Highly enantioselective synthesis of α-trichloromethyldihydropyrans catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1016/j.tet.2011.01.043

The enantioselective Michael addition of α-cyanoketones to α,β-unsaturated trichloromethyl ketones was firstly reported. With a phenylalanine-derived bifunctional piperazine/thiourea catalyst, a series of α-trichloromethyldihydropyrans were obtained with

Full text of DOI:10.1016/j.tet.2011.01.043

Tetrahedron 67 (2011) 1774e1780
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Highly enantioselective synthesis of
by bifunctional organocatalysts
a-trichloromethyldihydropyrans catalyzed
,b,
Hai-Feng Wang a, Peng Li a, Hai-Feng Cui a, Xiao-Wei Wang a, Jun-Kang Zhang a, Wen Liu b, Gang Zhao a
*
a Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 LingLing Lu, Shanghai 200032, China
b Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective Michael addition of
a
-cyanoketones to
a
,
b
-unsaturated trichloromethyl ketones
Received 13 December 2010
Received in revised form 10 January 2011
Accepted 14 January 2011
was firstly reported. With a phenylalanine-derived bifunctional piperazine/thiourea catalyst, a series of
-trichloromethyldihydropyrans were obtained with up to 95% ee and 99% yield.
Ó 2011 Elsevier Ltd. All rights reserved.
a
Available online 20 January 2011
Keywords:
Michael addition
Enantioselectivity
Trichloromethyl ketones
Dihydropyrans
Bifunctional organocatalysts
1. Introduction
Recently, our group have developed catalytic asymmetric Mi-
chael additions5 of -unsaturated ketoesters6d
-cyanoketones to
and CF3-substituted
-unsaturated ketones,6e providing facile
accesses to a series of chiral dihydropyrans. On the other hand,
trichloromethyl ketones are a kind of synthetically highly useful
structure, which could be easily converted to carboxylic acids,7
esters,8 and amides8,9 due to the good leaving ability of the tri-
a
a,b
Dihydropyrans are an important heterocyclic structure exten-
sively present in many biologically active compounds.1 For exam-
ples, the isolated natural products valtrat (1), isovaltrat (2), and
didrovaltrat (3) as sedatives exhibited weak to moderate cytotox-
icity against lung adenocarcinoma (A549), metastatic prostate
cancer (PC-3M), colon cancer (HCT-8), and hepatoma (Bel7402) cell
lines;2 loganin (4) exhibited significant anti-HCV entry and anti-
infectivity activities (Fig. 1).3 Consequently, numerous efforts have
been done for the construction of this kind of structures.4
a,b
chloromethyl group. However, the reactions of
a,b-unsaturated
trichloromethyl ketones as an electrophile have rarely been stud-
ied. As an extension of our previous works, we herein report the
reaction of
a
-cyanoketones with
a
,b
-unsaturated trichloromethyl
OR2
O
OIv
CO2Me
H
H
H
HO
R1O
AcO
O
O
CH3
CH3
O
H
Me
H
OGlc
Iv =
O
O
OIv
OIv
valtrat (1): R1 = lv, R2 = Ac
isovaltrat (2): R1 = Ac, R2 = lv
didrovaltrat (3)
loganin (4)
Fig. 1. Several natural compounds with a chiral dihydropyran structure.
* Corresponding author. Tel.: þ86 21 54925182; fax: þ86 21 64166128; e-mail address: zhaog@mail.sioc.ac.cn (G. Zhao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.043

H.-F. Wang et al. / Tetrahedron 67 (2011) 1774e1780
1775
ketones catalyzed by cinchona alkaloids or chiral thioureas,
affording a series of novel chiral -trichloromethyldihydropyrans in
high yields and with excellent enantioselectivities.
acids as chiral skeletons in this reaction. In all the cases examined,
only one diastereoisomer of the product 9a was observed.
Subsequent optimization efforts including screens of solvent,
catalyst loading, and temperature were then done with the optimal
catalyst 6j (Table 2). It was found that the reaction proceeded well
in many other solvents and the best result of 99% yield and 83% ee
was obtained in xylenes (Table 2, entry 2). Interestingly, when the
reaction was conducted in any one of the three pure isomers of
xylenes, both the reaction rate and ee value were significantly re-
duced (Table 2, entries 3e5). Pleasingly, reducing the catalyst
loading from 10 mol % to 5 mol % or 2 mol % increased the ee value
to 87% while maintaining the same excellent yield (Table 2, entries
16e17). Lowering the reaction temperature to ꢀ10 ꢁC could en-
hance the ee value to 90% with a similar yield, albeit with an ap-
parently prolonged reaction time (Table 2, entry 18). To summarize,
the present reaction was best performed with 2 mol % of 6j in xy-
lenes at ꢀ10 ꢁC.
a
2. Results and discussion
The Michael addition of 3-oxo-3-phenylpropanenitrile (7a) to
(E)-1,1,1-trichloro-4-phenylbut-3-en-2-one (8a) was selected as
a model reaction for catalyst evaluation. First, a series of bi-
functional cinchona alkaloid catalysts, with which we have
obtained good results in an intramolecular oxa-Michael reaction,10
were evaluated (Fig. 2 and Table 1). The quinine-derived catalyst 5b
was found to be the best one, providing the desired product 9a with
68% ee (Table 1, entry 2). The 1H and 13C NMR spectra of 9a revealed
a rapid equilibrium11 between the cyclic hemiketal 9a and the
Michael-type product 9a0 with a ratio of around 5:1 (9a:9a0) (Table
1), which is similar to the result of our previous work.6d In order to
improve the enantioselectivity, some bifunctional thiourea cata-
Having established the optimal conditions, we next explored the
scope of the reaction and representative results are listed in Table 3.
lysts derived from chiral a-amino acids previously developed by us
and others6,12 were next evaluated (Fig. 2 and Table 1). For catalysts
6aee with different amino acid skeletons, comparable or higher
enantioselectivities were observed than that obtained with the
cinchona alkaloid catalysts with 10 mol % catalyst loading, except
Generally, with cyanoketone 7a, for
a,b-unsaturated tri-
chloromethyl ketones 8aei, in which R1 were differently
substituted benzene rings, excellent yields and high ee values were
obtained irrespective of the electronic nature of the substituents on
the benzene ring (Table 3, entries 1e9). However, when the sub-
stituent was on the ortho position of the benzene ring, a slight drop
in the ee value was observed (Table 3, entries 7, 9). For the het-
erocyclic substrate 8k (R1¼furan-2-yl), good results were also
achieved (Table 3, entry 11). Notably, when R1 was an n-propyl
group, the reaction still proceeded efficiently to give the desired
for the -phenylglycine-derivated 6a (Table 1, entries 14e18). Fur-
L
ther variation in the tertiary amine moiety led to the piperazine/
thiourea catalyst 6j as the best one, with which the product 9a was
obtained with up to 78% ee. Notably, thioureas IeIV derived from
cinchona alkaloids and Takemoto’s catalyst V all gave inferior re-
sults (Table 1, entries 22e26), indicating the advantages of amino
R1
R1
N
5c: R1 = OMe, R2 = H;.
5e: R1 = H, R2 = H;
5a: R1 = OMe, R2 = H;
5b: R1 = OH, R2 = Bz;
5d: R1 = H, R2 = H;
5f: R1 = OH, R2 = H;
5h: R1 = OH, R2 = Bn;
H
R2O
N
5g: R1 = OH, R2 = H;
5i: R1 = OH, R2 = Bn;
N
OR2
5j: R1 = OH, R2 = Bz;
N
H
5k: R1 = OH, R2 = PHN;
R4
F3C
CF3
PHN =
N
CF3
H
N
R4
NH
NH
NH
S
N
S
O
CF3
I: R3 = OMe;
II: R3 = H;
O
N
N
H
CF3
III: R3 = OMe;
IV: R3 = H;
S
N
N
CF3
N
F3C
N
H
N
H
S
N
6j
F3C
N
H
N
H
Bn
V
CF3
R
CF3
N
R
CF3
S
N
S
S
F3C
N
H
N
H
F3C
N
N
H
Bn
F3C
N
H
N
H
R
H
6a: R = Ph; 6b: R = Bn;
6c: R = 4-BnO-Bn;
6d: R = i-Pr;
6f: R = Bn;
6h: R = H;
6i: R = Bn;
6g: R = 4-BnO-Bn;
6e: R = (S)-s-Bu;
Fig. 2. Bifunctional catalysts screened in this study.

1776
H.-F. Wang et al. / Tetrahedron 67 (2011) 1774e1780
Table 1
Table 3
Screening of cinchona alkaloid catalystsa
Examination of the reaction scope with catalyst 6ja
Entry
Catalyst (x)
t/h
Yield(%)b
ee(%)c
1
2
3
4
5
6
7
8
5a (20)
5b (20)
5c (20)
5d (20)
5e (20)
5f (20)
5g (20)
5h (20)
5i (20)
5j (20)
5k (20)
6a (10)
6b (10)
6c (10)
6d (10)
6e (10)
6f (10)
6g (10)
6h (10)
6i (10)
6j (10)
I (10)
9
12
9
9
9
91
96
84
81
89
98
84
89
81
66
86
91
86
91
96
81
95
86
86
94
95
94
96
94
89
86
44
68
Entry
7
R2, 8
t/h
67
9
Yield(%)b
ee(%)c
ꢀ36
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
C6H5, 8a
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
eee
94
92
95
99
98
93
98
99
97
97
87
96
94
84
66
64
Trace
90
90
90
90(>99
95
15
p-FC6H4, 8b
p-ClC6H4, 8c
p-BrC6H4, 8d
p-NO2C6H4, 8e
p-MeC6H4, 8f
o-ClC6H4, 8g
m-ClC6H4, 8h
2,4-diClC6H3, 8i
1-Naphthyl, 8j
Furan-2-yl, 8k
n-Pr, 8l
66
60
36
36
96
40
35
36
48
96
96
96
96
144
168
96
0
1
9
d
)
13
11
11
22
12
12
12
12
24
24
16
12
12
24
24
12
17
17
17
12
ꢀ10
51
90
9
ꢀ43
ꢀ61
ꢀ67
6
70
72
64
60
46
63
82e
90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
9
84e
90
10
11
12
13
14
15
16
17
86e
72e
89
C6H5, 8a
C6H5, 8a
C6H5, 8a
C6H5, 8a
88
90
87
eee
67
68
78
64
C6H5, 8a
a
Unless otherwise noted, the reaction was carried out with 7 (0.15 mmol), 8
(0.1 mmol), 6j (0.002 mmol), and xylenes (1.0 mL) at ꢀ10 ꢁC for an appropriate time.
b
Yield of the isolated product after column chromatography on silica gel.
Determined by HPLC analysis on a chiral column. Only a single diastereoisomer
II (10)
44
c
III (10)
IV (10)
V (10)
ꢀ29
ꢀ32
ꢀ42
was observed by 1H NMR analysis of the crude product. The absolute configuration
of 9d was determined as 4R, 6S by X-ray crystallographic analysis, and the other
products, 9aec and 9eep ere assigned by assuming that a similar catalytic mech-
anism was followed.
a
Unless otherwise noted, the reaction was carried out with 7a (0.15 mmol), 8a
(0.1 mmol), catalyst, and DCM (1.0 mL) at room temperature for appropriate time.
d
The enantioselectivity was determined after a single recrystallization.
The absolute configuration was assigned as 4S, 6S.
b
Yield of the isolated product after column chromatography on silica gel.
Determined by HPLC analysis on a chiral column. Only a single diastereoisomer
e
c
was observed by 1H NMR analysis of the crude product.
product in excellent yield, though a decrease in enantioselectivity
was observed (Table 3, entry 12). Next, various cyanoketones 7
were investigated with a,b-unsaturated trichloromethyl ketone 8a.
When R1 was an aromatic group, both electron-donating and
electron-withdrawing substituents on the benzene ring were tol-
erated to give the desired products in high ees, though reduced
yields and longer reaction times were observed for electron-do-
nating ones (Table 3, entry 13e15). When R1 was an alkyl group, it
was found that the steric hindrance of the substituent displayed
a dramatic influence on the reaction: while high ee and moderate
yield were obtained for 7e (R1¼n-propyl), the reaction hardly oc-
curred in the case of 7f bearing a bulky tert-butyl group (Table 3,
entries 16e17). The absolute configuration of product 9d, the ee
value of which could be increased to >99% after a single re-
crystallization (Table 3, entry 4), was determined as 4R, 6S by X-ray
crystallographic analysis (Fig. 3).13
Table 2
Optimization of reaction conditions with catalyst 6ja
Entry
x
Solvent
t/h
Yield(%)b
ee(%)c
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
Toluene
Xylenes
o-Xylene
m-Xylene
p-Xylene
PhCF3
CH2Cl2
CHCl3
CCl4
ClCH2CH2Cl
Et2O
THF
n-Hexane
MTBE
MeOH
10
6
98
99
97
97
99
99
95
97
98
97
99
97
98
98
98
97
96
94
78
83
56
57
52
75
78
83
80
77
81
57
60
70
3
10
10
10
10
24
45
10
45
16
72
72
12
12
9
9
10
11
12
13
14
15
16
17
18d
OH
O
CCl3
NC
Xylenes
Xylenes
Xylenes
84
87
90
2
2
9
67
a
Unless otherwise noted, the reaction was carried out with 7a (0.15 mmol), 8a
(0.1 mmol), 6j and solvent (1.0 mL) at room temperature for appropriate time.
Br
9d
b
Yield of the isolated product after column chromatography on silica gel.
c
Determined by HPLC analysis on a chiral column. Only a single diastereoisomer
was observed by 1H NMR analysis of the crude product.
d
The reaction was carried out at ꢀ10 ꢁC.
Fig. 3. ORTEP structure of compound 9d.

H.-F. Wang et al. / Tetrahedron 67 (2011) 1774e1780
1777
Tetrahydropyridine derivatives have exhibited hypotensive,
analgesic, anti-inflammatory, and antipyretic activities,14 even with
no observed toxicity at high doses.15 Studies also revealed that
some tetrahydropyridines could increase the cardiac output and
reduce the pulmonary and peripheral oedema at a low concentra-
tion without changes of heart rate,16 which may aid in the treat-
ment of congestive heart failure, a widespread and severe disease
with character of reduced myocardial contractility. After being
treated with NH4OAc and HOAc in EtOAc at reflux, dihydropyran 9a
could be converted directly to tetrahydropyridine 10 in 65% yield
with almost no loss in ee value, which demonstrated the utility of
the reaction (Scheme 1).
(5 mmol, 280 mg) in MeOH (4 mL) was added dropwise at 0 ꢁC and
the reaction was carried out at this temperature for 2 h (monitored
by TLC). The mixture was acidated to pH 4e7 and extracted with
ethyl acetate (20 mL). The organic phase was washed with brine
(10 mL) and dried over Na2SO4, and concentrated in vacuo. This
crude secondary alcohol was used without further purification.
Under argon atmosphere, the solution of crude secondary alcohol,
MnO2 (15 equiv), DCM (25 mL) was stirred at room temperature for
24e48 h. The residue was filtrated by Celite, concentrated in vacuo,
and purified by flash column chromatography on silica gel (petro-
leum ether) to give the substrates 8.
4.2.1. (E)-1,1,1-Trichloro-4-p-tolylbut-3-en-2-one (8f). Yellow solid.
Yield: 32%. Mp: 86e88 ꢁC. 1H NMR (400 MHz, CDCl3)
d 2.41 (s, 3H),
H
N
OH
CCl3
OH
CCl3
Ph
O
Ph
NH4OAc, HOAc, EtOAc
reflux (78 oC), 24h;
7.24e7.27 (m, 3H), 7.55 (d, J¼7.6 Hz, 2H), 7.98 (d, J¼16.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 21.7, 96.6, 114.8, 129.1, 129.9, 131.2, 142.7,
NC
NC
149.8, 180.2; MS (EI): m/z 262 (Mþ, 4%), 146 (11), 145 (100), 117 (20),
116 (7), 115 (29), 91 (11), 65 (5); HRMS (EI): m/z calcd for C11H9OCl3
Ph
9a
Ph
10
(Mþ): 261.9719, found: 261.9715; IR (KBr)
n 2912, 1708, 1599, 1566,
1513, 1446, 1184, 999 cmꢀ1
.
90% ee
65% yield, 89% ee
Scheme 1. Conversion of 9a to 10.
4.2.2. (E)-1,1,1-Trichloro-4-(2,4-dichlorophenyl)but-3-en-2-one
(8i). White solid. Yield: 30%. Mp: 96e98 ꢁC. 1H NMR (300 MHz,
3. Conclusion
CDCl3)
d
7.29e7.35 (m, 2H), 7.49 (d, J¼2.1 Hz, 1H), 7.69 (d, J¼8.4 Hz,
1H), 8.33 (d, J¼15.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 96.1, 118.5,
In conclusion, we have developed a highly enantioselective
organocatalytic Michael addition of -cyanoketones to -un-
saturated trichloromethyl ketones using a bifunctional piperazine/
thiourea catalyst. With a low catalyst loading of 2.0 mol %, a series
127.7, 128.8, 130.3, 130.6, 136.6, 137.8, 143.8, 179.4; MS (EI): m/z 318
(Mþ, 3%), 201 (65), 200 (11), 199 (100), 173 (16), 171 (24), 136 (28),
135 (20), 99 (19); HRMS (EI): m/z calcd for C10H5OCl5 (Mþ):
a
a,b
315.8783, found: 315.8788; IR (KBr)
n 1716, 1610, 1582, 1469, 1386,
of synthetically useful chiral
a-trichloromethyldihydropyrans
1314, 1100, 980 cmꢀ1
.
bearing a CCl3-substituted quaternary stereocenter were obtained
with excellent yields and up to 95% ee. Efforts towards applications
of the reaction to the synthesis of related biologically active natural
products are in progress in our laboratories.
4.2.3. (E)-1,1,1-Trichloro-4-(naphthalen-1-yl)but-3-en-2-one
(8j). Yellow solid. Yield: 26%. Mp: 107e109 ꢁC. 1H NMR (400 MHz,
CDCl3)
2H), 7.98 (d, J¼8.0 Hz, 1H), 8.25 (d, J¼8.0 Hz, 1H), 8.87 (d, J¼15.2 Hz,
1H); 13C NMR (100 MHz, CDCl3)
96.5, 118.2, 123.1, 125.4, 126.0,
d
7.46 (d, J¼15.2 Hz, 1H), 7.52e7.64 (m, 3H), 7.90e7.97 (m,
4. Experimental
4.1. General
d
126.6, 127.5, 129.0, 131.0, 131.7, 132.2, 133.8, 146.4, 180.0; MS (EI):
m/z 300 (6%), 298 (Mþ, 6), 182 (14), 181 (100), 153 (18), 152 (40), 151
(13), 76 (6); HRMS (EI): m/z calcd for C14H9OCl3 (Mþ): 297.9719,
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
found: 297.9724; IR (KBr)
n 2923, 1705, 1602, 1569, 1347, 1123, 978,
790 cmꢀ1
.
4.2.4. (E)-1,1,1-Trichloro-4-(furan-2-yl)but-3-en-2-one (8k). Yellow
solid. Yield: 10%. Mp: 42e44 ꢁC. 1H NMR (400 MHz, CDCl3)
6.56 (s,
d
1H), 6.83 (d, J¼2.8 Hz, 1H), 7.22 (d, J¼15.6 Hz, 1H), 7.59 (s, 1H), 7.73
(d, J¼15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 96.5, 113.2, 113.4,
118.5, 134.8, 146.3, 150.9, 180.3; MS (EI): m/z 240 (7%), 238 (Mþ, 7),
177 (6), 175 (8), 122 (8), 121 (100), 65 (25), 63 (6); HRMS (EI): m/z
the external standard. All chemical shifts (d) are given in parts per
calcd for C8H5O2Cl3 (Mþ): 237.9355, found: 237.9354; IR (KBr)
n
million. Data are reported as follows: chemical shift, multiplicity
(s¼single, d¼doublet, t¼triplet, q¼quartet, br¼broad, and
m¼multiplet) and coupling constants (Hertz), integration. Analyt-
ical high-performance liquid chromatography (HPLC) was carried
out on WATERS equipment using a chiral column. Melting points
were determined on an SGW X-4 apparatus, and are uncorrected.
Optical rotations were measured on a JASCO P-1030 Polarimeter at
2855, 1705, 1606, 1546, 1470, 1388, 1269, 986 cmꢀ1
.
4.2.5. (E)-1,1,1-Trichlorohept-3-en-2-one
(8l). Colorless
liquid.
Yield: 7%. 1H NMR (400 MHz, CDCl3)
d
0.98 (t, J¼7.2 Hz, 3H),
1.53e1.62 (m, 2H), 2.31e2.37 (m, 2H), 6.75 (d, J¼15.6 Hz, 1H),
7.31e7.39 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 13.6, 21.1, 35.0, 96.4,
119.8, 155.6, 179.7; MS (EI): m/z 179 ([MꢀCl]þ, 2%), 98 (7), 97 (100),
69 (8), 68 (6), 55 (81), 53 (5), 41 (21), 40 (4); HRMS (EI): m/z calcd
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).
for C7H9OCl3 (Mþ): 213.9719, found: 213.9718; IR (KBr)
n 2963,1724,
1677, 1628, 1460, 1101, 978, 830 cmꢀ1
.
4.3. Typical procedure for Michael reaction
4.2. Typical procedure for substrates 8f, 8iel preparation
A mixture of cyanoketone 7 (0.15 mmol), a,b-unsaturated tri-
To a 25 mL RBF was added
CHCl3 (20 mmol, 1.6 mL), and DMF (4 mL), the mixture was stirred
at room temperature for about 10 min, then a solution of KOH
a
,
b
-unsaturated aldehyde (5 mmol),
chloromethyl ketone 8 (0.1 mmol), and catalyst 6j (0.002 mmol) in
1.0 mL of xylene was stirred at ꢀ10 ꢁC for the appropriate times
until the disappearance of 8 (monitored by TLC). The reaction

1778
H.-F. Wang et al. / Tetrahedron 67 (2011) 1774e1780
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 products 9.
(43.1 mg, 98% isolated yield, 95% ee). [
a
]
26 ꢀ0.7 (c 0.86, EtOH). Mp:
D
152e154 ꢁC. 1H NMR (400 MHz, CD3OD)
d
2.83 (d, J¼5.6 Hz, 1H),
3.37 (s, 1H), 4.26 (d, J¼5.2 Hz, 1H), 5.54 (s, 1H), 7.53e7.59 (m, 3H),
7.76 (d, J¼7.6 Hz, 2H), 7.95 (d, J¼7.2 Hz, 2H), 8.36 (d, J¼7.6 Hz, 2H);
4.3.1. (4R, 6S)-6-Hydroxy-2,4-diphenyl-6-(trichloromethyl)-5,6-di-
13C NMR (100 MHz, CD3OD)
d 36.9, 51.9, 86.5, 100.4, 101.4, 116.5,
hydro-4H-pyran-3-carbonitrile (9a). White solid (37.3 mg, 94% iso-
122.4, 126.6, 126.7, 127.8, 129.6, 130.9, 146.2, 146.5, 162.2; MS
latedyield, 90% ee). [
a
]
D
25 ꢀ5.0 (c 0.93, CHCl3). Mp: 88e90 ꢁC.1H NMR
(ESI): m/z 461.0 ([MþNa]þ); HRMS (ESI): m/z calcd for
(400 MHz, CDCl3)
d
2.40 (dt, J1¼3.2 Hz, J2¼13.2 Hz, 1H), 2.80 (dd,
([C19H13Cl3N2O4þNa]þ): 460.9833, found: 460.9874; IR (KBr)
n
J1¼6.0 Hz, J2¼13.6 Hz,1H), 3.96 (d, J¼3.2 Hz,1H), 4.03 (dd, J1¼6.0 Hz,
J2¼12.8 Hz, 1H), 7.35e7.50 (m, 8H), 7.87 (dd, J1¼1.6 Hz, J2¼8.0 Hz,
3328, 2219, 1619, 1577, 1519, 1347, 1154, 833 cmꢀ1. The ee was
determined by HPLC analysis using a chiralcel AD column, hexane/
2-propanol: 4/1, flow rate: 0.75 mL/min, tR (minor)¼23.37 min, tR
2H); 13C NMR (100 MHz, CDCl3)
d 33.7, 38.4, 90.0, 101.3, 102.9, 118.2,
128.1,128.2,128.6,129.3,131.3,132.0,139.7,162.0; MS(ESI):m/z 417.9
(major)¼33.91 min, ¼254 nm.
l
([MþNa]þ); HRMS (MALDI): m/z calcd for ([C19H14Cl3NO2þNa]þ):
415.9970, found: 415.9982; IR (KBr)
n
3296, 2214, 1612, 1576, 1494,
4.3.6. (4R, 6S)-6-Hydroxy-2-phenyl-4-p-tolyl-6-(trichloromethyl)-5,6-
1338,1141, 827 cmꢀ1. The ee was determined by HPLC analysis using
dihydro-4H-pyran-3-carbonitrile (9f). White solid (38.0 mg, 93%
a chiralcel AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/
isolated yield, 90% ee). [
NMR (400 MHz, CDCl3)
a
]
d
29 ꢀ8.0 (c 0.95, CHCl3). Mp: 128e130 ꢁC.1H
D
min, tR (minor)¼19.86 min, tR (major)¼23.22 min,
l¼254 nm.
2.34e2.38 (m, 4H), 2.74 (dd, J1¼6.4 Hz,
J2¼13.6 Hz, 1H), 3.96 (dd, J1¼6.0 Hz, J2¼12.4 Hz, 1H), 4.31 (br s, 1H),
4.3.2. (4R,6S)-4-(4-Fluorophenyl)-6-hydroxy-2-phenyl-6-(tri-
7.20e7.25 (m, 4H), 7.40e7.49 (m, 3H), 7.83 (d, J¼7.2 Hz, 2H); 13C NMR
chloromethyl)-5,6-dihydro-4H-pyran-3-carbonitrile
(9b). White
(100 MHz, CDCl3) d 21.2, 33.7, 38.0, 90.3, 101.3, 103.0, 118.2, 128.0,
solid (37.8 mg, 92% isolated yield, 90% ee). [
a
d
]
28 ꢀ6.8 (c 0.95, CHCl3).
128.1,128.6,130.0,131.2,132.1,136.6,137.9,161.9; MS (ESI): m/z 430.1
D
Mp: 120e122 ꢁC. 1H NMR (400 MHz, CDCl3)
2.34 (t, J¼13.2 Hz,1H),
([MþNa]þ); HRMS (ESI): m/z calcd for ([C20H16Cl3NO2þNa]þ):
2.76 (dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 4.00 (dd, J1¼5.6 Hz, J2¼12.4 Hz,
1H), 4.35 (br s,1H), 7.10 (t, J¼8.4 Hz, 2H), 7.31e7.35 (m, 2H), 7.42e7.51
430.0139, found: 430.0143; IR (KBr) n 3204, 2226, 1617, 1514, 1448,
1337,1138, 836 cmꢀ1. The ee was determined by HPLC analysis using
(m, 3H), 7.84 (d, J¼7.6 Hz, 2H); 19F NMR (282 MHz, CDCl3)
d
ꢀ114.34
a chiralcel AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/
(s,1F); 13C NMR (100 MHz, CDCl3)
d
33.6, 37.7, 89.8,101.2,102.8,116.2
min, tR (minor)¼16.48 min, tR (major)¼19.47 min, ¼254 nm.
l
(d, J¼21.1 Hz), 118.1, 128.0, 128.6, 129.7, 129.8, 131.4, 131.9, 135.3 (d,
J¼3.0 Hz), 162.1 (d, J¼2.9 Hz), 162.5 (d, J¼245.7 Hz); MS (ESI): m/z
434.1([MþNa]þ);HRMS (ESI): m/zcalcd for ([C19H13FCl3NO2þNa]þ):
4.3.7. (4S, 6S)-4-(2-Chlorophenyl)-6-hydroxy-2-phenyl-6-(trichloro-
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9g). Yellowish solid
29
433.9888, found: 433.9898; IR (KBr)
n
3245, 2224, 1617, 1577, 1509,
(42.1 mg, 98% isolated yield, 82% ee). [
a]
þ31.8 (c 0.84, CHCl3).
D
1338,1158, 829 cmꢀ1. The ee was determined by HPLC analysis using
Mp: 139e141 ꢁC. 1H NMR (400 MHz, CDCl3)
d 2.16e2.22 (m, 1H),
a chiralcel AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/
2.85e2.87 (m, 1H), 4.36 (s, 1H), 4.67e4.69 (m, 1H), 7.22e7.50 (m,
min, tR (minor)¼25.10 min, tR (major)¼29.29 min,
l¼254 nm.
7H), 7.84 (d, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 32.1, 34.5,
88.9, 101.3, 102.8, 118.0, 127.8, 128.1, 128.6, 128.7, 129.3, 130.1, 131.4,
132.0, 134.2, 137.2, 163.0; MS (ESI): m/z 450.0 ([MþNa]þ); HRMS
(ESI): m/z calcd for ([C19H13Cl4NO2þNa]þ): 449.9593, found:
4.3.3. (4R, 6S)-4-(4-Chlorophenyl)-6-hydroxy-2-phenyl-6-(trichloro-
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9c). White solid
(40.6 mg, 95% isolated yield, 90% ee). [
a
]
29 ꢀ7.3 (c 1.00, CHCl3). Mp:
449.9599; IR (KBr) n 3232, 2225, 1610, 1568, 1474, 1341, 1141,
D
123e125 ꢁC. 1H NMR (400 MHz, CDCl3)
d
2.32 (t, J¼13.2 Hz, 1H),
824 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
2.75 (dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 3.99 (dd, J1¼6.0 Hz, J2¼12.4 Hz,
1H), 4.31 (br s, 1H), 7.29 (d, J¼8.0 Hz, 2H), 7.39 (d, J¼8.0 Hz, 2H),
7.42e7.51 (m, 3H), 7.83 (d, J¼7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
AD column, hexane/2-propanol: 19/1, flow rate: 0.75 mL/min, tR
(minor)¼33.30 min, tR (major)¼37.55 min, ¼254 nm.
l
d
33.5, 37.9, 89.4, 101.2, 102.8, 118.0, 128.0, 128.6, 129.4, 129.5, 131.4,
4.3.8. (4R, 6S)-4-(3-Chlorophenyl)-6-hydroxy-2-phenyl-6-(trichloro-
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9h). White solid
131.8, 134.0, 138.1, 162.3; MS (ESI): m/z 450.1 ([MþNa]þ); HRMS
(ESI): m/z calcd for ([C19H13Cl4NO2þNa]þ): 449.9593, found:
(42.5 mg, 99% isolated yield, 90% ee). [
a
d
]
28 ꢀ6.2 (c 0.85, CHCl3). Mp:
D
449.9590; IR (KBr)
n
3344, 2217, 1615, 1576, 1491, 1338, 1154,
110e112 ꢁC. 1H NMR (400 MHz, CDCl3)
2.33 (t, J¼12.8 Hz, 1H), 2.76
827 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
(dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 3.98 (dd, J1¼6.0 Hz, J2¼12.4 Hz, 1H),
4.37 (br s, 1H), 7.23e7.24 (m, 1H), 7.24e7.37 (m, 3H), 7.41e7.51 (m,
AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/min, tR
(minor)¼28.39 min, tR (major)¼34.34 min,
l¼254 nm.
3H), 7.83 (d, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 33.5, 38.2,
89.1, 101.2, 102.7, 118.0, 126.4, 128.1, 128.3, 128.5, 128.6, 130.6, 131.5,
131.8, 135.0, 141.7, 162.5; MS (ESI): m/z 450.0 ([MþNa]þ); HRMS
(ESI): m/z calcd for ([C19H13Cl4NO2 Na]þ): 449.9593, found:
4.3.4. (4R, 6S)-4-(4-Bromophenyl)-6-hydroxy-2-phenyl-6-(trichloro-
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9d). White solid
(47.0 mg, 99% isolated yield, 90% ee). [
a
d
]
29 ꢀ6.4 (c 0.94, CHCl3). Mp:
449.9589; IR (KBr) n 3244, 2220, 1596, 1573, 1497, 1335, 1139,
D
129e131 ꢁC. 1H NMR (400 MHz, CDCl3)
2.32 (t, J¼12.8 Hz,1H), 2.74
841 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
(dd, J1¼6.0 Hz, J2¼12.4 Hz, 1H), 3.97 (dd, J1¼6.0 Hz, J2¼12.4 Hz, 1H),
4.33 (br s, 1H), 7.23 (d, J¼8.4 Hz, 2H), 7.41e7.50 (m, 3H), 7.54 (d,
J¼8.0 Hz, 2H), 7.83 (d, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/min, tR
(minor)¼13.21 min, tR (major)¼15.97 min, ¼254 nm.
l
d
33.5, 38.0, 89.3, 101.2, 102.8, 118.0, 122.1, 128.1, 128.6, 129.8, 131.5,
4.3.9. (4S, 6S)-4-(2,4-Dichlorophenyl)-6-hydroxy-2-phenyl-6-(tri-
chloromethyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9i). White solid
131.8, 132.4, 138.7, 162.3; MS (ESI): m/z 495.8 ([MþNa]þ); HRMS
26
(ESI): m/z calcd for ([C19H13BrCl3NO2þNa]þ): 493.9088, found:
(44.9 mg, 97% isolated yield, 84% ee). [
a
]
þ20.2 (c 0.90, EtOH).
D
493.9089; IR (KBr)
n
3350, 2214, 1616, 1576, 1487, 1339, 1150,
Mp: 166e168 ꢁC. 1H NMR (400 MHz, CDCl3þCD3OD)
d 2.15e2.20 (m,
824 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
1H), 2.80e2.83 (m, 1H), 4.65 (s, 1H), 7.30e7.47 (m, 8H), 7.88 (d,
AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/min, tR
J¼6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3þCD3OD)
d 32.6, 34.3, 87.9,
(minor)¼33.61 min, tR (major)¼42.00 min,
l¼254 nm.
101.7, 103.0, 118.3, 126.8, 128.1, 128.5, 129.6, 129.8, 131.3, 132.1, 134.2,
134.8, 163.8; MS (ESI): m/z 484.0 ([MþNa]þ); HRMS (ESI): m/z calcd
4.3.5. (4R, 6S)-6-Hydroxy-4-(4-nitrophenyl)-2-phenyl-6-(trichloro-
methyl)-5,6-dihydro-4H-pyran-3-carbonitrile (9e). White solid
for ([C19H12Cl5NO2þNa]þ): 483.9203, found: 483.9187; IR (KBr)
n
3247, 2225, 1620, 1589, 1496, 1387, 1146, 823 cmꢀ1. The ee was

H.-F. Wang et al. / Tetrahedron 67 (2011) 1774e1780
1779
determined by HPLC analysis using a chiralcel AD column, hexane/2-
108e110 ꢁC. 1H NMR (400 MHz, CDCl3)
d
2.37 (t, J¼13.2 Hz,1H), 2.77
propanol: 19/1, flow rate: 0.75 mL/min, tR (minor)¼30.96 min, tR
(dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 3.98 (dd, J1¼6.0 Hz, J2¼12.0 Hz, 1H),
(major)¼35.47 min, ¼254 nm.
l
4.32 (br s, 1H), 7.33e7.43 (m, 5H), 7.56 (d, J¼8.8 Hz, 2H), 7.71 (d,
J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 33.5, 38.4, 90.6, 101.4,
4.3.10. (4R, 6S)-6-Hydroxy-4-(naphthalen-1-yl)-2-phenyl-6-(trichloro-
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9j). White solid
102.8, 117.9, 125.8, 128.1, 128.3, 129.3, 129.6, 130.8, 131.9, 139.3,
160.9; MS (ESI): m/z 493.9 ([MþNa]þ); HRMS (ESI): m/z calcd for
(43.0 mg, 97% isolated yield, 90% ee). [
a
d
]
28 þ71.7 (c 0.87, CHCl3). Mp:
([C19H13BrCl3NO2þNa]þ): 493.9088, found: 493.9080; IR (KBr)
n
D
114e116 ꢁC. 1H NMR (400 MHz, CDCl3)
2.33 (t, J¼12.8 Hz, 1H), 2.94
3234, 2224, 1616, 1589, 1487, 1331, 1160, 829 cmꢀ1. The ee was
determined by HPLC analysis using a chiralcel AD-H column, hex-
ane/2-propanol: 9/1, flow rate: 0.75 mL/min, tR (minor)¼15.61 min,
(dd, J1¼6.0 Hz, J2¼13.2 Hz, 1H), 4.35 (s, 1H), 4.97 (dd, J1¼6.0 Hz,
J2¼12.4 Hz, 1H), 7.41e7.61 (m, 7H), 7.84e7.99 (m, 4H), 8.12 (d,
J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
32.9, 33.6, 90.0, 101.4,
tR (major)¼19.46 min, ¼254 nm.
l
102.9, 122.1, 125.2, 125.8, 126.0, 126.9, 128.2, 128.6, 129.3, 131.4,
134.1, 136.0, 163.0; MS (ESI): m/z 466.0 ([MþNa]þ); HRMS (ESI): m/z
calcd for ([C23H16Cl3NO2þNa]þ): 466.0139, found: 466.0143; IR
4.3.15. (4R, 6S)-6-Hydroxy-2-(4-methoxyphenyl)-4-phenyl-6-(trichlo-
romethyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9o). White solid
(KBr)
n
3191, 2226, 1621, 1598, 1448, 1396, 1140, 819 cmꢀ1. The ee
(28.0 mg, 66% isolated yield, 90% ee). [
a
]
28 þ6.7 (c 0.93, CHCl3). Mp:
D
was determined by HPLC analysis using a chiralcel AD column,
77e79 ꢁC. 1H NMR (400 MHz, CDCl3)
d
2.36 (t, J¼12.8 Hz, 1H), 2.76
hexane/2-propanol: 9/1, flow rate: 0.75 mL/min, tR (minor)¼
(dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 3.84 (s, 3H), 4.00 (dd, J1¼6.0 Hz,
J2¼12.4 Hz, 1H), 4.19 (br s, 1H), 6.94 (d, J¼8.8 Hz, 2H), 7.35e7.43 (m,
16.67 min, tR (major)¼19.41 min, ¼254 nm.
l
5H), 7.83 (d, J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 33.6, 38.4,
4.3.11. (4S, 6S)-4-(Furan-2-yl)-6-hydroxy-2-phenyl-6-(trichloro-
55.5, 88.4, 101.2, 103.1, 113.9, 114.5, 114.6, 127.6, 128.1, 129.2, 129.7,
131.4, 140.0, 161.9; MS (ESI): m/z 448.0 ([MþNa]þ); HRMS (ESI): m/z
calcd for ([C20H16Cl3NO3þNa]þ): 446.0088, found: 446.0077; IR
methyl)-5,6-dihydro-4H-pyran-3-carbonitrile (9k). White solid
(33.4 mg, 87% isolated yield, 86% ee). [
a
]
d
28 ꢀ21.6 (c 0.84, CHCl3). Mp:
D
102e104 ꢁC. 1H NMR (400 MHz, CDCl3)
2.62 (t, J¼12.8 Hz,1H), 2.76
(KBr) n
3368, 2210, 1608, 1511, 1455, 1338, 1176, 832 cmꢀ1. The ee
(dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 4.17 (dd, J1¼6.0 Hz, J2¼12.8 Hz, 1H),
4.34 (br s,1H), 6.39 (s, 2H), 7.40e7.49 (m, 4H), 7.80 (d, J¼7.2 Hz,1H);
was determined by HPLC analysis using a chiralcel AS-H column,
hexane/2-propanol: 4/1, flow rate: 0.75 mL/min, tR (minor)¼
13C NMR (100 MHz, CDCl3)
d
29.9, 32.1, 88.1, 101.3,108.6, 110.7, 128.1,
15.81 min, tR (major)¼32.35 min, ¼254 nm.
l
128.5, 128.9, 129.3, 131.3, 131.9, 142.9, 151.3, 161.8; MS (ESI): m/z
406.0 ([MþNa]þ); HRMS (ESI): m/z calcd for ([C17H12Cl3NO3þNa]þ):
4.3.16. (4R, 6S)-6-Hydroxy-4-phenyl-2-propyl-6-(trichloromethyl)-5,6-
dihydro-4H-pyran-3-carbonitrile (9p). Colorless liquid (23.0 mg, 64%
405.9775, found: 405.9767; IR (KBr)
n
3267, 2220, 1619, 1577, 1448,
1336,1142, 822 cmꢀ1. The ee was determined by HPLC analysis using
isolated yield, 87% ee). [
a
]
25 ꢀ3.6 (c 0.77, CHCl3). 1H NMR (400 MHz,
D
a chiralcel AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/
CDCl3)
d
1.02 (t, J¼7.2 Hz, 3H), 1.66e1.72 (m, 2H), 2.19 (t, J¼12.4 Hz,
min, tR (minor)¼16.58 min, tR (major)¼20.20 min,
l¼254 nm.
1H), 2.48e2.63 (m, 2H), 2.67 (dd, J1¼6.0 Hz, J2¼13.6 Hz, 1H), 3.84
(dd, J1¼6.0 Hz, J2¼12.4 Hz, 1H), 3.97 (br s, 1H), 7.25e7.41 (m, 5H);
4.3.12. (4S, 6S)-6-Hydroxy-2-phenyl-4-propyl-6-(trichloromethyl)-
13C NMR (100 MHz, CDCl3)
d 13.3, 20.1, 33.6, 35.2, 37.0, 90.2, 100.8,
5,6-dihydro-4H-pyran-3-carbonitrile (9l). White solid (34.5 mg,
102.9, 117.5, 127.9, 128.0, 129.2, 139.7, 166.9; MS (EI): m/z 359 (Mþ,
2%), 131 (48), 129 (11), 104 (10), 103 (16), 77 (12), 71 (100), 43 (48),
41 (12); HRMS (EI): m/z calcd for C16H16NO2Cl3 (Mþ): 359.0247,
28
96% isolated yield, 72% ee). [
a
]
ꢀ4.0 (c 0.86, CHCl3). Mp:
D
110e112 ꢁC. 1H NMR (400 MHz, CDCl3)
d
1.01 (t, J¼7.2 Hz, 3H),
1.37e1.59 (m, 3H), 1.92e2.05 (m, 2H), 2.58e2.76 (m, 1H), 2.77e2.82
(m, 1H), 4.11 (s, 1H), 7.40e7.46 (m, 3H), 7.78 (d, J¼6.8 Hz, 1H); 13C
found: 359.0249; IR (KBr) n 3352, 2217, 1651, 1538, 1456, 1384, 1265,
739 cmꢀ1. The ee was determined by HPLC analysis using a chiralcel
NMR (100 MHz, CDCl3)
d
14.1, 19.5, 29.7, 30.2, 35.1, 90.7, 101.5, 103.3,
AS-H column, hexane/2-propanol: 4/1, flow rate: 0.75 mL/min, tR
118.3, 128.0, 128.5, 131.0, 132.2, 161.5; MS (ESI): m/z 382.0
(minor)¼8.78 min, tR (major)¼12.10 min, ¼254 nm.
l
([MþNa]þ); HRMS (ESI): m/z calcd for ([C16H16Cl3NO2þNa]þ):
382.0139, found: 382.0145; IR (KBr)
n 3319, 2223, 1611, 1575, 1446,
1378, 1146, 821 cmꢀ1. The ee was determined by HPLC analysis using
4.4. General procedure for synthesis of compound 10
a chiralcel AD column, hexane/2-propanol: 9/1, flow rate: 0.75 mL/
min, tR (minor)¼10.77 min, tR (major)¼14.58 min,
l
¼254 nm.
A mixture of compound 9a (0.1 mmol, 90% ee), NH4OAc
(1.2 mmol, 92 mg), and HOAc (1.0 mL) in EtOAc (1.0 mL) was stirred
at 78 ꢁC (reflux condition) for 24 h (monitored by TLC). Then the
reaction mixture was dissolved in EtOAc (10 mL), washed with
saturated NaHCO3 (10 mL) and brine (5 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (ethyl acetate/petroleum ether¼1:6)
to give the desired products 10.
4.3.13. (4R, 6S)-2-(4-Fluorophenyl)-6-hydroxy-4-phenyl-6-(trichloro-
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9m). Yellowish solid
(39.0 mg, 94% isolated yield, 89% ee). [
a
]
28 ꢀ4.5 (c 0.99, CHCl3). Mp:
D
128e130 ꢁC. 1H NMR (400 MHz, CDCl3)
d
2.37 (t, J¼12.8 Hz, 1H),
2.77 (dd, J1¼6.0 Hz, J2¼13.2 Hz, 1H), 3.99 (dd, J1¼6.0 Hz, J2¼12.4 Hz,
1H), 4.35 (br s, 1H), 7.11 (t, J¼8.4 Hz, 2H), 7.34e7.41 (m, 5H),
7.83e7.87 (m, 2H); 19F NMR (282 MHz, CDCl3)
d
ꢀ107.94 (s, 1F); 13
C
NMR (100 MHz, CDCl3)
d
33.6, 38.4, 90.0, 101.3, 102.9, 115.8 (d,
4.4.1. (4R)-6-Hydroxy-2,4-diphenyl-6-(trichloromethyl)-1,4,5,6-tet-
J¼21.9 Hz), 118.1, 128.1, 128.2, 129.3, 130.3, 130.4, 139.5, 161.0, 164.3
(d, J¼251.6 Hz); MS (ESI): m/z 434.0 ([MþNa]þ); HRMS (ESI): m/z
calcd for ([C19H13FCl3NO2þNa]þ): 433.9888, found: 433.9877; IR
rahydropyridine-3-carbonitrile (10). White solid (24.0 mg, 65%
25
isolated yield, 89% ee). [
a
]
D
ꢀ8.6 (c 1.00, CHCl3). Mp: 168e170 ꢁC.
1H NMR (400 MHz, CDCl3)
d
2.33 (t, J¼13.2Hz, 1H), 2.54 (dd,
(KBr)
n
3394, 2211, 1654, 1604, 1508, 1338, 1152, 836 cmꢀ1. The ee
J1¼4.4 Hz, J2¼13.2 Hz, 1H), 3.86 (s, 1H), 3.92 (dd, J1¼4.4 Hz,
J2¼13.2 Hz, 1H), 5.36 (s, 1H), 7.30e7.49 (m, 8H), 7.58 (d, J¼6.8 Hz,
was determined by HPLC analysis using a chiralcel AD-H column,
hexane/2-propanol: 9/1, flow rate: 0.75 mL/min, tR (minor)¼
2H); 13C NMR (100 MHz, CDCl3)
d 36.7, 38.6, 83.9, 87.3, 105.3, 119.6,
41.98 min, tR (major)¼54.25 min,
l¼254 nm.
127.8, 127.9, 128.2, 129.0, 129.1, 130.8, 134.7, 140.6, 153.6; MS (ESI):
m/z 415.0 ([MþNa]þ); HRMS (EI): m/z calcd for C19H15N2OCl3 (Mþ):
4.3.14. (4R, 6S)-2-(4-Bromophenyl)-6-hydroxy-4-phenyl-6-(trichloro-
392.0250, found: 392.0251; IR (KBr) n 3418, 2198, 1616, 1576, 1487,
methyl)-5,6-di-hydro-4H-pyran-3-carbonitrile (9n). White solid
1339, 1265, 739 cmꢀ1. The ee was determined by HPLC analysis
(39.7 mg, 84% isolated yield, 88% ee). [
a
]
D
28 ꢀ0.3 (c 0.99, CHCl3). Mp:
using a chiralcel AS-H column, hexane/2-propanol: 4/1, flow rate:

1780
H.-F. Wang et al. / Tetrahedron 67 (2011) 1774e1780
(p) Hinkle, R. J.; Lian, Y.; Speight, L. C.; Stevenson, H. E.; Spiachman, M. M.;
0.75 mL/min, tR (minor)¼19.14 min, tR (major)¼27.32 min,
¼254 nm.
ꢀ
Katkish, L. A.; Mattern, M. C. Tetrahedron 2009, 65, 6834; (q) Marko, I. E.; Dobbs,
l
ꢀ
A. P.; Scheirmann, V.; Chelle, F.; Bayston, D. J. Tetrahedron Lett. 1997, 38, 2899;
(r) Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1997, 38, 7143; (s)
Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623; (t) Dobbs, A. P.;
Acknowledgements
ꢀ
Martinovic, S. Tetrahedron Lett. 2002, 43, 7055; (u) Nguyen, V.-H.; Nishino, H.
Tetrahedron Lett. 2004, 45, 3373; (v) Yadav, J. S.; Sunitha, V.; Reddy, B. V. S.; Das,
P. P.; Gyanchander, E. Tetrahedron Lett. 2008, 49, 855.
The generous financial support from National Basic Research
ProgramofChina(973Program, 2010CB833300), theNationalNatural
ScienceFoundationofChina(No.20172064,203900502, 20532040Y),
QT Program, Shanghai Natural Science Council, and Excellent Young
Scholars Foundation of National Natural Science Foundation of China
(20525208).
5. For reviews of catalytic asymmetric Michael addition, see: (a) Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992; (b)
Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033; (c) Krause, N.; Hoffmann-
€
Roder, A. Synthesis 2001, 171; (d) Berner, O. M.; Tedeschi, L.; Enders, D. Eur.
J. Org. Chem. 2002, 1877; (e) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003,
€
42, 1688; (f) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007,
1279; (g) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007, 2065; (h) Tsogoeva,
ꢀ
S. B. Eur. J. Org. Chem. 2007, 1701; (i) Almasi, D.; Alonso, D. A.; Najera, C. Tet-
rahedron: Asymmetry 2007, 18, 299.
Supplementary data
6. For thiourea-catalyzed asymmetric Michael additions by our group: (a) Wang,
X.-S.; Yang, G.-S.; Zhao, G. Tetrahedron: Asymmetry 2008, 19, 709; (b) Wang, X.-
S.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Zhao, G.; Yang, G.-S. Tetrahedron: Asym-
metry 2008, 19, 2699; (c) Zhao, S.-L.; Zheng, C.-W.; Zhao, G. Tetrahedron:
Asymmetry 2009, 20, 1046; (d) Zhao, S.-L.; Zheng, C.-W.; Wang, H.-F.; Zhao, G.
Adv. Synth. Catal. 2009, 351, 2811; (e) Li, P.; Chai, Z.; Zhao, S.-L.; Yang, Y.-Q.;
Wang, H.-F.; Zheng, C.-W.; Cai, Y.-P.; Zhao, G.; Zhu, S.-Z. Chem. Commun. 2009,
7369; (f) Chen, X.-K.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.;
Cao, W.-G. Adv. Synth. Catal. 2010, 352, 1648.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.01.043.
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