reactive oxo-butenoate (Bode)10 to produce cyclopentenes
after an unusual room temperature decarboxylation.11
Even with the numerous reports of NHC-homoenolate
reactions, the factors governing the partitioning between
these competing 1,2- vs 1,4-addition pathways are cur-
rently not well understood. Additionally, efficient conju-
gate addition reactions of NHC-derived homoenolates to
enals have remained difficult to accomplishefficiently. Our
recent success employing Lewis acids with NHC catalysis
promoted us to investigate this reaction using a NHC/
Lewis acid approach to control the regio- and enantios-
electivity outcome.12 To the best of our knowledge, these
are the first examples of a highly diastereo- and enantio-
selective dimerization of these reactive unsaturated carbo-
nyl systems using cooperative catalysis NHC/Lewis acid
conditions.
Scheme 1. Competing NHC Homoenolate Pathways
Our studies to explore this carbene/Lewis acid possibi-
lity began by combining cinnamaldehyde (1a) in THF with
a stoichiometric amount of Lewis acid (1 equiv) in the
presence of azolium salt A (20 mol %) and DBU at 60 °C.
Several metal alkoxides were initially tested in this reac-
tion, but most of them provided the γ-butyrolactones (1,2
addition) or led to the decomposition of the starting
material.13 After extensive investigation, we discovered
that the use of Ti(Oi-Pr)4 afforded compound 2 as a sole
diastereoisomer as detected by NMR spectroscopy (Table 1,
entry 1). The evaluation of several of the available chiral
azolium salts revealed that phenylalanine-derived azolium
C and tryptophan-derived azolium E14 provided the high-
est levels of enantioselectivity (entries 3 and 5). Impor-
tantly, performing the reaction in the absence of Ti(Oi-Pr)4
did not afford any of 2, which confirmed the essential role of
the Lewis acid in this process (entry 6). At this stage, the
efficiency and selectivity of the transformation (58% yield,
66% ee) was encouraging, but not synthetically viable.
Lowering the temperature to improve the enantioselectiv-
ity resulted in a mixture of desired 2 and an intermediate
β-hydroxyester (16, Scheme 2), which was observed by 1H
NMR spectroscopy. We anticipated that the full elimina-
tion of water to yield compound 215 could be promoted
eq 1) that could be successful reaction partners in these
carbene-catalyzed processes, we have encountered what
can be viewed as a “vinylogous benzoin” limitation.6
Similarly, for NHC-generated homoenolate reactions,
many times the most reactive electrophile present is the
homoenolate precursor, or enal 1. Consequently, the
major product can be the γ-lactone product when the
XdY reactant does not possess the optimal reactivity
(Scheme 1, eq 2, major product).
While successful new homoenolate reactions have been
realized by judicious choice of electrophile to circumvent
the vinylogous benzoin pathway, we have also been in-
vestigating alternative strategies to engage NHC-homo-
enolates in more general reactions.7 An interesting minor
product that we have observed in these homoenolate type
reactions is the β-lactone product, resulting from the 1,4-
addition of the homoenolate (Scheme 1, eq 2, minor
product).8 This alternate dimerization pathway competes
with the more standard 1,2-addition which leads to
γ-lactones. Prior to the disclosure of our 1,4-addition
observation, both Nair and Bode reported variations of
this manifold combining enals and chalcones (Nair)9 or a
(10) (a) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem.
Soc. 2007, 129, 3520–3521. (b) Chiang, P.-C.; Kaeobamrung, J.; Bode,
J. W. J. Am. Chem. Soc. 2007, 131, 8714–8715. (c) Kaeobamrung, J.;
Bode, J. W. Org. Lett. 2009, 11, 677–680.
(4) For a review of Lewis base catalysis, see: Denmark, S. E.; Beutner,
G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638. For a review of NHC-
generated homoenolate methodology, see: Nair, V.; Vellalath, S.; Babu,
B. P. Chem. Soc. Rev. 2008, 37, 2691–2698.
(5) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
6205–6208. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 14370–14371.
(11) (a) Faulkner, D. J. Synthesis 1971, 175–189. (b) Marshall, J. A.;
Karas, L. J. J. Am. Chem. Soc. 1978, 100, 3615–3616. (c) Mulzer, J.;
€
Zippel, M.; Bruntrup, G. Angew. Chem., Int. Ed. 1980, 19, 465–466.
(d) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176–1185
and references cited therein.
(6) For the benzoin reaction, the acyl anion generated in situ adds to
the starting material benzaldehyde, thereby typically producing dimeric
products.
(7) (a) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905–908. (b) Chan,
A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558–4559. (c) Phillips,
E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 3107–3110. (d) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 5334–5335. (e) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc.
2008, 130, 2740–2741. (f) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2008, 130, 2416–2417.
(12) (a) Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A.
Nature Chem. 2010, 2, 766–771. (b) Cardinal-David, B.; Raup, D. E. A.;
Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 5345–5347. (c) Cohen, D. T.;
Cardinal-David, B.; Scheidt, K. A. Angew. Chem., Int. Ed. 2011
Early view. For other examples of NHC-metal cooperative catalysis, see:
(d) Nemoto, T.; Fukuda, T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 4365–
4368. (e) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243–
4246. (f) He, J.; Tang, S.; Liu, J.; Sun, Y.; Pan, X.; She, X. Tetrahedron
Lett. 2009, 50, 430–433. (g) Chen, Z.; Yu, X.; Wu, J. Chem. Commun.
2010, 46, 6356–6358 .
(13) Numerous metal alkoxides were examined including Mg(Ot-
Bu)2, Ba(Oi-Pr)2, and Sr(Oi-Pr)2.
(8) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 10098–10099.
(14) Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306–1315.
(15) The absolute and relative stereochemistry of compounds 2 was
determined by X-ray crystallography of a related derivative (see Sup-
porting Information) and additional assignments made by analogy.
(9) (a) Nair, V.; Vellalath, S.; Poonoth, S.; Suresh, E. J. J. Am. Chem.
Soc. 2006, 128, 8736–8737. (b) Nair, V.; Babu, B. P.; Vellalath, S.;
Varghese, V.; Raveendran, A. E.; Suresh, E. Org. Lett. 2009, 11, 2507–
2510.
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