Indium(III)-catalyzed asymmetric hetero-Diels-Alder reaction of brassard-type diene with aliphatic aldehydes

Article abstract of DOI:10.1021/ol2013999

A highly diastereo- and enantioselective hetero-Diels-Alder (HDA) reaction of a Brassard-type diene with aliphatic aldehydes has been developed. The chiral N,N′-dioxide L2/In(OTf)₃ complex was efficient toward the obtention of the corresponding

Full text of DOI:10.1021/ol2013999

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3868–3871
Indium(III)-Catalyzed Asymmetric Hetero-
DielsꢀAlder Reaction of Brassard-Type
Diene with Aliphatic Aldehydes
Lili Lin,† Yulong Kuang,† Xiaohua Liu,† and Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, China, and State Key Laboratory of
Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
xmfeng@scu.edu.cn
Received May 24, 2011
ABSTRACT
A highly diastereo- and enantioselective hetero-DielsꢀAlder (HDA) reaction of a Brassard-type diene with aliphatic aldehydes has been
developed. The chiral N,N0-dioxide L2/In(OTf)3 complex was efficient toward the obtention of the corresponding β-methoxy-γ-methyl R,β-
unsaturated δ-lactones in good yields (up to 86%) as well as dr and ee values (up to 97:3 cis/trans and 94% ee). In addition, the product 4a could be
easily transformed into the methyl-protected epi-prelactone B by hydrogenation.
δ-Lactones,1,2specificallyβ-hydroxy-γ-methyl-δ-lactones,3
are found as essential structural motifs in many bioac-
tive natural products, such as prelactones B, C, V;4
leiodermatolide;5 and discodermolide6 (Figure 1). The
hetero-DielsꢀAlder (HDA) reaction7 of Brassard’s
dienes8 1 and 2 with aldehydes was an efficient method
to synthesize δ-lactone structures (Scheme 1).9 And
also, combined with Winkler’s transformation of 4-al-
koxy-R,β-unsaturated δ-lactones to 2,3-dihydropyran-
4-ones,10 the scope of the methodology could be greatly
expanded. However, the terminal 2-fold substitutions
of Brassard’s diene enhanced the difficulty of control-
ling the enantioselectivity of the HDA reaction.11 As
a result, though electron-rich as the well-developed
† Sichuan University.
‡ Lanzhou University.
(1) For reviews, see: (a) Boucard, V.; Broustal, G.; Campagne, J. M.
Eur. J. Org. Chem. 2007, 225. (b) Mondon, M.; Gesson, J. P. Curr. Org.
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r
10.1021/ol2013999
Published on Web 06/28/2011
2011 American Chemical Society

Scheme 1. Construction of δ-Lactones through HDA Reactions
of Brassard Dienes with Aldehydes
Figure 1. Natural products containing a β-hydroxy-γ-methyl-δ-
lactone structure.
Danishefsky-type dienes,7,12 Brassard’s diene has been
less efficiently developed in the catalytic asymmetric
HDA reaction with aldehydes.13,14 As a developing
area, up to now, the HDA reactions of Brassard’s diene
1 with aromatic15 and aliphatic16 aldehydes have been
realized by chiral Ti(IV) complexes or a TADDOL
organocatalyst (Scheme 1A). At the same time, the
HDA reaction of Brassard-type diene 2 with aromatic
aldehydes has also been achieved by Cu(II)/Schiff base
complexes (Scheme 1B).17 However, to the best of our
knowledge, no efficient catalytic system has been de-
veloped for the asymmetric HDA reaction of Brassard-
type diene 2 with aliphatic aldehydes,18 although the
corresponding adducts could be easily transformed to
the building blocks existing in many natural products
(Figure 1) by hydrogenation. So, it is highly meaningful
to explore efficient catalytic systems for the asymmetric
HDA reaction of Brassard-type diene 2 with aliphatic
aldehydes.
It is well-known that the indium, which is three times as
abundant as silver, is particularly effective at activating
carbonyl groups.12b,19 On the other hand, the chiral N,
N0-dioxideꢀmetal complexes, which have a tunable chiral
environment via modifying their electronic properties or
steric hindrance, have been successfully applied in many
asymmetric reactions.20 Herein, we report our efforts in
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Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (b) Jørgensen,
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Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 4647. (b)
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(11) Togni, A. Organometallics 1990, 9, 3106.
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Hentemann, M. F.; Danishefsky, S. J. Chem.;Eur. J. 2002, 8, 3423. (b)
Yu, Z. P.; Liu, X. H.; Dong, Z. H.; Xie, M. S.; Feng, X. M. Angew.
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K. L. J. Am. Chem. Soc. 2002, 124, 14866. (e) Yamashita, Y.; Saito, S.;
Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793. (f) Unni,
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Roberson, M.; Jørgensen, K. A. Chem.;Eur. J. 2000, 6, 123. (i)
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Akiyama, T. Angew. Chem., Int. Ed. 2006, 45, 4796. (b) Chen, Z. L.; Lin,
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(18) 15% yield, 59/41 trans/cis, and 73% ee were obtained for
n-butanal. 58% yield, 10/90 cis/trans, and 62% ee were obtained for
(E)-but-2-enal.17
(19) For some asymmetric examples catalyzed by indium, see: (a) Lu,
J.; Hong, M. L.; Ji, S. J.; Teo, Y. C.; Loh, T. P. Chem. Commun. 2005,
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Org. Lett., Vol. 13, No. 15, 2011
3869

applying the chiral N,N0-dioxide/In(OTf)3 complex in the
diastereo- and enantioselective HDA reaction of Brassard-
type diene 2 with aliphatic aldehydes.
affected the reactivity and selectivity. When In(OAc)3 was
applied, a trace amount of product was obtained (Table 1,
entry 5). InBr3 and InCl3, which showed great ability in
carbonꢀcarbon bond-forming reactions,21 resulted in
very low yields and ee values with the dr even reversed
(Table 1, entries 6ꢀ7). When the reaction temperature
was lowered to 0 °C, the ee could be enhanced to 90%,
while the yield decreased to 41% and the ratio of
cis/trans slightly declined to 81:19 (Table 1, entry 2 vs
8). To our delight, using mixed solvents (toluene/THF =
2:1), meanwhile prolonging the reaction time, could
improve the yield to 84% with a slightly increased ratio of
cis/trans and maintained ee values (90% ee) (Table 1, entry
9). It is noteworthy that adding anhydrous Na2SO4 to the
system could prevent the system from instability caused by
In(OTf)3 absorbing moisture in air.
Figure 2. Representative chiral ligands used in this study.
Table 1. Evaluation of Reaction Parametersa
The model reaction was initiated with Brassard-type
diene 2 and isobutanal 3a for structural similarity with
the natural product prelactone B (Figure 1). Various chiral
N,N0-dioxides (Figure 2) coordinated with In(OTf)3 were
investigated in THF at rt. The results showed that both the
amide part and the amino acid backbone of the chiral
ligand affected the reaction greatly. Unfortunately, the N,
N0-dioxides derived from aromatic amines only gave race-
mic products, though they have exhibited great ability in
many other asymmetric reactions. For example, the N,N0-
dioxide L1 derived from 4-methoxyaniline supported the
racemic product in 52% yield (Table 1, entry 1). Compara-
tively, the N,N0-dioxides derived from aliphatic amines
could give the desired products in a variety of dr and ee
values (for details, see the Supporting Information). The N,
N0-dioxide L2 derived from diphenylmethanamine with L-
pipecolic acid backbone could give 89% yield, 87:13 cis/
trans, and 79% ee (Table 1, entry 2). Surprisingly, the cis-
yieldb
(%)
cis eec
(%)
entry
ligand
metal
cis/transc
1
L1
L2
L3
L4
L2
L2
L2
L2
L2
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OAc)3
InBr3
52
71:29
87:13
74:26
71:29
ND
0
2
89
79
4
3
67
4
54
29
ND
5f
4f
5
trace
15
6
29:71
32:68
81:19
85:15
7
InCl3
11
8d
9d,e
In(OTf)3
In(OTf)3
41
90
90
84
1
product was in the majority, determined by H NMR
a Unless otherwise noted, all reactions were performed with isobu-
tanal (0.25 mmol) and diene 2 (0.3 mmol) in the presence of 5 mol %
catalyst loading in 1.0 mL of THF at rt for 72 h. b Isolated yield.
c Determined by GC analysis. ND = Not determined. d The reaction
was performed at 0 °C. e The reaction was performed in 0.5 mL of THF
and 1.0 mL of toluene for 96 h. Anhydrous Na2SO4 (30 mg) was added.
f The ee value of trans-product.
analysis, while the trans-product was mainly obtained from
aromatic aldehydes in the Cu(II)/Schiff base catalytic
system.17 When L3 derived from L-proline or L4 derived
from L-ramipril acid was used, the ee values sharply de-
creased to 4% and 29%, respectively (Table 1, entries 3ꢀ4).
Besides, the counterion was another parameter strongly
(20) For selected examples of our recent work, see: (a) Li, W.; Wang,
J.; Hu, X. L.; Shen, K.; Wang, W. T.; Chu, Y. Y.; Liu, X. H.; Lin, L. L.;
Feng, X. M. J. Am. Chem. Soc. 2010, 132, 8532. (b) Xie, M. S.; Chen,
X. H.; Zhu, Y.; Gao, B.; Lin, L. L.; Liu, X. H.; Feng, X. M. Angew.
Chem., Int. Ed. 2010, 49, 3799. (c) Shang, D. J.; Xin, J. G.; Liu, Y. L.;
Zhou, X.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2008, 73, 630. (d) Liu,
Y. L.; Shang, D. J.; Zhou, X.; Zhu, Y.; Lin, L. L.; Liu, X. H.; Feng, X. M.
Org. Lett. 2010, 12, 180. (e) Cai, Y. F.; Liu, X. H.; Hui, Y. H.; Jiang, J.;
Wang, W. T.; Chen, W. L.; Lin, L. L.; Feng, X. M. Angew. Chem., Int.
Ed. 2010, 49, 6160. (f) Zheng, K.; Shi, J.; Liu, X. H.; Feng, X. M. J. Am.
Chem. Soc. 2008, 130, 15770. (g) Cao, W. D.; Liu, X. H.; Wang, W. T.;
Lin, L. L.; Feng, X. M. Org. Lett. 2011, 13, 600.
(21) (a) Loh, T. P.; Chua, G. L. Chem. Commun. 2006, 2739. (b) Shen,
Z. L.; Goh, K. K. K.; Cheong, H. L.; Wong, C. H. A.; Lai, Y. C.; Yang,
Y. S.; Loh, T. P. J. Am. Chem. Soc. 2010, 132, 15852. (c) Nishimoto, Y.;
Babu, S. A.; Yasuda, M.; Baba, A. J. Org. Chem. 2008, 73, 9465. (d)
Kiyokawa, K.; Yasuda, M.; Baba, A. Org. Lett. 2010, 12, 1520. (e)
Nishimoto, Y.; Yasuda, M.; Baba, A. Org. Lett. 2007, 9, 4931.
With the optimal reaction conditions in hand, the sub-
strate scope was then examined (Scheme 2). Obviously,
R-branched aliphatic aldehydes were beneficial for the results
(Scheme 2, 4aꢀ4d). Linear n-butanal gave 4c with only a
65:35 ratio of cis/trans and 72% ee. Monosubstituted
2-ethyl butanal and isobutanal provided 4a and 4b with
better selectivities (82:18 and 85:15 cis/trans, 84% ee and
90% ee, respectively). Bulkyl pivaldehyde yielded 4d with
the best results (86% yield, 97:3 cis/trans and 94% ee).
Cyclohexanal also reacted smoothly with Brassard-type
diene 2 to afford the corresponding 4e in 82% yield, 81:19
cis/trans, and 91% ee. After a single recrystallization, 4e
with 98:2 cis/trans and 99% ee could be achieved. Besides,
3870
Org. Lett., Vol. 13, No. 15, 2011

the absolute configuration of 4e was unambiguously de-
termined to be 5R,6S by single-crystal X-ray diffraction
analysis.22 (E)-But-2-enal was also examined, but a poor
yield was obtained with 88:12 cis/trans and 84% ee.23
at 40 °C under 4 MPa pressure, the product 4a could be
readily transformed into the methyl-protected epi-pre-
lactone B24 in quantitative yield and with basically
maintained dr and ee values (Scheme 3).
Scheme 2. Substrate Scope for the Catalytic Asymmetric HDA
Reaction of Brassard-Type Diene 2 with Aliphatic Aldehydes
Scheme 3. Scaled-up Version of HDA Reaction of Brassard-
Type Diene 2 with Isobutanal 3a and Hydrogenation of the
Product 4a
In summary, a highly diastereo- and enantioselective
hetero-DielsꢀAlder reaction of Brassard-type diene 2
with aliphatic aldehydes catalyzed by the chiral N,
N0-dioxide L2/In(OTf)3 complex has been developed. The
corresponding β-methoxy-γ-methyl-R,β-unsaturated-
δ-lactones were obtained in good yields as well as dr
and ee values. The cycloadducts could be easily trans-
formed into useful building blocks by hydrogenation.
Further efforts will be devoted to understanding the
reaction mechanism and applying this methodology to
synthesize other natural products.
To further evaluate the synthetic potential of the
catalytic system, a scaled-up synthesis of chiral 4a
was performed. As shown in Scheme 3, by treatment
of 2.5 mmol of isobutanal 3a under the optimized
reaction conditions, 0.31 g of the correspoinding 4a
was obtained without any loss in dr and ee values.
Meanwhile, by hydrogenation in the presence of Pd/C
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 20732003, 21021001,
and 20902060) and the Basic Research Program of China
(973 Program: 2010CB833300) for financial support. We
alsothank Sichuan UniversityAnalytical & Testing Center
for NMR analysis.
(22) CCDC 825023 (4e) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(23) The low reactivity led to the poor yield of 4f. In addition,
aromatic benzaldehyde also showed low reactivity in this catalytic
system, and the dr and ee value were not determined.
(24) For selected synthesis of epi-prelactones, see: (a) Srihari, P.;
Ravindar, K.; Somaiah, R.; Yadav, J. S. Synth. Commun. 2008, 38, 1389.
(b) Chandrasekhar, S.; Rambabu, C.; Prakash, S. J. Tetrahedron Lett.
2006, 47, 1213. (c) Sabitha, G.; Padmaja, P.; Reddy, K. B.; Yadav, J. S.
Tetrahedron Lett. 2008, 49, 919.
Supporting Information Available. Experimental proce-
dures, effects of ligand, metal, reaction temperature, and
spectral and analytical data for the products (PDF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3871