Highly enantioselective intermolecular stetter reactions of β-aryl acceptors: α-ketoester moiety as handle for activation and synthetic manipulations

Article abstract of DOI:10.1021/ol202040b

The use of β,γ-unsaturated-α-ketoesters in the intermolecular Stetter reaction furnishes 1,2,5-tricarbonyl compounds in high yield and excellent enantioselectivity. The α,δ-diketoesters generated using this methodology serve as useful synthetic building b

Full text of DOI:10.1021/ol202040b

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4942–4945
Highly Enantioselective Intermolecular
Stetter Reactions of β-Aryl Acceptors:
r-Ketoester Moiety as Handle for
Activation and Synthetic Manipulations
†
†
‡
Eduardo Sanchez-Larios, Karen Thai, Franc-ois Bilodeau, and Michel Gravel*
,†
ꢀ
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon,
SK S7N 5C9, Canada, and Research and Development, Boehringer Ingelheim (Canada)
Ltd., 2100 rue Cunard, Laval, QC H7S 2G5, Canada
michel.gravel@usask.ca
Received July 28, 2011
ABSTRACT
The use of β,γ-unsaturated-R-ketoesters in the intermolecular Stetter reaction furnishes 1,2,5-tricarbonyl compounds in high yield and excellent
enantioselectivity. The R,δ-diketoesters generated using this methodology serve as useful synthetic building blocks via chemo- and
diastereoselective transformations.
Organic transformations catalyzed by N-heterocyclic
carbenes (NHCs) have been an area of intensive research
in recent years.1 The Stetter reaction was first disclosed in
1973 and consists of the addition of an aldehyde-derived
acyl anion equivalent onto an electron-poor olefin (eq 1).2
reported the first enantioselective intramolecular Stet-
ter reaction.3 This pioneering work inspired others to
develop highly efficient catalysts and protocols achieving
high levels of enantioselectivity.4,5 However, the intermo-
lecular version of the Stetter reaction remains a challenge.
Enders and co-workers reported the first intermolecular
(3) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chem. Acta
1996, 79, 1899.
(4) For a review on enantioselective intramolecular Stetter Reac-
tions, see: (a) Read de Alaniz, J.; Rovis, T. Synlett 2009, 1189. See also:
(b) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025. (c)
Ever since, several research groups have worked inten-
sively toward the development of enantioselective versions
of this transformation. In 1996, Enders and co-workers
ꢀ
Mennen, S. M.; Blank, J. T.; Tran-Dube, M. B.; Imbriglio, J. E.; Miller,
J. S. Chem. Commun. 2005, 195. (d) Matsumoto, Y.; Tomioka, K.
Tetrahedron Lett. 2006, 47, 5843. (e) Liu, Q.; Rovis, T. J. Am. Chem.
Soc. 2006, 128, 2552. (f) Read de Alaniz, J.; Kerr, M. S.; Moore, J. L.;
Rovis, T. J. Org. Chem. 2008, 73, 2033. (g) Jia, M. Q.; Li, Y.; Rong, Z. Q.;
You, S. L. Org. Biomol. Chem. 2011, 9, 2072. (h) Rong, Z. Q.; Li, Y.;
Yang, G. Q.; You, S. L. Synlett 2011, 1033.
† University of Saskatchewan.
‡ Boehringer Ingelheim (Canada) Ltd.
(1) For reviews, see: (a) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc.
(5) For a related enantioselective NHC-catalyzed hydroacylation of
€
Rev. 2008, 37, 2691. (b) Enders, D.; Niemeier, O.; Henseler, A. Chem.
ꢀ
´
Rev. 2007, 107, 5606. (c) Marion, N.; Dıez-Gonzalez, D.; Nolan, S. P.
unactivated alkenes, see: Piel, I.; Steinmetz, M.; Hirano, K.; Frohlich,
R.; Grimmer, S.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 4983.
(6) (a) Enders, D.; Breuer, K. Comprehensive Asymmetric Catalysis,
Springer: Berlin, 1999; p1093. (b) Enders, D.; Balensiefer, T. Acc. Chem.
Res. 2004, 37, 534.
(7) For a formal Stetter reaction using a stoichiometrically-generated
acyl anion equivalent, see: Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932.
Angew. Chem., Int. Ed. 2007, 46, 2988. (d) Phillips, E. M.; Chan, A.;
Scheidt, K. A. Aldrichim. Acta 2009, 42, 55. (e) Moore, J. L.; Rovis, T.
Top. Curr. Chem. 2010, 291, 77.
(2) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl.
1973, 12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (c)
Stetter, H.; Kuhlmann, H. Organic Reactions; Paquette, L. A., Ed.; Wiley:
New York, 1991; Vol. 40, pp 407.
r
10.1021/ol202040b
Published on Web 08/16/2011
2011 American Chemical Society

enantioselective Stetter reaction, albeit delivering the product
in low yield (4%) and enantioselectivity (39% ee).6À8 In
2008, the same group reported an improved intermolecular
Stetter reaction with moderate enantioselectivities (up to
78% ee, Figure 1).
highly enantioenriched (g90% ee) products.16 An added
difficulty with the use of these acceptors is the ease of
racemization of the resulting products under the basic reac-
tion conditions.17 In addition, simple R,β-unsaturated ketone
acceptors have not delivered enantioenriched Stetter pro-
ducts with high efficiency.16 This shortcoming stands in
contrast to the widespread use of ketone acceptors in combi-
nation with achiral catalysts.2 In order to address these issues,
we decided to investigate the use of β,γ-unsaturated-R-
ketoesters18 as acceptors for the intermolecular Stetter reac-
tion. We reasoned that the highly electrophilic nature of these
acceptors would allow us to explore a wide range of catalysts
under mild conditions. Interestingly, the R-ketoester pro-
ducts obtained constitute a known family of cysteine protease
inhibitors.19 In addition, the unique functionalities present in
the resulting Stetter products would provide an ideal venue
for a variety of useful synthetic transformations.
Figure 1. Acceptors previously used in enantioselective inter-
molecular Stetter reactions.
We began our studies by comparing the reactivity of
a model acceptor (3a) with two other phenyl-substituted
acceptors, trans-chalcone (5) and β-nitrostyrene (6)
(Scheme 1).
Their work involved the use of either chalcone
derivatives9 or arylidenemalonates10 as acceptors with
N-benzyl triazolium precatalyst 1a. Concurrently, Rovis
and co-workers employed alkylidenemalonates as accep-
torsincombination withhighlyreactiveglyoxamides inthe
presence of N-aryl triazolium precatalyst 1b.11 This semi-
nal contribution disclosed the first examples of highly
enantioselective intermolecular Stetter reactions (up to
91% ee). This work was followed by an enantio- and
diastereoselective intermolecular Stetter reaction using al-
kylidene ketoamides achieving high levels of diastereo- and
enantioselectivity (up to 19:1 dr and 98% ee).12 In 2009, the
same group disclosed a remarkable study on the design of
the backbone-fluorinated NHC 1c.13 This newly designed
organocatalyst improved the enantioselectivities up to 96%
ee when β-alkyl nitroalkenes were used as Stetter
acceptors.14 Very recently, the research group led by Glorius
reported a highly enantioselective synthesis of amino acids
(up to 99% ee) by means of intermolecular Stetter reactions
using β-unsubstituted acrylates. In contrast to the other
manifolds, the key feature of this approach is a diastereo-
selective proton transfer during the Stetter reaction.15
Despite these great advances in the area, several limitations
remain. Most importantly, the use of β-aryl substituted
acceptors has not yet afforded synthetically useful yields of
Scheme 1. Competition Reactions Between Model Acceptor 3a
and trans-Chalcone (5) or β-Nitrostyrene (6)
Each competition reaction was performed in the pre-
sence of a thiazolium precatalyst and furfural (2a) as the
limiting reagent. Remarkably, the model acceptor 3a
proved to be at least 20 times more reactive than trans-
chalcone and β-nitrostyrene under these conditions, based
on the fact that 4a was the only product that could be
1
detected by H NMR spectroscopy upon complete con-
sumption of furfural.
(8) Johnson and co-workers disclosed a metallophosphite-catalyzed
conjugate addition of acylsilanes onto Michael acceptors, see: Nahm,
M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am. Chem. Soc. 2006,
128, 2751.
(9) Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989.
(10) Enders, D.; Han, J. Synthesis 2008, 3864.
Wethenset outtofind the optimalconditionsemploying
the model acceptor 3a in combination with furfural (2a)
(Table 1).
(11) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130,
14066.
(12) Liu, Q.; Rovis, T. Org. Lett. 2009, 11, 2856.
(13) DiRocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
(16) For a highly enantioselective but low yielding enzyme-catalyzed
€
Stetter reaction, see: Dresen, C.; Richter, M.; Pohl, M.; Ludeke, S.;
€
Muller, M. Angew. Chem., Int. Ed. 2010, 49, 6600.
Chem. Soc. 2009, 131, 10872.
(17) Liu, Q. Catalytic Asymmetric Stetter Reaction: Intramolecular
Desymmetrization of Cyclohexadienone and Intermolecular Reaction of
Glyoxamide, Ph.D. Thesis, Colorado State University, Fort Collins, CO,
2009; p. 48.
(14) Very recently, a study describing the use of catechol as an
additive in this system was reported: DiRocco, D. A.; Rovis, T. J. Am.
Chem. Soc. 2011, 133, 10402.
(18) For other NHC-catalyzed reactions using β,γ-unsaturated
R-ketoesters, see: (a) Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20661. (b) Cohen, D. T.;
Cardinal-David, B.; Scheidt, K. A. Angew. Chem., Int. Ed. 2011, 50,
1678.
(15) (a) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew. Chem., Int.
Ed. 2011, 50, 1410. See also: (b) Read de Alaniz, J.; Rovis, T. J. Am.
Chem. Soc. 2005, 127, 6284. (c) Liu, Q.; Rovis, T. J. Am. Chem. Soc.
2006, 128, 2552. (d) Liu, Q.; Rovis, T. Org. Lett. 2009, 11, 2856. (e)
ꢀ
Sanchez-Larios, E.; Holmes, J. M.; Daschner, C. L.; Gravel, M. Synth-
esis 2011, 1896.
(19) Otto, H. H.; Schirmeister, T. Chem. Rev. 1997, 97, 133.
Org. Lett., Vol. 13, No. 18, 2011
4943

the electron-donating effect of the methyl group on the
heteroaromatic ring. When the aromatic aldehyde methyl
4-formylbenzoate (2c) was used, the reaction proceeded to
form 4cin low yield and moderate enantioselectivity.22 The
use of pyridine-2-carboxaldehyde (2d) led to a more selec-
tive reaction (forming 4d) than the one using pyrazine-2-
carboxaldehyde (2e) (91 vs 87% ee). Remarkably, when
quinoline-2-carboxaldehyde (2f) was employed, it furn-
ished Stetter adduct 4f in excellent yield and very high
enantioselectivity (>98% ee).
Table 1. Optimization of the Reactiona
entry
NHC (x)
base
solvent
yield (%)b
ee (%)c
28d
1
1e (30)
1f (30)
1g (30)
1c (30)
1c (10)
1c (5)
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
20
0
Scheme 2. Scope of the Reaction a
2
3
96
90
98
92
20
80
86
89
90
82
4e
5e
6e
7e
1c (1)
a Unless otherwise noted, all reactions were performed by addition of
the base to a solution of 2a (1.5 equiv), 3a, and precatalyst in the
appropriate solvent (0.2 M) at 0 °C. b Yield of pure isolated products.
c Enantiomeric excess determined by HPLC analysis. d The opposite
enantiomer was obtained. e One equivalent of iPr2NEt was used. DBU
= 1,8-diazabiciclo[5.4.0]undec-7-ene
The screening of bases and solvents in the presence of an
achiral triazolium salt led us to find N,N-diisopropylethy-
lamine (iPr2NEt) and dichloromethane (CH2Cl2) as the
optimum base and solvent (see Supporting Information).
With this set of reaction conditions, various chiral triazo-
lium salts were evaluated. Rovis’ aminoindanol-derived
triazolium salt 1e20 gave poor yield and enantioselectivity
(Table 1, entry 1). The structurally related and bulkier
catalyst 1f proved to be unreactive under our reaction
conditions (entry 2). Rewardingly, the desired product was
obtained in good yield and good enantioselectivity when
catalyst 1g13 was used (entry 3). As was also observed by
Rovis et al. using nitroalkene acceptors,13 fluorinated
triazolium 1c substantially improved the enantioselectivity
relativetotriazolium1g(entry 4).21 It wasalsofound that a
stoichiometric amount of base was required with this
catalyst in order to achieve complete conversion. Interest-
ingly, it was also found that a reduction in the catalyst
loading noticeably improved the enantiomeric excess
(entries 5À6). Further reduction of the loading to 1 mol
% proved to be detrimental (entry 7).
Thereafter, we studied the scope of the reaction (Scheme
2). First, we investigated a variety of aldehydes in the
presence of the model acceptor 3a. When 5-methylfurfural
(2b) was employed, the reaction proved to be slower than
the one using furfural (2a) (4.5 h vs 15 min, respectively).
In both cases, the corresponding benzoin product was
formed instantaneously. In the case of 2b, subsequent
conversion of the benzoin product to the desired Stetter
product was found to be slower than for 2a, possibly due to
a General reaction conditions: 2 (0.15 mmol), 3 (0.1 mmol), 1c (5 mol
%), iPr2NEt (0.1 mmol) in CH2Cl2 (0.5 mL) at 0 °C for <5 min À4.5 h.
Yields of pure isolated products. Enantiomeric excess determined by
HPLC analysis on a chiral stationary phase. The absolute configuration
was tentatively assigned by analogy to ref. 13.
b 10 mol % of 1c was required.
Subsequently, the scope of the acceptor was studied.
The use of electron-poor aromatic groups such as 4-fluor-
ophenyl (4g) and 4-bromophenyl (4h) gave excellent en-
antioselectivity. Similarly, the use of an electron-withdrawing
meta-methoxy substituent resulted in an increased reactivity
on the acceptor (3i), generating the desired product 4i in
excellent yield and enantioselectivity. The addition of an
electron-donating para-methoxy substituent to this acceptor
did not adversely affect the reactivity or selectivity, furnishing
adduct 4j. The larger naphthalene substituent on 3k was well
tolerated, producing 4k in excellent yield and selectivity.
Heteroaromatic-substituted acceptors can also be used, as
shown by product 4l, which was obtained in good yield and
high enantioselectivity. These reactions can also be scaled up.
Indeed, the Stetter reaction yielding 4a was reproduced on ca.
3 mmol of acceptor 3a with similar results, provided that the
(20) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725.
(21) Um, J. M.; DiRocco, D. A.; Noey, E. L.; Rovis, T.; Houk, K. N.
J. Am. Chem. Soc. 2011, 133, 11249.
(22) Rovis and co-workers have observed that benzaldehyde fails to
react in the presence of β-alkyl nitroalkenes and 1c. See ref 13.
4944
Org. Lett., Vol. 13, No. 18, 2011

base was added dropwise as a solution in CH2Cl2. Another
remarkable feature of this methodology is the very short
reaction time associated with high enantioselectivities
(usually <5 min).
Scheme 3. Chemo- and Diastereoselective Transformations on
R,δ-Diketoesters 4a and 4h
The R,δ-diketoesters generated enantioselectively through
our procedure serve as excellent building blocks that can
undergo further chemo- and diastereoselective transforma-
tions. We envisioned that each carbonyl group could be
manipulated chemoselectively due to their different electronic
properties. For this part of the study, 4a was chosen as model
substrate. The first transformation was performed with L-
Selectride or Super-Hydride to reduce the more electrophilic
site, furnishing the alcohol 7a with excellent yield and
essentially complete diastereoselectivity (Scheme 3). Exam-
ples of diastereoselective reductions of 1,4-dicarbonyl com-
pounds directed by a 2-aryl or alkyl substituent are very
rare.23 Importantly, HPLC analysis of alcohol 7a confirmed
that reduction of the Stetter adduct occurred without erosion
of the enantiomeric excess. The single reduction product 7a
could be further functionalized to the N-protected amino
ester derivative 8a in moderate yield (unoptimized). Double
reduction of the ketone functionalities yielded the corre-
sponding diols 9a and 9h in excellent yield. Again, the R-
ketoester was reduced with high diastereoselectivity (>20:1)
whereas the aromatic ketone was reduced with good Felkin
selectivity (3À8:1). The brominated diol 9h was further
transformed into the 2,3,5-trisubstituted tetrahydrofuran
10h under mildly acidic conditions. Presumably, this trans-
formation occurs though an SN1 mechanism furnishing the
more thermodynamically stable 2,3-trans product. Com-
pound 10h was employed to determine the relative config-
uration at C3 and C5 via NOE experiments (see Supporting
Information for details). Complete reduction of the three
carbonyl groups was accomplished by consecutive reduction
to the 2,5-diol followed by reduction of the ester using
LiAlH4. The resulting triol was used without further purifica-
tion and subjected to oxidative cleavage of the diol to afford
the hemiacetal 12a. This hemiacetal could be further oxidized
with PCC to the 3,4-disubstituted lactone 13a in 95% yield.
The observed 3,4-cis relative configuration confirms the
stereochemical outcome of the second reduction of 4a,h
affording 9a,h and 11a (see Supporting Information).
In conclusion, we are reporting the first high yielding and
highly enantioselective intermolecular Stetter reactions on
β-aryl substituted acceptors, thus complementing current
methodologies. This method is operative with a variety of
heteroaromatic aldehydes and aromatic or heteroaromatic
acceptors. In addition, this represents a useful method to
prepare 1,2,5-tricarbonyl compounds, which are amenable
to a variety of synthetic transformations delivering R-hy-
droxy esters, R-amino acid derivatives, 2,5-dihydroxyesters,
2,3,5-trisubstituted tetrahydrofuran derivatives, and 3,
4-disubstituted lactones. Studies aimed at widening the
scope to less reactive aldehydes (aliphatic and aromatic)
and γ-alkyl acceptors are currently underway.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC) of Canada
(Discovery Grant to M.G.), the Canada Foundation for
Innovation, the University of Saskatchewan, and Boeh-
ringer Ingelheim (Canada) Ltd. (Industrial Cooperative
Research Scholarship in Synthetic Organic Chemistry to
K.T.) for financial support.
Supporting Information Available. Spectroscopic data
(1H and 13C NMR) and detailed experimental procedures
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) Zigterman, J. L.; Woo, J. C. S.; Walker, S. D.; Tedrow, J. S.;
Borths, C. J.; Bunel, E. E.; Faul, M. M. J. Org. Chem. 2007, 72, 8870.
Org. Lett., Vol. 13, No. 18, 2011
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