Enantio- and diastereoselective lntermolecular stetter reaction of glyoxamide and alkylidene ketoamides

Article abstract of DOI:10.1021/ol901081a

A triazolinylidene carbene catalyzed intermolecular Steuer reaction of glyoxamide and alkylidene ketoamides has been developed. 1,4-Dicarbonyl products are afforded In good to excellent yields, enantioselectivities, and diastereoselectivities. Further der

Full text of DOI:10.1021/ol901081a

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2856-2859
Enantio- and Diastereoselective
Intermolecular Stetter Reaction of
Glyoxamide and Alkylidene Ketoamides
Qin Liu and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received May 17, 2009
ABSTRACT
A triazolinylidene carbene catalyzed intermolecular Stetter reaction of glyoxamide and alkylidene ketoamides has been developed. 1,4-Dicarbonyl
products are afforded in good to excellent yields, enantioselectivities, and diastereoselectivities. Further derivatization of the products affords
useful intermediates for organic synthesis.
The Stetter reaction,1 the N-heterocyclic carbene (NHC)
catalyzed addition of aldehydes to Michael acceptors, is a
prototypical example of the emerging class of catalyzed
umpolung reactions.2 Following a seminal early report by
Enders and Teles,3 we4 and others5 have extensively investi-
gated the asymmetric intramolecular Stetter reaction. The
asymmetric intermolecular Stetter, on the other hand, has
remained a much more significant challenge.6 In 2008, Enders
reported an asymmetric intermolecular Stetter reaction of
aromatic aldehydes and chalcones proceeding in good yield and
modest selectivities.7 Concurrently, we reported the enantiose-
lective intermolecular Stetter reaction of glyoxamides 1 with
alkylidene malonates 2 (eq 1).8
(1) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl. 1973,
12, 81. (b) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407–496. (c)
Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534–541. (d)
Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632–2634. (e) Enders,
D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655. (f) Rovis,
T. Chem. Lett. 2008, 37, 2–7.
(2) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4,
1075–1077. (b) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239–
258.
(3) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim. Acta
1996, 79, 1899–1902.
(4) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298–10299. (b) Kerr, M. S.; Rovis, T. Synlett 2003, 1934–
1936. (c) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876–8877.
(d) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284–6289.
(e) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725–5728. (f) Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368–
6378. (g) Moore, J. L.; Kerr, M. S.; Rovis, T. Tetrahedron 2006, 62, 11477–
11482. (h) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552–2553. (i)
Liu, Q.; Rovis, T. Org. Process Res. DeV. 2007, 11, 598–604. (j) Read de
Alaniz, J.; Kerr, M. S.; Moore, J. L.; Rovis, T. J. Org. Chem. 2008, 73,
2033–2040. (k) Orellana, A.; Rovis, T. Chem. Commun. 2008, 730–732.
(5) (a) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025–
2035. (b) Mennen, S. M.; Blank, J. T.; Tran-Dube, M. B.; Imbriglio, J. E.;
Miller, S. J. Chem. Commun. 2005, 195–197. (c) Matsumoto, Y.; Tomioka,
K. Tetrahedron Lett. 2006, 47, 5843–5846.
A shortcoming of the use of alkylidene malonates 2 is the
need for the second ester group. We considered that the use of
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Published on Web 06/09/2009
 2009 American Chemical Society

alkylidene ketoacid derivatives would provide an opportunity
to incorporate synthetically useful substituents on the second
carbonyl (eq 2). However, the reaction would generate
mixtures of diastereomers, a situation that could be rectified
through the use of alkylidene ketoamides. We have already
demonstrated that the protonation event in the asymmetric
Stetter is highly diastereoselective,4d and it has been well-
documented that tertiary ꢀ-ketoamides, bearing a stereocenter
between the carbonyls, are configurationally stable due to
strong A1,3 strain in the enolate.9 Interestingly, catalytic
asymmetric transformations that generate ketoamide stereo-
centers are surprisingly rare.10
in 68% yield, 82% ee, and 6:1 dr (Table 1, entry 1). When
the diethylamide is employed, the product 9 is obtained
in similar yield, high dr, but lower ee (Table 1, entry 2).
The use of a phenylketone on the Michael acceptor results
in a nearly racemic product 10 (Table 1, entry 3). With
longer alkyl ketone substituents, the product 11 is formed
in 92% yield, 89% ee, and 5:1 dr (Table 1, entry 4). Lastly,
we found that optimal conditions involved conducting the
reaction at 0 °C (Table 1, entry 5).
A primary concern at the outset of this study was the
configurational stability of the newly formed stereocenters.
A control experiment using 20 mol % precatalyst 3 and 1
equiv of Hu¨nig’s base was performed in carbon tetrachloride
at 0 °C, shown in Table 2. It was found that the conversion
A Knoevenagel reaction of various ketoamides and
aldehydes generates the requisite substrates 5 as single
olefin isomers.11 Adducts were subjected to our previously
developed reaction conditions, Table 1. At ambient
Table 2. Control Experiment To Test for Epimerization
Table 1. Screen of Michael Acceptors
entry
time (h)
conversion (%)a
ee (%)b
entry
R
R′
product
yield (%)a
ee (%)b
drc
1
2
3
4
5
1
3
5
8
12
18
38
47
65
90
92
92
92
92
92
1
2
3
Me
Me
Et
Me
Me
Me
8
9
10
11
11
68
66
60
92
90
82
77
7
89
92
6:1
14:1
14:1
5:1
Ph
Et
4
a Reaction conducted with 1 equiv of 1 and 2 equiv of 12 at 0 °C. b See
Table 1.
5d
12:1
a Reaction conducted with 1 equiv of 7 and 2 equiv of Michael acceptor
at 23 °C. b Enantiomeric excess determined by HPLC analysis on a chiral
stationary phase. Diastereomer ratio determined by H NMR. d Reaction
c
1
conducted at 0 °C.
of 11 gradually increases with reaction time, with the
reaction complete in 12 h. Fortunately, no epimerization
was observed under these basic conditions, consistent with
our hypothesis.
temperature, the carbene derived from triazolium salt 3
catalyzes the reaction of glyoxamide 7 with ꢀ-keto-amide
derived Michael acceptors in good to excellent yield and
high diastereoselectivities. As shown in Table 1, with a
dimethylamide Michael acceptor, the product 8 is isolated
A series of Michael acceptors with different substitution
were then synthesized and tested using the optimized reaction
conditions, with the results shown in Table 3. When the
alkylidene substituent is a methyl group, the product 14 is
obtained in excellent yield and 89% ee, with 7:1 dr (Table
2, entry 1). Similar results are observed with other alkyl
substituents (Table 2, entry 3-5). The reaction also tolerates
a variety of functional groups; substrates with tethered benzyl
ether, olefin, and alkyne give desired products in excellent
enantioselectivities and good diastereoselectivities (Table 2,
entries 7, 9, 10). Compounds with tethered halogen or
protected aldehyde are also obtained in good yield and good
stereoselectivities (Table 2, entry 8, 11). Substrates with
different ketone R groups were also made and subjected to
the optimized reaction conditions. When R is propyl, the
Stetter adduct 34 is generated in 92% yield, 92% ee, and
11:1 dr (Table 2, entry 12). Finally, substrate 37 with a
tethered olefin on the ketone leads to product 38 in 94%
yield, 90% ee, and 9:1 dr.
(6) (a) Enders, D. In StereoselectiVe Synthesis; Springer-Verlag: Heidel-
berg, Germany, 1993. (b) Enders, D.; Breuer, K. ComprehensiVe Asymmetric
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In order to explain the stereochemistry of this transforma-
tion, a plausible mechanism is proposed in Scheme 1.
Reaction of glyoxamide 7 with carbene derived from 3 will
Org. Lett., Vol. 11, No. 13, 2009
2857

minimum on the energy surface should the conjugate
addition/protonation event be concerted.13 The Michael
acceptor 12 will approach I from the bottom face to avoid
interaction with the benzyl group in the catalyst, as shown
in III. The H-bond between the enol and the amide could
also play a directing role. An intramolecular proton transfer4d
will lead to the desired product 11.14
Table 3. Substrate Scope
The obtained 1,4-dicarbonyl compounds could be further
functionalized to useful building blocks for synthesis (Scheme
2). Reduction of 11 with Super Hydride at -78 °C affords
Scheme 2
a All reactions conducted with 1 equiv of 7 and 2 equiv of Michael
acceptor at 0 °C. b See Table 1. c See Table 1. d Reaction time ) 20 h.
hemiacetal 39 in 72% yield as a 1:1 mixture of diastereomers
at the acetal carbon. Treatment of 39 with dry HCl in
methanol at 65 °C gives tetra-substituted dihydrofuran 40,
which is a versatile intermediate15 and also is a common
substructure found in many natural products.16 During this
transformation, no epimerization is observed. When 39 is
treated with TFA in toluene at 110 °C for 48 h, chemose-
lective cleavage of the dimethylamide occurs to provide
lactone 4117 with three contiguous stereocenters in 72% yield.
Scheme 1
In conclusion, a highly enantio- and diastereoselective
intermolecular Stetter reaction was developed. Catalyzed by
(12) Dudding, T.; Houk, K. N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
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(14) The absolute configuration was confirmed by single crystal XRD
of 22; see Supporting Information.
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generate a nucleophilic olefin intermediate, which may be
one of two different isomers (I or II). Conjugate addition of
the favored intermediate I12 to 12 would transiently generate
stabilized carbanion IV, which may not even be a local
2858
Org. Lett., Vol. 11, No. 13, 2009

chiral triazolinylidene carbenes at 0 °C, reactions of gly-
oxamide and ꢀ-keto-amide derived Michael acceptors afford
1,4-dicarbonyl compounds in good to excellent yields,
enantioselectivities, and diastereoselectivities. A stereochem-
ical model is proposed to account for the absolute and relative
stereochemistry. The obtained product was further function-
alized to useful building blocks for organic synthesis.
Acknowledgment. We thank NIGMS (GM72586) for
support of this research. We thank Johnson & Johnson and
Eli Lilly for unrestricted support, and Susie Miller, Derek
Dalton and Kevin Oberg (CSU) for solving the crystal
structures of 11 and 22.
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Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds, NOE
of 12, and X-ray structures of 11 and 22. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901081A
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