Organocatalytic asymmetric inverse-electron-demand diels-alder reaction of electron-deficient dienes and crotonaldehyde

Article abstract of DOI:10.1002/anie.201002912

Another pathway for enals: The excellent β, γ-regioselectivity shown in the title reaction under dienamine catalysis efficiently gave highly diastereo- and enantioenriched cyclohexene derivatives with substantial substitution diversity (see scheme; EWG=el

Full text of DOI:10.1002/anie.201002912

Communications
DOI: 10.1002/anie.201002912
Asymmetric Synthesis
Organocatalytic Asymmetric Inverse-Electron-Demand Diels–Alder
Reaction of Electron-Deficient Dienes and Crotonaldehyde**
Jun-Long Li, Tai-Ran Kang, Si-Li Zhou, Rui Li, Li Wu, and Ying-Chun Chen*
The catalytic asymmetric Diels–Alder reaction has been
recognized as one of the most powerful and atom-economical
protocols to construct chiral six-membered crabocycles. Over
the past decades, numerous studies in this field have been
presented involving LUMO-lowering activation of electron-
deficient dienophiles by the catalysis of either metal-based[1]
or organic molecules.[2] On the other hand, the frontier
Scheme 1. Proposed inverse-electron-demand Diels–Alder reaction by
the HOMO-raising strategy. EWG=electron-withdrawing group
electron theory predicts that the suprafacial [4+2] cycloaddi-
tion could be controlled by the HOMO of the dienophile and
the LUMO of the diene in the Diels–Alder reaction with
inverse-electron-demand.[3] Although a diversity of asymmet-
ric inverse-electron-demand hetero-Diels–Alder reaction has
been well established,[4] examples of all-carbon-based cata-
lytic asymmetric versions have been rarely reported,[5] and all
fall into the LUMO-lowering strategy with the aid of Lewis
acids.[6]
some side reactions (Table 1, entry 1; BA = benzoic acid).
Solvent screening (Table 1, entries 2–5) indicated that higher
yield could be obtained in toluene and 1,4-dioxane with the
retention of stereoselectivity (Table 1, entries 4 and 5).
Similar results were given when o-fluorobenzoic acid
(OFBA) or acetic acid were used in 1,4-dioxane (Table 1,
entries 6 and 7), but almost no reaction occurred in the
absence of acid additive (Table 1, entry 8). In addition,
slightly better results were afforded by using a higher
concentration (compare Table 1, entry 9 and 10). A bulkier
catalyst 1b also provided similar stereocontrol, while a slower
reaction rate was observed (Table 1, entry 11). Notably, a
Recently our research group[7] has reported a highly a-
regio- and stereoselective inverse-electron-demand aza-
Diels–Alder reaction of a,b-unsaturated aldehydes by dien-
amine catalysis.[8] We observed a different reaction pattern for
crotonaldehyde, from which the dienamine intermediate that
is generated in situ exhibited b,g-selectivity, but only moder-
ate ee values were obtained. We envisaged that such catalytic
activity might be applicable to a properly designed electron-
deficient diene, as proposed in Scheme 1, thus an all-carbon-
based asymmetric inverse-electron-demand Diels–Alder
reaction could be developed via an unprecedented HOMO-
controlling pathway for the dienophile.[9]
Table 1: Screening studies for the organocatalytic inverse-electron-
demand Diels–Alder reaction.[a]
We initially investigated the possible reaction of readily
available diene 2a and crotonaldehyde catalyzed by the
combination of secondary amine 1a and benzoic acid in THF
at 258C.[10] Pleasingly, the reaction proceeded smoothly, and
diene 2a was consumed after 24 hours. The desired Diels–
Alder product 3a was isolated in excellent enantioselectivity
with a good d.r. ratio, while the yield was moderate owing to
Entry
1
Solvent
Acid
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
1a THF
BA
BA
BA
BA
57
45
37
70
71
75
70
<5
75
64
63
88:12 96
87:13
81:19
90:10 98
89:11 98
90:10 97
89:11 97
1a
1a
1a
1a
1a
1a
1a
1a
1a
CH2Cl2
MeCN
toluene
1,4-dioxane BA
1,4-dioxane OFBA
1,4-dioxane AcOH
1,4-dioxane
1,4-dioxane BA
1,4-dioxane BA
94
88
3[e]
4
[*] J.-L. Li, T.-R. Kang, S.-L. Zhou, L. Wu, Prof. Dr. Y.-C. Chen
Key laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
5
6
7
8
–
–
–
9[f]
10[h]
11[f]
89:11 98 (85)[g]
89:11 98
Fax: (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
1b 1,4-dioxane BA
91:9
97
Dr. R. Li, Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041(China)
[a] Unless noted otherwise, reactions were performed with 0.2 mmol of
2a, 0.4 mmol of crotonaldehyde, 10 mol% of 1, and acid in 2 mL of
solvent at 258C for 24 hours. [b] Yield of isolated product. [c] Determined
by 1H NMR analysis. [d] Determined by HPLC on a chiral stationary
phase after derivation (for the major isomer), see the Supporting
Information. [e] Reaction time of 48 hours. [f] In 1 mL of solvent. [g] Data
in parenthesis relate to the minor diastereomer. [h] In 4 mL of solvent.
TES=triethylsilyl, THF=tetrahydrofuran, TMS=trimethylsilyl.
[**] We are grateful for the financial support from the NSFC
(no. 20972101), the PCSIRTC (no. IRT0846), and the National Basic
Research Program of China (973 Program; no. 2010CB833300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002912.
6418
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Chemie
good ee value was also observed for the minor diastereomer
(Table 1, entry 9).
gained for dienes bearing either d-linear or -branched alkyl
groups (Table 2, entries 20–22).
Next, the new method for the synthesis of chiral cyclo-
hexene derivatives was explored with a variety of dienes 2 and
crotonaldehyde.[11] As summarized in Table 2, the reaction
showed substantial generality resulting in broad substrate
We have performed some synthetic transformations with
the multifunctional cycloadducts. As outlined in Scheme 2,
the partial hydrolysis of one cyano group and subsequent
Table 2: Substrate scope of the organocatalytic Diels–Alder reaction.[a]
Entry
R
R1, R2
EWG
Product,
d.r.[c]
ee
yield [%][b]
[%][d]
1
2
3
4
5
6
7
8
Ph
H, Et
H, Et
H, Et
H, Et
H, Et
H, Et
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
3a, 75
3b, 74
3c, 67
3d, 71
3e, 61
3 f, 72
3g, 68
3h, 74
3i, 75
3j, 72
3k, 76
3l, 68
3m, 72
3n, 70
3o, 66
3p, 80
89:11 98
84:16 98
89:11 98
89:11 97
o-ClC6H4
m-ClC6H4
p-ClC6H4
p-FC6H4
p-MeC6H4
93:7
98
90:10 97
90:10 97
87:13 96
90:10 99
87:13 97
81:19 94
89:11 99
90:10 96
87:13 99
Scheme 2. Synthetic transformations of cyclic adducts. Boc=tert-
butoxycarbonyl.
p-MeOC6H4 H, Et
1-napth
2-furyl
2-thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
m-ClC6H4
3,4-Cl2C6H3 H, H
Me
nPr
iPr
H, Et
H, Et
H, Et
9
10
11
12
13
14
15
16
17
18
19
20
21
22
decarboxylation could be easily realized by the treatment of
the alcohol of 3a with aqueous NaOH solution, thus affording
a conjugate nitrile 4 without affecting the enantiopurity.
Interestingly, under strong acidic conditions, a cascade cyano
group hydrolysis/imine formation/Friedel–Crafts reaction of
3a efficiently proceeded to deliver product 5 with a caged and
bridged polycyclic framework, and whose structure was
confirmed by X-ray analysis (see the Supporting Informa-
tion).[12,13] In addition, a decahydroisoquinoline derivative 6
was smoothly constructed from 3q (Figure 1) via a tandem
cyano group hydrogenation/reductive amination reaction.[14]
H, Me
H, nPr
H, nPent
H, iBu
H, H
-CH2C6H4- CN
H, H
H, H
92:8
99
89:11 91
CO2Et 3q, 44
CO2Et 3r, 48
CO2Et 3s, 52
CO2Et 3t, 45
CO2Et 3u, 43
94:6
95:5
93:7
92:8
99[e]
97
96
99
H, H
H, H
H, H
90:10 99
86:14 98
CN
3v, 57
[a] Reactions were performed with 0.2 mmol of 2, 0.4 mmol of croto-
naldehyde, 10 mol% of 1a, and PhCO2H in 1 mL of 1,4-dioxane at 258C
for 24–48 hours. [b] Yield of isolated product. [c] Determined by 1H NMR
analysis. [d] Determined by HPLC on a chiral stationary phase after
derivation (for the major isomer), see the Supporting Information.
[e] The absolute configuration of 3q was determined by X-ray analysis
after conversion into the 2,4-dinitrobenzenehydrozone derivative (see
Figure 1).[12] The other products were assigned by analogy. napth=
naphthyl.
scope. Substitution at the d position of the dienes had limited
effect on the reaction outcomes. Excellent enantioselectivity
with good d.r. ratios were obtained for a number of dienes
bearing electron-withdrawing or -donating aryl and hetero-
aryl groups (Table 2, entries 1–10). Various substituents at the
b position of the dienes could be well tolerated (Table 2,
Figure 1. ORTEP plot of the 2,4-dinitrobenzenehydrozone derivative of
enantiopure 3q drawn with ellipsoids at 30% probability
In conclusion, we have developed the first organocatalytic
asymmetric all-carbon-based inverse-electron-demand Diels–
Alder reaction of electron-deficient dienes and crotonalde-
hyde through a HOMO-activation strategy.[15] Highly dia-
stereo- and enantioenriched cyclohexene derivatives with
substantial substitution diversity were smoothly delivered (up
to 99% ee, d.r. up to 95:5). This method presented here may
be helpful for expanding the utilities of unsaturated aldehydes
entries 11–15). Notably,
a pentasubstituted diene also
afforded good results (Table 2, entry 16). The dienes con-
densed from ethyl cyanoacetate and enals could be success-
fully utilized. The products possessing three chiral centers,
including a quaternary carbon, were obtained in high enantio-
and diastereoselectivity, while the yields were fair (Table 2,
entries 17–19). Importantly, excellent stereocontrol was also
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Communications
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Received: May 14, 2010
Published online: July 29, 2010
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[12] CCDC 780401 (2,4-dinitrobenzenehydrozone derivative of 3q)
and CCDC 780402 (5) contain the supplementary crystallo-
graphic 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. The absolute configura-
tion of the hydrozone derivative of 3q was determined by
anomalous dispersion effects in diffraction measurements on the
crystal.
Keywords: asymmetric synthesis · crotonaldehyde · Diels–
Alder reaction · electron-deficient dienes · organocatalysis
.
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[15] For the proposed catalytic mechanism of this cycloaddition
reaction, see the Supporting Information.
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