A new class of enantioselective catalytic 2-pyrone Diels-Alder cycloadditions

Article abstract of DOI:10.1002/adsc.201000927

A highly enantioselective catalytic Diels-Alder (DA) cycloaddition of 2H-pyran-2,5-diones (synthon of 5-hydroxy-2-pyrones) has been developed with a Cinchona-derived thiourea as the catalyst. The conditions were optimized by using 0.2equiv. of the catalys

Full text of DOI:10.1002/adsc.201000927

FULL PAPERS
DOI: 10.1002/adsc.201000927
A New Class of Enantioselective Catalytic 2-Pyrone Diels–Alder
Cycloadditions
Wanqing Wu,a Long Min,a Lizhi Zhu,a and Chi-Sing Leea,*
a
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen
Graduate School, Shenzhen University Town, Xili, Shenzhen 518055, Peopleꢀs Republic of China
Fax : (+86)-755-2603-2701; phone (+86)-755-2603-2701; e-mail: lizc@szpku.edu.cn
Received: December 9, 2010; Revised: March 4, 2011; Published online: April 28, 2011
Supporting information for this article is available on the WWW under /dx.doi.org/10.1002/adsc.201000927.
Abstract: A highly enantioselective catalytic Diels– as the dienophiles. The structure/activity relation-
Alder (DA) cycloaddition of 2H-pyran-2,5-diones ships of the bifunctional catalyst and the effects of
(synthon of 5-hydroxy-2-pyrones) has been devel- the steric, electronic and hydrogen-bonding proper-
oped with a Cinchona-derived thiourea as the cata- ties of the dienophiles have been studied.
lyst. The conditions were optimized by using
0.2 equiv. of the catalyst and 0.1 equiv. of formic acid
in 2-propanol at room temperature, which afforded Keywords: asymmetric Diels–Alder reaction; enan-
the DA products in yields of up to 90% (exo/endo= tioselectivity; nitrostyrenes; organocatalysis; 2H-
5.5:1, 98% ee) with trans-b-nitrostyrene derivatives pyran-2,5-diones; thiourea-Cinchona derivatives
Introduction
tioselectivity.[4a] This reaction was first reported by
Nakataniꢀs group using a Brønsted base as the cata-
The Diels–Alder (DA) cycloaddition of 2-pyrones is a lyst in 1995.[5] Recently, Tanꢀs group reported an anal-
useful method in organic synthesis since it can pro- ogous DA cycloaddition of 3-hydroxy-2-pyridone
vide functionalized cyclohexadienes or bridged bicy- dienes using an aminoindanol catalyst with excellent
clic lactones in a single operation.[1] Indeed, this class enantioselectivity.[6]
of DA cycloadditions has been successfully utilized in
In the course of developing new methods for con-
natural product synthesis.[2] However, examples of struction of the tricyclic core of basiliolide B,[7] we
highly enantioselective catalytic 2-pyrone DA cyclo- have found that 2H-pyran-2,5-diones can be used as a
additions are still very limited, probably due to the synthon of 5-hydroxy-2-pyrones for DA cycloaddi-
partial aromatic character of 2-pyrones and their low tions.[8] As shown in Figure 1, 2H-pyran-2,5-dione 1
reactivity towards common dienophiles.[1,3] In 2007, reacted with trans-disubstituted dienophiles in the
Dengꢀs group reported a highly enantioselective cata- presence of a catalytic amount of dicyclohexylmethyl-
lytic DA cycloaddition of 3-hydroxy-2-pyrone using a amine or pyrrolidine in t-BuOH and afforded modest
Cinchona-derived bifunctional catalyst.[4] They pro- to good yields of the DA products with excellent exo
posed that the hydrogen bonding between the C-3 hy- selectivity. We herein report the development of this
droxy group of the 2-pyrone and the Brønsted base class of 2-pyrone DA cycloadditions into a highly
moiety of the catalyst is important for the high enan- enantioselective catalytic transformation.
Figure 1. DA cycloaddition of 2H-pyran-2,5-dione 1.
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Figure 2. Approaches for developing enantioselective catalytic DA cycloaddition of 2H-pyran-2,5-dione 1.
Activation of the substrates via enamine or imini- with 1. Since derivatives of Cinchona alkaloids, which
um formation has been a popular approach in devel- possess both hydrogen bond donor and acceptor moi-
oping organocatalytic transformations.[9] Recently, or- eties, have been demonstrated to be versatile Brønst-
ganic Brønsted acids and Brønsted bases have been ed base catalysts in many enantioselective reac-
shown to be a promising alternative in the field of or- tions,[12] we decided to study the catalytic activities of
ganocatalysis.[10] Since our previous study showed that a variety of Cinchona derivatives in the DA cycload-
dicyclohexylmethylamine and pyrrolidine are effec- dition. When quinine (5a) was used as the catalyst,
tive catalysts for the DA cycloaddition of 2H-pyran- the DA cycloaddition was finished in 7 h and afforded
2,5-diones, two approaches base on the structural a 33% yield of the DA products (exo/endo=2.5:1)
frameworks of the catalysts could be employed. As with À35% ee for the exo product (entry 9). Cinchona
shown in Figure 2, the enone moiety of 1 could be derivative 5b[4b,13] afforded a similar yield of the DA
either converted to an enamine diene with a chiral products with a higher exo/endo ratio but a lower ee
cyclic secondary amine or to an enolate diene with a value (entry 10). As thioureas are known to be able
chiral Brønsted base. These resulting diene intermedi- to activate carbonyl and nitro groups via efficient hy-
ates are anticipated to undergo DA cycloadditions drogen bonding interactions,[14–16] Cinchona thiourea
stereoselectively.
6a[16e] was employed. This bifunctional catalyst suc-
cessfully led to a complete reaction in 9 h and fur-
nished 73% yield of the DA products (exo/endo=
6.0:1) with 72% ee for the exo product (entry 11).
The DA cycloaddition conditions were then further
Results and Discussions
Thus the catalytic activities of a variety of cyclic sec- optimized by examining the effects of different sol-
ondary amines[9] for the DA cycloaddition of 2H- vents. Among the alcohol solvents used, i-PrOH
pyran-2,5-dione 1 with trans-b-nitrostyrene in t-BuOH showed the best result, providing 88% yield of the
were investigated (Figure 3). As shown in Table 1, l- DA products (exo/endo=7.0:1) with 94% ee for the
proline (3a) gave only 15% yield of the DA products exo product (entry 3, Table 2). The DA cycloaddition
(exo/endo=4.2:1) and very poor enantioselectivity went much moreslowly in toluene or CH2Cl2 and gave
(entry 1). Switching to l-prolinol (3b) improved the poor exo/endo ratios and modest enantioselectivity
yield to 46% (exo/endo=5.8:1) with 22% ee for the (entries 5 and 6). Switching the solvent to CH3CN,
exo product (entry 2). This encouraging result ethyl acetate, diethyl ether or THF led to higher dia-
prompted us to evaluate the catalytic activities of stereoselectivities (entries 7–10). Among these sol-
other l-proline derivatives. However, O-methyl-l-pro- vents, THF gave the highest exo/endo ratio (17:1)
linol (3c) could only slightly improve the ee value with 85% ee for the exo product (entry 10). After the
(entry 3) and the enantioselectivities obtained by study of the solvent effects, the effects of catalyst
using 3d–f were disappointing (entries 4–6). MacMil- loading and reaction temperature were also examined
lanꢀs catalysts (4a and 4b)[11] were found to be not ef- with i-PrOH as the solvent. As shown in Table 2, re-
fective for this DA cycloaddition, providing only trace ducing the catalyst loading to 0.05 or 0.1 equiv. de-
amount of the DA products in 7 days (entries 7 and creased the reaction rate dramatically (7–11 days) and
8). These results indicated that the l-phenylalanine gave low yields and poor selectivities (entries 11 and
derivatives could be too bulky for enamine formation 12). The DA cycloaddition proceeded much faster
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A New Class of Enantioselective Catalytic 2-Pyrone Diels–Alder Cycloadditions
Figure 3. Structures of the catalysts.
with 0.15 equiv. of the catalyst, but only a slightly (entries 5–7). Only the 4-chlorophenyl derivative
higher enantioselectivity was observed (entry 13). Sur- (6f)[17] provided a satisfactory ee value (86% ee) for
prisingly, a brief survey on the temperature effects the exo product (entry 7). The 4-fluoro- and 4-bromo-
showed that either increasing or decreasing the reac- phenyl derivative just gave 55 and 76% ee, respective-
tion temperature led to significant drops in ee values ly (data not shown). These results suggested that the
(entries 14 and 15).
electronic properties of the aromatic moiety of the
To investigate the structure/activity relationships of catalyst can considerably affect the enantioselectivity
the catalyst, a variety of Cinchona derivatives was of the DA product. The effects of the skeleton of dif-
employed as the catalyst for the DA cycloaddition. ferent Brønsted bases were also examined. Takemo-
As shown in Table 3, varying the catalyst structures toꢀs catalyst[16c] (7) afforded a higher yield of the DA
did not affect the yields of the DA products but led to products but a lower exo/endo ratio and a lower ee
significant changes in exo/endo ratios and ee values. value (entry 9). However, both Sibiꢀs catalyst[18] (8)
Urea 6b gave only modest selectivities (exo/endo= and Wangꢀs catalyst[19] (9) were found to be not effec-
4.8:1 with 66% ee for the exo product) (entry 2), sug- tive for the DA cycloaddition (entries 10 and 11),
gesting the thiourea is important for high selectivities. which indicated that the basicity of the Brønsted base
Switching to the hydrogenated derivative (6c) led to a is essential for the 2-pyrone DA cycloaddition.
higher exo/endo ratio but a slightly lower ee value
Since addition of acid may affect the basicity of the
(entry 3). Replacing the bis(trifluoro)phenyl by a Brønsted base and the hydrogen bondings between
phenyl group (6d)[17] also led to a lower exo/endo the substrates and the catalyst, the effects of acid ad-
ratio and a lower ee value (entry 4). Introducing a ditives in the DA cycloadditions with i-PrOH as the
methyl (6e), a halo or a methoxy substitute (6g) to solvent were first studied with different amounts of
the 4-position of the phenyl group caused significant formic acid. As shown in Table 4, the yields and enan-
drops in diastereoselectivity and enantioselectivity tioselectivity of the DA cycloaddition were found to
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Table 1. Enantioselective DA cycloaddition of 2H-pyran-2,5-
dione 1.[a]
Table 2. Optimization of the DA cycloaddition conditions.[a]
No. Solvent
T[b]
[8C]
x[c]
Time Yield dr[e]
ee
[%][d]
[%][f]
No.
Catalyst
Time
Yield
[%][b]
dr[c]
ee
[%][d]
1
2
MeOH
EtOH
r.t.
r.t.
r.t.
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
12 h
12 h
9 h
48
70
88
73
27
60
78
72
80
72
45
57
83
74
25
2.0:1 39
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
4a
4b
5a
5b
6a
5 d
3 d
3 d
2 d
18 h
7 d
7 d
7 d
7 h
10 h
9 h
15
46
40
51
53
36
trace
trace
33
4.2:1
5.8:1
5.5:1
5.1:1
6.3:1
5.7:1
n.d.[e]
n.d.[e]
2.5:1
4.2:1
6.0:1
<5
22
26
<5
<5
<5
n.d.[e]
n.d.[e]
À35
20
6.0:1 79
7.0:1 94
6.0:1 72
2.0:1 56
2.0:1 66
8.0:1 71
3
i-PrOH
4
t-BuOH r.t.
9 h
5
6
toluene
CH2Cl2
r.t.
r.t.
24 h
24 h
6 h
7
CH3CN r.t.
8
9
EtOAc
Et2O
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
7 h
9 h
9 h
12:1
14:1
17:1
75
75
85
9
10
11
10
11
12
13
14
15
THF
37
73
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
0.05 11 d
0.1 7 d
0.15 27 h
3.2:1 40
3.6:1 46
4.4:1 55
5.6:1 57
2.6:1 43
72
[a]
The general procedures were followed with t-BuOH as
the solvent.
Total isolated yields [%] of exo and endo products after
silica gel column chromatography.
0.2
9 h
3 d
À20 0.2
[b]
[c]
[d]
[e]
[a]
The general procedures were followed with the indicated
solvent.
T=reaction temperature.
x=equivalents of the catalyst used.
Total isolated yields [%] of exo and endo products after
silica gel column chromatography.
1
dr=exo/endo ratios, which were estimated by H NMR
[b]
[c]
[d]
(dexo =3.75 ppm and dendo =3.99 ppm).
The% ee of the exo product, determined by chiral
HPLC.
n.d.=not determined.
[e]
[f]
1
dr=exo/endo ratios, which were estimated by H NMR
(dexo =3.75 ppm and dendo =3.99 ppm).
The% ee of the exo product, determined by chiral
HPLC.
be very sensitive to the catalyst/acid ratio (entries 1–
4). The optimal ratio of catalyst/formic acid is 2:1,
which gave 90% yield of the DA products (exo/
endo=5.5:1) with 98% ee for the exo product
(entry 2). Switching to acetic acid or benzoic acid de- b-nitrostyrene derivatives as the dienophile were stud-
creased the yields and ee values gently (entries 5 and ied and the results are summarized in Table 5. Dieno-
6). Strong acid, such as TFA and TsOH led to much philes with 4-methyl- or 4-halophenyl substituents
slower reactions with low yields and poor enantiose- generally proceeded much more slowly (3-6 days) at
lectivity (entries 7 and 8). Since THF afforded the op- room temperature and gave slightly lower yields of
timal exo/endo ratio, the effects of the acid additive in the DA products with comparable exo/endo ratios
THF were also studied. Although the enantioselectivi- and ee values (entries 1–4, and 7). On the other hand,
ty was slightly improved, only a modest yield of the a strong electron-donating group (OMe) at the 4-posi-
DA products was obtained (entry 9).
tion led to a much lower ee value (entry 8). Interest-
With the optimal reaction condition in hand, the 2- ingly, switching the OMe to OH provided a much
pyrone DA cycloadditions of 1 with a variety of trans- higher enantioselectivity (entry 11). Moreover, dieno-
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A New Class of Enantioselective Catalytic 2-Pyrone Diels–Alder Cycloadditions
Table 3. DA cycloaddition with various catalysts.[a] Table 4. DA cycloaddition with various acid additives.[a]
No. Acid/Solvent
x[b]
Time Yield dr[d]
ee
No.
Catalyst
Time
Yield
[%][b]
dr[c]
ee
[%][c]
[%][e]
[%][d]
1
2
3
4
5
6
7
8
9
HCO2H/i-PrOH 0.05 7 h
65
90
43
65
85
74
38
13
66
5.0:1 65
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6f
6g
7
9 h
88
88
82
86
85
88
85
92
–
7.0:1
4.8:1
8.0:1
3.6:1
3.4:1
3.6:1
3.7:1
4.9:1
n.d.[e]
n.d.[e]
94
66
83
63
67
86
55
HCO2H/i-PrOH 0.1
HCO2H/i-PrOH 0.2
HCO2H/i-PrOH 0.4
44 h
2 d
2 d
5.5:1 98
5.4:1 61
5.0:1 74
5.0:1 80
6.0:1 80
8.0:1 32
n.d.[f] 30
13:1 90
12 h
12 h
12 h
12 h
12 h
12 h
14 h
10 d
10 d
AcOH/i-PrOH
PhCO2H/i-PrOH 0.1
TFA/i-PrOH
TsOH/i-PrOH
HCO2H/THF
0.1
17 h
37 h
5 d
16 d
16 h
0.1
0.1
0.1
63
8
9
n.d.[e]
n.d.[e]
[a]
trace
The general procedures were followed with an acid addi-
tive in the indicated solvent.
x=equivalent of the catalyst used.
Total isolated yields [%] of exo and endo products after
silica gel column chromatography.
dr=exo/endo ratios, which were estimated by H NMR
(dexo 3.75 ppm and dendo 3.99 ppm).
The% ee of the exo product, determined by chiral
HPLC.
[a]
The general procedures were followed with i-PrOH as
the solvent.
Total isolated yields [%] of exo and endo products after
silica gel column chromatography.
[b]
[c]
[b]
[c]
[d]
[e]
[d]
[e]
[f]
1
1
dr=exo/endo ratios, which were estimated by H NMR
(dexo =3.75 ppm and dendo =3.99 ppm).
The% ee of the exo product, determined by chiral
HPLC.
n.d.=not determined.
n.d.=not determined.
DA product 2a can be readily converted to an opti-
philes with the chloro group at different positions of cally enriched and highly functionalized a-hydroxycy-
the benzene ring did not show any significant effects clohexanone, which could be useful building blocks
on the efficiency and selectivities (entries 4–6) which for natural product synthesis. As shown in Scheme 1,
was similar to those bearing OMe or OH at the 3, 4- lactone ring opening of 2a using sodium methoxide in
positions of the phenyl group (entries 8, 9 and 10, 11). methanol afforded an 86% yield of 23, which is a
However, dienophiles with OMe or OH at the 2-posi- single diastereomer.
tion of the phenyl group gave a very sluggish reaction
Finally, the absolute configurations of DA product
(entry 10) or a non-selective reaction (entry 13). 2a were determined by means of X-ray crystallogra-
These results indicated that the hydrogen-bond donat- phy (Figure 4, b)[20] of the single crystals that were ob-
ing or accepting group of the dienophile closer to the tained by recrystallization of 2a (98% ee) from a hex-
reaction site showed greater influences on the reactiv- anes/dichloromethane solution. A transition state
ity and the selectivities of the DA cycloaddition. Fi- with 6a acting as a bifunctional catalyst was proposed.
nally, replacing the phenyl group with other aromatic As shown in Figure 4, c, the Brønsted base of the Cin-
rings (2-furanyl group) also provided good yields and chona derivative induced the enolization of 2H-
high enantioselectivity (entry 14).
pyran-2,5-dione to 5-hydroxy-2-pyrone and activated
the diene via hydrogen bondings with the 5-hydroxy
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Table 5. DA cycloaddition with various dienophiles.[a]
No. Ar
Product[b] Time Yield dr[d]
ee
[%][c]
[%][e]
Figure 4. (a) The absolute configurations of 2a, (b) X-ray
crystal structure of 2a, and (c) a proposed transition state
for the DA cycloaddition.
1
2
3
4
5
6
7
8
Ph
2a,b
32 h 90
5.5:1 98
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
3-Cl-C6H4
2-Cl-C6H4
4-Br-C6H4
4-MeO-C6H4 16a,b
3-MeO-C6H4 17a,b
2-MeO-C6H4 18a,b
4-HO-C6H4
3-HO-C6H4
2-HO-C6H4
2-furanyl
10a,b
11a,b
12a,b
13a,b
14a,b
15a,b
5 d
3 d
4 d
3 d
3 d
6 d
7 d
7 d
7 d
78
85
83
78
80
76
62
60
5.3:1 96
5.8:1 96
6.2:1 94
5.5:1 82
5.8:1 93
5.8:1 91
5.4:1 63
5.6:1 63
moiety and the thiourea moiety of the catalyst activat-
ed the dienophile via hydrogen bondings with the
nitro moiety.[21] The extensive hydrogen-bonding net-
work in this transition state should provide a good en-
vironment for high enantioselectivity.
9
10
11
12
13
14
trace n.d.[f] n.d.[f]
19a,b
20a,b
21a,b
22a,b
26 h 72
5.2:1 91
5.0:1 89
5.0:1 <5
5.3:1 96
3 d
3 d
3 d
70
61
81
Conclusions
[a]
[b]
The general procedures were followed.
In summary, we have developed a new class of enan-
tioselective catalytic 2-pyrone DA cycloaddition reac-
tions using Cinchona-derived thiourea 6a as the cata-
lyst. This bifunctional catalyst induced the equilibra-
tion of 2H-pyran-2,5-dione to the 5-hydroxy-2-pyrone,
which underwent DA cycloaddition with trans-b-nitro-
styrene derivatives in high efficiency and very good
stereoselectivities. With 6a (0.2 equiv.) and formic
acid (0.1 equiv.) in 2-propanol at room temperature,
this optimal condition afforded the DA cycloadducts
in yields up to 90% (exo/endo=5.5:1, 98% ee). The
results of the DA cycloaddition with a variety of
trans-b-nitrostyrene derivatives showed that the elec-
tronic and hydrogen-bonding properties of the sub-
stituent of the phenyl group exhibited great influence
on the yields and selectivities of the DA cycloaddi-
tion. Moreover, this enantioselective transformation
provided a quick access to highly functionalized
bridged bicyclic lactones and a-hydroxycyclohexa-
none derivatives in high optical purity. The utilities of
this reaction in natural product synthesis are being ac-
tively explored in our research group.
The circular dichroism spectra of DA adducts 2a, 10a–
17a, 19a–20a and 22a showed a negative Cotton effect
with absorption bands at 282–291 nm, indicating analo-
gous absolute configurations of these DA adducts. These
results are also consistent with the orders of elution in
HPLC.
[c]
Total isolated yields [%] of exo and endo products after
silica gel column chromatography.
[d]
[e]
1
dr=exo/endo ratios, which were estimated by H NMR.
The% ee of the exo product, determined by chiral
HPLC.
n.d.=not determined.
[f]
Scheme 1. Preparation of highly functionalized a-hydroxycy-
clohexanone from the DA product.
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A New Class of Enantioselective Catalytic 2-Pyrone Diels–Alder Cycloadditions
appropriate dienophile (0.75 mmol) was added. After anoth-
Experimental Section
er 30 min, 1 (33.9 mg, 0.15 mmol) was added. The resulting
mixture was monitored by TLC until the starting material
was consumed. The reaction was worked up by addition of a
saturated aqueous NH4Cl solution and the aqueous layer
was extracted with diethyl ether (ꢂ3). The combined ex-
tracts were washed with brine, dried over Na2SO4, filtered
and concentrated. The residue was then purified by silica gel
flash column chromatography and subsequently subjected to
HPLC analysis.
General Remarks
All air- and water-sensitive reactions were carried out under
a nitrogen atmosphere with dry solvents under anhydrous
conditions, unless otherwise noted. Reactions were moni-
tored by thin-layer chromatography (TLC) carried out on
0.25 mm Tsingdao silica gel plates (60F-254) that were ana-
lyzed by staining with KMnO4 (200 mL H2O of 1.5 g
KMnO4, 10 gK2CO3 and 1.25 mL of 10% aqueous NaOH).
Tsingdao silica gel (60, particle size 0.040–0.063 mm) was
used for flash column chromatography.
All the chemicals were purchased commercially and used
without further purification. Anhydrous THF was distilled
from sodium-benzophenone, and dichloromethane was dis-
tilled from calcium hydride. Yields refer to chromatographi-
cally, unless otherwise stated.
NMR spectra were recorded on either a Bruker Advance
300 (1H: 300 MHz, 13C: 75.5 MHz), or Bruker Advance 500
(1H: 500 MHz, 13C: 125.8 MHz). The following abbreviations
are used to explain the multiplicities: s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet, br=broad. High reso-
lution mass spectra were obtained from Applied Biosystems
(ABI) Q-Star Elite MALDI-TOF Mass Spectrometer. High
performance liquid chromatography analysis was performed
on an Agilent Technologies 1200 Series instrument, using a
Daicel Chiralcel OD-H column (250ꢂ4.6 mm) or Chiralpak
AD-H column (250ꢂ4.6 mm) with i-PrOH/hexane as the
eluent. Optical rotations were measured on a Perkin–Elmer
341 polarimeter. Melting points were uncorrected and deter-
mined on X-6 micro-melting point meter (Beijing Tech In-
strument Co., Ltd.). Crystallographic data were obtained
from an Oxford diffraction single crystal X-ray diffractome-
ter (Gemini S Ultra). All the IR spectra were recorded with
Nicolet 380 FT-IR spectrometer. Circular dichroism spectra
were obtained in dichloromethane with a Biologic MOS-450
spectropolarimeter.
tert-Butyl 2-{(1R,4R,7S,8S)-8-Nitro-3,6-dioxo-7-
phenyl-2-oxabicycloACTHUNGTRENNG[U 2.2.2]octan-1-yl}acetate (2a)
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.5:1, deter-
mined by integration of 1H NMR signal: dexo =3.75 ppm,
dendo =3.99 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a pale yellow solid; yield: 43 mg (76% yield, 98%
ee). The ee was determined by HPLC analysis (Daicel Chir-
alcel OD-H column: hexane/i-PrOH=75:25, flow rate=
0.5 mLminÀ1,
l=210 nm):
tminor =39.06 min,
tmajor =
43.62 min; [a]2D0: À15.6 (c 0.50 in CHCl3); mp 190–1918C;
1H NMR (500 MHz, CDCl3): d=7.39 (m, 3H), 7.06 (m,
2H), 5.10 (dd, J=7.0 Hz, 1.8 Hz, 1H), 4.73 (d, J=7.0 Hz,
1H), 3.75 (d, J=2.1 Hz, 1H), 3.06 (dd, J=19.5 Hz, 3.2 Hz,
1H), 2.92 (dd, J=19.5 Hz, 2.7 Hz, 1H), 2.64 (d, J=17.2 Hz,
1H), 2.37 (d, J=17.2 Hz, 1H), 1.43 (s, 9H); 13C NMR
(125 MHz, CDCl3): d=199.0, 166.9, 166.8, 133.8, 129.8,
129.5, 128.7, 87.6, 86.6, 82.4, 51.0, 41.1, 36.5, 35.3, 28.2; IR
(KBr): n=3068, 2982, 2940, 2919, 1779, 1753, 1732, 1458,
1379, 1368, 1246, 1232, 1103, 1022, 707 cmÀ1; HR-MS (ESI/
ACHTUNG-
TERNNUG
[M+H]+): m/z=376.1411, calcd. for C19H22NO7: 376.1396.
tert-Butyl 2-{(1R,4R,7S,8S)-8-Nitro-3,6-dioxo-7-p-
tolyl-2-oxabicyclo[2.2.2]octan-1-yl}acetate (10a)
AHCTUNGTRENNUNG
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.3:1, deter-
mined by integration of 1H NMR signal: dexo =3.73 ppm,
dendo =3.96 ppm). The title compound was isolated by flash
General Procedure for the Racemic Base-Catalyzed
Diels–Alder Cycloadditions
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a white solid; yield: 38 mg (66%, 96% ee). The ee
was determined by HPLC analysis (Daicel Chiralcel OD-H
column: hexane/i-PrOH=75:25, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =28.50 min, tmajor =31.06 min; [a]2D0: À12.6
(c 0.53 in CHCl3); mp=197–1988C; 1H NMR (500 MHz,
CDCl3): d=7.18 (d, J=7.9 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H),
5.08 (dd, J=7.0 Hz, 2.0 Hz, 1H), 4.66 (d, J=7.0 Hz, 1H),
3.73 (m, 1H), 3.05 (dd, J=19.4 Hz, 3.3 Hz, 1H), 2.90 (dd,
J=19.4 Hz, 2.9 Hz, 1H), 2.63 (d, J=17.2 Hz, 1H), 2.38 (d,
J=17.2 Hz, 1H), 2.35 (s, 3H), 1.45 (s, 9H); 13C NMR
(125 MHz, CDCl3): d=199.1, 167.0, 166.8, 139.6, 130.6,
130.5, 128.5, 87.7, 86.7, 82.3, 50.7, 41.1, 36.5, 35.3, 28.2, 21.2;
IR (KBr): n=3053, 2987, 2831, 2685, 2521, 2410, 2305, 2155,
2126, 2055, 1788, 1603, 1551, 1422, 1271, 1156, 986, 896,
To a stirred solution of 1 (23 mg, 0.1 mmol) and the appro-
priate dienophile (0.5 mmol) in t-BuOH (1.5 mL) was added
(c-Hex)2NMe (2.2 mL, 0.01 mmol). The resulting mixture
was stirred at room temperature and monitored by TLC
until the starting material was consumed. The reaction was
worked up by addition of a saturated aqueous NH4Cl solu-
tion and the aqueous layer was extracted with diethyl ether
(ꢂ3). The combined extracts were washed with brine, dried
over Na2SO4, filtered and concentrated. The residue was
then purified by silica gel flash column chromatography and
subsequently subjected to HPLC analysis. The relative con-
figurations of racemic 2a were determined by X-ray crystal-
lography,[20] and the relative configurations of 10a–22a were
determined by comparison with the 1H NMR of 2a.
708 cmÀ1; HR-MS (ESI/
[M+Na]+): m/z=412.1366, calcd. for
ACHTUNGTRENNUNG
General Procedure for the Asymmetric Diels–Alder
Cycloadditions
C20H23NO7Na: 412.1367.
To a solution of catalyst 6a (17.8 mg, 0.03 mmol) in i-PrOH
(1.0 mL, HPLC grade) was added formic acid (0.015 mmol,
0.6 mL). After stirring at room temperature for 30 min, the
Adv. Synth. Catal. 2011, 353, 1135 – 1145
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1141

Wanqing Wu et al.
FULL PAPERS
OD-H column: hexane/i-PrOH=75:25, flow rate=
tert-Butyl 2-{(1R,4R,7S,8S)-7-(4-Fluorophenyl)-8-
0.5 mLminÀ1,
l=210 nm);
t
minor =30.67 min,
tmajor =
nitro-3,6-dioxo-2-oxabicyclo
(11a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
42.28 min; [a]2D0: À11.9 (c 0.55 in CHCl3); mp 168–1698C;
1H NMR (300 MHz, CDCl3): d=7.36 (m, 2H), 7.09 (m,
1H), 6.93 (m, 1H), 5.05 (dd, 1H, J=7.1 Hz, 2.0 Hz), 4.77 (d,
1H, J=7.1 Hz), 3.77 (m, 1H), 3.05 (dd, 1H, J=19.5 Hz,
3.2 Hz), 2.93 (dd, 1H, J=19.4 Hz, 2.9 Hz), 2.66 (d, 1H, J=
17.3 Hz), 2.36 (d, 1H, J=17.3 Hz), 1.46 (s, 9H); 13C NMR
(75 MHz, CDCl3): d=198.9, 166.8, 166.7, 135.8, 135.6, 131.1,
129.9, 129.1, 126.5, 87.1, 86.2, 82.6, 50.2, 40.8, 36.4, 35.0,
28.2; IR (KBr): n=3054, 2987, 2831, 2685, 2521, 2410, 2305,
2155, 2126, 2054, 1789, 1604, 1551, 1422, 1271, 1156, 986,
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.8:1, deter-
mined by integration of 1H NMR signal: dexo =3.75 ppm,
dendo =3.98 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a white solid; yield: 45 mg (76%, 96% ee). The ee
was determined by HPLC analysis (Daicel Chiralpak AD-H
column: hexane/i-PrOH=85:15, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =22.01 min, tmajor =26.90 min; [a]2D0: À18.2
(c 0.52 in CHCl3); mp 209–2108C; 1H NMR (500 MHz,
CDCl3): d=7.08 (m, 4H), 5.02 (dd, J=7.2 Hz, 1.9 Hz, 1H),
4.76 (d, J=7.2 Hz, 1H), 3.75 (m, 1H), 3.06 (dd, J=19.5 Hz,
3.3 Hz, 1H), 2.90 (dd, J=19.5 Hz, 2.9 Hz, 1H), 2.64 (d, J=
17.2 Hz, 1H), 2.35 (d, J=17.2 Hz, 1H), 1.45 (s, 9H);
13C NMR (125 MHz, CDCl3): d=199.2, 166.8, 166.7, 130.6,
130.5, 117.0, 116.9, 87.6, 86.5, 82.5, 50.2, 41.0, 36.6, 35.1,
28.2; IR (KBr): n=3054, 2987, 2831, 2685, 2521, 2411, 2306,
2156, 2126, 2055, 1788, 1605, 1551, 1422, 1263, 1156, 986,
896, 693 cmÀ1
[M+Na]+): m/z=432.0818,
; HR-MS (ESI/CAHTUNTGRNUEGN
calcd. for C19H20NO7NaCl: 432.0821.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(2-Chlorophenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(14a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.8:1, deter-
mined by integration of 1H NMR signal: dexo =3.75 ppm,
dendo =3.98 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a light yellow solid; yield: 44 mg (71%, 93% ee). The
ee was determined by HPLC analysis (Daicel Chiralpak
OD-H column: hexane/i-PrOH=75:25, flow rate=
ACTHNUTRGNEUNG
896, 693 cmÀ1; HR-MS (ESI/[M+Na]+): m/z= 416.1120,
calcd. for C19H20NO7FNa: 416.1121.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(4-Chlorophenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(12a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
0.5 mLminÀ1,
l=210 nm):
tminor =37.05 min,
tmajor =
45.84 min; [a]2D0: À13.2 (c 0.53 in CHCl3); mp 180–1818C;
1H NMR (300 MHz, CDCl3): d=7.49 (m, 1H), 7.33 (m,
2H), 6.80 (m, 1H), 5.07 (d, 1H, J=7.4 Hz), 4.99 (m, 1H),
3.75 (m, 1H), 3.13 (dd, 1H, J=19.2 Hz, 2.9 Hz), 2.92 (m,
1H), 2.80 (d, 1H, J=17.2 Hz), 2.55 (d, 1H, J=17.3 Hz),
1.39 (s, 9H); 13C NMR (75 MHz, CDCl3): d=199.2, 166.7,
166.3, 135.6, 131.1, 130.7, 128.2, 127.9, 87.0, 86.9, 82.3, 48.0,
41.2, 36.7, 35.4, 28.1; IR (KBr): n=3054, 2987, 2831, 2685,
2521, 2410, 2305, 2155, 2126, 2055, 1789, 1604, 1551, 1422,
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=6.2:1, deter-
mined by integration of 1H NMR signal: dexo =3.76 ppm,
dendo =3.99 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a white solid; yield: 44 mg (71%, 94% ee). The ee
was determined by HPLC analysis (Daicel Chiralpak AD-H
column: hexane/i-PrOH=85:15, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =22.69 min, tmajor =32.16 min; [a]2D0: À13.8
(c 0.54 in CHCl3); mp 191–1928C; 1H NMR (500 MHz,
CDCl3): d=7.37 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H),
5.01 (dd, J=7.1 Hz, 1.9 Hz, 1H), 4.76 (d, J=7.1 Hz, 1H),
3.75 (dd, J=4.9 Hz, 2.7 Hz, 1H), 3.06 (dd, J=19.5 Hz,
3.2 Hz, 1H), 2.90 (dd, J=19.5 Hz, 2.8 Hz, 1H), 2.64 (d, J=
17.1 Hz, 1H), 2.35 (d, J=17.1 Hz, 1H), 1.45 (s, 9H);
13C NMR (125 MHz, CDCl3): d=199.1, 166.8, 166.6, 135.9,
132.3, 130.1, 130.0, 87.4, 86.4, 82.6, 50.3, 41.0, 36.5, 35.1,
28.2; IR (KBr): n=3054, 2987, 2831, 2685, 2521, 2410, 2305,
2155, 2126, 2055, 1789, 1604, 1551, 1422, 1256, 1156, 987,
ACTHNUTRGNEUNG
1271, 1156, 987, 896, 693 cmÀ1; HR-MS (ESI/[M+Na]+):
m/z=432.0816, calcd. for C19H20NO7NaCl: 432.0821.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(4-Bromophenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(15a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.8:1, deter-
mined by integration of 1H NMR signal: dexo =3.76 ppm,
dendo =3.99 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a white solid; yield: 44 mg (65%, 91% ee). The ee
was determined by HPLC analysis (Daicel Chiralpak AD-H
column: hexane/i-PrOH=90:10, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =41.93 min, tmajor =65.17 min; [a]2D0: À16.6
(c 0.51 in CHCl3); mp 178–1798C; 1H NMR (500 MHz,
CDCl3): d=7.52 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H),
5.01 (d, J=6.5 Hz, 1H), 4.75 (d, J=7.0 Hz, 1H), 3.76 (m,
1H), 3.06 (dd, J=19.5 Hz, 3.0 Hz, 1H), 2.90 (dd, J=
19.5 Hz, 2.5 Hz, 1H), 2.65 (d, J=17.5 Hz, 1H), 2.35 (d, J=
17.5 Hz, 1H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3):
d=199.0, 166.8, 166.6, 133.0, 132.8, 130.3, 124.0, 87.3, 86.3,
82.6, 50.3, 41.0, 36.5, 35.1, 28.2; IR (KBr): n=3054, 2987,
2831, 2685, 2521, 2410, 2305, 2155, 2126, 2055, 1789, 1603,
896, 693 cmÀ1
[M+Na]+): m/z=432.0829,
; HR-MS (ESI/CAHTUNTGRNUEGN
calcd. for C19H20NO7ClNa: 432.0826.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(3-Chlorophenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(13a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.5:1, deter-
mined by integration of 1H NMR signal: dexo =3.77 ppm,
dendo =3.99 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a light yellow solid; yield: 41 mg (66%, 82% ee). The
ee was determined by HPLC analysis (Daicel Chiralpak
1142
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1135 – 1145

A New Class of Enantioselective Catalytic 2-Pyrone Diels–Alder Cycloadditions
1551, 1422, 1271, 1156, 986, 896, 691 cmÀ1; HR-MS (ESI/
[M+Na]+): m/z=476.0317, calcd. for C19H20NO7BrNa:
476.0315.
A
mined by integration of 1H NMR signal: dexo =3.72 ppm,
dendo =3.96 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
1:1) as a pale yellow solid; yield: 35 mg (60%, 91% ee). The
ee was determined by HPLC analysis (Daicel Chiralpak
AD-H column: hexane/i-PrOH=85:15, flow rate=
TRENNUNG
tert-Butyl 2-{(1R,4R,7S,8S)-7-(4-Methoxyphenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(16a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
0.5 mLminÀ1,
l=210 nm):
tminor =31.03 min,
tmajor =
45.64 min; [a]2D0: À17.3 (c 0.55 in CHCl3); mp 101–1028C;
1H NMR (500 MHz, CDCl3): d=6.93 (d, J=8.6 Hz, 2H),
6.83 (d, J=8.6 Hz, 2H), 5.13 (br, 1H), 5.03 (dd, J=7.0 Hz,
1.8 Hz, 1H), 4.64 (d, J=7.1 Hz, 1H), 3.72 (m, 1H), 3.04 (dd,
J=19.4 Hz, 3.2 Hz, 1H), 2.88 (dd, J=19.4 Hz, 2.7 Hz, 1H),
2.64 (d, J=17.1 Hz, 1H), 2.38 (d, J=17.1 Hz, 1H), 1.45 (s,
9H); 13C NMR (125 MHz, CDCl3): d=199.3, 166.9, 166.8,
156.6, 130.1, 125.9, 116.7, 87.8, 86.8, 82.4, 50.3, 41.1, 36.6,
35.3, 28.2; IR (KBr): n=3692, 3054, 2987, 2831, 2685, 2521,
2410, 2305, 2155, 2126, 2055, 1788, 1604, 1551, 1422, 1271,
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.4:1, deter-
mined by integration of 1H NMR signal: dexo =3.73 ppm,
dendo =3.95 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a yellow oil; yield: 32 mg (52%, 63% ee). The ee was
determined by HPLC analysis (Daicel Chiralpak AD-H
column: hexane/i-PrOH=90:10, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =43.93 min, tmajor =50.46 min; [a]2D0: À7.1
ACTHNUTRGNEUNG
1156, 987, 896, 697 cmÀ1; HR-MS (ESI/[M+Na]+): m/z=
414.1157, calcd. for C19H21NO8Na: 414.1159.
1
(c 0.50 in CHCl3); H NMR (500 MHz, CDCl3): d=6.97 (d,
J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 5.05 (dd, J=7.0 Hz,
1.9 Hz, 1H), 4.64 (d, J=7.0 Hz, 1H), 3.81 (s, 3H), 3.72 (dd,
J=4.9 Hz, 2.7 Hz, 1H), 3.04 (dd, J=19.6 Hz, 3.2 Hz, 1H),
2.89 (dd, J=19.4 Hz, 2.8 Hz, 1H), 2.63 (d, J=17.1 Hz, 1H),
2.68 (d, J=17.1 Hz, 1H), 1.45 (s, 9H); 13C NMR (125 MHz,
CDCl3): d=199.3, 167.0, 166.9, 160.4, 129.8, 125.5, 115.2,
87.8, 86.8, 82.3, 55.5, 50.4, 41.1, 36.5, 35.3, 28.2; IR (KBr):
n=3054, 2987, 2831, 2685, 2521, 2410, 2305, 2156, 2126,
tert-Butyl 2-{(1R,4R,7S,8S)-7-(3-Hydroxyphenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(20a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.0:1, deter-
mined by integration of 1H NMR signal: dexo =3.74 ppm,
dendo =3.98 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a yellow oil; yield: 34 mg (58%, 89% ee). The ee was
determined by HPLC analysis (Daicel Chiralpak OD-H
column: hexane/i-PrOH=75:25, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =22.76 min, tmajor =26.83 min; [a]2D0: À15.2
2055, 1788, 1604, 1551, 1422, 1271, 1156, 986, 896, 696 cmÀ1
;
HR-MS (ESI/
ACHTUNGTRENNUNG
C20H23NO8Na: 428.1316.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(3-Methoxyphenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(17a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
1
(c 0.50 in CHCl3); H NMR (300 MHz, CDCl3): d=7.22 (m,
1H), 6.84 (m, 1H), 6.57 (m, 2H), 5.67 (br, 1H), 5.09 (dd,
1H, J=7.0 Hz, 2.0 Hz), 4.63 (d, 1H, J=7.0 Hz), 3.74 (m,
1H), 3.05 (dd, 1H, J=19.5 Hz, 3.2 Hz), 2.90 (dd, 1H, J=
19.4 Hz, 2.9 Hz), 2.67 (d, 1H, J=17.2 Hz), 2.42 (d, 1H, J=
17.2 Hz), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3): d=
199.1, 167.1, 167.0, 156.7, 135.2, 131.1, 120.6, 116.7, 115.8,
87.4, 86.4, 82.5, 50.7, 41.0, 36.3, 35.2, 28.2; IR (KBr): n=
3054, 2987, 2831, 2685, 2521, 2410, 2305, 2156, 2126, 2055,
1788, 1603, 1551, 1422, 1259, 1156, 987, 896, 691 cmÀ1; HR-
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.6:1, deter-
mined by integration of 1H NMR signal: dexo =3.74 ppm,
dendo =3.85 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a white solid; yield: 31 mg (51%, 63% ee). The ee
was determined by HPLC analysis (Daicel Chiralpak OD-H
column: hexane/i-PrOH=75:25, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =34.30 min, tmajor =48.46 min; [a]2D0: À8.2
(c 0.52 in CHCl3); mp 171–1728C; 1H NMR (300 MHz,
CDCl3): d=7.30 (m, 1H), 6.90 (m, 1H), 6.61 (m, 1H), 5.10
(dd, 1H, J=7.0 Hz, 2.0 Hz), 4.70 (d, 1H, J=7.0 Hz), 3.80 (s,
3H), 3.74 (m, 1H), 3.05 (dd, 1H, J=19.4 Hz, 3.2 Hz), 2.90
(dd, 1H, J=19.5 Hz, 2.9 Hz), 2.66 (d, 1H, J=17.2 Hz), 2.40
(d, 1H, J=17.2 Hz), 1.46 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=199.0, 167.0, 166.9, 160.4, 135.0, 130.9, 120.3,
115.2, 114.2, 87.5, 86.4, 82.4, 55.5, 50.7, 41.0, 36.4, 35.2, 28.2;
IR (KBr): n=3054, 2987, 2831, 2685, 2521, 2410, 2305, 2156,
2126, 2054, 1788, 1603, 1551, 1422, 1271, 1156, 987, 896,
MS
(ESI/
G
m/z=414.1155,
calcd.
for
C19H21NO8Na: 414.1159.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(2-Hydroxyphenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(21a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.0:1, deter-
mined by integration of 1H NMR signal: dexo =3.94 ppm,
dendo =4.18 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a yellow oil; yield: 30 mg (51%, 5% ee). The ee was
determined by HPLC analysis (Daicel Chiralpak AD-H
column: hexane/i-PrOH=85:15, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =17.69 min, tmajor =22.98 min; [a]2D0: À1.3
693 cmÀ1; HR-MS (ESI/
[M+Na]+): m/z=428.1313, calcd. for
ACHTUNGTRENNUNG
C20H23NO8Na: 428.1316.
tert-Butyl 2-{(1R,4R,7S,8S)-7-(4-Hydroxyphenyl)-8-
nitro-3,6-dioxo-2-oxabicyclo
(19a)
ACHTUNGTNER[NUNG 2.2.2]octan-1-yl}acetate
1
(c 0.50 in CHCl3); H NMR (300 MHz, CDCl3): d=8.02 (s,
The reaction was carried out following the general proce-
1H), 7.30 (m, 2H), 7.07 (m, 1H), 6.98 (m, 1H), 4.70 (dd,
dure to furnish the crude product (exo/endo=5.2:1, deter-
1H, J=17.4 Hz, 3.7 Hz), 3.94 (d, 1H, J=1.2 Hz), 3.41 (m,
Adv. Synth. Catal. 2011, 353, 1135 – 1145
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1143

Wanqing Wu et al.
FULL PAPERS
1H), 2.94 (d, 1H, J=16.1 Hz), 2.78 (d, 1H, J=16.1 Hz),
2.61 (dd, 1H, J=14.7 Hz, 4.8 Hz), 2.08 (m, 1H), 1.49 (s,
9H); 13C NMR (75 MHz, CDCl3): d=171.1, 166.7, 150.3,
130.7, 129.2, 123.3, 121.5, 118.3, 97.5, 88.8, 84.9, 78.4, 46.2,
40.1, 37.5, 35.7, 28.0; IR (KBr): n=3692, 3054, 2987, 2831,
2685, 2521, 2411, 2306, 2156, 2126, 2055, 1787, 1604, 1551,
1551, 1422, 1271, 1156, 986, 896, 691 cmÀ1; HR-MS (ESI/
ACHTUNG-
TERNNUG
[M+Na]+): m/z=430.1468, calcd. for C20H25NO8Na:
430.1472.
1422, 1263, 1156, 987, 896, 693 cmÀ1
;
HR-MS (ESI/
[M+Na]+): m/z=414.1158, calcd. for C19H21NO8Na:
414.1159.
-
Acknowledgements
TRENNUNG
The financial support for this project from the Guangdong
Natural Science Foundation (Grant No. 07009179) and
Peking University Shenzhen Graduate School is gratefully ac-
knowledged. A special acknowledgement is made to Prof.
Junmin Quan (Peking University Shenzhen Graduate
School) for his help on modelling the transition site of the
DA cycloaddition.
tert-Butyl 2-{(1R,4R,7R,8S)-7-(Furan-2-yl)-8-nitro-
3,6-dioxo-2-oxabicyclo[2.2.2]octan-1-yl}acetate (22a)
AHCTUNGTRENNUNG
The reaction was carried out following the general proce-
dure to furnish the crude product (exo/endo=5.3:1, deter-
mined by integration of 1H NMR signal: dexo =3.75 ppm,
dendo =3.98 ppm). The title compound was isolated by flash
column chromatography (silica gel, hexanes/ethyl acetate=
3:1) as a yellow oil; yield: 36 mg (65%, 96% ee). The ee was
determined by HPLC analysis (Daicel Chiralpak OD-H
column: hexane/i-PrOH=75:25, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =29.90 min, tmajor =35.85 min; [a]2D0: À16.8
References
[1] For reviews of DA cycloadditions of 2-pyrones, see:
a) K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner,
Tetrahedron 1992, 48, 9111–9171; b) B. T. Woodard,
G. H. Posner, Adv. Cycloaddit. 1999, 5, 47–83. For se-
lected work on functionalized benzene rings and cyclo-
hexadienes, see: c) D. L. Boger, M. D. Mullican, Tetra-
hedron Lett. 1983, 24, 4939–4942; d) T. Komiyama, Y.
Takaguchi, S. Tsuboi, Synlett 2006, 124–126. For select-
ed work on bridged bicyclic lactones, see: e) I. E.
Markꢃ, P. Seres, T. M. Swarbrick, I. Staton, H. Adams,
Tetrahedron Lett. 1992, 33, 5649–5652; f) G. H. Posner,
N. Johnson, J. Org. Chem. 1994, 59, 7855–7861; g) C.-
G. Cho, Y.-W. Kim, Y.-K. Lim, J.-S. Park, H. Lee, S.
Koo, J. Org. Chem. 2002, 67, 290–293; h) K. Afarinkia,
M. J. Bearpark, A. Ndibwami, J. Org. Chem. 2003, 68,
7158–7166.
1
(c 0.55 in CHCl3); H NMR (500 MHz, CDCl3): d=7.38 (s,
1H), 6.43 (d, 1H, J=3.2 Hz), 6.38 (m, 1H), 5.27 (dd, 1H,
J=5.9 Hz, 2.2 Hz), 5.11 (d, 1H, J=5.9 Hz), 3.75 (m, 1H),
2.95 (d, 2H, J=1.9 Hz), 2.74 (d, 1H, J=16.9 Hz), 2.45 (d,
1H, J=16.9 Hz), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3):
d=197.6, 167.0, 166.6, 146.2, 144.4, 111.7, 111.3, 85.1, 84.7,
82.5, 43.3, 41.0, 35.5, 34.8, 28.2; IR (KBr): n=3056, 2987,
2831, 2685, 2521, 2411, 2305, 2156, 2126, 2055, 1789, 1602,
1551, 1421, 1267, 1156, 990, 758, 736, 712 cmÀ1; HR-MS
(ESI/ACHTUNGTRENNUNG
[M+Na]+): m/z=388.1006, calcd. for C17H19NO8Na:
388.1003.
Synthesis of (1R,2S,3S,4R)-Methyl 4-(2-tert-Butoxy-2-
oxoethyl)-4-hydroxy-2-nitro-5-oxo-3-phenylcyclo-
hexanecarboxylate (23)
[2] a) E. J. Corey, A. P. Kozikowski, Tetrahedron Lett.
1975, 2389–2392; b) K. C. Nicolaou, J. J. Liu, C.-K.
Hwang, W.-M. Dai, R. K. Guy, J. Chem. Soc. Chem.
Commun. 1992, 1117–1118; c) K. C. Nicolaou, Z.
Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy,
C. F. Clalborne, J. Renaud, E. A. Couladouros, K. Paul-
vannan, E. J. Sorensen, Nature 1994, 367, 630–634;
d) G. H. Posner, D. G. Wettlaufer, J. Am. Chem. Soc.
1986, 108, 7373–7377; e) H. Okamura, H. Shimizu, Y.
Nakamura, T. Iwagawa, M. Nakatani, Tetrahedron Lett.
2000, 41, 4147–4150; f) H. Shimizu, H. Okamura, T.
Iwagawa, M. Nakatani, Tetrahedron 2001, 57, 1903–
1908; g) P. S. Baran, N. Z. Burns, J. Am. Chem. Soc.
2006, 128, 3908–3909; h) I.-J. Shin, E.-S. Choi, C.-G.
Cho, Angew. Chem. 2007, 119, 2353–2355; Angew.
Chem. Int. Ed. 2007, 46, 2303–2305.
To a solution of DA cycloadduct 2 (38 mg, 0.10 mmol) in
MeOH/CH2Cl2 (2 mL, 1:1) at 08C was added a 1.0M solu-
tion of sodium methoxide in MeOH (0.2 mL, 0.15 mmol)
dropwise under N2. The resulting mixture was stirred at 08C
and monitored by TLC until the starting material was con-
sumed. The reaction was then worked up by addition of a
saturated aqueous NH4Cl solution and the aqueous layer
was extracted with diethyl ether (ꢂ3). The combined ex-
tracts were washed with brine, dried over Na2SO4, filtered
and concentrated. The residue was purified by silica gel
flash chromatography (hexanes/ethyl acetate=3:1) to give
23 as a white solid; yield: 35 mg (86%, 97% ee); The ee was
determined by HPLC analysis (Daicel Chiralpak AD-H
column: hexane/i-PrOH=90:10, flow rate=0.5 mLminÀ1,
l=210 nm): tminor =22.09 min, tmajor =32.53 min; [a]2D0: À22.8
(c 0.50 in CHCl3); mp 102–1038C; 1H NMR (300 MHz,
CDCl3): d=7.31 (m, 3H), 6.89 (m, 2H), 6.27 (s, 1H), 5.98
(dd, 1H, J=11.7 Hz, 5.7 Hz), 4.09 (d, 1H, J=5.4 Hz), 3.74
(s, 3H), 3.71 (m, 1H), 3.55 (t, 1H, J=14.1 Hz), 2.84 (dd,
1H, J=14.4 Hz, 5.4 Hz), 2.44 (d, 1H, J=17.1 Hz), 2.09 (d,
1H, J=17.1 Hz), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3):
d=205.3, 173.2 171.2, 131.7, 129.5, 129.3, 129.2, 83.1, 82.9,
77.5, 57.1, 53.0, 40.9, 37.8, 36.7, 28.1; IR (KBr): n=3054,
2987, 2831, 2685, 2521, 2410, 2305, 2156, 2126, 2058, 1602,
[3] J. A. Gladysz, S. J. Lee, J. A. V. Tomasello, Y. S. Yu J.
Org. Chem. 1977, 42, 4170–4172.
[4] a) Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman,
L. Deng, J. Am. Chem. Soc. 2007, 129, 6364–6365;
b) R. P. Singh, K. Bartelson, Y. Wang, H. Su, X. Lu, L.
Deng, J. Am. Chem. Soc. 2008, 130, 2422–2423.
[5] a) H. Okarnura, T. Iwagawa, M. Nakatani, Tetrahedron
Lett. 1995, 36, 5939–5942; b) H. Okamura, Y. Naka-
mura, T. Iwagawa, M. Nakatani, Chem. Lett. 1996,
193–194; c) H. Okamura, K. Morishige, T. Iwagawa,
M. Nakatani, Tetrahedron Lett. 1998, 39, 1211–1214.
1144
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1135 – 1145

A New Class of Enantioselective Catalytic 2-Pyrone Diels–Alder Cycloadditions
[6] J. Y.-T. Soh, C.-H. Tan, J. Am. Chem. Soc. 2009, 131,
6904–6905.
[7] X. Zhou, W. Wu, X. Liu, C.-S. Lee, Org. Lett. 2008, 10,
5525–5528.
Rev. 1997, 97, 1609–1646; c) B. R . Linton, M. S. Good-
man, A. D. Hamilton, Chem. Eur. J. 2000, 6, 2449–
2455.
[16] For selected work on thiourea organocatalysts, see:
a) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901–4902; b) M. S. Sigman, P. Vachal, E. N.
Jacobsen, Angew. Chem. 2000, 112, 1336–1338; Angew.
Chem. Int. Ed. 2000, 39, 1279–1281; c) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672–12673; d) H. Li, Y. Wang, L. Tang, L. Deng, J.
Am. Chem. Soc. 2004, 126, 9906–9907; e) B. Vakulya,
S. Varga, A. Csampai, T. Sꢃos, Org. Lett. 2005, 7, 1967–
1969; f) R. P. Herrera, V. Sgarzani, L. Bernardi, A.
Ricci, Angew. Chem. 2005, 117, 6734–6737; Angew.
Chem. Int. Ed. 2005, 44, 6576–6579; g) T. Inokuma, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2006, 128,
9413–9419; h) S. C. Pan, J. Zhou, B. List, Angew.
Chem. 2007, 119, 618–620; Angew. Chem. Int. Ed.
2007, 46, 612–614; i) X. X. Jiang, Y. F. Zhang, A. S. C.
Chan, R. Wang, Org. Lett. 2009, 11, 153–156; j) X. X.
Jiang, Y. F. Zhang, X. Liu, G. Zhang, L. H. Lai, L. P.
Wu, J. N. Zhang, R. Wang, J. Org. Chem. 2009, 74,
5562–5567; k) X. X. Jiang, G. Zhang, D. Fu, Y. M. Cao,
F. F. Shen, R. Wang, Org. Lett. 2010, 12, 1544–1547;
l) X. X. Jiang, Y. M. Cao, Y. Q. Wang, L. P. Liu, F. F.
Shen, R. Wang, J. Am. Chem. Soc. 2010, 132, 15328–
15333.
[8] W. Wu, S. He, X. Zhou, C.-S. Lee, Eur. J. Org. Chem.
2010, 1124–1133.
[9] For selected reviews of asymmetric imminium catalysis,
see: a) G. Lelais, D. W. C. MacMillan, Aldrichimica
Acta 2006, 39, 79–87; b) B. List, Chem. Commun. 2006,
819–824. For selected reviews of asymmetric enamine
catalysis, see: c) P. I. Dalko, L. Moisan, Angew. Chem.
2004, 116, 5248–5286; Angew. Chem. Int. Ed. 2004, 43,
5138–5175; d) W. Notz, F. Tanaka, C. F. Barbas III,
Acc. Chem. Res. 2004, 37, 580–591.
[10] For recent reviews on organocatalysis, see: a) P. I.
Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248–
5286; Angew. Chem. Int. Ed. 2004, 43, 5138–5175;
b) K. N. Houk, B. List, Acc. Chem. Res. 2004, 37, 487;
c) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719–
724; d) A. Berkessel, H. Grçger, Asymmetric Organo-
catalysis, Wiley-VCH, Weinheim, 2005. For a selected
review on the use of Brønsted acids or bases as cata-
lysts in Diels–Alder reactions, see: e) J. Shen, C.-H.
Tan, Org. Biomol. Chem. 2007, ##5##6, 3229–3236.
[11] a) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J.
Am. Chem. Soc. 2000, 122, 4243–4244; b) A. B. Northr-
up, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
2458–2460.
[17] X. Li, H. Deng, B. Zhang, J. Li, L. Zhang, S. Luo, J.-P.
[12] Cinchona alkaloid 5b was first reported by: H. Brun-
ner, J. Bꢄgler, B. Nuber, Tetrahedron: Asymmetry 1995,
6, 1699–1702.
Cheng, Chem. Eur. J. 2010, 16, 450–455.
[18] M. P. Sibi, K. Itoh, J. Am. Chem. Soc. 2007, 129, 8064–
8065.
[13] For selected reviews on Cinchona-derived catalysts,
see: a) K. K. Acprzak, J. GawroÇski, Synthesis 2001, 7,
961–998; b) S.-K. Tian, Y. Chen, J. Hang, L. Tang, P.
Mcdaid, L. Deng, Acc. Chem. Res. 2004, 37, 621–631.
[14] For reviews on thiourea-based organocatalysts see:
a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289–296;
b) P. M. Pihko, Angew. Chem. 2004, 116, 2110–2113;
Angew. Chem. Int. Ed. 2004, 43, 2062–2064; c) Y. Take-
moto, Org. Biomol. Chem. 2005, 3, 4299–4306; d) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550–
1573; Angew. Chem. Int. Ed. 2006, 45, 1520–1543;
e) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743; f) S. J. Connon, Chem. Eur. J. 2006, 12,
5418–5427; g) S. J. Connon, Chem. Commun. 2008,
2499–2510.
[19] J. Wang, H. Li, W. Duan, L. Zu, W. Wang, Org. Lett.
2005, 7, 4713–4716.
[20] CCDC 802432 (for optically enriched 2a) and CCDC
733334 (for racemic 2a, previously reported in ref.[8]),
contain 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.
[21] a) D. A. Yalalov, S. B. Tsogoeva, S. Schmatz, Adv.
Synth. Catal. 2006, 348, 826–832; b) S. B. Tsogoeva, S.
Wei, Chem. Commun. 2006, 1451–1453; c) H. Uehara,
C. F. Barbas III, Angew. Chem. 2009, 121, 10032–
10036; d) B.-L. Li, Y.-F. Wang, S.-P. Luo, A.-G. Zhong,
Z.-B. Li, X.-H. Du, D.-Q. Xu, Eur. J. Org. Chem. 2010,
656–662.
[15] a) T. R. Kelly, M. K. Kim, J. Am. Chem. Soc. 1994, 116,
7072–7080; b) F. P. Schmidtchen, M. Berger, Chem.
Adv. Synth. Catal. 2011, 353, 1135 – 1145
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1145