(1R,2R)-DPEN-derived triazolium salts for enantioselective oxodiene Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2011.09.129

Enantioselective oxodiene Diels-Alder reactions catalyzed by (1R,2R)-DPEN-derived triazolium salts were realized successfully. With 0.5 mol % of (1R,2R)-DPEN-derived triazolium salt C and 150 mol % of Et₃N, the reactions of various α-chloroalde

Full text of DOI:10.1016/j.tet.2011.09.129

Tetrahedron 67 (2011) 9329e9333
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
(1R,2R)-DPEN-derived triazolium salts for enantioselective oxodiene
DielseAlder reactions
*
Zi-Qiang Rong, Min-Qiang Jia, Shu-Li You
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2011
Received in revised form 19 September 2011
Accepted 27 September 2011
Available online 5 October 2011
Enantioselective oxodiene DielseAlder reactions catalyzed by (1R,2R)-DPEN-derived triazolium salts
were realized successfully. With 0.5 mol % of (1R,2R)-DPEN-derived triazolium salt C and 150 mol % of
Et3N, the reactions of various a-chloroaldehydes (a-bromoaldehyde) with substituted enones led to 3,4-
dihydropyridinones and their derivatives in good yields, diastereoselectivities, and enantioselectivities
(up to 97% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
(1R,2R)-DPEN
DielseAlder reactions
N-Heterocyclic carbene
Organocatalysis
1. Introduction
Organocatalytic processes mediated by N-heterocyclic carbenes
(NHCs) have received considerable attention in the last two de-
cades.1 The inversion of the normal reactivity (umpolung) of al-
dehydes catalyzed by NHCs has become an intense area recently,
providing an unconventional access to the formation of carbone
carbon bond.2,3 The asymmetric reactions catalyzed by chiral NHCs
have also witnessed significant progress in the past ten years.4
DielseAlder reaction is one of the classic reactions that have been
widely used in organic synthesis.5,6 However, it was not until 2006
that Bode’s group reported the first example of asymmetric aza-
diene DielseAlder reactions catalyzed by chiral N-heterocyclic
carbenes.7 Subsequently, their group and others have reported the
application of this strategy to realize the catalytic asymmetric
oxodiene DielseAlder reactions successfully.8 The aminoindanol-
derived catalyst (Fig. 1) was found to be the most efficient cata-
lyst for the oxodiene DielseAlder reactions, providing the desired
products in high yields and excellent enantioselectivities.8a,b To our
knowledge, however, it is the only catalyst that was demonstrated
to catalyze this type of oxodiene DielseAlder reactions. The dis-
covery of novel NHC catalysts from readily available chiral sources
for oxodiene DielseAlder reactions remains highly desirable.
Fig. 1. The aminoindanol-derived catalyst.
2. Results and discussion
(1R,2R)-DPEN ((1R,2R)-(þ)-diphenyl ethylenediamine) has been
used widely as an excellent chiral source for chiral auxiliary and
ligands in organic synthesis.9 As part of our program aiming to the
development of novel chiral NHCs and NHC-catalyzed asymmetric
reactions,10 we have recently communicated that chiral triazolium
salts derived from (1R,2R)-DPEN functioned as efficient pre-
catalysts for the intramolecular Stetter reaction (Scheme 1).11
With 10 mol % of the catalyst, the intramolecular Stetter reaction
was realized in excellent yields with up to 97% ee. In this article, we
report the full account on the application of the (1R,2R)-DPEN-
derived triazolium salts to highly enantioselective oxodiene Dielse
Alder reactions, providing 3,4,6-trisubstituted dihydropyran-2-
ones products in good yields, diastereoselectivities and excellent
ees.
The chiral bicyclic triazolium salts (AeD) were easily prepared
from the commercially available (1R,2R)-DPEN (Scheme 2).11
Starting from commercially available (1R,2R)-1,2-diphenyl-1,2-
ethanediamine, (5R,6R)-5,6-diphenylpiperazin-2-one was synthe-
sized in 56% yield by the treatment with ethyl bromoacetate and
* Corresponding author. Tel.: þ86 21 54925085; fax: þ86 21 54925087; e-mail
address: slyou@sioc.ac.cn (S.-L. You).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.129

9330
Z.-Q. Rong et al. / Tetrahedron 67 (2011) 9329e9333
Table 1
Screening of chiral NHC catalysts
Scheme 1. Triazolium salts from (1R,2R)-DPEN for the enantioselective intramolecular
stetter reaction.
sodium hydroxide. After the protection with TsCl, the resulting
(5R,6R)-5,6-diphenyl-4-tosylpiperazin-2-one was subjected to the
triazolium salt synthesis developed by Rovis and co-workers.12 In
general, low to moderate yields could be obtained for the one-pot
reaction (27e63% yield). Unfortunately, when (perfluorophenyl)
hydrazine was used, there was only trace amount of the corre-
sponding triazolium salt could be formed even after several
attempts.
Entrya
Cat.
drb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
A
B
C
D
E
2:1
2:1
8:1
d
13
12
87
Trace
Trace
Trace
40
Trace
Trace
84
57
61
82
d
d
d
89
d
d
81
81
d
F
d
G
H
I
2:1
d
9
10
11
d
Ce
Cf
6:1
>20:1
90
a
Reaction conditions: 1a (0.54 mmol), 2a (0.34 mmol), 0.5 mol % cat., 150 mol %
Et3N in EtOAc (1.7 mL) at rt, 24 h.
b
Determined by 1H NMR.
Isolated yield.
Determined by HPLC analysis (Daicel Chiralpak AD-H).
With 1 mol % catalyst.
c
d
e
f
Scheme 2. Synthesis of triazolium salts from (1R,2R)-DPEN.
With 5 mol % catalyst.
affording the desired product in identical enantioselectivity but
with slightly decreased yield (entry 3). Several other bases, such as
DBU, DABCO, DBN, DMAP, pyridine, imidazole, and cesium car-
bonate were tested as the base, none of them afforded better results
than that of Et3N (entries 4e10, Table 2). As summarized in Table 3,
Our studies began with an initial examination of several readily
available chiral NHCs (Scheme 2) developed in our laboratory for
the oxodiene DielseAlder reactions of the racemic
a-chlor-
oaldehyde (rac-1) and heterodiene. As summarized in Table 1,
when triazolium salts AeD (0.5 mol %) were used together with
Et3N (150 mol %), variable results were obtained (entries 1e4, Table
1). Triazolium salts A and B could catalyze the reaction but with low
yields and moderate dr values. The reaction catalyzed by the NHC
derived from triazolium salt D, unfortunately, almost gave no de-
sired product. To our delight, triazolium salt C led to the oxodiene
DielseAlder reaction product 3a in excellent yield, good diaster-
eoselectivity and promising asymmetric induction (87% yield, 8:1
dr and 82% ee, entry 3, Table 1). In addition to the (1R,2R)-DPEN-
derived triazolium salts, camphor-derived triazolium salts, pre-
viously developed in our laboratory, were also tested in this oxo-
diene DielseAlder reaction. As shown in the Table 1 (entries 5e9),
NHC catalysts derived from triazolium salts E,F and H,I all displayed
low reactivity, affording trace amount of desired products. The NHC
catalyst derived from triazolium salt G led to the oxodiene Diel-
seAlder reaction product 3a in moderate yield (40%) but in good
enantioselectivity (89% ee). When the loading of cat. C was in-
creased to 1 mol %, 3a was obtained with almost the same dr and ee
values (Table 1, entry 10). When 5 mol % of C was applied, the dr
value of 3a was increased dramatically, but the ee value remained
the same (Table 1, entry 11).
Table 2
Screening of basesa
Entrya
Base
drb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
Et3N
KHMDS
DIEA
DBU
DABCO
DBN
Cs2CO3
DMAP
Pyridine
Imidazole
8:1
>20:1
11:1
Complex
1.3:1
Trace
Complex
1.9:1
87
20
77
d
66
d
d
44
d
d
82
81
82
d
43
d
d
74
d
d
Trace
Trace
With 0.5 mol % of the optimized triazolium salt C as the NHC
precursor in EtOAc, several conventional bases were tested and Et3N
was found to be the optimal one in terms of the yield, dr and ee of
the product (entries 1e7, Table 2). The reaction with KHMDS as the
base led to excellent dr value but with low yield (entry 2). With DIEA
as the base, the oxodiene DielseAlder reaction proceeded smoothly
10
a
Reaction conditions: 1a (0.54 mmol), 2a (0.34 mmol), 0.5 mol % C, 150 mol %
base in EtOAc (1.7 mL) at rt, 24 h.
b
Determined by 1H NMR.
Isolated yield.
Determined by HPLC analysis (Daicel Chiralpak AD-H).
c
d

Z.-Q. Rong et al. / Tetrahedron 67 (2011) 9329e9333
9331
various solvents, such as EtOAc, CH2Cl2, THF, toluene, and Et2O were
all tolerated to afford product 3a in moderate to good yields in this
reaction (entries 1e5, Table 3). Reaction in EtOAc led to an optimal
combination of yield (87%), diastereoselectivity (8:1 dr), and
enantioselectivity (82% ee).
chloroaldehyde could also be well applied in this reaction (entry 7,
Table 4). Alternatively, -unsaturated, -ketoesters including both
aromatic and aliphatic substituents proved to be suitable substrates
and afforded synthetically valuable products in moderate yields
and excellent enantioselectivities (entries 8e11, Table 4).
b
,g
a
The a-bromoaldehyde 4 was also tested under standard reaction
conditions. The corresponding product 3a was obtained in 89%
yield,10:1 dr and 81% ee, which were similar to those obtained with
Table 3
Optimization of solventsa
alpha-chloroaldehyde 1a, revealing a-bromoaldehydes as promis-
ing substrates in this reaction (Scheme 3).
Entrya
Solvent
drb
8:1
1:1
3:1
7:1
5.5:1
Yieldc (%)
eed (%)
1
2
3
4
5
EtOAc
CH2Cl2
THF
Toluene
Et2O
87
28
80
53
58
82
61
80
78
85
Scheme 3. NHC-Catalyzed oxodiene DielseAlder reaction with a-bromoaldehyde.
a
3. Conclusion
Reaction conditions: 1a (0.54 mmol), 2a (0.34 mmol), 0.5 mol % C, 150 mol %
Et3N in solvent (1.7 mL) at rt, 24 h.
b
Determined by 1H NMR.
Isolated yield.
Determined by HPLC analysis (Daicel Chiralpak AD-H).
In summary, we have developed a series of novel bicyclic tri-
azolium salts from readily available (1R,2R)-DPEN. The NHC catalyst
derived from the chiral triazolium salt C and Et3N is found to be
efficient for enantioselective oxodiene DielseAlder reaction,
affording 3,4-dihydropyridinones and their derivatives in good
yields, diastereoselectivities and enantioselectivities (up to 97% ee).
We believe that these (1R,2R)-DPEN-derived triazolium salts will
enable more asymmetric reaction in the future studies.
c
d
In the presence of 0.5 mol % of C, 150 mol % of Et3N in EtOAc at
room temperature, the reactions of various a-chloroaldehydes with
substituted enones have been tested to investigate the generality of
the reaction. The results were summarized in Table 4. A range of
aryl enones bearing electron-withdrawing (p-Br, p-Cl) or electron-
donating (p-Me, p-OMe) substituents on the aromatic ring were
suitable reaction partners (entries 1e5, Table 4). Furthermore, ali-
phatic substituted 4-oxo-enoate was tested, the desired product
was obtained in moderate yield and moderate level of enantiose-
4. Experimental
4.1. General methods
lectivity but excellent dr (entry 6, Table 4). Aliphatic substituted a-
Unless stated otherwise, all reactions were carried out in flame-
dried glassware under a dry argon atmosphere. All solvents were
purified and dried according to standard methods prior to use.
1H and 13C NMR spectra were recorded on a Varian instrument
(300 MHz and 75 MHz, respectively) and internally referenced to
tetramethylsilane signal or residual protio solvent signals. Data for
Table 4
NHC-Catalyzed oxodiene DielseAlder reactiona
1H NMR are recorded as follows: chemical shift (
d, ppm), multi-
plicity (s¼singlet, d¼doublet, t¼triplet, m¼multiplet or un-
resolved, br¼broad singlet, coupling constant(s) in Hz, integration).
Data for 13C NMR are reported in terms of chemical shift (
d, ppm).
4.2. General procedure for enantioselective oxodiene
DielseAlder reactions
Entrya Product R1
R2
R3
Time drb
(h)
Yieldc eed
(%)
(%)
A flame-dried Schlenk tube was cooled to room temperature
and filled with argon. To this flask were added -chloroaldehydes
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CO2Et 24
CO2Et 10
CO2Et 13
CO2Et 48
8:1 87
5:1 82
5:1 75
8:1 62
9:1 68
>20:1 40
8:1 65
>20:1 76
6:1 65
17:1 55
9:1 60
82
75
74
83
82
46
50
86
94
97
94
a
p-BreC6H4
p-CleC6H4
p-Tol
p-OMeeC6H4 CO2Et 36
c-Hex
(0.54 mmol, 1.6 equiv) and enones (0.34 mmol, 1.0 equiv). To this
mixture was added EtOAc (1.70 mL, 0.2 M), followed by addition of
triazolium salt C (1.1 mg, 0.0017 mmol, 0.5 mol %) and Et3N
(51.6 mg, 0.51 mmol, 1.5 equiv). The white Et3N$HCl salt pre-
cipitated in 10e30 min. The reaction was stirred at room temper-
ature. After the reaction was complete (monitored by TLC), water
was added and the mixture was extracted with EtOAc (3ꢀ20 mL).
The combined EtOAc extracts were washed with brine, dried over
anhydrous Na2SO4, and filtered. The solution was concentrated
under reduced pressure, and the residue was purified by silica gel
column chromatography to afford the product as a mixture of
diastereomers.
CO2Et 36
CO2Et 36
p-Tol 24
p-Tol 24
c-Hex 60
n-C9H19 Ph
n-C9H19 CO2Et
Ph
Ph
Ph
9
10
11
CO2Et
CO2Et
CO2Et
3j
3k
n-Pr
60
a
Reaction conditions: 1 (0.34 mmol), 2 (0.21 mmol), 0.5 mol % C, 150 mol % Et3N
in EtOAc (1.7 mL) at rt.
b
Determined by 1H NMR.
Isolated yield.
Determined by HPLC.
c
d

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Z.-Q. Rong et al. / Tetrahedron 67 (2011) 9329e9333
4.2.1. (3R,4R)-3-Benzyl-4,6-diphenyl-3,4-dihydro-2H-pyran-2-one
(s, 3H), 3.54 (dd, J¼4.5,14.4 Hz,1H), 3.22 (t, J¼6.3 Hz,1H), 3.01e2.94
(m, 1H), 2.76 (dd, J¼10.5, 14.1 Hz, 1H), 1.29 (t, J¼7.2 Hz, 3H).
(3a). White solid, 87% yield, 8:1 dr, 82% ee [Daicel Chiralpak AD-
H, hexane/2-propanol¼90/10, v¼1.0 mL minꢁ1
,
l
¼254 nm, t
(major)¼23.27 min, t (minor)¼36.83 min]; ½a D20
ꢂ
ꢁ81.0 (c 1.0,
4.2.6. (3R,4R)-Ethyl 3-benzyl-6-cyclohexyl-2-oxo-3,4-dihydro-2H-
CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.63e7.59 (m, 2H), 7.40e7.23
pyran-4-carboxylate (3f). White solid, 40% yield, >20:1 dr, 46% ee
(m, 6H), 7.17 (d, J¼7.2 Hz, 2H), 5.79 (d, J¼6.9 Hz, 1H), 5.74* (d,
J¼5.7 Hz, 1H), 4.21 (q, J¼6.9 Hz, 2H), 4.12* (q, J¼7.2 Hz, 2H), 3.54
(dd, J¼4.8, 14.4 Hz, 1H), 3.40e3.34* (m, 1H), 3.25 (t, J¼6.0 Hz, 1H),
3.14* (dd, J¼5.4, 13.5 Hz, 1H), 3.02e2.95 (m, 1H), 2.91* (dd, J¼9.0,
14.1 Hz, 1H), 2.77 (dd, J¼10.2, 14.4 Hz, 1H), 1.28 (t, J¼6.9 Hz, 3H),
1.23* (t, J¼6.9 Hz, 3H).
[Daicel Chiralcel OD-H, hexane/2-propanol¼90/10, v¼1.0 mL minꢁ1
,
l
¼254 nm, t (major)¼6.65 min, t (minor)¼7.54 min]; ½a D20
ꢁ74.2
ꢂ
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.33e7.21 (m, 3H), 7.15
(d, J¼6.6 Hz, 2H), 4.99 (d, J¼6.9 Hz, 1H), 4.27e4.12 (m, 2H), 3.48
(dd, J¼4.2,14.1 Hz,1H), 3.02 (t, J¼6.3 Hz,1H), 2.86e2.79 (m,1H), 2.67
(dd, J¼10.2, 14.1 Hz, 1H), 2.06e2.03 (m, 1H), 1.86e1.66 (m, 6H),
1.30e1.19 (m, 7H).
4.2.2. (3R,4R)-3-Benzyl-6-(4-bromophenyl)-4-phenyl-3,4-dihydro-
2H-pyran-2-one (3b). White solid, 82% yield, 5:1 dr, 75% ee [Daicel
4.2.7. (3R,4R)-Ethyl 3-decyl-2-oxo-6-phenyl-3,4-dihydro-2H-pyran-
Chiralpak AD-H, hexane/2-propanol¼90/10, v¼1.0 mL minꢁ1
,
4-carboxylate (3g). White solid, 65% yield, 8:1 dr, 50% ee [Daicel
l
¼254 nm, t (major)¼39.80 min, t (minor)¼102.66 min]; ½a D20
ꢂ
Chiralpak AD-H, hexane/2-propanol¼90/10, v¼1.0 mL minꢁ1
,
ꢁ66.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.52e7.49 (m, 5H),
l
¼254 nm, t (minor)¼10.49 min, t (major)¼16.47 min]; ½a D20
ꢁ75.7
ꢂ
7.34e7.23 (m, 4H), 7.18e7.16 (m, 2H), 5.81 (d, J¼6.6 Hz,1H), 5.73* (d,
J¼5.7 Hz,1H), 4.22 (q, J¼6.9 Hz, 2H), 4.13* (q, J¼7.2 Hz, 2H), 3.54 (dd,
J¼4.5, 14.4 Hz, 1H), 3.39e3.35* (m, 1H), 3.25 (t, J¼6.3 Hz, 1H), 3.14*
(dd, J¼5.4, 13.8 Hz, 1H), 3.03e2.96 (m, 1H), 2.92* (dd, J¼9.0, 13.8 Hz,
1H), 2.76 (dd, J¼10.5, 14.1 Hz, 1H), 1.29 (t, J¼6.9 Hz, 3H), 1.24* (t,
J¼6.6 Hz, 3H).
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.66e7.63 (m, 2H),
7.39e7.36 (m, 3H), 5.89 (d, J¼6.6 Hz, 1H), 4.23e4.13 (m, 2H), 3.53 (t,
J¼6.6 Hz, 1H), 2.75 (q, J¼6.3 Hz, 1H), 2.11e2.02 (m, 1H), 1.47e1.44
(m, 3H), 1.28e1.23 (m, 17H), 0.88 (t, J¼6.9 Hz, 3H).
4.2.8. (3R,4R)-Ethyl 3-decyl-2-oxo-4-p-tolyl-3,4-dihydro-2H-pyran-
6-carboxylate (3h). Pale yellow solid, 76% yield, >20:1 dr, 86% ee
4.2.3. (3R,4R)-Ethyl 3-benzyl-6-(4-chlorophenyl)-2-oxo-3,4-dihydro-
2H-pyran-4-carboxylate (3c). White solid, 75% yield, 5:1 dr, 74% ee
[Daicel Chiralcel OD-H, hexane/2-propanol¼97/3, v¼1.0 mL minꢁ1
,
l
¼254 nm, t (major)¼12.84 min, t (minor)¼17.63 min]; ½a D20
ꢁ146.0
ꢂ
[Daicel
Chiralpak
AD-H,
hexane/2-propanol¼80/20,
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.12 (d, J¼8.1 Hz, 2H),
v¼1.0 mL minꢁ1
,
l
¼254 nm, t (major)¼24.94 min, t (minor)¼
6.98 (d, J¼7.8 Hz, 2H), 6.69 (d, J¼6.3 Hz, 2H), 4.32 (q, J¼6.9 Hz, 2H),
3.77 (t, J¼7.2 Hz, 1H), 2.80 (q, J¼6.9 Hz, 1H), 2.32 (s, 3H), 1.74e1.60
(m, 2H), 1.34 (t, J¼7.2 Hz, 3H), 1.26e1.22 (m, 16H), 0.88 (t, J¼6.9 Hz,
3H).
65.41 min]; ½a 2D0
ꢂ
ꢁ94.4 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.58e7.52 (m, 2H), 7.37e7.22 (m, 7H), 7.18e7.16 (m, 2H), 5.79 (d,
J¼6.9 Hz, 1H), 5.72* (d, J¼5.7 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 4.12* (q,
J¼7.2 Hz, 2H), 3.53 (dd, J¼4.8, 14.4 Hz, 1H), 3.41e3.34* (m, 1H), 3.26
(q, J¼6.3 Hz, 1H), 3.13* (dd, J¼5.4, 13.5 Hz, 1H), 3.02e2.96 (m, 1H),
2.91* (dd, J¼9.0, 14.1 Hz, 1H), 2.76 (dd, J¼10.5, 14.1 Hz, 1H), 1.29 (t,
J¼6.9 Hz, 3H), 1.23* (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.2.9. (3R,4R)-Ethyl
3-benzyl-2-oxo-4-p-tolyl-3,4-dihydro-2H-py-
ran-6-carboxylate (3i). White solid, 65% yield, 6:1 dr, 94% ee [Daicel
Chiralpak AD-H, hexane/2-propanol¼90/10, v¼1.0 mL minꢁ1
,
d
170.8, 170.0, 168.4, 168.2, 151.4, 150.0, 137.8, 136.6, 135.4, 130.1,
l
¼254 nm, t (major)¼17.02 min, t (minor)¼30.69 min]; ½a D20
ꢁ313.3
ꢂ
129.2, 128.9, 128.7, 128.7, 128.4, 127.1, 126.8, 126.0, 98.4, 96.4, 61.8,
61.6, 42.5, 41.9, 41.2, 40.4, 35.2, 33.1, 14.0, 13.9; IR (thin film): nmax
(cmꢁ1)¼1771, 1718, 1493, 1370, 1327, 1270, 1181, 1131, 850, 767, 735,
700, 618; MS (EI, m/z, rel intensity) 370 (Mþ, 7), 296 (14), 139 (18),
91 (100); HRMS (EI) calcd for C21H19O4Cl (Mþ): 370.0972. Found:
370.0975. Mp 116e119 ꢃC.
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.34e7.21 (m, 3H),
7.15e7.06 (m, 4H), 6.91 (d, J¼7.8 Hz, 2H), 6.64 (d, J¼6.6 Hz, 1H), 4.30
(q, J¼7.2 Hz, 2H), 3.58 (t, J¼6.3 Hz, 1H), 3.29e3.21 (m, 2H), 2.41 (dd,
J¼10.8, 15.9 Hz, 1H), 2.34 (s, 3H), 1.33 (t, J¼7.2 Hz, 3H).
4.2.10. (3R,4R)-Ethyl 3-benzyl-4-cyclohexyl-2-oxo-3,4-dihydro-2H-
pyran-6-carboxylate (3j). Colorless oil, 55% yield, 17:1 dr, 97% ee
4.2.4. (3R,4R)-Ethyl
ran-4-carboxylate (3d). White solid, 62% yield, 8:1 dr, 83% ee
3-benzyl-2-oxo-6-p-tolyl-3,4-dihydro-2H-py-
[Daicel Chiralcel AS-H, hexane/2-propanol¼95/5, v¼1.0 mL minꢁ1
,
l
¼254 nm, t (major)¼21.69 min, t (minor)¼35.58 min]; ½a D20
ꢂ
[Daicel
Chiralpak
AD-H,
hexane/2-propanol¼90/10,
ꢁ129.9 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.34e7.21 (m,
v¼1.0 mL minꢁ1
,
l
¼254 nm, t (major)¼26.37 min, t (minor)¼
5H), 6.48 (d, J¼6.3 Hz, 1H), 4.31 (q, J¼7.5 Hz, 2H), 3.39 (dd, J¼5.4,
14.1 Hz, 1H), 2.98e2.91 (m, 1H), 2.78 (dd, J¼9.0, 14.4 Hz, 1H), 2.43
(dd, J¼6.6, 11.1 Hz, 1H), 1.76e1.62 (m, 5H), 1.48e1.44 (m, 1H), 1.35 (t,
J¼7.5 Hz, 3H), 1.28e1.05 (m, 4H), 0.98e0.88 (m, 1H).
65.19 min]; ½a 2D0
ꢂ
ꢁ125.2 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.51e7.49 (m, 2H), 7.32e7.22 (m, 3H), 7.18e7.15 (m, 4H), 5.74 (d,
J¼6.9 Hz, 1H), 4.21 (q, J¼6.9 Hz, 2H), 3.54 (dd, J¼3.9, 14.1 Hz, 1H),
3.22 (t, J¼6.0 Hz, 1H), 3.01e2.94 (m, 1H), 2.76 (dd, J¼10.8, 13.8 Hz,
1H), 2.35 (s, 3H), 1.28 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.2.11. (3R,4R)-Ethyl 3-benzyl-2-oxo-4-propyl-3,4-dihydro-2H-py-
d
170.2, 168.9, 152.3, 139.6, 138.0, 129.1, 129.0, 128.8, 128.7, 126.7,
ran-6-carboxylate (3k). Colorless oil, 60% yield, 9:1 dr, 94% ee
124.6, 97.0, 61.5, 42.6, 40.4, 33.1, 21.2, 14.0; IR (thin film): nmax
(cmꢁ1)¼1769, 1719, 1495, 1369, 1321, 1228, 1178, 1132, 1081, 819,
764, 748, 698; MS (EI, m/z, rel intensity) 350 (Mþ, 14), 276 (18), 259
(18), 119 (30), 91 (100); HRMS (EI) calcd for C22H22O4 (Mþ):
350.1518. Found: 350.1516. Mp 127e130 ꢃC.
[Daicel Chiralcel AS-H, hexane/2-propanol¼90/10, v¼1.0 mL minꢁ1
,
l
¼254 nm, t (major)¼10.65 min, t (minor)¼18.61 min]; ½a D20
ꢁ97.5
ꢂ
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.34e7.19 (m, 5H), 6.58
(d, J¼6.9 Hz, 1H), 4.29 (q, J¼7.5 Hz, 2H), 3.35 (dd, J¼5.7, 14.4 Hz, 1H),
2.98e2.91 (m, 1H), 2.76 (dd, J¼9.6, 14.4 Hz, 1H), 2.47e2.38 (m, 1H),
1.66e1.59 (m, 1H), 1.45e1.18 (m, 6H), 0.89 (t, J¼6.9 Hz, 3H).
4.2.5. (3R,4R)-Ethyl 3-benzyl-6-(4-methoxyphenyl)-2-oxo-3,4-
dihydro-2H-pyran-4-carboxylate (3e). Pale yellow solid, 68% yield,
9:1 dr, 82% ee [Daicel Chiralpak AS-H, hexane/2-propanol¼80/20,
Acknowledgements
v¼1.0 mL minꢁ1
,
l
¼254 nm, t (minor)¼36.04 min, t (major)¼
We thank the National Basic Research Program of China (973
Program 2009CB825300) and National Natural Science Foundation
of China (20821002, 20972177, 21025209) for generous financial
support.
40.10 min]; ½a 2D0
ꢂ
ꢁ88.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.54 (d, J¼8.7 Hz, 2H), 7.34e7.23 (m, 4H), 7.18e7.16 (m, 2H), 6.88
(d, J¼8.7 Hz, 2H), 5.66 (d, J¼6.9 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 3.81

Z.-Q. Rong et al. / Tetrahedron 67 (2011) 9329e9333
9333
Soc. 2008, 130, 12590; (g) Phillips, E. M.; Roberts, J. M.; Scheidt, K. A. Org. Lett.
2010, 12, 2830; (h) Enders, D.; Grossmann, A.; Fronert, J.; Raabe, G. Chem.
Commun. 2010, 6282; (i) O’Toole, S. E.; Rose, C. A.; Gundala, S.; Zeitler, K.;
Connon, S. J. J. Org. Chem. 2011, 76, 347.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.129.
5. For recent reviews, see: (a) Boger, D. L.; Weinreb, S. M. Hetero DielseAlder
Methodology in Organic Synthesis; Academic: San Diego, 1987, Chapter 2; (b)
Evans, D. A.; Johnson, J. S. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.
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