Organocatalytic asymmetric Diels-Alder reaction of furan under high pressure

Article abstract of DOI:10.3987/COM-09-S(S)85

A new method for the asymmetric Diels-Alder reaction between furan and acrolein has been developed through the combined use of chiral organocatalysts and high pressure (yield up to 91%; endo-adduct up to 19% ee, exo-adduct up to 26% ee).

Full text of DOI:10.3987/COM-09-S(S)85

HETEROCYCLES, Vol. 80, No. 2, 2010
799
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 799 - 804. © The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2009, Accepted, 15th September, 2009, Published online, 16th September, 2009
DOI: 10.3987/COM-09-S(S)85
ORGANOCATALYTIC ASYMMETRIC DIELS-ALDER REACTION OF
FURAN UNDER HIGH PRESSURE1
Akiko Mimoto, Keiji Nakano, Yoshiyasu Ichikawa, and Hiyoshizo Kotsuki*
Laboratory of Natural Product Chemistry, Faculty of Science, Kochi University,
Akebono-cho, Kochi 780-8520, Japan
e-mail: kotsuki@kochi-u.ac.jp
Abstract – A new method for the asymmetric Diels-Alder reaction between furan
and acrolein has been developed through the combined use of chiral
organocatalysts and high pressure (yield up to 91%; endo-adduct up to 19% ee,
exo-adduct up to 26% ee).
The Diels-Alder reaction is one of the most important synthetic methodologies in furan chemistry, since it
has been well-established that the corresponding cycloadducts, 7-oxabicyclo[2.2.1]heptene derivatives,
are useful for producing both natural and unnatural biologically interesting molecules.2 However, furans
are generally less-reactive dienes for the Diels-Alder reaction due to their intrinsic aromaticity,3 and
hence additional activation techniques, e.g., Lewis acid catalysis and high-pressure chemistry, are
required to obtain a sufficient amount of the desired adducts.4 In addition, whereas the asymmetric
version in this field is very important for preparing optically active substances, a few examples of
catalytic asymmetric processes have been reported, and the development of new methods remains a
significant challenge.5,6
Over the past decade, remarkable progress has been achieved in the development of asymmetric
organocatalysis as modern synthetic transformations, mainly because they are less toxic and more
environmentally friendly than traditional metal-catalyzed systems.7 In particular, recent reports of
successful organocatalytic asymmetric Diels-Alder reactions by MacMillan and his group8 prompted us to
examine the applicability of their synthetic strategy to the asymmetric Diels-Alder reaction of furan.9 We
describe here our preliminary results on this subject with the combined use of asymmetric organocatalysis
and high pressure.
To investigate the catalyst activity and enantioselectivity, we first examined the utility of MacMillan-type
ꢀ ꢀ
This paper is dedicated to Professor Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 2, 2010
1. organocat, HQ (cat.)
O
O
CH2Cl2 / DMF
S
H
+
+
S
O
0.8 GPa, rt, 20 h
2. NaBH4, MeOH
OH
CHO
2
OH
H
1
(4 : 1)
(S)-4 (exo)
(S)-3 (endo)
O
O
Me
N
Me
N
organocat =
or
HQ = hydroquinone
C6F5
N
H
N
H
Ph
Ph
5
6
Scheme 1. Organocatalytic asymmetric Diels-Alder reaction of furan at high pressure
organocatalysts, chiral imidazolidinones 5 and 6, in our system (Scheme 1). For example, when a mixture
of furan (1, 4 equiv) and acrolein (2) containing 10 mol% of 5 together with PhCO2H in CH2Cl2/DMF (4 :
1) was reacted at 0.8 GPa and rt for 20 h,10 the desired endo- and exo-adducts 3 and 4 were obtained, after
NaBH4 reduction, in a combined yield of 59% and in a ratio of 56 : 44. Chiral HPLC analysis using a
Chiralpak AS column revealed that the enantioselectivity of each adduct was disappointingly low: 7% ee
for (S)-3 and 3% ee for (S)-4.11 We also carried out the same reaction at a lower pressure: the reaction
slowed sharply at 0.2 GPa, and the adducts were obtained in only 15% yield with no appreciable
enhancement in enantioselectivity. Similar results were obtained with catalyst 6: 0.2 GPa, 20 h, 22%
yield; 3/4 = 46 : 54, 7% ee for (R)-3 and 8% ee for (R)-4.
The fact that bond-formation and ionization both have a large negative activation volume12 implies that
the iminium ion-activation mode through intermediate 7 proposed by MacMillan et al.8 should also be
favorable in our system (Scheme 2). Despite this expectation, the essentially non-asymmetric induction
shown in Scheme 1 means that the subtle differences in a LUMO energy between acrolein (2) and
iminium ion 7 may be overridden at high pressure.13,14
‡
O
Me
N
5 or 6
O
O
O
O
R
N
CHO
Ph
CHO
non-chiral
CHO
2
H
chiral
7
Scheme 2. Proposed transition state for the organocatalytic asymmetric Diels-Alder reaction
Based on this consideration, we then searched for other types of chiral amine-based organocatalysts. The
results are summarized in Table 1.10

HETEROCYCLES, Vol. 80, No. 2, 2010
801
Table 1. Organocatalytic asymmetric Diels-Alder reaction of furan at high pressure
1. organocat, HQ (cat.)
rt, 20 h
O
O
H
+
+
O
2. NaBH4, MeOH
OH
CHO
2
OH
H
1
(4 : 1)
4 (exo)
3 (endo)
organocat
COOH
Ph
Ph
Ph
N
H
COOH
COOH
N
H
N
H
N
H
COOH
H2N
COOH H2N
COOH
OH
8
13
9
10
11
12
pressure
(GPa)
yield
(%)a
endo/exo
ratiob
ee (%)c
entry
solvent
organocat
3
4
3 (R)
1 (S)
4 (S)
7 (R)
3 (S)
3 (S)
13 (S)
3 (S)
11 (S)
3 (R)
19 (R)
1 (R)
0 (--)
3 (S)
10 (R)
13 (R)
4 (R)
2 (R)
0 (--)
1 (S)
5 (R)
3 (S)
1 (S)
25 (S)
2 (S)
21 (S)
5 (R)
20 (R)
1 (R)
1 (R)
1 (R)
6 (S)
14 (S)
26 (S)
1
2
8 (20 mol%)
8 (20 mol%)
8ꢀ(20 mol%)
8 (10 mol%)
8ꢀ(20 mol%)
8 (10 mol%)
8 (50 mol%)
8 (20 mol%)
8 (20 mol%)
9 (10 mol%)
9 (50 mol%)
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.4
0.2
0.8
0.8
0.8
0.8
0.8
0.8
0.4
0.2
CH2Cl2
MeCN
i-PrOH
38
70
62ꢀ
72
74ꢀ
89
18d
33
5
53 : 47
55 : 45
61 : 39
56 : 44
57 : 43
51 : 49
64 : 36
51 : 49
56 : 44
57 : 43
42 : 58
54 : 46
56 : 44
54 : 46
44 : 56
41 : 59
48: 52
3ꢀ
4ꢀ
5
CH2Cl2 / i-PrOH (4 : 1)
DMF
6
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
7
8
9
10
11
12
13
14
15
16
17
76
26d
91
82
41
45e
33
22
10 (10 mol%)
11 (10 mol%)
12 (10 mol%)
13 (10 mol%)
13 (10 mol%)
13 (10 mol%)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
CH2Cl2 / DMF (4 : 1)
a Isolated yield.
b Determined by 1H NMR (400 MHz).
c Determined by chiral HPLC using a Chiralpak AS column.
d Considerable polymerization was observed.
e The Michael adduct 14 was formed as a major by-product.
OH
HO
O
14

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HETEROCYCLES, Vol. 80, No. 2, 2010
The use of L- or D-proline (8 or 9) as a chiral organocatalyst showed no remarkable improvement in
enantioselectivity, even under a variety of conditions (entries 1-11). However, the enantioselectivity
tended to be enhanced with an increase in the amount of catalyst and with a decrease in pressure (entries 7,
9, 11).15 Furthermore, the chirality of the catalyst directs the enantiofacial attack of the reagent, which
leads to a reversal of enantiomers of the respective cycloadducts 3 and 4 (entries 7 and 11). Other types of
organocatalysts such as L-phenylalanine (10), L-glutamic acid (11), and diphenylprolinol 12 were found
to be less effective (entries 12-14).
Finally, when L-indolinecarboxylic acid (13) was used as a catalyst at 0.2 GPa, a slightly improved result
(26% ee) was obtained for the exo-isomer 4 (entry 17). However, carrying out the experiments under a
variety of conditions could not provide a significant improvement in both enantioselectivity and product
yield, but the formation of Michael-type adduct 14 was observed as a major by-product (entry 15).
The combined use of high pressure and organocatalysis was shown to be quite useful for promoting the
asymmetric Diels-Alder reaction of furan with acrolein.16 The enantioselectivity observed here is not yet
high enough for practical application, and hence additional studies are needed to identify much more
effective chiral organocatalysts. Further studies are now in progress in our laboratory.
ACKNOWLEDGEMENTS
The present work was supported in part by funds for Scientific Research on Priority Areas of MEXT, as
well as by a Special Research Grant for Green Science from Kochi University.
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HETEROCYCLES, Vol. 80, No. 2, 2010
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10.
11.
All high-pressure reactions were performed in the presence of a catalytic amount of hydroquinone
to avoid the polymerization of acrolein. Based on the solubility of the catalyst, a CH2Cl2/DMF
mixed solvent system was selected as the best reaction media.
HPLC conditions: Chiralpak AS, ꢀ = 210 nm, 5% 2-propanol/hexane, flow rate = 1.0 mL/min;
retention times: 20.04 min for (S)-3, 21.94 min for (R)-3, 15.51 min for (S)-4, 17.95 min for (R)-4.
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D
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It can not preclude the possibility that the reaction of furan with iminium ion 7 may be a
kinetically disfavored process under high pressure due to its sterically crowding structure.
In many cases the longer reaction periods reduced the enantioselectivity of cycloadducts.
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standardized conditions (10 mol% of 13, CH2Cl2/DMF = 4 : 1, 0.2 GPa, rt, 24 h).
15.
16.