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