Bifunctional cinchona alkaloids-catalyzed asymmetric [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones

Article abstract of DOI:10.1016/j.tet.2011.03.069

A highly enantioselective [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones was realized with readily available cinchona alkaloids as the catalysts. Using this reaction, a series of highly functionalized δ-lactones with adjacen

Full text of DOI:10.1016/j.tet.2011.03.069

Tetrahedron 67 (2011) 3337e3342
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Bifunctional cinchona alkaloids-catalyzed asymmetric [4þ2] cycloaddition
reaction of b,g-unsaturated a-keto esters with oxazolones
,
a,
*
Yin Ying a, Zhuo Chai b, Hai-Feng Wang b, Peng Li b, Chang-Wu Zheng b, Gang Zhao b , Yue-Peng Cai
*
a School of Chemistry and Environment, Key Lab of Technology on Electrochemical Energy Storage and Power Generation in Guangdong Universities, South China Normal University,
Guangzhou 510006, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective [4þ2] cycloaddition reaction of
b,g-unsaturated a-keto esters with oxazolones
was realized with readily available cinchona alkaloids as the catalysts. Using this reaction, a series of
Received 23 February 2011
Received in revised form 16 March 2011
Accepted 22 March 2011
highly functionalized
high yields (up to 97%) and with good-to-excellent enantioselectivities (up to 97% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
d-lactones with adjacent a-quaternary-b-tertiary stereocenters were obtained in
Available online 26 March 2011
Keywords:
Asymmetric catalysis
[4þ2] Cycloaddition
b,g-Unsaturated a-keto esters
Bifunctional catalysts
1. Introduction
nucleophilic and electrophilic sites would allow the formation
chiral six-membered oxygenated heterocycles.
Chiral six-membered oxygenated heterocycles are one of the
most common structural motifs present in numerous biologically
active compounds. Consequently, a myriad of methods have been
developed for their stereoselective construction.1 Recently, our
With orthogonal nucleophilic and electrophilic reactive sites,
the oxazolone then came to our sight as a suitable candidate for the
above purpose. Oxazolones, also known as azlactones, have been
utilized as versatile partners in a range of different reactions.8 Gong
and co-workers reported a three-component cyclization reaction
between enals, aryl amines, and oxazolones to give chiral 3-amino-
group has engaged in the chemistry of
ters as a versatile reaction partner in a series of organocatalyzed
reactions.2e7 Compared to simple
-unsaturated ketones, these
b,g-unsaturated a-keto es-
a
,
b
d
-lactones.9 As our work is in progress, Feng and co-workers
keto esters not only usually demonstrated better reactivities due to
their enhanced electrophilicity, but also allowed facile conversions
of the corresponding products to many other useful structure
mainly based on the ready convertibility of the ester group. Some
previous works from our group and others2b,d,f,g,3a,cej,len,4c,5a,i have
reported an asymmetric bisguanidine-catalyzed inverse-electron-
demand hetero-DielseAlder reaction of oxazolones with chal-
cones.10 We now report here the cycloaddition of
a
b,
g-unsaturated
-keto esters with oxazolones.11 With readily available cinchona
alkaloid catalysts, the reaction could be completed within several
hours at room temperature to provide highly functionalized
demonstrated the utility of b,g-unsaturated a-keto esters to pre-
pare chiral six-membered oxygenated heterocycles with certain
nucleophiles. In most of these works, both the alkene and carbonyl
groups in the keto esters served as electrophilic sites. We recently
discovered a cinchona alkaloids-catalyzed unexpected Michael
d-lactones with adjacent a-quaternary-b-tertiary stereocenters in
high yields and enantioselectivities.
2. Results and discussion
addition/oxa-nucleophilic rearrangement reaction of
b,g-un-
saturated
a
-keto esters with substituted malonates.2a In this re-
The reaction of 4-methyl-2-phenyloxazol-5(4H)-one 1a with
(E)-methyl 2-oxo-4-phenylbut-3-enoate 2a was selected as model
reaction for the optimization of reaction parameters. With our ex-
action, the carbonyl oxygen atom of the keto esters was found to act
as a nucleophile after the initial Michael addition. Thus, we as-
sumed that the use of a reaction partner with rightly positioned
perience in the reactions of
b,g-unsaturated a
-keto esters,2 we
began the initial catalyst evaluation with several cinchona alkaloids
(Table 1). The commercially available quinine 4a catalyst gave the
desired product 3a in a highly encouraging 82% yield and 70% ee
* Corresponding authors. Tel.: þ86 21 54925182; fax: þ86 21 64166128 (G.Z.);
tel.: þ86 20 33033475; fax: þ86 20 85215865 (Y.-P.C.); e-mail addresses: zhaog@
sioc.ac.cn (G. Zhao), caiyp@scnu.edu.cn (Y.-P. Cai).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.069

3338
Y. Ying et al. / Tetrahedron 67 (2011) 3337e3342
Table 1
With the best catalyst 4m, a variety of solvents were examined
Screening of different catalystsa
for the model reaction (Table 2). This reaction showed an excellent
tolerance of solvents of different types: most solvents examined
gave comparable good yields and enantioselectivities, and in-
variably exclusive diastereoselectivity. The only significantly lower
yields obtained in the case of n-hexane may be ascribed to the poor
solubility of the catalyst in this solvent (entry 5). In view of both the
yield and enantioselectivity, the present reaction was best per-
formed with 20 mol % of 4m in Et2O at room temperature (entry 4).
O
O
O
O
N
NHCOPh
Me
4 (20 mol%)
OMe
Ph
+
O
Ph
CH2Cl2
RT, 3 h
Me
O
MeOOC
Ph
1a
2a
3a
Entry
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4m
4m
4m
82
86
85
52
62
58
62
82
80
94
67
92
92
85
79
75
ꢀ70
ꢀ91
ꢀ85
ꢀ3
ꢀ5
ꢀ60
12
90
90
91
87
Table 2
Effect of the solvent on the reactiona
O
O
O
O
N
NHCOPh
4m (20 mol%)
solvent, RT, t
OMe
Ph
+
O
Ph
Me
Ph
Me
O
MeOOC
9
1a
2a
3a
10
11
12
13
14d
15e
16f
92
94
92
79
Entry
Solvent
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
CH2Cl2
Toluene
CHCl3
3
3
3.5
3
8
4
4
5
5
92
87
89
92
42
82
84
95
85
82
94
95
95
95
69
93
92
92
93
93
50
Et2O
a
Unless otherwise noted, the reaction was conducted with 0.11 mmol of 1a,
0.1 mmol of 2a, and 20 mol % of 4 in 1.0 mL of CH2Cl2.
n-Hexane
PhCF3
Xylene
THF
ClCH2CH2Cl
MTBE
b
Isolated yields after column chromatography on silica gel.
Determined by chiral HPLC analysis on a chiral column OD column. Only a single
c
diastereoisomer was observed by 1H and 13C NMR.
d
Compound 4m of 15 mol % was used.
Compound 4m of 10 mol % was used.
Compound 4m of 5 mol % was used.
6
e
a
f
Unless otherwise noted, the reaction was conducted with 0.11 mmol of 1a and
0.10 mmol of 2a in the presence of 20 mol % of 4m in 1.0 mL of solvent.
b
Isolated yields after column chromatography on silica gel.
with exclusive diastereoselectivity (entry 1). While catalysts 4b and
4c with a free phenolic hydroxyl group and a protected alcohol
moiety improved the results further, catalysts with both hydroxyl
groups protected (4d) or exposed (4e) gave extremely poor results
(entries 2e5). Such a phenomenon highlights the importance of the
bifunctionality of the catalyst in this reaction. Two bifunctional
thiourea catalysts 4f and 4g, which we have previously used to
c
Determined by chiral HPLC analysis on an OD chiral column. Only a single
diastereoisomer was observed by 1H and 13C NMR.
Having established the optimum reaction conditions, various
b,g-unsaturated a-keto esters were first tested to explore the re-
action scope and the results were presented in Table 3. A broad
substrate scope was observed here with the desired products
obtained in high yields, excellent ee values and exclusive diaster-
eoselectivity. Substrates 2aeg with various differently substituted
phenyl groups (R1) on the alkene moiety, all worked well for the
reaction, irrespective of the electronic nature or position of the
substituents on the benzene ring (entries 1e7). Substrates bearing
electron-donating substituents seemed to exhibit a higher ee value
than those with electron-withdrawing ones (entries 6 and 7).
Heterocyclic substrate 2h (R1¼furan-2-yl) was also well tolerated
(entry 8). In addition, variation in the substituents on the ester
catalyze other reactions of
b,g-unsaturated a
-keto esters,2b,d,f,g
provided much inferior results here (entries 6 and 7). Changing
the skeleton from quinine to quinidine in general led to similar
results to their quinine counterparts, except that products of the
opposite absolute configuration (entries 8e13). The optimal cata-
lyst 4m gave the desired product in 92% yield and 94% ee (entry 13).
Unfortunately, decreasing the loading amount of the catalyst was
found to be detrimental to both the yield and enantioselectivity
(entries 14e16) (Fig. 1).
OMe
OR
CF3
4a: R = Me, R' = H
H
N
4b: R = H, R' = Bn
4c: R = H, R' = Bz
4d: R = Me, R' = Bn
4e: R = H, R' = H
N
S
Bn
CF3
F3C
H
N
N
HN
H
N
H
N
H
OR'
N
N
S
4g
CF3
4f
R
N
OH
N
OH
N
4h: R = H
4i: R = Me
4j: R= Ph
OH
N
O
O
O
N
N
4k: R = CF3
H
H
H
4m
4l
Fig. 1. Structures of chiral catalysts used in this reaction.

Y. Ying et al. / Tetrahedron 67 (2011) 3337e3342
3339
Table 3
Scope study with different b,g-unsaturated a
-keto estersa
O
O
O
O
NHCOPh
OR2
4m (20 mol%)
R1
+
O
Ph
Me
Et2O, RT, t
N
O
Me
R2OOC
R1
1a
2
3
Entry
R1, R2, 2
C6H5, Me, 2a
p-BrC6H4, Me, 2b
p-MeC6H4, Me, 2c
m-FC6H4, Me, 2d
o-FC6H4, Me, 2e
p-EtOC6H4, Me, 2f
p-NO2C6H4, Me, 2g
Furan-2-yl, Me, 2h
C6H5, p-Br-Bn, 2i
C6H5, Et, 2j
t (h)
3
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
3
3
3.5
4
4
2.5
5
3.5
3
4
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
95
85
88
91
95
88
90
96
90
92
d
95
94
93
87
88
97
90
95
94
90
91
d
Fig. 2. ORTEP structure of compound 3p.
the oxazolone ring;11 route II is the inverse-electron-demand het-
ero-DielseAlder (IEDDA) mechanism as proposed by Feng and co-
workers10 for the related reaction with chalcones. In route II, the
reaction may proceed in an endo way under the catalysis of the
bifunctional catalyst. Considering the exclusive diastereoselectivity
observed in the present reaction (consistent with the Feng’s
observation), route II should be the preferred one in our case.13
9
10
11
12
3j
C6H5, i-Pr, 2k
C6H5CH2CH2, Et, 2l
3k
4
dd
a
Unless otherwise noted, the reaction was conducted with 0.11 mmol of 1a and
0.10 mmolof2 inthe presence of20 mol % of4min1.0 mL ofEt2O for appropriate time.
b
Isolated yields after column chromatography on silica gel.
c
Determined by chiral HPLC analysis on
a chiral column. Only a single
diastereoisomer was observed by 1H and 13C NMR.
3. Conclusion
d
No product was observed.
In summary, we have developed a highly enantioselective and
moiety (R2) of the substrate did not bring in significant changes in
the yield and ee value (entries 9e11). Unfortunately, no product
was observed when substrate with aliphatic substituent
(R1¼C6H5CH2CH2, R2¼Et) was screened (entry 12).
diastereoselective cyclization reaction of oxazolones with
saturated -keto esters by using readily available cinchona alka-
loids as the catalysts. This reaction provides an easy access to highly
b,g-un-
a
functionalized chiral
tiary stereocenters.
d-lactones with adjacent a-quaternary-b-ter-
Next, several oxazolones bearing different substituents were also
examinedtoexplorethereactionscopefurther(Table 4). Comparedto
the model substrate 1a (R3¼Me, R4¼Ph), the substratewith bulkier R3
substituent, which was directly linked to reactive site, demonstrated
both poorer yield and ee value, together with a longer reaction time
(entries 1 and 2). Varying the substituents on the benzene ring of R4
may also lead to some changes to the result to certain extent (entries
3e5). However, the diastereoselectivity remained exclusive in all
these cases examined. The absolute configuration of the product 3p
was determined to be 4R,5SbyX-raycrystallographicanalysis,andthe
others were assigned by analogy (Fig. 2).12
4. Experimental section
4.1. General
Unless otherwise indicated, chemicals and solvents were pur-
chased from commercial suppliers and purified by standard tech-
niques. Flash column chromatography was performed using silica
gel. For thin-layer chromatography (TLC), silica gel plates (HSGF
254) were used and compounds were visualized by irradiation with
UV light or by treatment with a solution of phosphomolybdic acid
in ethanol followed by heating. The 1H NMR and 13C NMR spectra
were recorded on a DPX-400 (100 MHz) with TMS as the internal
standard. 19F NMR spectra were recorded at 282 MHz with CFCl3 as
Table 4
a
Scope study with different oxazolones
O
O
O
NHCOR4
O
N
1
R4
O
OMe
4m (20 mol%)
R1
R3
+
the external standard. All chemical shifts (d) are given in parts per
R3
MeOOC
R1
Et2O, RT, t
O
million. Data are reported as follows: chemical shift, multiplicity
(s¼single, d¼doublet, t¼triplet, q¼quartet, br¼broad, and
m¼multiplet) and coupling constants (Hz), integration. Analytical
high-performance liquid chromatography (HPLC) was carried out
on WATERS equipment using a chiral column. Melting points were
determined on a SGW X-4 apparatus, and are uncorrected. Optical
rotations were measured on a JASCO P-1030 Polarimeter at
2a R1 = Ph
3
2b R1 =p-BrC6H4
2m R1 =m-BrC6H4
Entry
R3, R4, 1
2
t (h)
3
Yieldb (%)
eec (%)
1
2
3
4
5
Bn, Ph, 1b
i-Bu, Ph, 1c
Bn, Ph, 1b
Bn, m-BrC6H4, 1d
Bn, m-ClC6H4, 1e
2a
2a
2b
2m
2m
5
8
3
5
6
3l
80
44
94
92
82
87
20
93
90
3m
3n
3o
3p
l
¼589 nm. IR spectra were recorded on a PerkineElmer 983G in-
strument. Elementary analysis was taken on a Vario EL III ele-
mentary analysis instrument. Mass spectra analysis was performed
on API 200 LC/MS system (Applied Biosystems Co. Ltd).
83 (>99d)
a
Unless otherwise noted, the reaction was conducted with 0.11 mmol of 1 and
0.10 mmol of 2 in the presence of 20 mol % of 4m in 1.0 mL of Et2O.
b
Isolated yields after column chromatography on silica gel.
4.2. Typical procedure for synthesis of product 3
c
Determined by chiral HPLC analysis on
a chiral column. Only a single
diastereoisomer was observed by 1H and 13C NMR.
A mixture of 4-methyl-2-phenyloxazol-5(4H)-one (0.11 mmol)
(1a), (E)-methyl-2-oxo-4-phenylbut-3-enoate (2a), and catalyst 4m
(9 mg, 0.02 mmol) in 1.0 mL of ethyl ether was stirred at room
temperature for 3 h until the disappearance of 2a (monitored by
TLC). The reaction mixture was then concentrated, and the residue
was purified by flash column chromatography on silica gel (ethyl
acetate/petroleum ether¼1/10) to give the desired product 3a.
d
The enantioselectivity was determined after a single recrystallization.
Currently, two mechanisms may be proposed for this reaction as
shown in Scheme 1. As we originally intended, route I involves
a catalyzed Michael addition as the stereocontrol step, followed by
intramolecular O-acylation of the new born enolate and opening of

3340
Y. Ying et al. / Tetrahedron 67 (2011) 3337e3342
O
O
Michael addition
acylation
ring-opening
R4
O
*
R3
N
route I
CO2R2
R1
*
O
NHCOR4
R3
R1
O
O
O
N
1
OR2
R4
4m
O
H
R1
+
O
N
R3
R2OOC
O
OR
2
3
N
IEDDA
route II
4m
OR2
H
O
O
O
O
R4
endo
R3
N
1
R1
2
Scheme 1. Proposed possible catalytic mechanism for the formation of product 3.
4.2.1. (4R,5S)-Methyl
dihydro-4H-pyran-2-carboxylate (3a). White solid (32.6 mg, 91%
isolated yield, 95% ee).
ꢀ189.0 (c 1.00, CHCl3). Mp:
135e137 ꢁC; 1H NMR (400 MHz, CDCl3)
4.85 (d, J¼6.8 Hz, 1H), 6.82 (d, J¼6.8 Hz, 1H), 6.99 (s, 1H), 7.13e7.24
(m, 5H), 7.29e7.47 (m, 5H); 13C NMR (100 MHz, CDCl3)
169.4,
5-benzamido-5-methyl-6-oxo-4-phenyl-5,6-
160.0, 141.1, 137.8 (d, J¼6.3 Hz), 134.4, 131.7, 130.5 (d, J¼8.0 Hz),
128.6, 126.6, 123.6 (d, J¼2.5 Hz), 117.3, 115.4 (d, J¼20 Hz), 115.2 (d,
[a
]
J¼22 Hz), 59.2, 52.9, 46.4, 22.4; 19F NMR (282 MHz, CDCl3)
ꢀ112.7
d
D24
d
2.04 (s, 3H), 3.93 (s, 3H),
(s, 1F); MS (ESI): 384.1 ([Mþ1]þ); HRMS (EI) calcd for C21H18FNO5
([Mþ]): 383.1169, found 383.1163; IR (KBr)
n 3417, 1775, 1742, 1666,
d
1607,1518,1150, 779 cmꢀ1. The ee was determined by HPLC analysis
using a chiralcel PC-2 column, hexane/2-propanol: 9/1, flow rate:
0.70 mL/min, tR (minor)¼23.28 min, tR (major)¼25.28 min.
167.2, 160.1, 140.8, 135.3, 134.6, 131.6, 128.9, 128.5, 128.4, 127.9,
126.6, 118.0, 59.4, 52.8, 46.9, 22.4; MS (ESI): 366.3 ([Mþ1]þ); HRMS
(EI) calcd for C21H19NO5 ([Mþ]): 365.1263, found 365.1261; IR (KBr)
n
3421, 1772, 1663, 1706, 1486, 1283, 1107, 721 cmꢀ1. The ee was
4.2.5. (4R,5S)-Methyl 5-benzamido-4-(2-fluorophenyl)-5-methyl-6-
oxo-5,6-dihydro-4H-pyran-2-carboxylate (3e). White solid (34.5 mg,
determined by HPLC analysis using a chiralcel OD column, hexane/
2-propanol: 19/1, flow rate: 0.70 mL/min, tR (minor)¼19.33 min,
tR (major)¼24.50 min.
91% isolated yield, 88% ee). [
a
]
137.7 (c 1.00, CHCl3). Mp:
D24
116e118 ꢁC; 1H NMR (400 MHz, CDCl3)
d
2.04 (s, 3H), 3.95 (s, 3H), 4.89
(d, J¼6.4 Hz,1H),6.80(d, J¼6.8 Hz,1H),6.90e6.96(m, 3H),7.04(s,1H),
4.2.2. (4R,5S)-Methyl 5-benzamido-4-(4-bromophenyl)-5-methyl-6-
7.18e7.23 (m, 1H), 7.36e7.46 (m, 2H), 7.46e7.51 (m, 3H); 13C NMR
oxo-5,6-dihydro-4H-pyran-2-carboxylate (3b). White solid (44.2 mg,
(100 MHz, CDCl3)
d
169.1, 167.3, 162.8 (d, J¼246.0 Hz), 160.0, 141.1,
D24
95% isolated yield, 94% ee). [
a]
148.6 (c 1.00, CHCl3). Mp:
137.8 (d, J¼7.0 Hz), 134.4,131.7,130.5 (d, J¼8.0 Hz),128.6,126.6, 123.7
(d, J¼2.5 Hz), 117.3, 115.4 (d, J¼22.0 Hz), 115.0 (d, J¼22.0 Hz, 1C), 59.2,
133e135 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.99 (s, 3H), 3.91 (s, 3H),
4.83 (d, J¼6.8 Hz, 1H), 6.75 (d, J¼7.2 Hz, 1H), 6.99e7.02 (m, 3H),
52.9, 46.5, 22.4; 19F NMR (282 MHz, CDCl3)
d
ꢀ112.7 (s,1F); MS (ESI):
7.32e7.37 (m, 4H), 7.46e7.48 (m, 3H); 13C NMR (100 MHz, CDCl3)
384.1 ([Mþ1]þ); HRMS (EI) calcd for C21H18FNO5 ([Mþ]): 383.1169,
d
169.1, 167.1, 160.0, 141.0, 134.4, 132.1, 131.9, 129.6, 128.7, 128.6, 126.7,
found 383.1165; IR (KBr) n 3417, 1775, 1742, 1666, 1607, 1488, 1440,
122.5, 117.5, 59.2, 52.9, 46.2, 22.3; MS (ESI): 446.0 ([Mþ1]þ); HRMS
1185, 717 cmꢀ1. The ee was determined by HPLC analysis using
a chiralcel PC-2 column, hexane/2-propanol: 9/1, flow rate: 0.70 mL/
min, tR (minor)¼22.93 min, tR (major)¼24.93 min.
(EI) calcd for C21H18BrNO5 ([Mþ]): 443.0368, found 443.0373; IR
(KBr) n
3411, 1742, 1650, 1489, 1281, 1185, 1010, 731 cmꢀ1. The ee was
determined by HPLC analysis using a chiralcel AD column, hexane/2-
propanol: 19/1, flow rate: 0.70 mL/min, tR (minor)¼57.76 min, tR
(major)¼80.86 min.
4.2.6. (4R,5S)-Methyl 5-benzamido-4-(4-ethoxyphenyl)-5-methyl-6-
oxo-5,6-dihydro-4H-pyran-2-carboxylate (3f). White solid (39.0 mg,
95% isolated yield, 97% ee). [
a]
D25
201.9 (c 1.00, CHCl3). Mp: 77e79 ꢁC;
4.2.3. (4R,5S)-Methyl 5-benzamido-5-methyl-6-oxo-4-p-tolyl-5,6-
1H NMR (400 MHz, CDCl3)
d
1.34 (t, J¼7.2 Hz, 3H), 1.99 (s, 3H),
dihydro-2H-pyran-2-carboxylate (3c). White solid (32.0 mg, 85%
3.90e3.95 (m, 5H), 4.78 (d, J¼6.8 Hz, 1H), 6.70e6.72 (m, 2H), 6.78 (d,
J¼7.5 Hz, 1H), 6.98 (s, 1H), 7.01e7.03 (m, 2H), 7.33e7.35 (m, 2H),
isolated yield, 93% ee). [
NMR (400 MHz, CDCl3)
a
d
]
186.3 (c 1.20, CHCl3). Mp: 74e76 ꢁC; 1H
D24
1.93 (s, 3H), 2.16 (s, 3H), 3.83 (s, 3H), 4.72
7.44e7.47 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 169.5, 167.2, 160.2,
(d, J¼6.8 Hz, 1H), 6.71 (d, J¼6.8 Hz, 1H), 6.90 (s, 1H), 6.93 (s, 4H),
158.9, 140.5, 134.6, 131.6, 129.0, 128.5, 126.8, 118.4, 114.8, 114.8, 63.4,
7.18e7.28 (m, 2H), 7.35e7.39 (m, 3H); 13C NMR (100 MHz, CDCl3)
59.6, 52.8, 46.1, 22.3, 14.7; MS (ESI): 432.1 ([MþNa]þ); HRMS (EI)
d
169.5, 167.2, 160.2, 140.7, 136.2, 134.8, 132.2, 131.4, 129.6, 128.5,
calcd for C23H23NO6 ([Mþ]): 409.1525, found 409.1531; IR (KBr)
n
127.8, 126.7, 118.3, 59.3, 52.6, 46.4, 22.3, 20.8; MS (ESI): 402.1
3406, 1783, 1740, 1669, 1284, 1173, 764, 708 cmꢀ1. The ee was de-
termined by HPLC analysis using a chiralcel AD column, hexane/2-
propanol: 80/20, flow rate: 0.70 mL/min, tR (minor)¼15.96 min, tR
(major)¼20.16 min.
([MþNa]þ); HRMS (EI) calcd for C22H21NO5 ([Mþ]): 379.1420, found
379.1422; IR (KBr)
n 3421, 2954, 1770, 1670, 1607, 1514, 1249, 1145,
803 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
OD column, hexane/2-propanol: 19/1, flow rate: 0.70 mL/min,
tR (minor)¼21.86 min, tR (major)¼25.13 min.
4.2.7. (4R,5S)-Methyl
oxo-5,6-dihydro-4H-pyran-2-carboxylate (3g). Yellow solid (36.2 mg,
88% isolated yield, 90% ee). [ 286.9 (c 1.45, CHCl3). Mp:
134e136 ꢁC; 1H NMR (400 MHz, CDCl3)
5-benzamido-5-methyl-4-(4-nitrophenyl)-6-
4.2.4. (4R,5S)-Methyl 5-benzamido-4-(3-fluorophenyl)-5-methyl-6-
a]
D25
oxo-5,6-dihydro-4H-pyran-2-carboxylate
(3d). White
solid
d 2.02 (s, 3H), 3.93 (s, 3H),
D24
(32.5 mg, 88% isolated yield, 87% ee). [
a]
136.5 (c 1.00, CHCl3).
d 2.04 (s, 3H), 3.95 (s,
5.02 (d, J¼6.8 Hz, 1H), 6.76 (d, J¼6.8 Hz, 1H), 7.08 (s, 1H), 7.31e7.38
Mp: 119e121 ꢁC; 1H NMR (400 MHz, CDCl3)
(m, 4H), 7.47e7.49 (m, 3H), 8.06e8.08 (m, 2H); 13C NMR (100 MHz,
3H), 4.89 (d, J¼7.2 Hz,1H), 6.80 (d, J¼6.8 Hz,1H), 6.88e6.96 (m, 3H),
CDCl3) d 168.8, 167.1, 159.8, 147.8, 142.9, 141.6, 133.7, 132.1, 129.0,
7.04 (s, 1H), 7.18e7.23 (m, 1H), 7.36e7.42 (m, 2H), 7.48e7.51 (m,
128.8, 126.6, 124.0, 116.0, 58.9, 53.1, 46.6, 22.5; MS (ESI): 411.1
3H); 13C NMR (100 MHz, CDCl3)
d
169.1, 167.4, 162.8 (d, J¼246 Hz),
([Mþ1]þ); HRMS (EI) calcd for C21H18N2O7 ([Mþ]): 410.1114, found

Y. Ying et al. / Tetrahedron 67 (2011) 3337e3342
3341
410.1118; IR (KBr)
n
3412, 1743, 1521, 1347, 1292, 1185, 852, 700 cmꢀ1
.
isolated yield, 87% ee).
[
a
]
ꢀ145.2 (c 0.25, CHCl3). Mp:
D23
The ee was determined by HPLC analysis using a chiralcel AD col-
umn, hexane/2-propanol: 80/20, flow rate: 0.70 mL/min, tR
(minor)¼25.46 min, tR (major)¼55.06 min.
191e193 ꢁC; 1H NMR (400 MHz, CDCl3)
d
3.33 (d, J¼13.6 Hz, 1H),
3.95 (s, 3H), 4.21 (d, J¼14.4 Hz, 1H), 5.00 (d, J¼6.4 Hz, 1H), 6.59 (s,
1H), 6.86 (d, J¼6.4 Hz, 1H), 7.09e7.11 (m, 2H), 7.16e7.27 (m, 7H),
7.27e7.31 (m, 4H), 7.39e7.41 (m, 1H); 13C NMR (100 MHz, CDCl3)
4.2.8. (4R,5S)-Methyl 5-benzamido-4-(furan-2-yl)-5-methyl-6-oxo-
d 167.9, 167.4, 160.2, 140.7, 135.5, 134.8, 134.4, 131.6, 130.7, 128.9,
5,6-dihydro-4H-pyran-2-carboxylate (3h). Yellow solid (32.0 mg,
128.6, 128.5, 128.4, 128.2, 127.6, 126.6, 117.9, 64.8, 53.0, 47.3, 38.9;
90% isolated yield, 95% ee). [
a
]
282.2 (c 0.90, CHCl3). Mp:
MS (ESI): 442.1 ([Mþ1]þ); IR (KBr)
n 3419, 1768, 1739, 1510, 1280,
D25
155e157 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.93 (s, 3H), 3.89 (s, 3H),
1108, 981, 737 cmꢀ1. Anal. Calcd for C24H23NO5: C, 73.46; H, 5.25; N,
3.17. Found: C, 73.65; H, 5.51; N, 3.06. The ee was determined by
HPLC analysis using a chiralcel AD-H column, hexane/2-propanol:
80/20, flow rate: 0.70 mL/min, tR (minor)¼24.50 min, tR (major)¼
65.83 min.
5.03 (d, J¼6.8 Hz, 1H), 6.66 (d, J¼6.8 Hz, 1H), 6.81e6.20 (m, 2H), 7.10
(s, 1H), 7.37e7.38 (m, 2H), 7.43e7.47 (m, 1H), 7.52e7.54 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 169.1, 167.4, 160.3, 148.5, 143.2, 141.5,
134.5, 131.6, 128.7, 126.7, 114.6, 110.5, 109.5, 58.2, 53.4, 40.1, 21.6; MS
(ESI): 378.1 ([MþNa]þ); HRMS (EI) calcd for C19H17NO6 ([Mþ]):
355.1056, found 355.1054; IR (KBr)
n
3400, 1782, 1743, 1663, 1519,
4.2.13. (4R,5S)-Methyl 5-benzamido-5-isobutyl-6-oxo-4-phenyl-5,6-
dihydro-4H-pyran-2-carboxylate (3m). White solid (22.0 mg, 44%
1170, 764, 708 cmꢀ1.The ee was determined by HPLC analysis using
a chiralcel AD column, hexane/2-propanol: 9/1, flow rate: 0.70 mL/
min, tR (minor)¼31.86 min, tR (major)¼35.66 min.
144.5 (c 0.95, CHCl3). Mp: 116e118 ꢁC;
0.91 (d, J¼6.8 Hz, 3H), 0.93 (d, J¼6.8 Hz,
D24
d
isolated yield, 20% ee). [
a
]
1H NMR (400 MHz, CDCl3)
3H), 1.68e1.78 (m, 1H), 1.94 (dd, J1¼6.8 Hz, J2¼8.4 Hz, 1H), 2.92 (dd,
J1¼6.8 Hz, J2¼8.4 Hz, 1H), 3.91 (s, 3H), 4.78 (d, J¼6.4 Hz, 1H), 6.74 (d,
J¼6.4 Hz, 1H), 6.89 (s, 1H), 7.10e7.12 (m, 2H), 7.19e7.21 (m, 3H),
7.31e7.33 (m, 2H), 7.38e7.42 (m, 3H); 13C NMR (100 MHz, CDCl3)
4.2.9. (4R,5S)-4-Bromobenzyl-5-benzamido-5-methyl-6-oxo-4-phe-
nyl-5,6-dihydro-4H-pyran-2-carbpxylate (3i). White oil (50.2 mg,
96% isolated yield, 94% ee). [
a
]
89.7 (c 1.20, CHCl3). Mp: 66e68 ꢁC;
D24
1H NMR (400 MHz, CDCl3)
d
2.04 (s, 3H), 4.85 (d, J¼6.8 Hz, 1H), 5.30
d 169.2, 167.0, 160.2, 140.9, 135.2, 134.9, 131.5, 128.9, 128.6, 128.3,
(s, 2H), 6.83 (d, J¼6.8 Hz, 1H), 6.99 (s, 1H), 7.13 (s, 1H), 7.14e7.16 (m,
2H), 7.23e7.25 (m, 3H), 7.33e7.37 (t, J¼8.4 Hz, 4H), 7.43e7.46 (m,
128.2, 126.5, 118.0, 63.1, 52.8, 48.1, 41.7, 25.0, 23.8, 23.4; MS (ESI):
408.3 ([Mþ1]þ); HRMS (EI) calcd for C24H25NO5 ([Mþ]): 407.1733,
2H), 7.55 (d, J¼6.8 Hz,1H); 13C NMR (100 MHz, CDCl3)
d
169.7, 167.3,
found 407.1732; IR (KBr) n 3413, 1762, 1741, 1656, 1514, 1277, 1140,
159.5,140.7,135.3,134.6,133.7,131.9,131.6,130.3,129.0,128.5,128.4,
127.9, 126.6, 122.9, 118.5, 67.0, 59.4, 47.0, 29.6, 22.4; MS (ESI): 520.0
([Mþ1]þ); HRMS (EI) calcd for C20H16NO5 ([Mꢀp-Br-Bn]þ):
1112, 710 cmꢀ1. The ee was determined by HPLC analysis using
a chiralcel AS-H column, hexane/2-propanol: 80/20, flow rate:
0.70 mL/min, tR (minor)¼8.47 min, tR (major)¼9.47 min.
350.1028, found 350.1031; IR (KBr)
n 3418, 1738, 1667, 1514, 1151,
699 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
AD column, hexane/2-propanol: 19/1, flow rate: 0.70 mL/min, tR
(minor)¼47.28 min, tR (major)¼55.72 min.
4.2.14. (4R,5S)-Methyl 5-benzamido-5-benzyl-4-(4-bromophenyl)-6-
oxo-5,6-dihydro-4H-pyran-2-carboxylate (3n). White solid (47.0 mg,
D23
94% isolated yield, 93% ee). [
a
]
ꢀ145.2 (c 0.25, CHCl3). Mp:
108d110 ꢁC; 1H NMR (400 MHz, CDCl3)
d
3.36 (d, J¼13.6 Hz, 1H),
4.2.10. (4R,5S)-Ethyl 5-benzamido-5-methyl-6-oxo-4-phenyl-5,6-di-
3.99 (s, 3H), 4.20 (d, J¼14.0 Hz, 1H), 5.03 (d, J¼6.4 Hz, 1H), 6.68 (s,
1H), 6.86 (d, J¼6.8 Hz, 1H), 7.08e7.12 (m, 4H), 7.25e7.26 (m, 3H),
7.36e7.41 (m, 6H), 7.45e7.47 (m, 1H); 13C NMR (100 MHz, CDCl3)
hydro-4H-pyran-2-carboxylate (3j). White solid (34.0 mg, 90% iso-
lated yield, 90% ee). [
a]
322.0 (c 0.85, CHCl3). Mp: 160e162 ꢁC; 1H
D22
NMR (400 MHz, CDCl3)
d
1.41 (t, J¼7.2 Hz, 3H), 2.05 (s, 3H),
d 167.8, 167.1, 160.1, 141.0, 134.5, 134.2, 134.0, 132.1, 131.7, 130.0, 129.9,
4.36e4.42 (q, J¼7.2 Hz, 2H), 4.85 (d, J¼7.2 Hz, 1H), 6.81 (d, J¼6.8 Hz,
128.7, 128.5, 127.7, 126.6, 122.5, 117.2, 64.6, 53.0, 46.7, 38.9; MS (ESI):
1H), 7.00 (s, 1H), 7.14e7.17 (m, 2H), 7.23e7.25 (m, 3H), 7.33e7.36 (m,
520.1 ([Mþ1]þ); HRMS (EI) calcd for C27H22BrNO5 ([Mþ]): 519.0681,
2H), 7.43e7.45 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
169.5, 167.2,
found 519.0679; IR (KBr) n 3413, 1742, 1668, 1509, 1282, 1112, 1096,
159.7,140.9,135.4,134.6,131.6,128.9,128.5,128.4,127.9,126.6,117.7,
901 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
PC-2 column, hexane/2-propanol: 7/3, flow rate: 0.70 mL/min, tR
(minor)¼9.48 min, tR (major)¼20.23 min.
62.3, 59.4, 46.9, 22.4, 14.1; MS (ESI): 402.1 ([MþNa]þ); HRMS (EI)
calcd for C22H21NO5 ([Mþ]): 379.1420, found 379.1418; IR (KBr)
n
3420, 1770, 1738, 1669, 1514, 1279, 1109, 759 cmꢀ1. The ee was de-
termined by HPLC analysis using a chiralcel AD column, hexane/2-
propanol: 80/20, flow rate: 1.0 mL/min, tR (minor)¼9.57 min, tR
(major)¼10.90 min.
4.2.15. (4R,5S)-Methyl 5-benzyl-5-(3-bromobenzamido)-4-(3-bro-
mophenyl)-6-oxo-5,6-dihydro-4H-pyran-2-carboxylate (3o). White
solid (40.0 mg, 92% isolated yield, 90% ee). [
a]
29.5 (c 0.45,
D23
CHCl3). Mp: 155e157 ꢁC; 1H NMR (400 MHz, CDCl3)
d
3.32 (d,
4.2.11. (4R,5S)-Isopropyl
5,6-dihydro-4H-pyran-2-carboxylate (3k). White solid (35.5 mg,
92% isolated yield, 91% ee). [ 114.6 (c 0.76, CHCl3). Mp:
174e176 ꢁC; 1H NMR (400 MHz, CDCl3)
(d, J¼6.4 Hz, 3H), 2.05 (s, 3H), 4.84 (d, J¼6.4 Hz, 1H), 5.20e5.27 (m,
1H), 6.78 (d, J¼6.4 Hz, 1H), 7.00 (s, 1H), 7.15e7.17 (m, 2H), 7.23e7.25
(m, 3H), 7.33e7.37 (m, 2H), 7.43e7.46 (m, 3H); 13C NMR (100 MHz,
5-benzamido-5-methyl-6-oxo-4-phenyl-
J¼14.0 Hz,1H), 3.97 (s, 3H), 4.13 (d, J¼14.0 Hz,1H), 4.95 (d, J¼6.4 Hz,
1H), 6.57 (s, 1H), 6.81 (d, J¼6.4 Hz, 1H), 7.08e7.17 (m, 5H), 7.22e7.23
a
]
D23
(m, 4H), 7.34e7.42 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 167.0,
d
1.38 (d, J¼6.4 Hz, 3H), 1.40
166.9, 160.0, 140.7, 136.0, 134.3, 134.1, 133.8, 132.3, 130.3, 130.2,
129.4, 128.6, 127.4, 122.6, 119.7, 117.2, 64.7, 53.0, 46.9, 39.2; MS
(ESI): 598.0 ([Mþ1]þ); HRMS (ESI) calcd for C25H18Br2NO3
([MꢀCOOMe]þ): 537.9653, found 537.9652; IR (KBr)
n 3392, 1769,
CDCl3)
d
169.6, 167.2, 159.2, 141.2, 135.5, 134.6, 131.6, 128.9, 128.5,
1738, 1669, 1497, 1579, 1265, 827 cmꢀ1. The ee was determined by
HPLC analysis using a chiralcel PC-2 column, hexane/2-propanol: 5/
1, flow rate: 0.70 mL/min, tR (minor)¼12.32 min, tR (major)¼
18.98 min.
128.3, 127.9, 126.6, 117.4, 70.3, 59.4, 46.9, 22.4, 21.8; MS (ESI): 416.1
([MþNa]þ); HRMS (EI) calcd for C22H20NO5 ([MꢀMe]þ): 378.1341,
found 378.1337; IR (KBr) n 3432, 1764, 1720, 1671, 1520, 1309, 1097,
917, 707 cmꢀ1. The ee was determined by HPLC analysis using
a chiralcel AD column, hexane/2-propanol: 80/20, flow rate:
1.0 mL/min, tR (minor)¼8.03 min, tR (major)¼10.05 min.
4.2.16. (4R,5S)-Methyl
obenzamido)-6-oxo-5,6-dihydro-4H-pyran-2-carboxylate
(3p). White solid (40.0 mg, 82% isolated yield, 83% ee). [ 218.0
(c 2.26, CHCl3). Mp: 146e148 ꢁC; 1H NMR (400 MHz, CDCl3)
(d, J¼14.0 Hz, 1H), 3.97 (s, 3H), 4.13 (d, J¼14.0 Hz, 1H), 4.95 (d,
5-benzyl-4-(3-bromophenyl)-5-(3-chlor-
a
]
D23
d
3.32
4.2.12. (4R,5S)-Methyl 5-benzamido-5-benzyl-6-oxo-4-phenyl-5,6-
dihydro-4H-pyran-2-carboxylate (3l). White solid (35.0 mg, 80%

3342
Y. Ying et al. / Tetrahedron 67 (2011) 3337e3342
(p) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.dEur. J. 2007, 13,
9478.
J¼6.4 Hz, 1H), 6.57 (s, 1H), 6.81 (d, J¼6.4 Hz, 1H), 7.08e7.17 (m, 5H),
7.22e7.23 (m, 4H), 7.34e7.42 (m, 4H); 13C NMR (100 MHz, CDCl3)
4. FriedeleCrafts reaction: (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 160; (b) Jørgensen, K. A. Synthesis 2003,
1117; (c) van Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, F. P. J. T.; Jørgensen,
K. A. Org. Biomol. Chem. 2003, 1, 1953; (d) Wu, Y.-C.; Liu, L.; Li, H.-J.; Wang, D.;
Chen, Y.-J. J. Org. Chem. 2006, 71, 6592; (e) Faita, G.; Mella, M.; Toscanini, M.;
Desimoni, G. Tetrahedron 2010, 66, 3024; (f) Liu, Y.-L.; Shang, D.-J.; Zhou, X.;
Zhu, Y.; Lin, L.-L.; Liu, X.-H.; Feng, X.-M. Org. Lett. 2010, 12, 180; (g) Lv, J.; Li, X.;
Zhong, L.; Luo, S.-Z.; Cheng, J.-P. Org. Lett. 2010, 12, 1096.
5. Michael additions and oxa-Michael additions: (a) Halland, N.; Velgaard, T.;
Jørgensen, K. A. J. Org. Chem. 2003, 68, 5067; (b) Unaleroglu, C.; Temelli, B.;
Demir, A. S. Synthesis 2004, 2574; (c) Unaleroglu, C.; Aytac, S.; Temelli, B. Het-
erocycles 2007, 71, 2427; (d) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte,
M. Angew. Chem., Int. Ed. 2008, 47, 593; (e) Xiong, X.; Ovens, C.; Pilling, A. W.;
Ward, J. W.; Dixon, D. J. Org. Lett. 2008, 10, 565; (f) Herrera, R. P.; Monge, D.;
Martin-Zamora, E.; Fernandez, R.; Lassaletta, J. M. Org. Lett. 2007, 9, 3303; (g)
Lao, J.-H.; Zhang, X.-J.; Wang, J.-J.; Li, X.-M.; Yan, M.; Luo, H.-B. Tetrahedron:
Asymmetry 2009, 20, 2818; (h) Zhou, L.; Lin, L.-L.; Wang, W.-T.; Ji, J.; Liu, X.-H.;
Feng, X.-M. Chem. Commun. 2010, 3601; (i) Yao, W.-J.; Pan, L.-J.; Wu, Y.-H.; Ma,
C. Org. Lett. 2010, 12, 2422.
d
166.9, 166.6, 159.9, 141.2, 136.3, 134.9, 133.9, 131.8, 131.4, 130.4,
129.9, 128.6, 127.8, 127.0, 126.5, 124.5, 123.0, 116.7, 64.7, 53.0, 46.8,
39.0; MS (ESI): 554.2 ([Mþ1]þ); IR (KBr)
n 3391, 1768, 1738, 1497,
1265, 1009, 821,701 cmꢀ1. Anal. Calcd for C27H21BrClNO5: C, 58.45;
H, 3.82; N, 2.52. Found: C, 58.81; H, 3.82; N, 2.38. The ee was de-
termined by HPLC analysis using a chiralcel OD-H column, hexane/
2-propanol: 80/20, flow rate: 0.70 mL/min, tR (minor)¼11.46 min, tR
(major)¼14.99 min.
Acknowledgements
The generous financial support from the National Basic Research
Program of China (973 Program, 2010CB833300), National Natural
Science Foundation of China (Nos. 20032006, 20532040), and
Excellent Young Scholars Foundation of National Natural Science
Foundation of China (20525208).
6. Hydrogenations: (a) Meng, Q. H.; Zhu, L. F.; Zhang, Z. G. J. Org. Chem. 2008, 73,
7209; (b) Guo, M. J.; Li, D.; Sun, Y. H.; Zhang, Z. G. Synlett 2004, 741.
7. Formal [3þ3] annulation: Cao, C. L.; Sun, X. L.; Kang, Y. B.; Tang, Y. Org. Lett.
2007, 9, 4151.
8. For reviews, see: (a) Mosey, R. A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymmetry
2008, 19, 2755; (b) Hewlett, N. M.; Hupp, C. D.; Tepe, J. J. Synthesis 2009, 2825;
(c) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432; (d) Burke, M.
D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46; (e) Alba, A.-N. R.; Rios, R.
Chem. Asian J. 2011, 6, 720 (Early View). For selected examples, see: (f) Seebach,
D.; Jaeschke, G.; Gottwald, K.; Matsuda, K.; Formisano, R.; Chaplin, D. A. Tet-
rahedron 1997, 53, 7539; (g) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63,
3154; (h) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727; (i) Trost, B. M.;
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.069.
References and notes
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ꢀ
Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A.
ꢀ
ꢀ
J. Am. Chem. Soc. 2008, 130, 12031; (n) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem.
Soc. 2008, 130, 14088; (o) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2. Organocatalyzed reactions of
b,g-unsaturated a-keto esters reported by our
ꢀ
2009, 131, 3430; (p) Alba, A.-N. R.; Companyo, X.; Valero, G.; Moyano, A.; Rios, R.
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11. During the preparation of this paper, Terada also reported the reaction between
Organocatalyzed reactions of b,g-unsaturated a-keto esters reported by other
group, see Refs. 3e7.
b
,
g
-unsaturated
a-keto esters and for oxazolones using axially chiral guanidine
catalysts. Their system requires
enantioselectivities for most substrates do not exceed 90% ee: Chem.dEur. J.
2011, 17, 1760.
a
low reaction temperature (ꢀ60 ꢁC) and
3. DielseAlder and hetero-DielseAlder reactions: (a) Boger, D. L.; Robarge, K. D. J.
Org. Chem. 1988, 53, 3373; (b) Sera, A.; Ueda, N.; Itoh, K.; Yamada, H. Hetero-
cycles 1996, 43, 2205; (c) Thorhauge, J.; Johannsen, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 1998, 37, 2404; (d) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey,
J. M. Angew. Chem., Int. Ed. 1998, 37, 3372; (e) Evans, D. A.; Johnson, J. S.; Olhava,
E. J. J. Am. Chem. Soc. 2000, 122, 1635; (f) Leconte, S.; Dujardin, G.; Brown, E. Eur.
J. Org. Chem. 2000, 639; (g) Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen,
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12. Crystal data: MW¼554.81, Monoclinic, space group P2(1), final R indices [I>2
s
ꢁ
ꢁ
ꢁ
(I)], R1¼0.0458, wR2¼0.1055, a¼14.930(5) A, b¼10.005(4) A, c¼17.163(6) A,
3
ꢁ
a
¼90ꢁ,
b
¼90.923(7)ꢁ,
g
¼90 , V¼2525.5(15) A , crystal size 0.360ꢂ0.320ꢂ0.
ꢁ
235 mm3, T¼293(2) K, Z¼4, D¼1.459 Mg/m3, Reflections collected/unique
14,733/10,149 (Rint¼0.0247), 10,149 data, 3 restraints, 641 parameters, absolute
structure parameter 0.016(7). Largest diffraction peak and hole: 0.574 and ꢀ0.
ꢁꢀ3
359 e A . CCDC 806009 contains the supplementary crystallographic data for
3p. These data can be obtained free of charge from the Cambridge Crystallo-
graphic Data center via www.ccdc.cam.ac.uk/data_request/cif.
13. Our results and Feng’s implies that the use of bifunctional catalysts might favor
the IEDDA mechanism. In Ref. 11, where guanidine was used as the catalyst,
good-to-excellent diastereoselectivities were observed and the authors pre-
ferred route I based on some experimental studies.