1987, 28, 337–340.
[22] For example, Flobufen and Tanomastat (BAY 12–9566): E. M.
Bengtson, J. R. Rigas, Drugs 1999, 58, 57–69.
[23] For the selective reduction of similar compounds, see J. M. Kalle-
meyn, M. M. Mulhern, Y.-Y. Ku, Synlett 2011, 535–538.
Received: July 8, 2012
Revised: October 11, 2012
Published online: November 14, 2012
Chem. Eur. J. 2012, 18, 16297 – 16301
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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