Catalytic asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates

Article abstract of DOI:10.1021/ja805680z

An asymmetric intermolecular Stetter reaction of glyoxamide and alkylidenemalonates has been developed. Catalyzed by a novel N-heterocyclic carbene, the Stetter adducts are formed in good yield and excellent enantioselectivity. The presence of a sensitive epimerizable stereocenter is tolerated under these mildly basic reaction conditions if a bulky amine base is used. The products may be further elaborated to provide synthetically useful intermediates. Copyright

Full text of DOI:10.1021/ja805680z

Published on Web 10/04/2008
Catalytic Asymmetric Intermolecular Stetter Reaction of Glyoxamides with
Alkylidenemalonates
Qin Liu, Ste´phane Perreault, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received July 30, 2008; E-mail: rovis@lamar.colostate.edu
Table 1. Glyoxamide Screen
The inversion of the normal mode of reactivity (Umpolung) of
aldehydes catalyzed by cyanide or heteroazolium salt derived
carbenes (2) opens up new synthetic pathways for the construction
of carbon-carbon bonds.1 An application of this concept is the
conjugate addition of acyl-anion equivalents (3) to electrophilic
alkenes (4) for the formation of 1,4-dicarbonyl compounds, a
transformation known as the Stetter reaction (eq 1).2,3 Building on
some key early studies of Enders,4 we have recently reported several
examples of triazolylidene carbene-catalyzed asymmetric intra-
Entry
R
Catalyst
Product (8)
Yield (%)a
ee (%)b
1
2
3
4
5
6
EtO
BnHN
Me2N
(CH2)4N
(CH2)4N
(CH2)4N
9
9
9
9
10
11
a
b
c
d
d
d
100
51
24
50
trace
12
23
<5
42
51
-
5,6
molecular Stetter reactions.
65
a All reactions conducted with 1 equiv of 6 and 2 equiv of 7 at
ambient temperature. b Enantiomeric excess determined by HPLC
analysis on a chiral stationary phase.
While catalysts and reaction protocols are well established for
the enantioselective intramolecular version, the asymmetric inter-
molecular Stetter reaction remains a challenge. Two reports by
Enders and co-workers describe intermolecular examples utilizing
n-butanal and chalcone, albeit with low enantiomeric excess and
yield.7-9 In a related process, Johnson has published an asymmetric
metallophosphite-catalyzed Stetter-like reaction of acyl silanes.10,11
A close examination of Stetter’s pioneering work on this reaction
reveals that Michael acceptors bearing ꢀ-substituents often result in
diminished reactivity and are typically restricted to chalcones or other
highly activated alkenes such as fumarates.2c Interestingly, thiaz-
olylidene-catalyzed addition of glyoxamides to ꢀ-substituted Michael
acceptors seems to be an exception to this tendency.12 We envisioned
that this combination of aldehyde with electrophilic alkene could result
in an enantioselective transformation using enantioenriched N-hetero-
cyclic carbenes (NHC) as catalysts. Herein, we report the application
of the new triazolium salt 9 as precatalyst in the asymmetric
intermolecular Stetter reaction of glyoxamides and alkylidenemalonates.
We began our study by screening different aldehyde partners. The
test reaction involved exposure of glyoxamides (or glyoxylate ester)
6a-d and Michael acceptor 7 to a catalytic amount of the phenyl-
alanine-derived precatalyst 9 and triethylamine (Table 1). First, ethyl
glyoxylate was found to be very reactive for this transformation, but
the enantioselectivity is not promising with our current catalysts (entry
1). A secondary glyoxamide affords racemic product (entry 2) while
a tertiary one gives a 42% ee in 24% yield (entry 3). Generally, tertiary
amides derived from cyclic amines proved best, with the desired Stetter
adduct 8d isolated in a promising 50% yield and 51% ee (entry 4).
Electron-deficient carbenes proved optimal for this transformation
(entry 4-6). The N-phenyl analogue 10 is unreactive while triazolium
salt precatalyst 11 leads to the desired Stetter adduct with 65% ee but
only 12% isolated yield (entry 6). These results reinforce the impact
of the N-aryl substituent on carbene activity.13 Further optimization
revealed that yields are higher in nonpolar solvents, CCl4 being optimal,
and the enantioselectivity is constant in a series of polar and nonpolar
solvents, suggesting a concerted enantio-determining step.14
To improve the enantioselectivity, sterically different alkylidene-
malonates (12a-c) were prepared and reacted with the pyrrolidine-
derived glyoxamide 6d (eq 2). A change from dimethylmalonate
12a to di-tert-butylmalonate 12c gives rise to an enantiomeric excess
increase of 30% without loss of reactivity. A second screen of
glyoxamides using alkylidenemalonate 12c revealed that the mor-
pholine-derived substrate 6e is the best partner for this reaction
(eq 3).
During the course of our investigation, it was found that using an
equivalent of base leads to increased yield, presumably by affording
more triazolylidene carbene catalyst at equilibrium. Catalyst activity
was also prolonged by adding MgSO4 to scavenge residual water. We
also noticed that the previous conditions using triethylamine at room
temperature result in some epimerization of the R-ketoamide products.
9
14066 J. AM. CHEM. SOC. 2008, 130, 14066–14067
10.1021/ja805680z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Intermolecular Stetter Reaction of
Glyoxamide 6e
disubstituted lactone 17. Importantly, this sequence of events leads to
no epimerization, affording the final material in 90% ee.
In conclusion, we have developed an enantioselective inter-
molecular Stetter reaction involving glyoxamides. A variety of
ꢀ-substituted alkylidenemalonates undergo this reaction in good
yield with high asymmetric induction in the presence of a
phenylalanine-derived carbene catalyst. Studies aimed at improving
the efficiency of the catalyst and enlarging the reaction scope to
different types of aldehydes and Michael acceptors are currently
underway.
Acknowledgment. We thank NIGMS (GM72586), Eli Lilly,
Johnson and Johnson, and Boehringer Ingelheim for support. We
thank Susie Miller, Kevin Oberg and Derek Dalton (CSU) and
Joseph H. Reibenspies (Texas A&M) for crystal structures. We
thank Harit Vora (CSU) for the synthesis of catalyst 9. S.P. thanks
the FQRNT for a postdoctoral fellowship. T.R. thanks the Monfort
Family Foundation for a Monfort Professorship.
Supporting Information Available: Experimental procedures,
characterization, 1H/13C NMR spectra; CIF file for 16 and 18. This
material is available free of charge via the Internet at http://pubs.acs.org.
a All reactions conducted using 0.16 mmol 6e with 2 equiv of 12.
b See footnote, Table 1. c Reaction time: 3 h. d Reaction time: 28 h.
References
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239–258. (b)
Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326–1328.
(2) (a) Stetter, H.; Schrecke, M. Angew. Chem., Int. Ed. Engl. 1973, 12, 81.
(b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639–647. (c) Stetter,
H.; Kuhlmann, H. Org. React. 1991, 40, 407–496.
Fortunately, decreasing the temperature to -10 °C and employing a
bulkier base such as Hu¨nig’s base considerably reduced the erosion
of this sensitive stereocenter15 (eq 4).16
A series of Michael acceptors with different alkyl groups at the
ꢀ-position was synthesized and subjected to the optimized reaction
conditions (Table 2). By lowering the temperature and using 100 mol%
Hu¨nig’s base, Stetter adduct 14c has been isolated in 84% yield and
90% ee (entry 1). Longer alkyl chains offer nearly the same results
(entry 3-5). However, a methyl substituent is more vulnerable to
epimerization (entry 2). In fact, a 12 h reaction time led to product
14d in 97% yield with 81% ee. Stopping the reaction after 3 h resulted
in 68% yield and 87% ee. Substrate 12h, containing a bulkier iso-
butyl side-chain, requires a longer reaction time (28 h) without any
loss of enantioselectivity (entry 6).17 The reaction is also tolerant of a
wide range of functional groups, such as benzyl ether, alkyl chloride,
thioacetal, and alkene (entries 7-10).
A 2 mmol scale experiment allowed us to isolate pure Stetter adduct
14c in 92% yield and 90% ee along with a 100% recovery of excess
12c (Scheme 1). The R-ketoamide product can be further functionalized
to afford different useful intermediates. Chemo- and diastereoselective
reduction of the ketone affords the secondary alcohol 15 in 8:1 dr,
favoring the syn diastereomer.18 Concomitant deprotection of the esters
and lactonization can be accomplished in neat formic acid leading to
16. Finally, thermal decarboxylation was performed to provide
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2040. For the syntheses of the triazolium salts, see: (i) Kerr, M. S.; Read
de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725–5728.
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Org. Chem. 2004, 2025–2035. (b) Mennen, S. M.; Blank, J. T.; Tran-Dube,
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Berlin, 1999; 1093-1104. (b) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534–541.
(8) Scheidt has reported the asymmetric conjugate addition of a stoichiomet-
rically generated acyl anion equivalent to nitrocyclohexene mediated by a
thiourea; see: Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2006, 128, 4932–4933.
(9) While this manuscript was in review, an asymmetric intermolecular Stetter
involving chalcones appeared: Enders, D.; Han, J.; Henseler, A. Chem.
Commun. 2008, 3989–3991.
(10) Nahm, M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am. Chem.
Soc. 2006, 128, 2751–2756.
(11) For addition of acyl-silanes to chalcones generating racemic product, see:
Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
126, 2314–2315.
Scheme 1. R-Ketoamide Functionalization
(12) Stetter, H.; Skobel, H. Chem. Ber. 1987, 120, 643–645.
(13) Rovis, T. Chem. Lett. 2008, 37, 2–7.
(14) See Supporting Information.
(15) Similar products have been assembled using other strategies: (a) Uyeda,
C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229. (b) Enders,
D.; Bonten, M. H.; Raabe, G. Angew. Chem., Int. Ed. 2007, 46, 2314–
2316. (c) Enders, D.; Bonten, M. H.; Raabe, G. Synlett 2007, 885–888.
(16) Glyoxamide is consumed in <5 min to form benzoin adduct prior to the
appearance of any Stetter product, also noted by Enders (see ref 9).
(17) A Michael acceptor with an iso-propyl ꢀ-substituent was subjected to the
same reaction conditions at 23 °C but did not afford any Stetter adduct.
(18) Absolute configuration and relative stereochemistry were assigned by X-ray
structure analysis of 16 and 18. The opposite diastereomer of 15 is formed
in Et2O at-78 °C (3:1 dr).
JA805680Z
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