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Aldol Reactions of Ketone Donors
Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from the MEXT (Japan).
References
[1] a) K. Mueller, C. Faeh, F. Diederich, Science 2007, 317,
1881–1886; b) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330; c) P.
Wang, L.-W. Feng, L. Wang, J.-F. Li, S. Liao, Y. Tang, J.
Am. Chem. Soc. 2015, 137, 4626–4629; d) S. Kawamura,
H. Egami, M. Sodeoka, J. Am. Chem. Soc. 2015, 137,
4865–4873.
[2] Examples of aldol reactions of aryl trifluoromethyl ke-
tones: a) S. Sasaki, K. Kikuchi, T. Yamauchi, K. Higa-
shiyama, Synlett 2011, 1431–1434; b) N. Hara, R.
Tamura, Y. Funahashi, S. Nakamura, Org. Lett. 2011,
13, 1662–1665; c) N. Duangdee, W. Harnying, G. Rulli,
J.-M. Neudoerfl, H. Grçger, A. Berkessel, J. Am.
Chem. Soc. 2012, 134, 11196–11205; d) C. G. Kokotos,
J. Org. Chem. 2012, 77, 1131–1135; e) Y. Zheng, H.-Y.
Xiong, J. Nie, M.-Q. Hua, J.-A. Ma, Chem. Commun.
2012, 48, 4308–4310; f) J. Lin, T. Kang, Q. Liu, L. He,
Tetrahedron: Asymmetry 2014, 25, 949–955; g) W.
Yang, Y.-M. Cui, W, Zhou, L. Li, K.-F. Yang, Z.-J.
Zheng, Y. Lu, L.-W. Xu, Synlett 2014, 25, 1461–1465;
h) H. Zong, H. Huang, G. Bain, L. Song, J. Org. Chem.
2014, 79, 11768–11773; i) S. Luo, H. Xu, L. Chen, J.-P.
Cheng, Org. Lett. 2008, 9, 1775–1778; j) L.-H. Qiu, Z.-
X. Shen, C.-Q. Shi, Y.-H. Liu, Y.-W. Zhang, Chin. J.
Chem. 2005, 23, 584–588.
Scheme 6. Vinylogous aldol reactions of b-methyl-sustituted
cyclic enones. Reaction conditions: ketone 1 (1.0 equiv.),
enone (5.0 equiv.), and DBU (0.1 equiv.) at 258C.
the respective products. For the aldol products from
the reactions of b-keto esters, enantiomerically pure
forms of the products were concisely obtained by the
resolution of the enamines of the aldol products with
a homochiral amine. The reactions were easily per-
formed on small scale to gram scale. The DBU cataly-
sis methods reported here efficiently provided prod-
ucts including those that were previously difficult to
synthesize, that were synthesized only in slow reac-
tions, and/or that required preactivation/protection
and deprotection steps. Our DBU catalysis methods
are complementary to other methods including orga-
nocatalytic methods, such as amine-based organoca-
talysis methods involving formation of enamines in
situ, and Mukaiyama aldol methods.[12] Further devel-
opment of the DBU catalysis method is underway in
our laboratory.
[3] D. Zhang, S. Johnson, H.-L. Cui, F. Tanaka, Asian J.
Org. Chem. 2014, 3, 391–394.
[4] a) K. Rohr, R. Mahrwald, Adv. Synth. Catal. 2008, 350,
2877–2880; b) X. Huang, X. Chen, Y. Chen, A. Zhang,
X. Li, Tetrahedron: Asymmetry 2008, 19, 2529–2535.
[5] a) W. T. Teo, W. Rao, C. J. H. Ng, S. W. Y. Koh, P. W. H.
Chan, Org. Lett. 2014, 16, 1248–1251, and the Support-
ing Information; b) B. Andersh, E. T. Nguyen, R. J. Van
Hoveln, D. K. Kemmerer, D. A. Baudo, J. A. Graves,
M. E. Roark, W. B. Bosma, J. Org. Chem. 2013, 78,
4563–4567; c) Y. Wu, C. Du, C. Hu, Y. Li, Z. Xie, J.
Org. Chem. 2011, 76, 5075–4081.
Experimental Section
[6] Recently, organobase-catalyzed aldol reactions of b-
keto esters that give g-hydroxy-b-keto esters have been
reported: P. B. Thakur, K. Sirisha, A. V. S. Sarma, J. B.
Nanubolu, H. M. Meshram, Tetrahedron 2013, 69,
6415–6423.
[7] a) S. E. Denmark, J. R. Heemstra, G. L. Beutner,
Angew. Chem. 2005, 117, 4760–4777; Angew. Chem. Int.
Ed. 2005, 44, 4682–4698; b) G. Casiraghi, L. Battistini,
C. Curti, G. Rassu, F. Zanardi, Chem. Rev. 2011, 111,
3076–3154; c) S. V. Pansare, E. K. Paul, Chem. Eur. J.
2011, 17, 8770–8779.
General Procedure
To a mixture of donor ketone (2.5 mmol) and 1 (0.5 mmol)
was added DBU (0.05 mmol), and the mixture was stirred at
room temperature (258C) until 1 was consumed (monitored
by TLC). The reaction mixture was diluted with hexane-
EtOAc and purified by silica gel flash column chromatogra-
phy (hexane/EtOAc =8:1 to 4:1) to give 3.
[8] The diastereomers mixture fractions of the enamines
can be purified further to give each diastereomer as the
pure form.
Acknowledgements
We thank Dr. Michael Chandro Roy, Research Support Divi-
sion, Okinawa Institute of Science and Technology Graduate
University for mass analyses. This study was supported by
the Okinawa Institute of Science and Technology Graduate
University and by the Grant-in-Aid for Scientific Research on
[9] X-ray crystal structures: CCDC 1401982 (compound
5a-1) contains the supplementary crystallographic data
for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Adv. Synth. Catal. 2015, 357, 3458 – 3462
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