Angewandte
Chemie
DOI: 10.1002/anie.201000590
Asymmetric Catalysis
Asymmetric Three-Component Inverse Electron-Demand Aza-Diels–
Alder Reaction: Efficient Synthesis of Ring-Fused
Tetrahydroquinolines**
Mingsheng Xie, Xiaohong Chen, Yin Zhu, Bo Gao, Lili Lin, Xiaohua Liu, and Xiaoming Feng*
Tetrahydroquinoline derivatives have attracted considerable
attention because of their important biological activities.[1]
For their construction, one of the most powerful strategies is
the inverse electron-demand aza-Diels–Alder (IEDDA)
reaction of N-arylimines with electron-rich alkenes (dieno-
philes).[2–8] In 1996, the first catalytic asymmetric IEDDA
reaction, using cyclopentadiene and vinylethers as dieno-
philes, was reported by Kobayashi and Ishitani using chiral
binaphthol–ytterbium complexes.[6a] Subsequently, amino-
diol–titanium complexes[6b] and chiral phosphoric acids[7]
have been developed for the stereoselective IEDDA reac-
tions, and great breakthroughs in reactivity and enantiose-
lectivity had been made with vinylethers,[7a] enecarbamates,[7b]
and vinylindoles[7c] as dienophiles. However, with cyclopen-
tadiene as the dienophile, the asymmetric IEDDA reaction
has been less well-developed, especial the three-component
version,[9] and a combination of high enantioselectivities and
good yield have not yet been obtained simultaneously. In
contrast to those heteroatom-containing dienophiles, it is
relatively difficult to find an efficient catalyst for cyclo-
pentadiene, which contains only carbon atoms. As the ring-
fused tetrahydroquinoline derivatives, such as 1, exhibit
potential biological activities in treating tumors,[10a] and 2a,
2b in preventing some diseases,[10b] an effective catalyst for
this IEDDA transformation is highly desirable.
affords ring-fused tetrahydroquinolines with three contiguous
stereocenters in a one-pot manner under mild conditions.
Initially, we examined the three-component reaction
between benzaldehyde, 2-aminophenol, and cyclopentadiene,
promoted by N,N’-dioxide L1 with various metals. As shown
in Table 1, La(OTf)3, Y(OTf)3 and Yb(OTf)3 gave racemic
ring-fused tetrahydroquinoline 6a in trace yield with good
diastereoselectivities (Table 1, entries 1–3). Only Sc(OTf)3
afforded the desired 6a with improved results (36% yield,
92:8 d.r., 41% ee; Table 1, entry 4). Encouraged by the
results, a series of N,N’-dioxides that contained different
sterically hindered amide substituents were tested (Table 1,
entries 4–6). N,N’-dioxide L3, which contained bulkier iso-
propyl group at the ortho positions of aniline groups, was
more successful (99% yield, 94:6 d.r., 93% ee; Table 1,
entry 6 versus entries 4 and 5). As for the amino acid
backbone, l-ramipril-acid-derived N,N’-dioxide L5 exhibited
superior enantioselectivity (98%) and lower diastereoselec-
tivity (81:19) compared with those derived from l-proline and
l-pipecolic acid (Table 1, entry 8 versus entries 6 and 7). To
our delight, improved diastereoselectivity (96:4) was
observed when the molar ratio of ligand to central metal
was changed to 2:1 (Table 1, entry 9). Furthermore, when the
catalyst loading was decreased to 5 mol%, excellent results
could also be obtained by increasing the substrate concen-
tration (90% yield, 96:4 d.r., 97% ee; Table 1, entry 10).
Furthermore, when the catalyst loading was further lowered
to 2.5 mol%, similar results could still be obtained with longer
reaction time (Table 1, entry 11). This process is also tolerant
to air and moisture. However, when aniline or 2-methoxyani-
line were tested, only trace amounts of the products were
obtained, which indicated that the hydroxy group on the
aniline was essential for the reaction to proceed (Table 1,
entries 12–13).
Using the excellent chiral N,N’-dioxides scaffolds,[11]
herein, we report an asymmetric three-component IEDDA
reaction with cyclopentadiene as the dienophile, promoted by
5 mol% of an N,N’-dioxide–Sc(OTf)3 complex, to afford ring-
fused tetrahydroquinoline derivatives in high yields, excellent
diastereoselectivities (up to > 99:1 d.r.), and enantioselectiv-
ities (90 to over 99% ee). Notably, the asymmetric reaction
[*] M. S. Xie, X. H. Chen, Y. Zhu, Dr. B. Gao, Dr. L. L. Lin, Dr. X. H. Liu,
Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[**] We appreciate the financial support from the National Natural
Science Foundation of China (Nos. 20732003 and 20872097),
PCSIRT (No. IRT0846) and National Basic Research Program of
China (973 Program) (No. 2010CB833300). We also thank Sichuan
University Analytical & Testing Center for NMR spectroscopic
analysis.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 3799 –3802
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3799