Highly enantio- and diastereoselective allylic alkylation of Morita-Baylis-Hillman carbonates with allyl ketones

Article abstract of DOI:10.1021/jo400496z

The asymmetric allylic alkylation of Morita-Baylis-Hillman (MBH) carbonates with allyl ketones has been developed. The α-regioselective alkylation adducts, containing a hexa-1,5-diene framework with important synthetic value, were achieved in up to 83% yield, >99% ee, and 50:1 dr by using a commercially available Cinchona alkaloid as the catalyst. From the allylic alkylation adduct, a cyclohexene bearing two adjacent chiral centers was readily prepared.

Full text of DOI:10.1021/jo400496z

Note
pubs.acs.org/joc
Highly Enantio- and Diastereoselective Allylic Alkylation of Morita−
Baylis−Hillman Carbonates with Allyl Ketones
Guanghu Tong,†,‡ Bo Zhu,†,‡ Richmond Lee,§ Wenguo Yang,‡ Davin Tan,§ Caiyun Yang,†,‡
Zhiqiang Han,†,‡ Lin Yan,†,‡ Kuo-Wei Huang,§ and Zhiyong Jiang*,†,‡
†Institute of Chemical Biology, Henan University, Kaifeng, Henan, 475004, PR China
‡Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan, 475004, PR
China
§KAUST Catalysis Center and Division of Chemical and Life Sciences and Engineering, King Abdullah University of Science and
Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia
S
* Supporting Information
ABSTRACT: The asymmetric allylic alkylation of Morita−Baylis−
Hillman (MBH) carbonates with allyl ketones has been developed.
The α-regioselective alkylation adducts, containing a hexa-1,5-diene
framework with important synthetic value, were achieved in up to
83% yield, >99% ee, and 50:1 dr by using a commercially available
Cinchona alkaloid as the catalyst. From the allylic alkylation adduct,
a cyclohexene bearing two adjacent chiral centers was readily
prepared.
n recent years, allyl ketones, involving an allyl group and
ketone moieties, have been widely employed as valuable
then gets rid of an α-proton of electron-withdrawing group
(EWG)-activated allyl to generate a EWG-stabilized allylic
anion. It is easy to find that α-, proton-shifted α- and γ-selective
adducts should be the feasible products. At the same time, both
α- and γ-selective adducts contain a hexa-1,5-diene framework,
which has been recognized as an important structural feature in
many bioactive natural products.39−44 Therefore, it is valuable
to investigate the asymmetric allylic alkylation of MBH
carbonates with EWG-activated ally compounds. In 2011,
Chen and co-workers presented an allylic alkylation of MBH
carbonates with allylic sulfones (EWG = sulfone). The γ-
regioselective alkylation products were obtained with good to
excellent enantioselectivities catalyzed by (DHQD)2AQN
(Figure 1).17 When they increased the reaction temperature
to 50 °C and utilized (DHQD)2PYR as the catalyst, the α-
selective product could be produced; however, the yield,
enantio- and diastereoselectivity were not satisfactory (48%
yield, 82% ee, 3.5:1 dr).17 Herein, we wish to report the first
allylic alkylation of MBH carbonates with allyl ketones (EWG =
ketone) in excellent enantio- and diastereoselectivities with
special α-regioselectivity, furnishing synthetically valuable chiral
hexa-1,5-diene compounds as products. Most importantly, a
cyclohexene, containing two adjacent chiral centers, could be
synthesized conveniently from the α-selective allylic alkylation
adduct (Figure 1).
I
intermediates in organic synthesis of natural and non-natural
products.1−4 For example, allyl phenyl ketone was utilized as an
important precursor to prepare the natural products including
(−)-lobeline,1 (−)-sedamine1 and (−)-allosedamine.2 Further-
more, Δ2-isoxazolines could be readily prepared from allyl
ketones through a tandem oximation−cyclization protocol.3,4
However, to date to the best of our knowledge, no example has
been reported on their application in asymmetric catalysis. It is
thus our goal to develop some efficient organocatalytic variants
to allow easy access to various chiral biologically interesting
molecules from allyl ketones.5
As much effort has been devoted to asymmetric Morita−
Baylis−Hillman (MBH) reactions,6 recently, there has been an
increasing interest focused on the enantioselective trans-
formation of MBH products. In particular, by converting the
hydroxy group into a leaving group, the MBH adducts, such as
acetates and carbonates, can undergo the asymmetric allylic
alkylation with various nucleophiles by the metal-free catalysis
of tertiary amines and phosphines,7,8 to access substantial
C-,9−20 N-,21−26 O-,27−31 P-,32−34 and S-allylic35 and spirocy-
clic36−38 compounds. Since 2011, our group has successively
established the allylic alkylation of bis(phenylsulfonyl)methane
(BSM),18 fluoro-bis(phenylsulfonyl)methane (FBSM),18 N-
itaconimides20 and water31 with MBH carbonates by using
modified Cinchona alkaloids as the catalyst. Inspired by these
progresses and extending our research interest, we wondered if
such an activation strategy could be applied to the fascinating
allyl ketones.
As an initial study, we examined with allyl phenyl ketone 1a
and MBH carbonate 2a as the model substrates in the presence
of DABCO in CH2Cl2 at 25 °C. The α-regioselective adduct
As Figure 1 shows, under a Lewis base catalyst, tert-butoxide
would be derived from the expulsion of MBH carbonate, which
Received: March 12, 2013
Published: April 17, 2013
© 2013 American Chemical Society
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Note
a
Table 1. Optimization of the Reaction Conditions
t
yield
b
ee
(%)
c
d
entry
catalyst
solvent
(h)
(%)
dr
1
QD
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
acetone
CH3CN
DMF
48
48
48
48
48
48
48
48
24
24
24
24
67
96
26
32
41
44
52
38
49
41
76
67
55
38
72
44
51
17
73:27
41:59
80:20
88:12
70:30
65:35
65:35
72:28
88:12
95:5
2
HQN
3
(DHQD)2PYR
(DHQ)2PYR
(DHQD)2AQN
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2AQN
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
84
4
−39
79
5
6
70
7
7
8
−15
86
9
10
11
12
92
76
94:6
CH3OH
CH3CN
CH3CN
87
79:21
e
f
13
95
95:5
g
14
96
97:3
a
Unless otherwise noted, the reaction was carried out with 0.15 mmol
of 1a, 0.05 mmol of 2a and 0.005 mmol of catalyst in 0.5 mL of
b
c
solvent. Isolated yield. ee of major diastereomer was determined by
Chiral HPLC. Determined by HPLC. The reaction was conducted at
10 °C, 1.0 mmol scale in 1.0 mL of solvent. 16:1 dr was determined
d
e
f
g
1
by crude H NMR. The reaction was conducted at 0 °C. QD =
quinidine, HQN = hydroquinine, (DHQD)2PYR = hydroquinidine-
2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQ)2PYR = hydroquinine-
2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)2AQN = hydro-
quinidine (anthraquinone-1,4-diyl) diether, (DHQ)2PHAL = hydro-
quinine 1,4-phthalazinediyl diether, (DHQD)2PHAL = hydroquini-
dine 1,4-phthalazinediyl diether, (DHQ)2AQN = hydroquinine
anthraquinone-1,4-diyl diether.
Figure 1. Two regioselective protocols of allylic alkylations of MBH
carbonates with different EWG-activated allyl compounds.
3aa was delighted to be achieved with 100% conversion and 6:1
dr in 12 h. Encouraged by the results, we examined the
stereoselective variant of the reaction between 1a and 2a in the
presence of several commercially available Cinchona alkaloids as
Lewis base catalysts at 25 °C (Table 1). Quinidine and
hydroqunine showed the low reactivities and poor enantio- and
diastereoselectivities (Table 1, entries 1−2). Then, a series of
C2-symmetric (bis)cinchona alkaloids, which contain rigid
enzyme-like pockets,45 was screened under the same conditions
(Table 1, entries 3−8). (DHQD)2PYR showed good catalytic
activity; 3aa was achieved in 41% yield with good
enantioselectivity (84% ee) and moderate diastereoselectivity
(80:20 dr) (Table 1, entry 3). Next, we investigated the effects
of solvent (Table 1, entries 9−12). The best-performing solvent
with regard to reactivity and yield was acetonitrile, giving 3aa in
67% yield with 92% ee and 95:5 dr in 24 h (Table 1, entry 10).
Lowering the temperature to 10 °C increased ee to 95% and dr
to 95:5 in a reasonable reaction time (Table 1, entry 13).
Higher enantio- and diastereoselectivities could be obtained
when the reaction temperature was decreased to 0 °C, but the
reaction rate became sluggish (Table 1, entry 14).
With the optimized conditions established (10 mol %
(DHQD)2PYR as catalyst in CH3CN at 10 °C), we first
evaluated the performance of the reactions between allyl phenyl
ketone 1a and various MBH carbonates 2, and the results are
summarized in Table 2. The corresponding allylic alkylation
adducts were obtained in 68−82% yields with 90−95% ee and a
dr of 13:1 to 50:1. The results showed that introducing various
aryl substituents onto MBH carbonates did not affect the ee
value (Table 2, entries 1−12). Also, excellent ee value could be
obtained when the phenyl group of MBH carbonate was
replaced with hetereoaromatic group, such as thiophene (Table
2, entry 13).
Subsequently, the scope of the allylic alkylation reaction with
respect to various allyl ketones 1 and MBH carbonate 2a was
examined (Table 3, entries 1−6). In all the example studies, the
desired α-regioselective allylic alkylation adducts were achieved
in excellent results (up to >99% ee and 33:1 dr) with the
exception of 3fa (97% ee but 3:1 dr), indicating that the ortho-
substitutent of allyl ketones 1 should decrease the reaction
diastereoselectivity. The absolute configurations of the allylic
alkylation adducts were assigned on the basis of X-ray
crystallographic analysis of a single crystal of 3ga.46 Excellent
enantioselectivities and diastereoselectivities were also observed
for the reactions between some allyl ketones 1 and MBH
carbonates 2 bearing different aryl substituents, which gave
corresponding adducts 3eh, 3ej, 3hj and 3hl with up to 98% ee
and 50:1 dr (Table 3, entries 7−10).
As Scheme 1 shows, in the presence of 10 equiv of tert-butyl
lithium in THF at 50 °C, the α-selective allylic alkylation
adduct 3aa could be transformed to the desired chiral
cyclohexene 4 with 51% yield in 10 min and without
compromising ee. In this context, the allylic alkylation described
here provides an unprecedent and efficient protocol to furnish
the asymmetric synthesis of biologically important cyclohexenes
with two adjacent chiral centers.47−50
In summary, we have developed the first highly enantio- and
diastereoselective allylic alkylation of allyl ketones with MBH
carbonates catalyzed by a commercially available Cinchona
alkaloid. Several α-regioselective alkylation adducts, containing
a hexa-1,5-diene framework with important synthetic value,
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The Journal of Organic Chemistry
Note
were obtained in 53−83% yields with 90 to >99% ee and a dr of
3:1 to 50:1. The synthetic method reported provides easy
access to a biologically important cyclohexene bearing two
adjacent chiral centers.
Table 2. Allylic Alkylation of Allyl Phenyl Ketone 1a with
MBH Carbonates 2
a
EXPERIMENTAL SECTION
■
General Procedure. MBH carbonate 2 (0.1 mmol, 1.0 equiv) and
(DHQD)2PYR (8.8 mg, 0.01 mmol, 0.1 equiv) were dissolved in
acetonitrile (1.0 mL) in 4 mL sample vials and stirred at 10 °C for 30
min. Then allylic ketone 1 (0.3 mmol, 3.0 equiv) was added. The
reaction mixtures were stirred and maintained at 10 °C, and the
reaction progress was monitored by TLC. Upon complete
consumption of 2, the reaction mixtures were loaded onto a short
silica gel column, followed by separation with flash chromatography
using gradient elution with petroleum ether/ethyl acetate (10:1 to
5:1). After removal of solvent under a vacuum, the corresponding
adducts 3 were obtained.
b
c
d
entry
2 Ar
t (h)
3
yield (%)
ee (%)
dr
1
2b, 4-FC6H4
2c, 4-ClC6H4
2d, 4-BrC6H4
2e, 2,4-Cl2C6H3
2f, 3-FC6H4
96
72
72
96
96
96
96
72
60
96
96
96
72
3ab
3ac
3ad
3ae
3af
77
75
80
82
73
71
70
72
70
68
70
72
79
93
92
92
91
93
93
94
94
94
93
95
91
90
20:1
20:1
20:1
20:1
14:1
25:1
25:1
25:1
50:1
14:1
25:1
25:1
13:1
2
3
3aa, (3R,4S)-(−)-Methyl 4-benzoyl-2-methylene-3-phenyl-
hex-5-enoate. Yellow wax: 23 mg (0.1 mmol), 72% yield; 95% ee;
dr = 20:1; [α]2D2 −219.68 (c 0.40, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.48 (t, J
= 7.6 Hz, 2H), 7.29 (d, J = 4.2 Hz, 4H), 7.21 (m, 1H), 6.14 (s, 1H),
5.61 (m, 2H), 5.05−4.94 (m, 2H), 4.84 (dd, J = 11.3, 8.7 Hz, 1H),
4.61 (d, J = 11.3 Hz, 1H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 199.1, 166.7, 142.3, 139.8, 136.9, 135.1, 133.2, 129.0, 128.7, 128.5,
128.4, 128.2, 126.8, 123.8, 119.9, 55.0, 51.9, 48.7; HRMS (ESI) m/z
321.1487 (M + H+), calc. for C21H21O3 321.1491. The ee was
determined by HPLC analysis: AMYLOSE-2 (4.6 mm i.d. × 250 mm);
hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 230 nm;
retention time 9.8 min (major) and 12.6 min (minor).
4
5
6
2g, 3-ClC6H4
2h, 3-BrC6H4
2i, 2-FC6H4
3ag
3ah
3ai
7
8
9
2j, 2-ClC6H4
2k, 4-CH3C6H4
2l, 3-CH3OC6H4
2m, 2-naphthyl
2n, 2-thienyl
3aj
10
11
12
13
3ak
3al
3am
3an
a
The reaction was carried out with 0.3 mmol of 1a, 0.1 mmol of 2 and
b
c
0.01 mmol of (DHQD)2PYR in 1.0 mL of CH3CN. Isolated yield. ee
values were determined by chiral HPLC analysis. Determined by
crude H NMR.
3ab, (3R,4S)-(−)-Methyl 4-benzoyl-3-(4-fluorophenyl)-2-
d
methylenehex-5-enoate. Yellow oil: 26 mg (0.1 mmol), 77%
1
yield; 93% ee; dr = 20:1; [α]2D2 −238.69 (c 0.26, CHCl3); H NMR
1
(400 MHz, CDCl3) δ 8.02 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.4 Hz,
1H), 7.48 (t, J = 7.6 Hz, 2H), 6.97 (t, J = 8.7 Hz, 2H), 6.14 (s, 1H),
5.66−5.51 (m, 2H), 5.01 (dd, J = 13.6, 7.9 Hz, 2H), 4.78 (dd, J = 11.3,
8.8 Hz, 1H), 4.59 (d, J = 11.3 Hz, 1H), 3.63 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.9, 166.6, 162.9, 160.5, 142.1, 136.7, 135.6, 135.0,
133.3, 130.5, 130.4, 128.7, 128.4, 123.9, 120.2, 115.2, 115.0, 55.1, 51.9,
48.0; HRMS (ESI) m/z 361.1208 (M + Na+), calc. for C21H19FO3Na
361.1210. The ee was determined by HPLC analysis: AMYLOSE-2;
hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm;
retention time 8.5 min (major) and 13.9 min (minor).
Table 3. Allylic Alkylation between β,γ-Unsaturated Ketones
1 and MBH Carbonates 2
a
b
c
d
entry
1, Ar1
2
3
yield (%)
ee (%)
dr
1
2
1b, 2-FC6H4
2a
2a
2a
2a
2a
2a
2h
2j
3ba
3ca
3da
3ea
3fa
68
71
77
68
67
83
65
71
72
53
>99
90
92
94
97
98
96
96
92
96
20:1
20:1
33:1
33:1
3:1
3ac, (3R,4S)-(−)-Methyl 4-benzoyl-3-(4-chlorophenyl)-2-
1c, 4-ClC6H4
methylenehex-5-enoate. Yellow oil: 27 mg (0.1 mmol), 75%
yield; 92% ee; dr = 20:1; [α]2D2 −188.92 (c 0.27, CHCl3); H NMR
3
1d, 4-MeOC6H4
1e, 3-MeOC6H4
1f, 2-MeOC6H4
1g, 2-thienyl
1
4
(400 MHz, CDCl3) δ 8.01 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.3 Hz,
1H), 7.48 (t, J = 7.5 Hz, 2H), 7.26−7.15 (m, 4H), 6.14 (s, 1H), 5.65−
5.50 (m, 2H), 5.01 (dd, J = 13.8, 7.0 Hz, 2H), 4.83−4.71 (m, 1H),
4.58 (d, J = 11.4 Hz, 1H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 198.8, 166.5, 141.9, 138.5, 136.7, 134.8, 133.3, 132.6, 130.4, 128.8,
128.7, 128.6, 128.4, 128.4, 124.1, 120.3, 54.9, 51.9, 48.2; HRMS (ESI)
m/z 377.0927 (M + Na+), calc. for C21H19ClO3Na 377.0920. The ee
was determined by HPLC analysis: AMYLOSE-2; hexane/2-propanol
= 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time 8.9
min (major) and 12.5 min (minor).
5
6
3ga
3eh
3ej
20:1
13:1
50:1
25:1
13:1
7
1e, 3-MeOC6H4
1e, 3-MeOC6H4
1h, 3-BrC6H4
1h, 3-BrC6H4
8
9
2j
3hj
3hl
10
2l
a
The reaction was carried out with 0.3 mmol of 1, 0.1 mmol of 2 and
b
c
0.01 mmol of (DHQD)2PYR in 1.0 mL of CH3CN. Isolated yield. ee
values were determined by chiral HPLC analysis. Determined by
crude H NMR.
d
3ad, (3R,4S)-(−)-Methyl 4-benzoyl-3-(4-bromophenyl)-2-
1
methylenehex-5-enoate. Yellow oil: 32 mg (0.1 mmol), 80%
yield; 92% ee; dr = 20:1; [α]2D2 −267.33 (c 0.32, CHCl3); H NMR
1
Scheme 1. Preparation of Chiral Cyclohexene 4 from Allylic
Alkylation Adduct 3aa
(400 MHz, CDCl3) δ 8.01 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.3 Hz,
1H), 7.48 (t, J = 7.5 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1
Hz, 2H), 6.14 (s, 1H), 5.65−5.50 (m, 2H), 5.02 (dd, J = 13.7, 7.9 Hz,
2H), 4.84−4.73 (m, 1H), 4.56 (d, J = 11.3 Hz, 1H), 3.63 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 198.7, 166.5, 141.8, 139.0, 136.7, 134.8,
133.3, 131.4, 130.8, 128.7, 128.6, 128.4, 124.2, 120.7, 120.4, 54.8, 52.0,
48.3; HRMS (ESI) m/z 421.0417 (M + Na+), calc. for C21H19BrO3Na
421.0415. The ee was determined by HPLC analysis: AMYLOSE-2;
hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm;
retention time 10.2 min (major) and 14.1 min (minor).
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Note
1
3ae, (3S,4S)-(−)-Methyl 4-benzoyl-3-(2,4-dichlorophenyl)-2-
methylenehex-5-enoate. Pale yellow oil: 32 mg (0.1 mmol), 82%
70% yield; 94% ee; dr = 50:1; [α]2D2 −252.98 (c 1.90, CHCl3); H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.3
Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.21 (t, J =
7.3 Hz, 1H), 7.14 (t, J = 7.1 Hz, 1H), 6.22 (s, 1H), 5.78−5.57 (m,
2H), 5.26 (d, J = 11.2 Hz, 1H), 5.05−4.92 (m, 2H), 4.86 (s, 1H), 3.61
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.6, 166.6, 162.6, 160.1,
140.6, 136.7, 134.7, 133.3, 130.6, 130.6, 128.7, 128.5, 128.4, 128.4,
127.0, 125.0, 123.9, 123.9, 120.2, 115.6, 115.4, 54.1, 51.9, 42.3; HRMS
(ESI) m/z 377.0919 (M + Na+), calc. for C21H19ClO3Na 377.0920.
The ee was determined by HPLC analysis: AMYLOSE-2; hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 230 nm; retention
time 8.3 min (minor) and 9.9 min (major).
yield; 91% ee; dr = 20:1; [α]2D2 −278.56 (c 0.32, CHCl3); H NMR
1
(400 MHz, CDCl3) δ 8.05−7.99 (m, 2H), 7.62−7.55 (m, 1H), 7.48 (t,
J = 7.6 Hz, 2H), 7.37 (d, J = 2.1 Hz, 1H), 7.28 (s, 1H), 7.19 (dd, J =
8.4, 2.1 Hz, 1H), 6.23 (s, 1H), 5.71−5.58 (m, 2H), 5.20 (d, J = 11.3
Hz, 1H), 5.01 (dd, J = 13.7, 3.0 Hz, 2H), 4.83 (s, 1H), 3.61 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 198.2, 166.3, 136.5, 136.2, 135.9,
133.8, 133.4, 132.9, 129.4, 128.7, 128.4, 127.0, 126.0, 120.7, 51.9;
HRMS (ESI) m/z 411.0529 (M + Na+), calc. for C21H18Cl2O3Na
411.0531. The ee was determined by HPLC analysis: AMYLOSE-2;
hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm;
retention time 7.7 min (minor) and 8.6 min (major).
3ak, (3R,4S)-Methyl 4-benzoyl-2-methylene-3-p-tolylhex-5-
enoate. Yellow oil: 23 mg (0.1 mmol), 68% yield; 93% ee; dr = 14:1;
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.3 Hz, 2H), 7.57 (t, J =
3af, (3R,4S)-Methyl 4-benzoyl-3-(3-fluorophenyl)-2-methyl-
enehex-5-enoate. Yellow oil: 25 mg (0.1 mmol), 73% yield; 93% ee;
1
dr = 14:1; H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 5.4 Hz, 2H),
7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.09 (d,
J = 7.9 Hz, 2H), 6.11 (s, 1H), 5.69−5.52 (m, 2H), 5.05−4.94 (m, 2H),
4.83 (dd, J = 11.2, 8.7 Hz, 1H), 4.57 (d, J = 11.2 Hz, 1H), 3.63 (s, 3H),
2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 166.7, 142.5,
136.9, 136.8, 136.3, 135.2, 133.1, 129.0, 128.9, 128.7, 128.4, 123.6,
119.8, 55.0, 51.9, 48.4, 21.1; HRMS (ESI) m/z 357.1464 (M + Na+),
calc. for C22H22O3Na 357.1467. The ee was determined by HPLC
analysis: AMYLOSE-2; hexane/2-propanol = 80/20; flow rate 1.0 mL/
min; 25 °C; 230 nm; retention time 9.2 min (major) and 13.2 min
(minor).
7.62−7.54 (m, 1H), 7.52−7.44 (m, 2H), 7.25 (d, J = 2.2 Hz, 1H), 7.07
(d, J = 6.1 Hz, 1H), 6.99 (d, J = 10.0 Hz, 1H), 6.89 (dd, J = 11.8, 4.8
Hz, 1H), 6.16 (d, J = 4.0 Hz, 1H), 5.67−5.50 (m, 2H), 5.01 (dd, J =
10.5, 7.2 Hz, 2H), 4.78 (t, J = 8.3 Hz, 1H), 4.60 (d, J = 9.3 Hz, 1H),
3.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.7, 166.5, 164.0,
142.6, 141.8, 136.7, 134.8, 133.3, 129.7, 129.6, 128.7, 128.6, 128.4,
124.9, 124.3, 120.3, 115.8, 115.6, 113.9, 113.7, 55.0, 52.0, 48.5; HRMS
(ESI) m/z 361.1215 (M + Na+), calc. for C21H19FO3Na 361.1216. The
ee was determined by HPLC analysis: AMYLOSE-2; hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time 8.3 min (major) and 12.3 min (minor).
3al, (3R,4S)-(−)-Methyl 4-benzoyl-3-(3-methoxyphenyl)-2-
methylenehex-5-enoate. Yellow foam: 25 mg (0.1 mmol), 70%
yield; 95% ee; dr = 25:1; [α]2D2 −267.40 (c 1.90, CHCl3); H NMR
1
3ag, (3R,4S)-(−)-Methyl 4-benzoyl-3-(3-chlorophenyl)-2-
methylenehex-5-enoate. Yellow oil: 25 mg (0.1 mmol), 71%
(400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.3 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 7.7
Hz, 1H), 6.84 (s, 1H), 6.75 (dd, J = 8.2, 2.4 Hz, 1H), 6.13 (s, 1H),
5.69−5.54 (m, 2H), 5.06−4.96 (m, 2H), 4.81 (dd, J = 11.3, 8.7 Hz,
1H), 4.57 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.64 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 199.1, 166.7, 159.4, 142.2, 141.5, 136.8, 135.1,
133.2, 129.2, 128.7, 128.3, 123.9, 121.5, 119.9, 115.1, 111.7, 55.2, 55.0,
51.9, 48.7; HRMS (ESI) m/z 373.1418 (M + Na+), calc. for
C22H22O4Na 373.1416. The ee was determined by HPLC analysis:
AMYLOSE-2; hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25
°C; 254 nm; retention time 13.1 min (major) and 15.4 min (minor).
3am, (3R,4S)-(−)-Methyl 4-benzoyl-2-methylene-3-(naph-
thalen-2-yl)hex-5-enoate. Colorless foam: 27 mg (0.1 mmol),
yield; 93% ee; dr = 25:1; [α]2D2 −205.49 (c 0.32, CHCl3); H NMR
1
(400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.3 Hz,
1H), 7.48 (t, J = 7.6 Hz, 2H), 7.20 (m, 4H), 6.17 (s, 1H), 5.69−5.49
(m, 2H), 5.02 (dd, J = 13.6, 6.6 Hz, 2H), 4.84−4.71 (m, 1H), 4.58 (d,
J = 11.4 Hz, 1H), 3.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.6,
166.4, 142.1, 141.6, 136.6, 134.7, 134.0, 133.3, 129.5, 128.8, 128.7,
128.6, 128.4, 127.6, 127.0, 124.3, 120.4, 54.9, 52.0, 48.3; HRMS (ESI)
m/z 377.0919 (M + Na+), calc. for C21H19ClO3Na 377.0920. The ee
was determined by HPLC analysis: AMYLOSE-2; hexane/2-propanol
= 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time 8.5
min (major) and 10.5 min (minor).
3ah, (3R,4S)-(−)-Methyl 4-benzoyl-3-(3-bromophenyl)-2-
72% yield; 91% ee; dr = 25:1; [α]2D2 −275.77 (c 0.60, CHCl3); H
1
methylenehex-5-enoate. Pale yellow oil: 28 mg (0.1 mmol), 70%
yield; 94% ee; dr = 25:1; [α]2D2 −249.32 (c 1.70, CHCl3); H NMR
1
NMR (400 MHz, CDCl3) δ 8.09−8.03 (m, 2H), 7.78 (m, 4H), 7.62−
7.56 (m, 1H), 7.53−7.41 (m, 5H), 6.18 (s, 1H), 5.70−5.57 (m, 2H),
5.04−4.87 (m, 3H), 4.79 (d, J = 11.5 Hz, 1H), 3.61 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 178.8, 168.4, 143.3, 139.2, 138.2, 131.4, 128.8,
128.6, 128.5, 127.6, 127.5, 127.1, 126.4, 124.7, 123.0, 108.7, 54.4, 44.1,
43.2, 26.5; HRMS (ESI) m/z 371.1646 (M + H+), calc. for C25H23O3
371.1647. The ee was determined by HPLC analysis: AD-H; hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 210 nm; retention
time 8.2 min (minor) and 9.1 min (major).
(400 MHz, CDCl3) δ 8.06−7.99 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H),
7.48 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 1.6 Hz, 1H), 7.37−7.31 (m, 1H),
7.23 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.17 (s, 1H), 5.65−
5.51 (m, 2H), 5.03 (dd, J = 13.7, 8.1 Hz, 2H), 4.77 (dd, J = 11.4, 8.7
Hz, 1H), 4.57 (d, J = 11.4 Hz, 1H), 3.64 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.6, 166.4, 142.4, 141.6, 136.7, 134.7, 133.3, 131.7,
130.0, 129.8, 128.7, 128.4, 128.1, 124.4, 122.3, 120.4, 54.9, 52.0, 48.4;
HRMS (ESI) m/z 399.0599 (M + H+), calc. for C21H20O3Br 399.0596.
The ee was determined by HPLC analysis: AMYLOSE-2; hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time 8.2 min (major) and 10.0 min (minor).
3an, (3S,4S)-Methyl 4-benzoyl-2-methylene-3-(thiophen-2-
yl)hex-5-enoate. Dark yellow oil: 26 mg (0.1 mmol), 79% yield; 90%
ee; dr = 13:1; 1H NMR (400 MHz, CDCl3) δ 8.05−8.00 (m, 2H), 7.57
(m, 1H), 7.47 (dd, J = 10.4, 4.7 Hz, 3H), 7.17 (dd, J = 5.0, 1.3 Hz,
1H), 6.92 (m, 2H), 6.14 (s, 1H), 5.78−5.63 (m, 2H), 5.15−5.06 (m,
2H), 4.91−4.87 (m, 2H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 198.8, 166.5, 143.6, 142.0, 136.5, 134.8, 133.3, 128.7, 128.5, 128.5,
126.6, 126.3, 124.8, 124.4, 120.3, 56.0, 52.0, 44.3; HRMS (ESI) m/z
327.1056 (M + H+), calc. for C19H19O3S 327.1055. The ee was
determined by HPLC analysis: AD-H (4.6 mm i.d. × 250 mm);
hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 210 nm;
retention time 6.1 min (minor) and 6.9 min (major).
3ai, (3S,4S)-(−)-Methyl 4-benzoyl-3-(2-fluorophenyl)-2-
methylenehex-5-enoate. Pale yellow wax: 24 mg (0.1 mmol),
72% yield; 94% ee; dr = 25:1; [α]2D2 −228.01 (c 1.50, CHCl3); H
1
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.3
Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.32 (td, J = 7.6, 1.5 Hz, 1H), 7.19
(td, J = 7.3, 1.5 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.04−6.95 (m, 1H),
6.20 (s, 1H), 5.74−5.56 (m, 2H), 5.13−4.88 (m, 4H), 3.64 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 198.6, 166.6, 162.5, 160.1, 140.6,
136.7, 134.7, 133.3, 130.6, 130.6, 128.7, 128.5, 128.4, 128.4, 127.2,
127.0, 125.0, 123.9, 123.9, 120.2, 115.6, 115.4, 54.1, 51.9, 42.3; HRMS
(ESI) m/z 361.1217 (M + Na+), calc. for C21H19FO3Na 361.1216. The
ee was determined by HPLC analysis: AMYLOSE-2; hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time 8.6 min (minor) and 11.8 min (major).
3ba, (3R,4S)-(−)-Methyl 4-(2-fluorobenzoyl)-2-methylene-3-
phenylhex-5-enoate. Yellow oil: 23 mg (0.1 mmol), 68% yield;
>99% ee; dr = 20:1; [α]2D2 −198.76 (c 1.50, CHCl3); H NMR (400
1
MHz, CDCl3) δ 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.52 (m, 1H), 7.29−
7.26 (m, 4H), 7.23−7.11 (m, 3H), 6.19 (s, 1H), 5.70 (s, 1H), 5.62−
5.44 (m, 1H), 4.99 (t, J = 12.7 Hz, 2H), 4.78 (dd, J = 11.4, 8.7 Hz,
1H), 4.59 (dd, J = 11.4, 1.8 Hz, 1H), 3.65 (s, 3H); 13C NMR (100
3aj, (3S,4S)-(−)-Methyl 4-benzoyl-3-(2-chlorophenyl)-2-
methylenehex-5-enoate. Pale yellow wax: 25 mg (0.1 mmol),
5070
dx.doi.org/10.1021/jo400496z | J. Org. Chem. 2013, 78, 5067−5072

The Journal of Organic Chemistry
Note
MHz, CDCl3) δ 197.7, 197.6, 166.8, 162.6, 160.0, 142.6, 139.9, 134.6,
134.5, 134.4, 131.3, 131.3, 129.0, 128.2, 126.7, 124.6, 124.6, 123.7,
120.1, 116.8, 116.6, 59.3, 59.2, 51.9, 48.3; HRMS (ESI) m/z 339.1400
(M + H+), calc. for C21H20FO3 339.1396. The ee was determined by
HPLC analysis: AD-H; hexane/2-propanol = 80/20; flow rate 1.0 mL/
min; 25 °C; 254 nm; retention time 13.4 min (minor) and 14.9 min
(major).
3ca, (3R,4S)-Methyl 4-(4-chlorobenzoyl)-2-methylene-3-
phenylhex-5-enoate. Colorless solid: mp 135.5−137.9 °C; 25 mg
(0.1 mmol), 71% yield; 90% ee; dr = 20:1; [α]2D2 −263.58 (c 2.50,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 2H), 7.45
(d, J = 8.6 Hz, 2H), 7.30−7.27 (m, 4H), 7.23−7.17 (m, 1H), 6.13 (s,
1H), 5.64−5.52 (m, 2H), 4.99 (t, J = 12.9 Hz, 2H), 4.79 (dd, J = 11.3,
8.7 Hz, 1H), 4.57 (d, J = 11.3 Hz, 1H), 3.63 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.1, 166.8, 142.4, 139.9, 139.8, 135.2, 135.0, 130.0,
129.2, 129.1, 128.5, 127.0, 124.1, 120.3, 55.2, 52.1, 49.0; HRMS (ESI)
m/z 355.1108 (M + H+), calc. for C21H20O3Cl 355.1101. The ee was
determined by HPLC analysis: AD-H; hexane/2-propanol = 95/05;
flow rate 1.0 mL/min; 25 °C; 254 nm; retention time 8.2 min (minor)
and 10.2 min (major).
analysis: AD-H; hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
25 °C; 210 nm; retention time 5.3 min (minor) and 6.6 min (major).
3eh, (3R,4S)-Methyl 3-(3-bromophenyl)-4-(3-methoxyben-
zoyl)-2-methylenehex-5-enoate. Yellow oil: 28 mg (0.1 mmol),
65% yield; 96% ee; dr = 13:1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d,
J = 7.7 Hz, 1H), 7.51 (dd, J = 2.4, 1.7 Hz, 1H), 7.42−7.36 (m, 2H),
7.36−7.32 (m, 1H), 7.24−7.13 (m, 3H), 6.17 (s, 1H), 5.64−5.51 (m,
2H), 5.02 (dd, J = 13.6, 10.1 Hz, 2H), 4.73 (dd, J = 11.4, 8.7 Hz, 1H),
4.56 (d, J = 11.4 Hz, 1H), 3.85 (s, 3H), 3.65 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.5, 166.4, 159.9, 142.3, 141.6, 138.0, 134.7, 131.7,
130.0, 129.8, 129.7, 128.0, 124.4, 122.3, 120.9, 120.4, 119.8, 112.8,
55.4, 55.0, 52.0, 48.3; HRMS (ESI) m/z 429.0702 (M + H+), calc. for
C22H22O4Br 429.0701. The ee was determined by HPLC analysis: AD-
H; hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 210
nm; retention time 6.2 min (minor) and 8.1 min (major).
3ej, (3S,4S)-(−)-Methyl 3-(2-chlorophenyl)-4-(3-methoxy-
benzoyl)-2-methylenehex-5-enoate. Yellow oil: 27 mg (0.1
mmol), 71% yield; 96% ee; dr = 50:1; [α]2D2 −281.75 (c 1.71,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.53
(dd, J = 2.4, 1.7 Hz, 1H), 7.43−7.29 (m, 3H), 7.20 (td, J = 7.5, 1.4 Hz,
1H), 7.17−7.07 (m, 2H), 6.23 (s, 1H), 5.75−5.60 (m, 2H), 5.26 (d, J
= 11.2 Hz, 1H), 4.98 (dd, J = 13.9, 3.0 Hz, H), 4.82 (s, 1H), 3.85 (s,
3H), 3.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.4, 166.5,
159.9, 140.7, 138.0, 137.4, 135.3, 134.1, 129.7, 129.7, 127.9, 126.6,
125.6, 120.9, 120.3, 119.7, 112.8, 55.4, 51.9; HRMS (ESI) m/z
385.1212 (M + H+), calc. for C22H22O4Cl 385.1207. The ee was
determined by HPLC analysis: AD-H; hexane/2-propanol = 90/10;
flow rate 1.0 mL/min; 25 °C; 210 nm; retention time 6.6 min (minor)
and 9.7 min (major).
3hj, (3S,4S)-(−)-Methyl 4-(3-bromobenzoyl)-3-(2-chloro-
phenyl)-2-methylenehex-5-enoate. Colorless oil: 31 mg (0.1
mmol), 72% yield; 92% ee; dr = 25:1; [α]2D2 −132.32 (c 1.70, CHCl3);
1H NMR (400 MHz, CDCl3) δ 8.13 (t, J = 1.7 Hz, 1H), 8.06−7.93
(m, 1H), 7.70 (m, 1H), 7.40−7.31 (m, 3H), 7.21 (m, 1H), 7.17−7.09
(m, 1H), 6.23 (s, 1H), 5.72−5.59 (m, 2H), 5.23 (d, J = 11.5 Hz, 1H),
5.04−4.94 (m, 2H), 4.81 (s, 1H), 3.62 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.3, 166.5, 138.4, 137.1, 136.1, 135.2, 133.7, 131.4, 130.3,
129.7, 128.7, 128.4, 128.0, 126.9, 126.7, 126.6, 125.8, 123.1, 120.8,
51.9; HRMS (ESI) m/z 433.0203 (M + H+), calc. for C21H19O3ClBr
433.0206. The ee was determined by HPLC analysis: AMYLOSE-2;
hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm;
retention time 7.2 min (minor) and 8.2 min (major).
3da, (3R,4S)-(−)-Methyl 4-(4-methoxybenzoyl)-2-methylene-
3-phenylhex-5-enoate. Yellow oil: 27 mg (0.1 mmol), 77% yield;
92% ee; dr = 33:1; [α]2D2 −112.37 (c 0.71, CHCl3); H NMR (400
1
MHz, CDCl3) δ 8.02 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 4.3 Hz, 4H),
7.20 (m, 1H), 6.95 (d, J = 8.9 Hz, 2H), 6.13 (s, 1H), 5.66−5.52 (m,
2H), 5.01−4.90 (m, 2H), 4.77 (dd, J = 11.5, 8.7 Hz, 1H), 4.59 (d, J =
11.5 Hz, 1H), 3.87 (s, 3H), 3.63 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.6, 166.7, 163.6, 142.3, 140.0, 135.5, 130.7, 129.8, 129.1,
128.2, 126.7, 123.7, 119.6, 113.9, 55.5, 54.7, 51.9, 48.6; HRMS (ESI)
m/z 351.1597 (M + H+), calc. for C22H23O4 351.1596. The ee was
determined by HPLC analysis: IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 85/15; flow rate 1.0 mL/min; 25 °C; 210 nm; retention
time 7.0 min (minor) and 7.8 min (major).
3ea, (3R,4S)-(−)-Methyl 4-(3-methoxybenzoyl)-2-methylene-
3-phenylhex-5-enoate. Yellow oil: 24 mg (0.1 mmol), 68% yield;
1
94% ee; dr = 33:1; [α]2D2 −241.11 (c 0.82, CHCl3); H NMR (400
MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.36 (m, 4H),
7.20 (dd, J = 10.8, 4.2 Hz, 1H), 7.16−7.09 (m, 2H), 6.23 (s, 1H),
5.74−5.61 (m, 2H), 5.26 (d, J = 11.2 Hz, 1H), 4.98 (dd, J = 13.6, 3.0
Hz, 2H), 4.82 (s, 1H), 3.85 (s, 3H), 3.61 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.4, 166.5, 159.9, 140.7, 138.1, 137.5, 135.3, 134.2,
129.7, 129.7, 127.9, 126.6, 125.6, 120.9, 120.3, 119.7, 112.8, 55.4, 51.9;
HRMS (ESI) m/z 351.1592 (M + H+), calc. for C22H23O4 351.1596.
The ee was determined by HPLC analysis: AMYLOSE-2; hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time 8.7 min (minor) and 10.0 min (major).
3hl, (3R,4S)-Methyl 4-(3-bromobenzoyl)-3-(3-methoxyphen-
yl)-2-methylenehex-5-enoate. Yellow oil: 28 mg (0.1 mmol), 53%
1
yield; 96% ee; dr = 13:1; H NMR (400 MHz, CDCl3) δ 8.11 (t, J =
1.7 Hz, 1H), 7.96 (m, 1H), 7.69 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H),
7.21 (t, J = 7.9 Hz, 1H), 6.91−6.80 (m, 2H), 6.79−6.71 (m, 1H), 6.14
(s, 1H), 5.66−5.53 (m, 2H), 5.02 (t, J = 13.3 Hz, 2H), 4.74 (dd, J =
11.4, 8.6 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H), 3.80 (s, 3H), 3.65 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 197.8, 166.6, 159.5, 142.1,
141.2, 138.6, 136.0, 134.6, 131.4, 130.3, 129.2, 128.7, 128.4, 126.9,
124.0, 123.1, 121.4, 120.3, 115.1, 111.8, 55.2, 55.1, 52.0, 48.8; HRMS
(ESI) m/z 429.0695 (M + H+), calc. for C22H22O4Br 429.0701. The ee
was determined by HPLC analysis: AMYLOSE-2; hexane/2-propanol
= 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time 10.0
min (major) and 13.5 min (minor).
4, (1R,2R)-(−)-Methyl 3-benzoyl-2-phenylcyclohex-3-enecar-
boxylate. 0.63 mL of tBuLi solution (1.6 M in pentane) (10 equiv)
was added dropwise into a solution of 3aa (0.1 mmol) in 5 mL of dry
THF at −78 °C. After being stirred for 10 min at that temperature, the
mixture was slowly warmed up to 50 °C and stirred for 10 min. Then
the mixture was cooled to 0 °C, quenched by NH4Cl (Sat.) solution,
extracted by ethyl acetate, dried over Na2SO4, and purified by flash
chromatography using gradient elution with petroleum ether/ethyl
acetate (20:1 to 10:1) to afford 4, 16 mg (0.1 mmol), 51% yield as a
colorless foam: 95% ee; [α]2D2 −97.94 (c 0.25, CHCl3); 1H NMR (400
MHz, CDCl3) 7.61 (d, J = 7.9 Hz, 2H), 7.44 (dt, J = 14.2, 7.5 Hz, 4H),
7.23−7.12 (m, 4H), 6.77 (s, 1H), 4.76 (d, J = 4.9 Hz, 1H), 3.56 (s,
3H), 2.97−2.87 (m, 1H), 2.67−2.60 (m, 1H), 2.43−2.29 (m, 1H),
2.04−1.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 196.1, 173.5,
3fa, (3R,4S)-Methyl 4-(2-methoxybenzoyl)-2-methylene-3-
phenylhex-5-enoate. Yellow wax: 23 mg (0.1 mmol), 67% yield;
97% ee; dr = 3:1; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 7.7, 1.7
Hz, 1H), 7.49−7.42 (m, 1H), 7.26 (s, 1H), 7.25 (s, 2H), 7.20−7.14
(m, 1H), 7.14−7.05 (m, 1H), 7.02−6.96 (m, 2H), 6.20 (s, 1H), 5.76
(s, 1H), 5.55 (m, 1H), 5.01−4.86 (m, 3H), 4.56 (d, J = 11.4 Hz, 1H),
3.94 (s, 3H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 201.3,
166.6, 158.1, 142.6, 140.4, 135.4, 133.5, 131.3, 129.1, 128.8, 128.3,
128.1, 128.0, 126.5, 124.1, 120.8, 119.2, 111.7, 59.0, 55.5, 51.8, 48.6;
HRMS (ESI) m/z 351.1600 (M + H+), calc. for C22H23O4 351.1596.
The ee was determined by HPLC analysis: CHIRALCEL IA (4.6 mm
i.d. × 250 mm); hexane/2-propanol = 99/1; flow rate 1.0 mL/min; 25
°C; 254 nm; retention time 27.5 min (minor) and 31.2 min (major).
3ga, (3R,4S)-(−)-Methyl 2-methylene-3-phenyl-4-(thio-
phene-2-carbonyl)hex-5-enoate. Yellow solid: mp 138.5−140.2
°C; 27 mg (0.1 mmol), 83% yield; 98% ee; dr = 20:1; [α]2D2 −244.87 (c
1
1.20, CHCl3); H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 3.8, 1.0
Hz, 1H), 7.67 (dd, J = 4.9, 1.1 Hz, 1H), 7.28 (d, J = 4.4 Hz, 4H), 7.18
(m, 2H), 6.17 (s, 1H), 5.72 (s, 1H), 5.68−5.54 (m, 1H), 5.07−4.94
(m, 2H), 4.61 (m, 2H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.8, 166.6, 144.0, 141.9, 139.6, 135.1, 134.2, 132.1, 129.0, 128.3,
126.8, 124.1, 119.9, 57.0, 51.9, 48.4; HRMS (ESI) m/z 327.1050 (M +
H+), calc. for C19H19O3S 327.1055. The ee was determined by HPLC
5071
dx.doi.org/10.1021/jo400496z | J. Org. Chem. 2013, 78, 5067−5072

The Journal of Organic Chemistry
Note
143.0, 139.5, 139.0, 138.4, 131.6, 129.2, 129.1, 128.1, 128.1, 127.1,
120.0, 51.3, 44.6, 40.6, 29.7, 25.5; HRMS (ESI) m/z 321.1491 (M +
H+), calc. for C21H21O3 321.1492. The ee was determined by HPLC
analysis: AD-H; hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
25 °C; 254 nm; retention time 7.4 min (minor) and 9.6 min (major).
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ASSOCIATED CONTENT
* Supporting Information
■
S
General information, HPLC spectra of chiral products,
crystallographic data of 3ga, and NMR spectra of the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) Lin, A.; Mao, H.; Zhu, X.; Ge, H.; Tan, R.; Zhu, C.; Cheng, Y.
Chem.Eur. J. 2011, 17, 13676.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chmjzy@henu.edu.cn.
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (No. 21072044, 21202034), the Program
for New Century Excellent Talents in University of Ministry of
Education (NCET-11-0938), Excellent Youth Foundation of
Henan Scientific Committee (114100510003) and Specialized
Research Fund for the Doctoral Program of Higher Education
(20104103120002) are greatly appreciated. We also thank
Professor Choon-Hong Tan (Nanyang Technological Univer-
sity, Singapore) and Professor Fuwei Li (Lanzhou Institute of
Chemical Physics, PR China) for their generous help in high
resolution mass spectrum analysis.
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