Asymmetric cycloaddition of β,γ-unsaturated α-ketoesters with electron-rich alkenes catalyzed by a chiral Er(OTf)3/N,N'- dioxide complex: Highly enantioselective synthesis of 3,4-dihydro-2H-pyrans

Article abstract of DOI:10.1002/chem.201100520

The asymmetric inverse-electron-demand hetero-Diels-Alder (HDA) reactions of β,γ-unsaturated α-ketoesters with electron-rich alkenes were investigated, with an N,N'-dioxide/erbium(III) complex employed as the catalyst. Quantitative conversion of the β,γ-u

Full text of DOI:10.1002/chem.201100520

DOI: 10.1002/chem.201100520
Asymmetric Cycloaddition of b,g-Unsaturated a-Ketoesters with Electron-
Rich Alkenes Catalyzed by a Chiral ErACHTNUTRGNENG(U OTf)3/N,N’-Dioxide Complex: Highly
Enantioselective Synthesis of 3,4-Dihydro-2H-pyrans**
Yin Zhu, Mingsheng Xie, Shunxi Dong, Xiaohu Zhao, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*[a]
Abstract: The asymmetric inverse-elec-
tron-demand hetero-Diels–Alder
(HDA) reactions of b,g-unsaturated a-
ketoesters with electron-rich alkenes
were investigated, with an N,N’-diox-
(up to >99:1 d.r.) were observed for a
broad range of substrates by using a
0.5–0.05 mol% catalyst loading under
mild reaction conditions. The reaction
could be scaled up to the gram scale
with the same results. In addition, this
was the first application of Er(OTf)3 to
the asymmetric inverse-electron-
demand HDA reaction and it behaved
as an efficient catalyst. Moreover, the
synthetic utility of this methodology
was demonstrated with the synthesis of
key intermediates of some natural
products.
AHCTUNGTRENNUNG
ide/erbiumACHTUNGTRENNUNG(III) complex employed as
the catalyst. Quantitative conversion of
the b,g-unsaturated a-ketoesters and
excellent enantioselectivities (up to
>99% ee) and diastereoselectivities
Keywords: asymmetric catalysis
·
cycloaddition · erbium · heterocy-
cles · N,N’-dioxides
Introduction
The importance of substituted 3,4-dihydro-2H-pyrans and
related tetrahydropyran derivatives in synthetic chemistry is
illustrated by the general occurrence of these motifs in the
synthesis of a vast range of natural products and bioactive
compounds.[1,2] As examples (Scheme 1), xyloketal A is an
interesting lead compound in the treatment of Alzheimerꢀs
disease,[2h,i,3] ligstroside, isolated from extra virgin olive, im-
parts bitterness, pungency, and astringency,[2j,4] and blephar-
ocalyxin D exhibits significant in vitro antiproliferative ac-
tivity against human fibrosarcoma HT-1080 and murine
colon 26-L5 carcinoma cells.[5]
Among the numerous methods for synthesizing the 3,4-di-
hydro-2H-pyrans, the inverse-electron-demand hetero-
Diels–Alder (HDA) reactions[6–9] of a,b-unsaturated carbon-
yl compounds with electron-rich alkenes (dienophiles) have
been demonstrated to afford a facile synthesis of these core
structures. To the best of our knowledge, only a few effec-
tive catalytic systems have been reported. After the early
studies,[10–12] Evans et al.[13] and Jørgensen and co-workers[14]
respectively reported enantioselective HDA reactions cata-
Scheme 1. Natural and bioactive products containing 3,4-dihydro-2H-
pyran subunits.
[a] Y. Zhu, M. Xie, S. Dong, X. Zhao, Dr. L. Lin, Dr. X. Liu,
Prof. Dr. X. Feng
lyzed by oxazoline/copper(II) complexes with good results
at almost the same time. Subsequently, a chiral Schiff base/
CrIII complex was applied to the HDA reactions of a,b-unsa-
turated aldehydes.[8e,f] Recently, two examples catalyzed by
oxazoline/copper(II) complexes were presented.[15,16] How-
ever, most of the HDA reactions were performed at ex-
tremely low temperatures (generally À788C) and with rela-
tively high catalyst loadings (generally 2–10 mol%). There-
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (P. R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[**] OTf: Trifluoromethanesulfonate.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100520.
8202
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8202 – 8208

FULL PAPER
Table 1. Catalytic asymmetric HDA reaction of b,g-unsaturated a-ke-
toester 1a with 2,3-dihydrofuran (2) promoted by metal/L catalysts.
fore, the development of a milder and efficient new catalytic
system is still in great demand.
N,N’-Dioxide ligands are excellent chiral scaffolds because
they can coordinate with various different metals and have
been shown to be highly efficient in many asymmetric reac-
tions.[17] Herein, we report the asymmetric inverse-electron-
demand HDA reaction of b,g-unsaturated a-ketoesters 1,
Entry[a]
Metal
Cu(OTf)2
Fe(acac)2
Sc(OTf)3
La(OTf)3
Eu(OTf)3
Ho(OTf)3
(OTf)3
Tb(OTf)3
Yb(OTf)3
Lu(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
L
Yield [%][b]
endo/exo[c]
ee [%][d]
promoted by 0.05–0.5 mol% of an N,N’-dioxide/ErACTHNUTRGNEUNG(OTf)3
1
2
3
4
5
6
7
8
G
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
trace
trace
83
73
96
42
91
>99
93
81
>99
87
>99
93
>99
93
93
n.d.[e]
n.d.[e]
92:8
90:10
93:7
91:9
94:6
94:6
93:7
94:6
95:5
92:8
98:2
n.d.[e]
n.d.[e]
5
complex under mild reaction conditions (generally 08C), to
give the adducts with excellent diastereoselectivities (up to
>99:1 d.r.) and enantioselectivities (up to >99% ee) for a
broad range of b,g-unsaturated a-ketoesters and alkenes.
[f]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
7
E
13
13
19
20
22
23
23
38
84
61
97
55
96
G
This was the first application of ErACTHNUTRGNENUG(OTf)3, an important lan-
Y
G
thanide metal salt, which features advantages in stability, re-
covery, and electropositive properties,[18] to the asymmetric
inverse-electron-demand HDA reaction.
G
9
G
10
11
12[g]
13[g]
14[g]
15[h]
16[h]
17[g]
E
Er
Er
Er
Er
Er
Er
Er
G
R
E
Results and Discussion
N
95:5
T
>99:1
>99:1
>99:1
AHCTUNGTRENNUNG
Initially, N,N’-dioxide L1 (Scheme 2) was complexed in situ
with various metals to catalyze the HDA reaction between
b,g-unsaturated a-ketoester 1a and 2,3-dihydrofuran (2;
A
[a] Unless otherwise noted, all reactions were carried out with 10 mol%
of L/metal (1:1), 1a (0.1 mmol), and 2 (30 mL, 4.0 equiv) in CH2Cl2
(1.0 mL) under N2 at 08C for 48 h. [b] Yield of isolated product. [c] De-
termined by chiral HPLC analysis; the isomer of 3a was confirmed by
1H NMR spectroscopy. [d] Determined by chiral HPLC analysis; the ab-
solute configuration of endo-3a (3aS,4S,7aR) was determined by compari-
son with literature data. [e] n.d.: not determined. [f] acac: acetylacetone.
[g] Reaction time: 2 h. [h] Reaction time: 15 min.
tions of the aniline moieties decreased the enantioselectivity
(61% ee; Table 1, entry 14). N,N’-dioxide L5, which con-
tained bulkier isopropyl groups, displayed excellent results
(>99% yield, >99:1 d.r., 97% ee), and an extremely short
reaction time was needed (15 min; Table 1, entry 15). The
chiral backbone of the N,N’-dioxide also had a significant
impact on the enantioselectivity of the reaction. l-Pipecolic
acid derivative N,N’-dioxide L5 was superior to l-proline de-
rived L6 and l-ramipril acid derived L7 (Table 1, entry 15
Scheme 2. Chiral ligands used in the study.
Table 1, entries 1–11). As shown in Table 1, many metal/L1
complexes gave poor results in the HDA reaction (Table 1,
versus entries 16 and 17). Therefore, the ErACTHGNUTRENNU(G OTf)3/L5 com-
entries 1–7). Tb
which belong to the lanthanide metal salts, gave similar
enantioselectivities (20–23% ee; Table 1, entries 8–11).
However, ErACHTUNGTRENNUNG(OTf)3 was more suitable than the others be-
cause of its higher yield (>99%) and better diastereoselec-
tivity (95:5 d.r.; Table 1, entry 11 versus entries 8–10). Fur-
ther optimization of the reaction conditions was then aimed
(OTf)3, Yb
E
E
(OTf)3
plex was chosen as the best catalyst (Table 1, entry 15).
With the optimized catalyst in hand, other reaction pa-
rameters were explored (Table 2). It was found that the sol-
vent also affected the reaction greatly (Table 2, entries 1–7).
The reaction in CH2ClCH2Cl provided an excellent yield (>
99%) and diastereoselectivity (>99:1 d.r.), but the enantio-
selectivity of the adduct was slightly diminished (Table 2,
entry 2 versus entry 1). The use of CHCl3 led to a dramatic
loss of enantioselectivity and reactivity (Table 2, entry 3).
Et2O, THF, and CH3CN gave high yields and moderate
enantioselectivities (Table 2, entries 4–6). Toluene is not
suitable, because the reaction in this solvent provided 3a
with low enantioselectivity and yield (Table 2, entry 7).
Thus, CH2Cl2 was proven to be the best solvent for the
HDA reaction. Furthermore, reduction of the catalyst load-
ing to 0.5 mol% led to no loss of yield, enantioselectivity, or
diastereoselectivity (Table 2, entry 8). When the catalyst
at improving the efficiency of the ErACTHNUTRGENUN(G OTf)3 catalyst with
other structures of N,N’-dioxide ligand (Scheme 2), includ-
ing changes to both the chiral backbone and the steric hin-
drance of the aniline moiety (Table 1, entries 12–17). Steri-
cally hindered L2 enhanced the enantioselectivity, with
38% ee, 92:8 d.r., and 87% yield (Table 1, entry 12). To our
delight, a remarkable improvement was achieved by em-
ploying the more hindered L3, and an ee value of up to
84% was obtained (Table 1, entry 13). However, N,N’-diox-
ide L4 with two methyl groups substituted at the ortho posi-
Chem. Eur. J. 2011, 17, 8202 – 8208
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8203

X. Feng et al.
Table 2. Optimization of the reaction conditions.
Table 3. Substrate scope of the asymmetric HDA reactions of b,g-unsatu-
rated a-ketoesters 1 and 2,3-dihydrofuran (2).
Entry[a] Solvent
t
x
Yield
endo/
ee
[mol%] [%][b]
exo[c]
[%][d]
Entry[a] R1
R2 Product t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
CH2ClCH2Cl 15 min 10
CHCl3
Et2O
15 min 10
>99
>99
>99
>99
>99
98
>99:1
>99:1
98:2
95:5
89:11
97:3
97
95
13
44
63
55
50
97
97
92
97
1
2
3
4
Ph
Ph
4-MeC6H4
Me 3a
Et 3b
Me 3c
2
2
2
2
2
36
2
2
24
2
>99
86
>99
>99
>99
81
>99
95
90
97 (3aS,4S,7aR)
97 (3aS,4S,7aR)
24 h
24 h
24 h
24 h
24 h
2 h
10
10
10
10
97
95
97
92
97
99
94
97
97
4-MeOC6H4 Me 3d
3-MeOC6H4 Me 3e
3-NO2C6H4 Me 3 f
4-ClC6H4
2-ClC6H4
2,4-Cl2C6H3 Me 3i
4-BrC6H4
4-FC6H4
THF[e]
CH3CN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
6[d]
7
10
45
94:6
Me 3g
Me 3h
0.5
0.075
0.05
0.5
>99
>99
>99
>99
>99:1
>99:1
>99:1
>99:1
8
9
10
11
9
24 h
2 h
10[f]
11[g]
Me 3j
Me 3k
>99
98
2 h
2
[a] Unless otherwise noted, all reactions were carried out with x mol% of
L5/Er(OTf)3 (1:1), 1a (0.1 mmol), and 2 (30 mL, 4.0 equiv) in solvent
(1.0 mL) under N2 at 08C. [b] Yield of isolated product. [c] Determined
by chiral HPLC analysis; the isomer of 3a was confirmed by 1H NMR
spectroscopy. [d] Determined by HPLC analysis. [e] THF: tetrahydrofur-
12
13
Me 3l
12
12
99
93
97
94
ACHTUNGTRENNUNG
Me 3m
14
2-naphthyl
2-thienyl
Me
Me 3n
Me 3o
Et 3p
12
12
12
92
93
50
98
95
an. [f] The reaction was carried out with 0.05 mol% of L5/Er
1a (0.1 mmol), and 2 (30 mL, 4.0 equiv) in CH2Cl2 (1.0 mL) under N2 at
258C. [g] The reaction was carried out with 0.5 mol% of L5/Er(OTf)3
ACHTUNGRTENUN(NG OTf)3 (1:1),
15
16[e]
89 (3aS,4S,7aR)
AHCTUNGTRENNUNG
(1:1), 1a (0.1 mmol), and 2 (30 mL, 4.0 equiv) in CH2Cl2 (1.0 mL) under
an air atmosphere at 08C.
[a] Unless otherwise noted, all reactions were carried out with 0.5 mol%
of L5/Er(OTf)3 (1:1), 1 (0.1 mmol), and 2 (30 mL, 4.0 equiv) in CH2Cl2
AHCTUNGTRENNUNG
(1.0 mL) under N2 at 08C and the diastereoselectivity of the product was
>99:1. [b] Yield of isolated product. [c] Determined by chiral HPLC
analysis; the absolute configurations of endo-3a, 3b, and 3p were deter-
mined by comparison with literature data. [d] The reaction was carried
out at 358C. [e] The reaction was carried out at À208C.
loading was further lowered to 0.075 mol%, the reaction
was carried out smoothly with excellent results, but a longer
reaction time was required (Table 2, entry 9).[19] The catalyst
loading could even be decreased to 0.05 mol% at 258C, in
which case the enantioselectivity was reduced to 92% ee
(Table 2, entry 10). It is also notable that the process is toler-
ant to air and moisture (Table 2, entry 11). Therefore, the
with good outcomes (Table 3, entries 14 and 15). Moreover,
good enantioselectivity was observed with an aliphatic b,g-
unsaturated a-ketoester (50% yield, >99:1 d.r., 89% ee;
Table 3, entry 16).[20]
optimal reaction conditions were L5/ErACTHNURTGNENG(U OTf)3 (0.5 mol%),
1a (0.1 mmol), and 2 (0.4 mmol) in CH2Cl2 (1.0 mL) at 08C.
Next, under the optimized conditions, the substrate scope
of the HDA reaction was evaluated; the corresponding
products were obtained in mostly high yields (50 to >99%)
with excellent diastereoselectivities (>99:1 d.r.) and ee
values (89–99%). When the effect of the ester group of the
b,g-unsaturated a-ketoesters was tested, an ethyl group
showed lower reactivity than the methyl group (Table 3,
entry 2 versus entry 1), although the diastereoselectivity and
enantioselectivity were both excellent. The aromatic ke-
toesters underwent the HDA reactions to give the optically
active adducts in excellent yields (81 to >99%), diastereo-
selectivities (>99:1 d.r.), and ee values (in the range of 92–
99%), regardless of the electronic and steric properties of
the substituents (Table 3, entries 3–12). However, the 3-
NO2C6H4-substituted b,g-unsaturated a-ketoester needed
more time and a higher temperature to complete the con-
version (Table 3, entry 6). Furthermore, the substrate with a
cinnamyl group also gave an excellent yield and ee value
(Table 3, entry 13). Condensed-ring and heteroaromatic b,g-
unsaturated a-ketoesters were also found to be excellent
substrates for the reaction and afforded the desired products
The synthesis of 3,4-dihydro-2H-pyrans with an extremely
low catalyst loading is propitious for atom economy and in-
dustrial synthesis. Although the asymmetric HDA reactions
of b,g-unsaturated a-ketoesters with 2,3-dihydrofuran had
been reported,[13,14,16] most of these transformations required
10 mol% or more of catalyst loading for sufficient formation
of the product and maintenance of the enantioselectivity. In
our studies, for most substrates, excellent enantioselectivities
(95–99% ee) and diastereoselectivities (>99:1 d.r.) with
good yields (78 to >99%) were obtained by using
0.075 mol% catalyst, albeit with somewhat longer reaction
times (Table 4). This is the first example of the asymmetric
inverse-electron-demand HDA reaction of a,b-unsaturated
carbonyl compounds and electron-rich alkenes with such a
low amount of catalyst (0.075 mol%).
Subsequently, we carried out a generality study of the cat-
alytic cycloaddition with other electron-rich alkenes as part
of an expansion of the reaction (Scheme 3).[21] Compared
with the reaction with 2,3-dihydrofuran (2), the cycloaddi-
tion of 3,4-dihydro-2H-pyran required a higher temperature
to achieve complete conversion (Scheme 3, equation 1).
8204
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8202 – 8208

Enantioselective Synthesis of 3,4-Dihydro-2H-pyrans
FULL PAPER
Table 4. Asymmetric HDA reactions of b,g-unsaturated a-ketoesters 1
and 2,3-dihydrofuran (2) with 0.075 mol% catalyst loading.
Acyclic vinyl ethers were found to be very efficient dieno-
philes in this reaction (98 to >99% yields, 99:1 d.r., and 96–
99% ee; Scheme 3, equation 2). In our previous studies, the
L5/Cu
of b,g-unsaturated a-ketoesters and cyclopentadiene.[22] It is
interesting that L5/Er(OTf)3 worked as well as L5/Cu(OTf)2
ACHTUNGRTEN(NGNU OTf)2 complex could efficiently catalyze the reaction
A
ACHTUNGTRENNUNG
with moderate chemoselectivity and excellent enantioselec-
tivity (Scheme 3, equation 3). It is notable that the more
sterically hindered alkene 9, which afforded product 15 with
a quaternary carbon center, gave excellent results (>99%
yield, >99% d.r., >99% ee; Scheme 3, equation 4). Vinyl
sulfides also functioned efficiently as dienophiles to give
products 16a,b and 17a,b stereoselectively (Scheme 3, equa-
tions 5 and 6). However, the reactivity of phenyl-
Entry[a]
R1
Product
t [h]
Yield [%][b]
ee [%][c]
1[d]
2[d]
3
Ph
3a
3c
3d
3g
3h
3j
12
12
24
12
12
12
12
>99
>99
>99
>99
84
97
97
95
97
99
97
97
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-FC6H4
4[d]
5
6
7
98
97
3k
8
3l
24
93
96
AHCTUNGTREG(NNUN vinyl)sulfane was lower than that of other electron-rich al-
kenes (Scheme 3, equation 5).
9
10
2-naphthyl
2-thienyl
3n
3o
24
24
78
90
98
95
The low catalyst loading and inexpensive starting materi-
als and catalyst for this HDA reaction offered a practical
way to scale up production. As shown in Scheme 4, with
treatment of 5 mmol of the starting material under the opti-
mized conditions, the reaction proceeded smoothly, and the
desired addition product 3a was obtained in >99% yield
with >99:1 d.r. and 97% ee.
[a] Unless otherwise noted, all reactions were carried out with
0.075 mol% of L5/Er(OTf)3 (1:1), 1 (0.1 mmol), and 2 (60 mL, 8.0 equiv)
in CH2Cl2 (1.0 mL) under N2 at 08C, and the diastereoselectivity of the
product was >99:1. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis. [d] The quantity of 2 used was 30 mL (4.0 equiv).
ACHTUNGTRENNUNG
Moreover, the reaction could
be amplified to the gram scale
with a good ee value and excel-
lent yield in the presence of
only 0.05 mol% of catalyst at
258C.
The potential biological ac-
tivities exhibited by the 3,4-di-
hydro-2H-pyrans and the de-
rived ring-fused tetrahydropyr-
ans[2] mean that the structural
elaboration of this core is ex-
tremely important (Scheme 5).
Reduction of 13a smoothly
generated the primary allylic al-
cohol 18 in excellent yield (>
99%) without loss of the dia-
stereo- and enantioselectivity
(99:1 d.r., 99% ee); this product
might exhibit biological activi-
ty.[23] To show an example of
potential transformations on
the ring-fused bicyclic HDA ad-
ducts, we subjected compound
12 to catalytic hydrogenation in
the presence of Pd/C. Hydroge-
nation of the 3,4-dihydro-2H-
pyran ring occured highly selec-
tively to give the tetrahydropyr-
an as a single isomer. The de-
sired product 19 was obtained
in 81% yield and without loss
of enantioselectivity (94% ee).
Scheme 3. Enantioselective inverse-electron-demand HDA reactions of alkenes 4–11 with 1.
This compound could be con-
Chem. Eur. J. 2011, 17, 8202 – 8208
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8205

X. Feng et al.
Figure 1. Investigation of the nonlinear effect.
Scheme 4. The gram-scale asymmetric synthesis of 3a.
plex seemed to be more active than the heterochiral one,
which resulted in the positive NLE.[26]
Conclusion
The general and highly enantioselective inverse-electron-
demand hetero-Diels–Alder reaction of b,g-unsaturated a-
ketoesters and electron-rich alkenes catalyzed by an N,N’-di-
oxide/erbiumACTHUNTGRNEUNG(III) complex with a remarkably low catalyst
loading (0.5–0.05 mol%) was successfully established.
Under mild conditions, a series of substituted 3,4-dihydro-
2H-pyrans were obtained in excellent yields (up to >99%)
with excellent enantioselectivities (up to >99% ee) and dia-
stereoselectivities (up to >99:1 d.r.) by an operationally
simple protocol. We have shown that the HDA adducts can
be reduced to the corresponding dihydropyran and tetrahy-
dropyran derivatives with potential biological activity with-
out loss of optical purity. Meanwhile, a positive nonlinear
correlation was observed. Further studies of the reaction
mechanism of the catalytic system are under way.
Experimental Section
Scheme 5. Reduction of compounds 12 and 13a, and an example of the
Preparation of the catalytic solution (c=0.002mol LÀ1): A mixture of Er-
synthetic application of this methodology.
AHCTUNGRTEG(NUNN OTf)3 (6.1 mg, 0.01 mmol) and N,N’-dioxide L5 (6.5 mg, 0.01 mmol)
were added to a volumetric flask (5 mL). Anhydrous THF (5.0 mL) was
then added.
verted into bicyclic lactone 20 through a series of steps.[24]
Moreover, ring-cleavage reactions of the hexahydro-2H,5H-
Representative experimental procedure (Table 2, entry 8): A dry reaction
tube was charged with catalyst solution (250 mL; 0.5 mol% loading).
After the solvent was removed in vacuo, b,g-unsaturated a-ketoester 1a
(0.1 mmol) was weighed into the flask under nitrogen and kept at ambi-
ent temperature for 0.5h. CH2Cl2 (1.0 mL) was then added. The mixture
was stirred at 258C for 30 min and then cooled to 08C. Subsequently, 2,3-
dihydrofuran (2; 30 mL) was added at 08C, and the reaction mixture was
stirred for an additional 2 h. The residue was purified by flash chroma-
tography on silica gel to afford the desired product 3a.
pyranoACHTUNGTRENNUNG
[2,3-b]pyran-2-one ring system[25] might lead to the
formation of 21, which was a suitable intermediate target
for blepharocalyxin D.[5,24]
To gain insight into the origin of the stereoinduction, the
nonlinear effect (NLE) for the present system was investi-
gated by varying the ee value of the chiral N,N’-dioxide L5.
As shown in Figure 1, a positive non
ACHTUNGTRENNUNG
General experimental procedure for the scale-up reaction: A mixture of
b,g-unsaturated a-ketoester 1a (5 mmol, 0.95 g), ErACTHUNRGTNEUNG(OTf)3 (15.4 mg,
served, which suggests that the complex [(L5)2ErAHCTUNTGRENNUNG
0.025 mmol), and N,N’-dioxide L5 (16.2 mg, 0.025 mmol) was added to a
flask under nitrogen and kept at ambient temperature for 0.5 h. Anhy-
drous CH2Cl2 (50 mL) was then added, and the solution was stirred at
258C for 0.5 h. Subsequently, 2,3-dihydrofuran (2; 1.5 mL) was added at
08C, and the reaction mixture was stirred for an additional 24 h. The resi-
might be involved at the step before the reactive intermedi-
ate. The racemate complex was thermodynamically more
stable than the chiral one. As found in Girard and Kaganꢀs
excellent review of nonlinear effects, the homochiral com-
8206
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8202 – 8208

Enantioselective Synthesis of 3,4-Dihydro-2H-pyrans
FULL PAPER
due was purified by flash chromatography on silica gel (ethyl acetate/pe-
troleum ether, 1:4) to afford the desired product 3a. The procedure of
the scaled-up reaction in the presence of 0.05 mol% of catalyst at 258C
was similar to the procedure described above.
[7] For reviews of inverse-electron-demand Diels–Alder reactions, see:
a) A. R. Katritzky, S. Rachwal, B. Rachwal, Tetrahedron 1996, 52,
15031–15070; b) P. Buonora, J.-C. Olsen, T. Oh, Tetrahedron 2001,
57, 6099; c) V. V. Kouznetsov, Tetrahedron 2009, 65, 2721–2750.
[8] For selected examples of inverse-electron-demand HDA reactions,
see: a) G. Desimoni, G. Faita, M. Mella, F. Piccinini, M. Toscanini,
Eur. J. Org. Chem. 2007, 1529–1534; b) G. Desimoni, G. Faita, M.
Toscanini, M. Boiocchi, Chem. Eur. J. 2007, 13, 9478–9485; c) Y.
Zhao, X.-J. Wang, J.-T. Liu, Synlett 2008, 1017–1020; d) K. Juhl,
K. A. Jørgensen, Angew. Chem. 2003, 115, 1536–1539; Angew.
Chem. Int. Ed. 2003, 42, 1498–1501; e) K. Gademann, D. E. Chavez,
E. N. Jacobsen, Angew. Chem. 2002, 114, 3185–3187; Angew. Chem.
Int. Ed. 2002, 41, 3059–3061; f) X. Gao, D. G. Hall, J. Am. Chem.
Soc. 2003, 125, 9308–9309; g) J. S. Yadav, B. V. S. Reddy, V. Sunitha,
K. S. Reddy, Adv. Synth. Catal. 2003, 345, 1203–1206; h) D. A.
Evans, J. S. Johnson, C. S. Burgey, K. R. Campos, Tetrahedron Lett.
1999, 40, 2879–2882; i) Z. M. Ismail, H. M. R. Hoffmann, Angew.
Chem. 1982, 94, 862–863; Angew. Chem. Int. Ed. Engl. 1982, 21,
General experimental procedure for hydrogenation of compound 12: Pd/
C (0.025 mol, 6.19 mg, 10% equiv) was added to a solution of the HDA
product 12 (>99:1 d.r., 94% ee, 0.25 mmol, 68.6 mg) in MeOH (3.0 mL)
at room temperature. Under an H2 atmosphere, the mixture was allowed
to stir for 48 h. Filtration followed by removal of the solvent under re-
duced pressure and silica gel flash column chromatography (ethyl ace-
tate/petroleum ether, 1:8) afforded ring-fused tetrahydropyran 19 (81%
yield, >99:1 d.r., 94% ee).
General experimental procedure for hydrogenation of compound 13a:
LiAlH4 (1.175 mol, 46.9 mg, 2.5 equiv) was added portionwise to a solu-
tion of the HDA product 13a (0.47 mol, 124.1 mg) in anhydrous Et2O
(10 mL) in a 50 mL flask under nitrogen with ice cooling. The reaction
mixture was then stirred at room temperature. After 24 h, the mixture
was hydrolyzed with saturated aqueous Na2SO4 solution (80 mL) and
stirred for a few minutes. The mixture was then filtered through celite
and dried. Filtration followed by removal of solvent under reduced pres-
sure and silica gel flash column chromatography (ethyl acetate/petroleum
ether, 1:9) afforded primary allylic alcohol 18 (>99% yield, 99:1 d.r. and
99% ee).
ˇ
859–860; j) D. Dvorꢂk, Z. Arnold, Tetrahedron Lett. 1982, 23, 4401–
4402; k) S. Samanta, J. Krause, T. Mandal, C.-G. Zhao, Org. Lett.
2007, 9, 2745–2748.
[9] For selected examples of the diastereoselective inverse-electron-
demand HDA reaction, see: a) D. L. Boger, K. D. Robarge, J. Org.
Chem. 1988, 53, 3373–3377; b) L. F. Tietze, C. Schneider, A. Grote,
Chem. Eur. J. 1996, 2, 139–148; c) S. C. Johnson, C. Crasto, S. M.
Hecht, Chem. Commun. 1998, 1019–1020; d) G. Dujardin, S. Rossi-
gnol, E. Brown, Tetrahedron Lett. 1996, 37, 4007–4010; e) G. Dujar-
din, S. Rossignol, E. Brown, Synthesis 1998, 763–770; f) R. R.
Schmidt, M. Maier, Tetrahedron Lett. 1985, 26, 2065–2068.
[10] a) L. F. Tietze, P. Saling, Synlett 1992, 281–282; b) L. F. Tietze, P.
Saling, Chirality 1993, 5, 329–333.
[11] For the work of Tietze and co-workers on the inverse-electron-
demand HDA reaction, see: a) L. F. Tietze, G. Schulz, Liebigs Ann.
1995, 1921–1924; b) L. F. Tietze, C. Schneider, A. Montenbruck,
Angew. Chem. 1994, 106, 1031–1032; Angew. Chem. Int. Ed. Engl.
1994, 33, 980–982; c) L. F. Tietze, A. Montenbruck, C. Schneider,
Synlett 1994, 509–510; d) L. F. Tietze, C. Schneider, Synlett 1992,
755–756.
Acknowledgements
We appreciate the financial support from the National Natural Science
Foundation of China (grant nos. 20732003 and 21021001), PCSIRT (grant
no. IRT0846), and the National Basic Research Program of China
(973 Program: grant no. 2011CB808600). We also thank Sichuan Univer-
sity Analytical & Testing Centre for NMR analysis and the State Key
Laboratory of biotherapy for HRMS analysis.
[1] a) G. Desimoni, G. Tacconi, Chem. Rev. 1975, 75, 651–692; b) D. L.
Boger, S. M. Weinreb, Hetero Diels–Alder Methodology in Organic
Synthesis, Academic Press, New York, 1987; c) S. Redon, X. Panne-
coucke, X. Franck, F. Outurquin, Org. Biomol. Chem. 2008, 6, 1260–
1267.
[12] a) E. Wada, H. Yasuoka, S. Kanemasa, Chem. Lett. 1994, 1637–
1640; b) E. Wada, W. Pei, H. Yasuoka, U. Chin, S. Kanemasa, Tetra-
hedron 1996, 52, 1205–1220; c) E. Wada, H. Yasuoka, S. Kanemasa,
Chem. Lett. 1994, 145–148.
[13] a) D. A. Evans, J. S. Johnson, J. Am. Chem. Soc. 1998, 120, 4895–
4896; b) D. A. Evans, E. J. Olhava, J. S. Johnson, J. M. Janey, Angew.
Chem. 1998, 110, 3553–3557; Angew. Chem. Int. Ed. 1998, 37, 3372–
3375; c) D. A. Evans, J. S. Johnson, E. J. Olhava, J. Am. Chem. Soc.
2000, 122, 1635–1649.
[14] a) J. Thorhauge, M. Johannsen, K. A. Jørgensen, Angew. Chem.
1998, 110, 2543–2546; Angew. Chem. Int. Ed. 1998, 37, 2404–2406;
b) H. Audrain, J. Thorhauge, R. G. Hazell, K. A. Jørgensen, J. Org.
Chem. 2000, 65, 4487–4497; c) W. Zhuang, J. Thorhauge, K. A. Jør-
gensen, Chem. Commun. 2000, 459–460; d) H. Audrain, K. A. Jør-
gensen, J. Am. Chem. Soc. 2000, 122, 11543–11544.
[2] For examples of natural and bioactive unnatural products containing
tetrahydropyrans and the dihydropyran moiety, see: a) J. W. Westley,
R. H. Evans, T. Williams, A. Stempel, J. Chem. Soc. D 1970, 71–72;
b) L. F. Tietze, G. Kettschau, Top. Curr. Chem. 1997, 189, 1–120;
c) G. R. Pettit, C. L. Herald, D. L. Doubek, D. L. Herald, E. Arnold,
J. Clardy, J. Am. Chem. Soc. 1982, 104, 6846–6848; d) T. Higa, J.
Tanaka, M. Komesu, D. C. Gravalos, J. L. F. Puentes, G. Bernardi-
nelli, C. W. Jefford, J. Am. Chem. Soc. 1992, 114, 7587–7588; e) M.
Kobayashi, S. Aoki, I. Kitagawa, Tetrahedron Lett. 1994, 35, 1243–
1246; f) D. G. Kang, D. H. Choi, J. K. Lee, Y. J. Lee, M. K. Moon,
S. N. Yang, T. O. Kwon, J. W. Kwon, J. S. Kim, H. S. Lee, Planta
Med. 2007, 73, 1436–1440; g) W. Q. Yang, D. J. Shang, Y. L. Liu, Y.
Du, X. M. Feng, J. Org. Chem. 2005, 70, 8533–8537; h) K. Krohn,
M. Riaz, U. Flçrke, Eur. J. Org. Chem. 2004, 1261–1270; i) Z. L. Xu,
Y. Y. Li, Q. Xiang, Z. Pei, X. L. Liu, B. T. Lu, L. Chen, G. L. Wang,
J. Y. Pang, Y. C. Lin, J. Med. Chem. 2010, 53, 4642–4653; j) A. B.
Smith, III, J. B. Sperry, Q. Han, J. Org. Chem. 2007, 72, 6891–6900.
[3] A. B. Holmes, G. R. Stephenson, Chem. Ind. 2001, 738–739.
[4] G. Montedoro, M. Servili, M. Baldioli, R. Selvaggini, E. Miniati, A.
Macchioni, J. Agric. Food Chem. 1993, 41, 2228–2234.
[15] S. Barroso, G. Blay, M. C. MuÇoz, J. R. Pedro, Adv. Synth. Catal.
2009, 351, 107–111.
[16] Y. J. Shin, C.-E. Yeom, M. J. Kim, B. M. Kim, Synlett 2008, 89–93.
[17] For selected asymmetric examples based on chiral N,N’-dioxides,
see: a) S. K. Chen, Z. R. Hou, Y. Zhu, J. Wang, L. L. Lin, X. H. Liu,
X. M. Feng, Chem. Eur. J. 2009, 15, 5884–5887; b) M. Kokubo, C.
Ogawa, S. Kobayashi, Angew. Chem. 2008, 120, 7015–7017; Angew.
Chem. Int. Ed. 2008, 47, 6909–6911; c) S. Kobayashi, M. Kokubo, K.
Kawasumi, T. Nagano, Chem. Asian J. 2010, 5, 490–492; d) D. H.
Chen, Z. L. Chen, X. Xiao, Z. G. Yang, L. L. Lin, X. H. Liu, X. M.
Feng, Chem. Eur. J. 2009, 15, 6807–6810; e) K. Zheng, J. Shi, X. H.
Liu, X. M. Feng, J. Am. Chem. Soc. 2008, 130, 15770–15771; f) K.
Shen, X. H. Liu, W. T. Wang, G. Wang, W. D. Cao, W. Li, X. L. Hu,
L. L. Lin, X. M. Feng, Chem. Sci. 2010, 1, 590–595; g) Y. H. Hui, J.
Jiang, W. T. Wang, W. L. Chen, Y. F. Cai, L. L. Lin, X. H. Liu, X. M.
Feng, Angew. Chem. 2010, 122, 4386–4389; Angew. Chem. Int. Ed.
[5] a) Y. Tezuka, M. S. Ali, A. H. Banskota, S. Kadota, Tetrahedron
Lett. 2000, 41, 5903–5907; b) M. S. Ali, A. H. Banskota, Y. Tezuka,
I. Saiki, S. Kadota, Biol. Pharm. Bull. 2001, 24, 525–528.
[6] For recent reviews of HDA reactions of carbonyl compounds, see:
a) K. A. Jørgensen, Angew. Chem. 2000, 112, 3702–3733; Angew.
Chem. Int. Ed. 2000, 39, 3558–3588; b) H. Pellissier, Tetrahedron
2009, 65, 2839–2877.
Chem. Eur. J. 2011, 17, 8202 – 8208
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8207

X. Feng et al.
2010, 49, 4290–4293; h) M. S. Xie, X. H. Chen, Y. Zhu, B. Gao,
L. L. Lin, X. H. Liu, X. M. Feng, Angew. Chem. 2010, 122, 3887–
3890; Angew. Chem. Int. Ed. 2010, 49, 3799–3802; i) Y. L. Liu, D. J.
Shang, X. Zhou, X. H. Liu, X. M. Feng, Chem. Eur. J. 2009, 15,
2055–2058; j) L. Zhou, L. L. Lin, W. T. Wang, J. Ji, X. H. Liu, X. M.
Feng, Chem. Commun. 2010, 46, 3601–3603; k) Y. F. Cai, X. H. Liu,
Y. H. Hui, J. Jiang, W. T. Wang, W. L. Chen, L. L. Lin, X. M. Feng,
Angew. Chem. 2010, 122, 6296–6300; Angew. Chem. Int. Ed. 2010,
49, 6160–6164; l) W. Li, J. Wang, X. L. Hu, K. Shen, W. T. Wang,
Y. Y. Chu, L. L. Lin, X. H. Liu, X. M. Feng, J. Am. Chem. Soc. 2010,
132, 8532–8533.
[20] The reaction gives 100% conversion, but the product is presumably
unstable on the column during purification; see reference [9a].
[21] The absolute configurations of endo-5a (2R,4R), endo-8a
(4R,4aS,7aS), endo-10b (2S,4R), and endo-11b (2S,4R) were deter-
mined by comparison with literature data, the endo:exo ratios were
determined by HPLC analysis, and the isomers of 4a–11a, 10b, and
1
11b were confirmed by H NMR spectroscopy.
[22] Y. Zhu, X. H. Chen, M. S. Xie, S. X. Dong, Z. Qiao , L. L. Lin,
X. H. Liu, X. M. Feng, Chem. Eur. J. 2010, 16, 11963–11968.
[23] S. Leconte, G. Dujardin, E. Brown, Eur. J. Org. Chem. 2000, 639–
643.
[18] a) A. Procopio, R. Dalpozzo, A. D. Nino, L. Maiuolo, M. Nardi, M.
Oliverio, B. Russo, Carbohydr. Res. 2007, 342, 2125–2131; b) D.
Hannachi, N. Ouddai, H. Chermette, Dalton Trans. 2010, 39, 3673–
3680; c) A. Procopio, M. Gaspari, M. Nardi, M. Oliverio, R. Romeo,
Tetrahedron Lett. 2008, 49, 1961–1964; d) A. Procopio, R. Dalpozzo,
A. D. Nino, M. Nardi, M. Oliverio, B. Russo, Synthesis 2006, 2608–
2612; e) A. Procopio, R. Dalpozzo, A. D. Nino, B. Russo, A. Tagar-
elli, Synthesis 2006, 332–338; f) R. Dalopozzo, A. D. Nino, L.
Maiuolo, M. Nardi, A. Procopio, A. Tagarelli, Synthesis 2004, 496–
498.
[24] W. Li, K. T. Mead, L. T. Smith, Tetrahedron Lett. 2003, 44, 6351–
6353.
[25] For related reactions, see: a) D. R. Mootoo, B. Fraser-Reid, Carbo-
hydr. Res. 1988, 174, 99–112; b) N. Cohen, B. Schaer, G. Saucy, R.
Borer, L. Todaro, A.-M. Chiu, J. Org. Chem. 1989, 54, 3282–3292;
c) I. Ungureanu, P. Klotz, A. Schoenfelder, A. Mann, Tetrahedron
Lett. 2001, 42, 6087–6091.
[26] For a review of nonlinear effects, see: C. Girard, H. B. Kagan,
Angew. Chem. 1998, 110, 3088–3127; Angew. Chem. Int. Ed. 1998,
37, 2922–2959.
[19] We attempted to use a 0.075 mol% catalyst loading as one of the
optimal reaction conditions, but some of the substrates had low re-
activity.
Received: February 16, 2011
Revised: March 17, 2011
Published online: June 6, 2011
8208
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8202 – 8208