a,b-unsaturated aldehydes or cinnamaldehydes with strongly
donating substituents (Table 2, entries 1, 11–13), presumably as
a consequence of the reduced electrophilicity of these substrates.
The solvent compatibility of this reaction was also studied in an
effort to disprove the existence of concentrated organic phases.
Analogous to our findings in the nornicotine-catalyzed aqueous
Distinct from other organocatalysts, nornicotine, a natural
product, functions only under aqueous conditions, providing a
unique scaffold for the future development of ‘‘green’’ organoca-
talytic reactions. While the yields achieved using this methodology
currently are not synthetically viable, the aqueous compatibility
and low catalyst loading of nornicotine-catalyzed reactions relative
to other organocatalysts justify further research endeavors.
We acknowledge The Skaggs Institute for Chemical Biology
and the National Institutes of Health for financial support (DA
15700). A.P.B. was supported by an NIH Kirschstein NRSA
postdoctoral fellowship (DA 18507).
4,10
aldol reaction,
no reduced product was formed when
cinnamaldehyde was exposed to nornicotine (20 mol%) and the
Hantzsch ester in THF or chloroform, while this reaction
proceeded in acceptable yield under aqueous conditions utilizing
4
as a hydride source (Table 2, entry 3). Clearly, the catalytic
mechanism of this reaction is unique since it requires an aqueous
environment, possibly as the result of the involvement of explicit
Notes and references
10
water molecules to achieve catalysis.
The current debate over aqueous organocatalysis ‘‘in water’’ or
1
2
P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138.
Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 958; Y. Hayashi, S. Aratake,
T. Okano, J. Takahashi, T. Sumiya and M. Shoji, Angew. Chem., Int.
Ed., 2006, 45, 5527; N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe,
F. Tanaka and C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 734;
Y. Y. Peng, Q. P. Ding, Z. Li, P. G. Wang and J. P. Cheng, Tetrahedron
Lett., 2003, 44, 3871; N. Mase, K. Watanabe, H. Yoda, K. Takabe,
F. Tanaka and C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 4966;
A. Cordova, W. Notz and C. F. Barbas, III, Chem. Commun., 2002,
3
‘
‘in the presence of water’’ led us to pursue a synthetically viable,
organocatalyzed reaction that occurs dissolved in an aqueous
solution without any organic co-solvent. There is a fundamental
distinction between an organocatalyst that functions dissolved in
water versus an amphiphilic organocatalyst that catalyzes a
reaction in the organic phase of a biphasic mixture. Towards this
goal, aqueous soluble 4-carboxycinnamaldehyde could be reduced
under the established reaction conditions in the absence of co-
solvent in 66% yield (Table 2, entry 5), whereas the corresponding
control reaction in the absence of nornicotine formed the product
in only 5% yield (Table 2, entry 6). Interestingly, the reaction rate
was much faster for 4-carboxycinnamaldehyde than the other
substrates examined, most notably the methyl ester analog
3024; P. Dziedzic, W. Zou, J. Hafren and A. Cordova, Org. Biomol.
Chem., 2006, 4, 38; H. Torii, M. Nakadai, K. Ishihara, S. Saito and
H. Yamamoto, Angew. Chem., Int. Ed., 2004, 43, 1983; Y. S. Wu,
Y. Chen, D. S. Deng and J. Cai, Synlett, 2005, 1627; L. Cheng, X. Wu
and Y. Lu, Org. Biomol. Chem., 2007, 5, 1018; V. Singh and V. K. Singh,
Org. Lett., 2007, 9, 1117.
3
A. P. Brogan, T. J. Dickerson and K. D. Janda, Angew. Chem., Int. Ed.,
2006, 45, 8100; Y. Hayashi, Angew. Chem., Int. Ed., 2006, 45, 8103;
D. G. Blackmond, A. Armstrong, V. Coombe and A. Wells, Angew.
Chem., Int. Ed., 2007, 46, 3798.
4 T. J. Dickerson and K. D. Janda, J. Am. Chem. Soc., 2002, 124, 3220.
(Table 2, entry 4). Presumably, this is explained by the modest
aqueous solubility of many of the other substrates, however,
further study into the mechanism of this reaction is required before
this difference can be conclusively explained.
5
6
7
8
T. J. Dickerson and K. D. Janda, Proc. Natl. Acad. Sci. U. S. A., 2002,
9, 15084.
T. J. Dickerson and K. D. Janda, Proc. Natl. Acad. Sci. U. S. A., 2003,
100, 8182.
A. P. Brogan, T. J. Dickerson, G. E. Boldt and K. D. Janda, Proc. Natl.
Acad. Sci. U. S. A., 2005, 102, 10433.
S. G. Ouellet, J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem. Soc.,
9
As further evidence suggesting that nornicotine functions unlike
other organocatalysts, dibenzylamine and proline, two recognized
9,14
organocatalysts that are soluble in water, were tested and found
to provide minimal product formation over the corresponding
control reaction using substrate 4-carboxycinnamaldehyde in the
absence of organic co-solvent (19% yield for dibenzylamine and
2005, 127, 32.
9 J. W. Yang, M. T. Hechavarria Fonseca and B. List, Angew. Chem., Int.
Ed., 2004, 43, 6660; J. W. Yang, M. T. Hechavarria Fonseca, N. Vignola
and B. List, Angew. Chem., Int. Ed., 2004, 44, 108.
14% yield for proline in 1 h vs. 66% yield for nornicotine in 30 min).
1
0 T. J. Dickerson, T. Lovell, M. M. Meijler, L. Noodleman and
K. D. Janda, J. Org. Chem., 2004, 69, 6603; C. J. Rogers, T. J. Dickerson,
A. P. Brogan and K. D. Janda, J. Org. Chem., 2005, 70, 3705;
C. J. Rogers, T. J. Dickerson and K. D. Janda, Tetrahedron, 2006, 62,
In light of this disparity in catalytic efficiency between organoca-
talysts with closely related molecular structures, it is apparent
that nornicotine operates by a unique mechanism allowing for
efficient organocatalysis under completely aqueous conditions.
Furthermore, the nornicotine-catalyzed reduction of a,b-unsatu-
rated aldehydes is compatible with a range of cinnamaldehyde
substrates and the addition of organic co-solvent is only needed in
cases where the substrate possesses limited aqueous solubility.
352.
11 B. M. Trost, Science, 1991, 254, 1471.
12 E. Booker and U. Eisner, J. Chem. Soc., Perkin Trans. 1, 1975, 929.
13 T. Fujita, M. Nakajima, Y. Soeda and I. Yamamoto, Pestic. Biochem.
Physiol., 1971, 1, 151.
4 B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc., 2000,
122, 2395.
1
4
954 | Chem. Commun., 2007, 4952–4954
This journal is ß The Royal Society of Chemistry 2007