Angewandte
Chemie
DOI: 10.1002/anie.201203316
Cyclization
Catalytic Asymmetric [4+2] Annulation Initiated by an Aza-Rauhut–
Currier Reaction: Facile Entry to Highly Functionalized
Tetrahydropyridines**
Zugui Shi, Peiyuan Yu, Teck-Peng Loh,* and Guofu Zhong*
The Rauhut–Currier (RC) reaction, also known as the
vinylogous Morita–Baylis–Hillman reaction, was discovered
in 1963 by Rauhut and Currier.[1] However, as a result of the
low reactivity and selectivity, it did not attract a lot of
attention during the last half century. The achievement of
Moore and co-workers on the synthesis of the Waihoensene
ring system represents the first practical example of utilizing
an intramolecular RC reaction as a key step in organic
synthesis.[2] Krische and co-workers and Roush and co-
workers then independently developed a phosphine-cata-
lyzed intramolecular RC reaction for the synthesis of five-
and six-membered ring systems with high efficiency.[3a,b] The
first enantioselective intramolecular RC reaction was
reported by Miller and co-workers.[4] Shortly thereafter,
Seidel and Gladysz realized a catalytic asymmetric version
by using a chiral rhenium-containing phosphine catalyst.[5]
After such pioneering work, intensive investigations were
devoted to this field. Among the remarkable achievements
documented, the majority of them focused on the intra-
molecular reaction [Scheme 1, Eq. (1)],[6] with a few examples
reported on the catalytic intermolecular reaction, especially
an asymmetric version.[7] Merging an intermolecular RC
reaction with subsequent reactions in a cascade reaction, thus
forming optically active heterocycles [Eq. (2)], would be of
great synthetic importance and significance in terms of atom
economy. However, there are only a few reports on using this
strategy in a catalytic asymmetric manner.[8]
Chiral tetrahydropyridines are important organic syn-
thons. They can be readily reduced to piperidines, which
frequently occur in many natural products of biological
relevance.[9] Existing methodologies for their preparation are
largely attributed to the aza-Diels–Alder reaction of N-
sulfonly-1-aza-1,3-butadiene with electron-rich dieno-
philes,[10] and the [4+2] annulation reaction of 2-methylene-
but-3-enoate with imines,[11] which are either limited by
a narrow substrate scope or restricted by rigorous reaction
conditions. Thus, the development of a more general and
efficient protocol is highly desirable. As part of our long-
standing interest in organocatalysis,[12] and on the basis of our
recent achievement,[13] we report herein an alternative
approach to the synthesis of enantioenriched tetrahydropyr-
idines by a catalytic asymmetric [4+2] annulation pathway
initiated by an aza-Rauhut–Currier reaction using chiral
phosphine catalysts derived from natural amino acids. To the
best of our knowledge, this is the first example of the catalytic
asymmetric cross-aza-Rauhut–Currier reaction.
The development of chiral phosphine catalysts based on
the skeletons of natural amino acids has seen remarkable
progress in recent years.[14] Considering their easy accessibil-
ity, low cost, and good asymmetric induction, our preliminary
studies were carried out using the chiral phosphine catalysts
derived from l-leucine (Figure 1). To our delight, 20 mol% of
4a catalyzed the model reaction of methyl vinyl ketone (1;
MVK) with the N-benzenesulfonyl-1-aza-1,3-diene 2a to
produce the desired product in 64% yield with modest
diastereo- and enantioselectivity (Table 1, entry 1). Various
N-sulfonyl-1-aza-1,3-dienes were then tested to elucidate the
effect of protecting groups on the stereoselective induction,
and the N-tosyl-1-aza-1,3-diene 2b proved to be a good choice
(entries 2–4).
Other chiral phosphines derived from natural amino acids
or chiral a-hydroxy acids were then examined. The catalyst
4b, which was effective in the [3+2] cycloaddition of
chalcones with allenes,[14a] showed no asymmetric induction
(Table 1, entry 5). Notably, the TBS-protected catalyst 4e
delivered the product in almost a racemic manner, whereas 4 f
bearing a free hydroxy group afforded the corresponding
product in 47% ee (entries 8 and 9). These results indicated
Scheme 1. Catalytic Rauhut–Currier reaction initiated cyclization.
EWG=electron-withdrawing group.
[*] Z. Shi, P. Yu, Prof. Dr. G. Zhong
College of Materials, Chemistry and Chemical Engineering
Hangzhou Normal University
16 Xue-Lin Street, Hangzhou 310036, Zhejiang (China)
E-mail: zgf@hznu.edu.cn
Z. Shi, P. Yu, Prof. Dr. T. P. Loh, Prof. Dr. G. Zhong
Division of Chemistry and Biological Chemistry, Nanyang Techno-
logical University, 21 Nanyang Link, Singapore 637371 (Singapore)
Prof. Dr. T. P. Loh
Department of Chemistry
University of Sciences and Technology of China
Hefei 230026, Anhui (China)
E-mail: teckpeng@ntu.edu.sg
[**] Research support from the Hangzhou Normal University (China) is
gratefully acknowledged. We thank Dr. Y.-X. Li for the X-ray
crystallographic analysis.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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