ORGANIC
LETTERS
2012
Vol. 14, No. 5
1306–1309
Highly Chemoselective Reduction of Carbonyl
Groups in the Presence of Aldehydes
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Gulluzar Bastug, Steve Dierick, Frederic Lebreux, and Istvan E. Marko*
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Universite Catholique de Louvain, Laboratory of Organic and Medicinal Chemistry, Batiment
Lavoisier, Place Louis Pasteur 1 bte L4.01.02., B-1348 Louvain-la-Neuve, Belgium
Received January 23, 2012
ABSTRACT
The exquisite ability of diethylaluminum benzenethiolate to efficiently discriminate between aldehydes and other carbonyl functions enables the
chemoselective in situ reduction of ketones and methyl esters in the presence of aldehydes. This potent strategy avoids the usual drawbacks of
traditional protecting group methodologies and could be extended to various other transformations.
Functional Group Interconversions (FGIs) form a cen-
tral theme in organic chemistry.1 Among them, modifying
the oxidation state of carbonyl groups is of crucial
importance.1,2 The chemoselective reduction of aldehydes
in the presence of less reactive carbonyl functions can be
easily achieved using specially designed reagents.3 How-
ever, the opposite transformation, i.e. the reduction of a
carbonyl group, such as a ketone or an ester, in the
presence of an aldehyde remains elusive.
Although specific protecting groups for aldehydes have
been introduced,4 several drawbacks still persist. In parti-
cular, their use in polyfunctional molecules is sometimes
difficult and unselective. Moreover, this protecting group
methodology requires a three-step process: protection,
reaction, and deprotection. Accordingly, it is hardly sur-
prising that modern synthetic endeavors, aimed at effi-
ciency and convergency, will try to avoid such practice by
attempting to minimize the number of steps, decreasing the
amount of byproduct and saving time.5
A more elegant strategy can solve most of these short-
comings. Indeed, the aldehyde can be reversibly trans-
formed in situ in an unreactive derivative, leaving other
untouched carbonyl groups to react. This principle has
been successfully applied by Reetz and Yamamoto for the
chemoselective alkylation of ketones in the presence of
aldehydes.6 In his pioneering work, Luche used lantha-
noids for the hemiacetalization of aldehydes, enabling the
selective reduction of ketones.7 Unfortunately, this aque-
ous system displays moderate selectivities and is limited to
aliphatic substrates. In a one-pot procedure, Paradisi
preferentially converted aldehydes into imines before re-
ducing ketones with an alumino-hydride reagent, even-
tually releasing the unreacted aldehydes.8 However, the
intermediate imine is too reactive to extend this methodol-
ogy to other transformations.
As part of an ongoing research program, aimed at the
efficient assembly of R-methylene-γ-butyrolactones, we
have recently reported a novel tandem Claisenꢀene rear-
rangement (Scheme 1).9 In the course of this process,
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
Wiley: New-York, 1995.
(2) (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis;
VCH: Weinheim, 1996. (b) Hudlickꢀy, T.; Reed, J. W. The Way of Synthesis;
Wiley-VCH: Weinheim, 2007.
(3) Burke, S. D.; Danheiser, R. L. Handbook of Reagents for Organic
Synthesis. Oxidizing and Reducing Agents; Wiley: Chichester, 1999.
(6) (a) Reetz, M. T.; Wenderoth, B.; Peter, R. J. Chem. Soc., Chem.
Commun. 1983, 406. (b) Maruoka, K.; Araki, Y.; Yamamoto, H.
Tetrahedron Lett. 1988, 3101.
(7) (a) Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187. (b)
Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848.
(8) Paradisi, M. P.; Zecchini, G. P.; Ortar, G. Tetrahedron Lett. 1980,
21, 5085.
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(4) (a) Kocienski, P. J. Protecting Groups, 3th ed.; Thieme: Stuttgart,
2004. (b) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007.
(5) (a) Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784. (b)
Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. (c)
Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38,
3010. (d) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193.
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(9) Leclercq, C.; Marko, I. E. Tetrahedron Lett. 2005, 46, 7229.
r
10.1021/ol300188e
Published on Web 02/17/2012
2012 American Chemical Society