Communications
DOI: 10.1002/anie.200902216
Asymmetric Aminocatalysis
Organocatalytic Regio- and Stereoselective Inverse-Electron-Demand
Aza-Diels–Alder Reaction of a,b-Unsaturated Aldehydes and N-Tosyl-
1-aza-1,3-butadienes**
Bo Han, Zhao-Quan He, Jun-Long Li, Rui Li, Kun Jiang, Tian-Yu Liu, and Ying-Chun Chen*
Aminocatalysis, the activation of carbonyl compounds by
enamines, iminium ions, or the SOMO-activation strategy, has
become a fundamental approach in asymmetric synthesis.[1]
Moreover, the catalytic modes of amines are still under
expansion.[2] Recently, Jørgensen and co-workers developed
dienamine catalysis by inverting the inherent reactivity of a,b-
unsaturated aldehydes, which acted as nucleophiles for direct
enantioselective g amination with diethyl azodicarboxylate.[3]
However, the synthetic potential of dienamine catalysis seems
to be underestimated, and very limited progress has been
Scheme 1. Proposed inverse-electron-demand aza-Diels–Alder reaction
of a dienamine intermediate generated in situ as an electron-rich
olefin. Ts=4-toluenesulfonyl.
made to date[4] in spite of the extensive studies on asymmetric
aminocatalysis over the past decade.
The development of efficient methodologies that enable
simpler, cheaper, and more concise approaches to the
generation of structural complexity with exquisite levels of
stereocontrol remains a preeminent goal in modern organic
chemistry. Recently, we presented a highly enantioselective
inverse-electron-demand aza-Diels–Alder reaction of N-sul-
fonyl 1-aza-1,3-butadienes[5] and aliphatic aldehydes to form
optically pure piperidines through enamine activation.[6–8] We
were fascinated by the possible and conceptually unprece-
dented application of dienamine catalysis in an inverse-
electron-demand aza-Diels–Alder reaction of a,b-unsatu-
rated aldehydes with electron-deficient N-sulfonyl 1-aza-1,3-
butadienes to construct chiral piperidine derivatives bearing
(10 mol%).[10] The reaction proceeded smoothly with exclu-
sive a regioselectivity. The chiral hemiaminal 4a (an E/Z
mixture) was isolated as the sole product. The oxidation of 4a
with pyridinium chlorochromate (PCC) gave a separable
mixture of lactam 5a and its Z isomer 6a. Excellent enantio-
selectivity was observed for the formation of the E isomer 5a
(Table 1, entry 1). Similar results were obtained when the
Table 1: Optimization of the inverse-electron-demand aza-Diels–Alder
reaction of 2a and 3a under dienamine catalysis.[a]
several functional groups in
a straightforward manner
(Scheme 1).[9] We wondered whether the chemo-, regio-,
and stereoselectivity of this complicated reaction could be
controlled simultaneously in an elegant manner.
We initially investigated the reaction of N-tosyl-1-aza-1,3-
butadiene (2a) and hexen-2-al (3a) in a mixture of THF and
H2O at room temperature under the catalysis of the chiral
secondary amine 1a (10 mol%) and benzoic acid
Entry
1
Solvent
Yield [%][b]
5a/6a
E/Z[c]
ee
[%][d]
[*] B. Han, Z.-Q. He, J.-L. Li, K. Jiang, Dr. T.-Y. Liu, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the
Education Ministry
1
2
3
4
5
6
1a
1a
1a
1a
1b
1c
1a
1a
THF/H2O
51/23
56/24
55/30
–
49/20
38/17
68/8
60/9
2.2:1
2.3:1
1.8:1
–
2.4:1
2.2:1
8.1:1
6.7:1
96
97
94
–
97
98
99
98
CH3CN/H2O
dioxane/H2O
CH3CN
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
Department of Medicinal Chemistry
West China School of Pharmacy
Sichuan University, Chengdu, 610041 (China)
Fax: (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
7[e]
8[e,f]
Dr. R. Li, Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041 (China)
[a] Reaction conditions (unless otherwise noted): 2a (0.1 mmol), 3a
(0.2 mmol), 1 (10 mol%), BzOH (10 mol%), room temperature, 8–12 h.
[b] Yield of the isolated product. [c] The E/Z ratio was calculated from the
yields of 5a and 6a. [d] The ee value was determined by HPLC analysis on
a chiral stationary phase. [e] The reaction was carried out at À108C for
12 h. [f] AcOH: 10 mol%. Bz=benzoyl, TMS=trimethylsilyl, TES=tri-
ethylsilyl, TBS=tert-butyldimethylsilyl.
[**] We are grateful for the financial support of the NSFC (20772084)
and Sichuan Province Government (07ZQ026-027).
Supporting information for this article is available on the WWW
5474
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5474 –5477