Enantioselective intramolecular Morita-Baylis-Hillman reaction using chiral bifunctional phosphinothiourea as an organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2010.04.061

Chiral cyclohexane-based phosphinothioureas were found to be efficient organocatalysts for the enantioselective intramolecular Morita-Baylis-Hillman reaction of ω-formyl-enone. Among the solvents screened, t-BuOH was the best one which provided good yield

Full text of DOI:10.1016/j.tetasy.2010.04.061

Tetrahedron: Asymmetry 21 (2010) 903–908
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Tetrahedron: Asymmetry
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Enantioselective intramolecular Morita–Baylis–Hillman reaction using
chiral bifunctional phosphinothiourea as an organocatalyst
Kui Yuan a, Hong-Liang Song a, Yinjun Hu a, Jian-Fei Fang a, Xin-Yan Wu a,b,
*
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral cyclohexane-based phosphinothioureas were found to be efficient organocatalysts for the enantio-
Received 9 March 2010
Accepted 20 April 2010
Available online 16 June 2010
selective intramolecular Morita–Baylis–Hillman reaction of
x-formyl-enone. Among the solvents
screened, t-BuOH was the best one which provided good yield and enantioselectivity. Moreover in the
presence of 3 mol % of phosphinothiourea 2b, the desired products were obtained in good-to-excellent
yields with up to 98% ee under mild reaction conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
phinothiourea is highly efficient for the intermolecular MBH reac-
tion between enone and aldehyde.9a Therefore, we have begun to
The Morita–Baylis–Hillman (MBH) reaction is a powerful tool to
construct densely functionalized -methylene-b-hydroxycarbonyl
examine the cyclohexane-based phosphinothiourea 2 for the intra-
molecular MBH reaction of -formyl-enone in order to explore
a
x
derivatives which could serve as valuable building blocks in organ-
ic synthesis.1 During the past decade, much effort was devoted to
promote the efficiency of this reaction.1,2 In an asymmetric version,
various chiral catalysts have been developed for intermolecular
MBH reactions.3 However, the exploration of the enantioselective
intramolecular MBH reaction is still a challenge and reports in this
area appear scarce. The first enantioselective intramolecular MBH
reaction was reported by Fráter in 1992,4 using (ꢀ)-CAMP as a cat-
alyst to provide the corresponding adduct with 14% ee. A major
contribution in this area was the accomplishment of a proline-cat-
alyzed intramolecular MBH reaction of hept-2-enedial, providing
98% ee with 74% yield by Hong et al. in 2005.5 Another enantiose-
lective organocatalytic intramolecular MBH reaction, using pipeco-
linic acid and N-methylimidazole as a cocatalytic system, was
developed by Miller with 84% ee.6 In the field of metal-catalyzed
reactions, Gladysz et al. reported the chiral rhenium-containing
more efficient catalysts (see Fig. 1).
2. Results and discussion
In our previous work, the phosphinothiourea 2a demonstrated a
high efficiency in the enantioselective MBH reaction between aro-
matic aldehydes with MVK.9a Therefore, we initiated our studies
with cyclohexane-based phosphinothiourea 2a (10 mol % catalyst
loading) as the catalyst and 3a as the substrate. The reaction was
performed at 25 °C in CH2Cl2 and we obtained the MBH product
4a in 81% yield with poor enantioselectivity (20% ee, Table 1, entry
1). Catalyst screening showed that phosphinothiourea 2b provided
the desired product in nearly quantitative yield with 76% ee (entry
2). Comparatively, amino acid-derived phosphinothiourea 1 could
complete this reaction with a shorter time to afford the product
with the same enantioselectivity (opposite configuration) but lower
yield (entry 8 vs 2). As illustrated in Table 1, compared to the cyclo-
hexane-based organocatalysts with aromatic thioureas, the corre-
sponding organocatalysts bearing aliphatic group at the thiourea
moieties provided poor enantioselectivity and a longer time was re-
quired to accomplish the reaction (entries 5–7 vs 2–4). Catalyst 2c
containing an electron-rich group at a phenyl ring provided poor
yield together with by-products. On the other hand, catalysts con-
taining an electron-deficient substituent at a phenyl group could
improve the enantioselectivity (entries 2 and 4 vs 1 and 3). Decreas-
ing the catalyst loading of 2b to 5 mol % gave the MBH product in
90% yield with 82% ee (entry 9). However, further decreasing the
catalyst loading to 3 mol % resulted in an obvious decrease in yield
without the enhancement of enantioselectivity (entry 10 vs 9).
phosphine
(g
5-C5H5)Re(NO)(PPh3)(CH2PAr2)-catalyzed intramo-
lecular MBH reaction with 74% ee.7
It is well known that a phosphine (PR3) could activate the Mi-
chael acceptor to catalyze the diastereoselective intramolecular
MBH reaction,8 and chiral thiourea derivatives were efficient cata-
lysts for the intermolecular MBH reactions.3h–k,9 Very recently we
have developed a new family of phosphinothioureas derived from
amino acids and demonstrated their utility in the asymmetric
intramolecular MBH reaction;
L-phenylalanine-derived phos-
phinothiourea 1 could provide the cyclic products with up to 84%
ee.10 We have also found that the cyclohexane-based phos-
* Corresponding author. Tel.: +86 21 64252011; fax: +86 21 64252758.
E-mail address: xinyanwu@ecust.edu.cn (X.-Y. Wu).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.061

904
K. Yuan et al. / Tetrahedron: Asymmetry 21 (2010) 903–908
CF3
2a: R = C6H5
S
2b: R = 3,5-(CF3)2C6H3
2c: R = 4-MeOC6H4
2d: R = 4-ClC6H4
2e: R = n-C12H25
2f: R = c-C6H11
S
R
N
NH
H
Bn
HN
N
CF3
H
PPh2
2g: R = C6H5CH2
PPh2
1
2
Figure 1. Structures of the phosphinothiourea catalysts.
temperature from 25 °C to 40 °C provided almost the same enanti-
oselectivity (entry 21 vs 23). Therefore, the reaction conditions
using 3 mol % of 2b in t-BuOH (0.1 M) at 25 °C were chosen for fur-
ther investigation.
Table 1
Catalysts screening for the intramolecular MBH reaction of 3aa
O
OH
O
O
10 mol% Catalyst
Under the optimized conditions, the enantioselective intramo-
º
CH2Cl2, 25 C
lecular MBH reaction involving various
x-formyl-enone substrates
was investigated. As indicated in Table 3, all the substituted aro-
matic enones were converted to the corresponding products in
86–98% yields (entries 1–9 and 11–14), except substrate 3j bearing
an ortho-methyl group at the phenyl ring (63% yield, entry 10). The
substrates 3k–n with electron-rich substituents could obtain
excellent enantioselectivity (entries 11–14 and 90–98% ee). And
lower enantioselectivity was observed for the meta-substituted
substrates compared to their relevant para-substituted analogues
(entries 4 vs 5, 6 vs 7, and 11 vs 12). However, an ortho-substituent
at the phenyl group in the cases of substrates 3c and 3j had a del-
eterious effect on enantioselectivity, probably due to the ortho-ef-
fect (entries 3 and 10). The thiophene analogue 3o exhibited low
reactivity to give the corresponding adducts in 73% yield with
76% ee (entry 15). By comparing the specific rotation values with
those reported in the literature,6 the MBH adducts were assigned
an (S)-configuration.
The intramolecular MBH reaction of 3p and 3q was also inves-
tigated under the optimized conditions (Scheme 1). The five-mem-
bered ring enone 3p was converted to the corresponding product
4p with 42% yield and 89% ee after a reaction time of three days.
However, the seven-membered ring precursor 3q could not be cy-
clized under the typical conditions even after seven days. The re-
sults indicated that six-membered ring products could be easily
formed under the typical conditions. This is probably due to the ef-
fect of the strain that was generated from cyclization of intermedi-
ate to the product.
The phosphinothiourea 2b showed considerable stability toward
air oxidation. A single crystal could be obtained from a solution of 2b
in ethyl acetate/n-heptane or CH2Cl2/n-heptane by slow evapora-
tion.12 The X-ray analysis further confirmed the structure of 2b
(Fig. 2).
According to the above-mentioned experimental results and re-
lated reports,3h–k,9,10 a probable mechanism for the chiral phos-
phinothiourea-catalyzed intramolecular MBH was proposed
(Scheme 2). The thiourea moiety could activate the aldehyde moiety
by forming a hydrogen-bond with the oxygen atom of the carbonyl.
A nucleophilic addition of the phosphine to the b-position of the Mi-
chael acceptor generates an enolate. The cyclohexyl scaffold forces
the phosphinoyl-associated enolate to attack the activated carbonyl
from the si-face to generate the product with an (S)-configuration.
4a
3a
Entry
Catalyst
Time (days)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
1
2b
2b
4.5
1.5
1.5
1.5
4.5
4.5
4.5
0.5
3
81
99
42
76
80
63
90
83
90
59
20
76
25
49
26
36
20
ꢀ76
9d
10e
82
4
82
a
Unless stated otherwise, the reactions were performed with 10 mol % organo-
catalyst, 0.2 mmol 3a in 1.0 mL CH2Cl2 (0.2 M) at 25 °C.
b
Isolated yields.
c
The ee was determined by chiral HPLC, and the absolute configuration was
determined by comparison of specific rotation with that of a literature report.6
d
Using 5 mol % 2b as catalyst.
Using 3 mol % 2b as catalyst.
e
Next, 5 mol % of phosphinothiourea 2b was used to evaluate the
effect of solvent on the reaction (Table 2). In non-protic solvents ex-
cept CHCl3 and CH2Cl2, poor yields were obtained and a longer time
was required (entries 1–8). Nonpolar solvents such as n-hexane and
toluene afforded moderate enantioselectivity (entries 1 and 2). The
best enantioselectivity was obtained in acetone (91% ee), although
the chemical yield was unsatisfactory (64%, entry 6). Compara-
tively, a rate acceleration was observed in protic solvents, which
could act as a shuttle to reduce the proton-transfer energy to acti-
vate this reaction.11 Moreover tertiary alcohols provided better
enantioselectivity than secondary and primary alcohols (entries
15 and 16 vs 9–14). Among them, t-BuOH afforded the desired ad-
duct in 87% yield with 86% ee within 1.5 days, which was a more
suitable solvent in terms of enantioselectivity and yield (entry 15).
Encouraged by these results, we continued optimizing the reac-
tion conditions, including the substrate concentration, catalyst
loading and reaction temperature. As summarized in Table 2, the
substrate concentration was reduced from 0.4 M to 0.1 M with an
increase of the enantioselectivity from 76% ee to 86% ee (entries
17–19). However, lowering the substrate concentration from
0.1 M to 0.05 M did not have an appreciable effect on enantioselec-
tivity but caused a slight decrease in the chemical yield (entry 20
vs 19). The MBH reaction could be performed with a reduced
amount of catalyst loading, where an analogous result (85% ee,
92% yield) was achieved with 3 mol % and 5 mol % of catalyst (en-
try 21 vs 19), but further lowering of the catalyst loading to 1 mol %
led to a pronounced decrease in the yield (entry 22 vs 21). More-
over, the enantioselectivity and yield of the MBH reaction were
insensitive to the reaction temperature. Increasing the reaction
3. Conclusion
In summary, the chiral cyclohexane-based phosphinothiourea
2b was an efficient organocatalyst for the enantioselective intra-
molecular MBH reaction of
x-formyl-a,b-unsaturated carbonyl
compounds; using alcohols as a solvent could promote this
reaction. With 3 mol % of 2b in t-BuOH, the intramolecular MBH

K. Yuan et al. / Tetrahedron: Asymmetry 21 (2010) 903–908
905
Table 2
Reaction condition optimization of the intramolecular MBH reaction of 3a
O
OH
O
O
2b
º
Solvent, T C
4a
3a
Entry
Solvent
2b (mol %)
M (mol/L)
T (°C)
Time (days)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
n-Hexane
Toluene
CHCl3
CH2Cl2
THF
Acetone
CH3CN
DMF
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
1
3
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.3
0.1
0.05
0.1
0.1
0.1
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40
3
3
3
3
3
3
3
3
3
2.5
2
2
2
2
1.5
2
1.5
1.5
1.5
1.5
2
25
25
88
90
10
64
73
Trace
70
95
75
94
91
86
87
87
94
93
93
90
92
64
93
72
40
57
82
88
91
86
n.d.c
3
51
53
77
56
54
86
80
76
80
86
87
85
85
84
MeOH
EtOH
n-PrOH
i-PrOH
n-BuOH
i-BuOH
t-BuOH
t-Pentanol
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
3
1.5
a
b
c
Isolated yields.
Determined by chiral HPLC.
Not determined.
reaction could be carried out at room temperature to provide the
desired products in up to 98% ee and good-to-excellent yields
(up to 98%) without special precautions such as an inert atmo-
sphere. Further efforts are currently underway with a focus on
designing new bifunctional catalysts to improve the reaction
enantioselectivity and extend the substrate scope.
PE/EA/CH2Cl2) to afford the intramolecular MBH adduct 414 and
the ee value was determined by HPLC analysis with chiral column.
4.2.1. (S)-2-Benzoyl-1-hydroxycyclohex-2-ene 4a6,14
HPLC analysis (OD-H column, k = 254 nm, eluent: n-hexane/i-
propanol = 95/5, flow rate: 0.9 mL/min): tR = 13.4 min (minor),
16.6 min (major); ½a D25
¼ ꢀ36:1 (c 0.42, CHCl3, 85% ee).
ꢁ
4. Experimental
4.2.2. (S)-(6-Hydroxycyclohex-1-enyl)(4-nitrophenyl)
methanone 4b
4.1. General experimental
1H NMR (CDCl3, 400 MHz): d 8.29 (d, J = 8.0 Hz, 2H), 7.80 (d,
J = 8.0 Hz, 2H), 6.73 (s, 1H), 4.79 (s, 1H), 3.38 (s, 1H), 2.43–2.25 (m,
2H), 1.98–1.86 (m, 3H), 1.70–1.65 (m, 1H); 13C NMR
(CDCl3, 100 MHz): d 197.0, 149.5, 149.1, 143.4, 140.3, 130.0, 123.5,
All commercially available reagents were used without purifica-
tion and solvents were dried and distilled before use. 1H NMR and
13C NMR were recorded on a Bruker 400 spectrometer. Optical
rotations were measured on a WZZ-2A digital polarimeter at the
wavelength of the sodium D-line (589 nm). IR spectra were re-
corded on a Nicolet Magna-I 550 spectrometer. High Resolution
Mass spectra (HRMS) were recorded on a KE465 LCT Premier/XE
spectrometer. X-ray crystallographic data were collected on a Bru-
ker SMART APEX diffractometer at 293 (2) K. HPLC analysis was
performed on Waters 510 with 2487 detector using Daicel Chir-
alpak AS-H, AD-H, or Chiralcel OD-H column.
63.3, 29.8, 26.7, 17.3; IR (KBr, cmꢀ1):
m
3425, 2940, 2866, 1652,
1601, 1522, 1350, 1268, 987, 855, 726; HRMS (ESI) calcd for
13H13NO4Na ([M+Na]+)- 270.0742, found: 270.0750. HPLC analysis
C
(AS-H column, k = 254 nm, eluent: n-hexane/i-propanol = 90/10, flow
rate: 0.9 mL/min): tR = 20.5 min (minor), 44.9 min (major).
4.2.3. (S)-(2-Bromophenyl)(6-hydroxycyclohex-1-enyl)
methanone 4c14
HPLC analysis (AS-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 7.7 min (minor),
17.0 min (major).
4.2. General procedure for the asymmetric intramolecular MBH
reactions
Phosphinothiourea 2b (3.3 mg, 0.006 mmol) was added to a
solution of aldehyde 38a,13 (0.2 mmol) in dry t-BuOH (2.0 mL) at
room temperature. The mixture was stirred at the same tempera-
ture (monitoring by TLC). After the reaction was completed, the
solvent was removed under reduced pressure and the residue
was purified by a flash column chromatography (SiO2, eluent:
4.2.4. (S)-(3-Bromophenyl)(6-hydroxycyclohex-1-enyl)
methanone 4d14
HPLC analysis (AD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 13.9 min (minor),
12.2 min (major); ½a D25
¼ ꢀ8:7 (c 0.23, CHCl3, 63% ee).
ꢁ

906
K. Yuan et al. / Tetrahedron: Asymmetry 21 (2010) 903–908
Table 3
2b-Catalyzed intramolecular MBH reactiona
O
OH
O
O
3 mol% 2b
Ar
Ar
º
t-BuOH, 25 C
4a-o
3a-o
Entry
1
Product
Time (days)
2
Yieldb (%)
92
eec (%)
85
O
OH
4a
O
OH
2
3
1.5
98
97
39
16
4b
O2N
Br
O
O
OH
OH
2
4c
4
5
6
3
92
90
95
63
75
65
4d
Br
O
OH
2
4e
Br
O
OH
2.5
4f
Cl
O
OH
7
8
2
2
90
93
79
83
4g
Cl
O
OH
4h
F
O
OH
9
4
5
92
63
83
66
4i
CH3
O
O
OH
OH
10
4j
11
2.5
96
90
4k
CH3

K. Yuan et al. / Tetrahedron: Asymmetry 21 (2010) 903–908
907
Table 3 (continued)
Entry
Product
Time (days)
Yieldb (%)
eec (%)
O
OH
12
13
2.5
90
93
97
4l
H3C
O
O
OH
4
92
4m
O
OH
14
6
86
73
98
76
4n
N
S
O
OH
15
7
4o
a
The reactions were conducted with 3 mol % 2b, 0.2 mmol 3 in 2.0 mL t-BuOH (0.1 M) at 25 °C.
Isolated yields.
Determined by chiral HPLC.
b
c
O
OH
O
O
3 mol% 2b
º
t-BuOH, 25 C
n
n
3p: n = 0
3q: n = 2
4p: n = 0, 42% yield, 89% ee
4q: n = 2, no reaction
Scheme 1. The intramolecular MBH reaction of 3p and 3q.
4.2.5. (S)-(4-Bromophenyl)(6-hydroxycyclohex-1-enyl)
methanone 4e6,14
HPLC analysis (AD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 8.8 min (minor),
15.2 min (major); ½a D25
¼ ꢀ20:0 (c 0.35, CHCl3, 75% ee).
ꢁ
4.2.6. (S)-(3-Chlorophenyl)(6-hydroxycyclohex-1-enyl)
methanone 4f
1H NMR (CDCl3, 400 MHz): d 7.62 (s, 1H), 7.54–7.50 (m, 2H),
7.38 (t, J = 8.0 Hz, 1H), 6.73 (t, J = 4.0 Hz, 1H), 4.74 (s, 1H), 3.35 (s,
1H), 2.41–2.23 (m, 2H), 1.97–1.85 (m, 3H), 1.71–1.63 (m, 1H);
13C NMR (CDCl3, 100 MHz): d 197.3, 147.3, 139.7, 139.2, 134.1,
Figure 2. X-ray crystal structure of phosphinothiourea 2b.
131.6, 129.3, 128.9, 127.1, 63.4, 29.5, 26.2, 17.1; IR (KBr, cmꢀ1):
m
4.2.8. (S)-(4-Fluorophenyl)(6-hydroxycyclohex-1-enyl)
3441, 2937, 2865, 1644, 1567, 1455, 1248, 1081, 988, 745; HRMS
methanone 4h14
(ESI) calcd for
C
13H13O2ClNa ([M+Na]+): 259.0502, found:
HPLC analysis (AD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 0.8 mL/min): tR = 18.2 min (minor),
259.0518. HPLC analysis (AS-H column, k = 254 nm, eluent: n-hex-
ane/i-propanol = 90/10, flow rate: 0.9 mL/min): tR = 7.5 min (min-
16.2 min (major); ½a D25
¼ ꢀ31:8 (c 0.33, CHCl3, 83% ee).
ꢁ
or), 16.3 min (major); ½a D25
¼ ꢀ16:3 (c 0.40, CHCl3, 65% ee).
ꢁ
4.2.9. (S)-(6-Hydroxycyclohex-1-enyl)(naphthalen-2-yl)
methanone 4i14
4.2.7. (S)-(4-Chlorophenyl)(6-hydroxycyclohex-1-enyl)
methanone 4g6,14
HPLC analysis (OD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 95/5, flow rate: 1.0 mL/min): tR = 13.2 min (minor),
HPLC analysis (AS-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 8.3 min (minor),
17.0 min (major); ½a D25
¼ ꢀ36:8 (c 0.38, CHCl3, 83% ee).
ꢁ
16.4 min (major); ½a D25
¼ ꢀ21:3 (c 0.46, CHCl3, 79% ee).
ꢁ

908
K. Yuan et al. / Tetrahedron: Asymmetry 21 (2010) 903–908
ane/i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 7.5 min (min-
or), 16.3 min (major).
CF3
O
OH
S
Ar
Acknowledgments
N
N
CF3
H
Ph
Ph
H
P
We are grateful for the financial support from National Natural
Science Foundation of China (20772029), the Program for New
Century Excellent Talents in University (NCET-07-0286), the Fun-
damental Research Funds for the Central Universities, and State
Key Laboratory of Elemento-organic Chemistry.
O
O
H
Ar
si-attack
Scheme 2. Proposed transition state.
References
1. For reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52,
8001–8062; (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103,
811–891; (c) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511–4574.
2. For reviews, see: (a) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049–3052; (b)
Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581–1588; (c)
Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614–4628;
(d) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1–48; (e) Ma, G.-
N.; Jiang, J.-J.; Shi, M.; Wei, Y. Chem. Commun. 2009, 5496–5514.
3. Selected papers on asymmetric intermolecular MBH reactions, see: (a) Markó, I.
E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015–1024; (b) Hayase, T.;
Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Commun. 1998, 1271–1272; (c)
Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998, 2533–2534;
(d) Iwabuchi, Y.; Nakatani, M.; Yodoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219–10220; (e) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41,
4507–4510; (f) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125,
12094–12095; (g) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003,
5, 3741–3743; (h) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth. Catal. 2004, 346,
1106–1110; (i) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293–
4296; (j) Xu, J.; Guan, Y.; Yang, S.; Ng, Y.; Peh, G.; Tan, C.-H. Chem. Asian J. 2006,
1, 724–729; (k) Berkessel, A.; Roland, K.; Neudörfl, J. M. Org. Lett. 2006, 8, 4195–
4198; (l) Vasbinder, M. M.; Imbriglio, J. E.; Miller, S. J. Tetrahedron 2006, 62,
11450–11459; (m) Shi, M.; Liu, X.-G. Org. Lett. 2008, 10, 1043–1046; (n) Tang,
H.; Zhao, G.; Zhou, Z.; Gao, P.; He, L.; Tang, C. Eur. J. Org. Chem. 2008, 126–135.
4. Roth, F.; Gygax, P.; Fráter, G. Tetrahedron Lett. 1992, 33, 1045–1048.
5. Chen, S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S. Tetrahedron Lett. 2005, 46, 8899–
8903.
4.2.10. (S)-(6-Hydroxycyclohex-1-enyl)(o-tolyl)methanone 4j6,14
HPLC analysis (AS-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 0.9 mL/min): tR = 6.4 min (minor),
12.7 min (major); ½a D25
¼ ꢀ7:6 (c 0.46, CHCl3, 66% ee).
ꢁ
4.2.11. (S)-(6-Hydroxycyclohex-1-enyl)(m-tolyl)methanone 4k14
HPLC analysis (AS-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 0.9 mL/min): tR = 7.0 min (minor),
17.2 min (major); ½a D25
¼ ꢀ32:0 (c 0.39, CHCl3, 90% ee).
ꢁ
4.2.12. (S)-(6-Hydroxycyclohex-1-enyl)(p-tolyl)methanone 4l7,14
HPLC analysis (AD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 15.3 min (minor),
17.1 min (major); ½a D25
¼ ꢀ48:6 (c 0.36, CHCl3, 93% ee).
ꢁ
4.2.13. (S)-(6-Hydroxycyclohex-1-enyl)(4-methoxyphenyl)
methanone 4m14
HPLC analysis (AS-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 1.0 mL/min): tR = 14.9 min (minor),
40.1 min (major); ½a D25
¼ ꢀ51:0 (c 0.31, CHCl3, 97% ee).
ꢁ
6. Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2005, 7, 3849–3851.
7. Seidel, F.; Gladysz, J. A. Synlett 2007, 986–988.
8. (a) Richards, E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.; Brown, P. M.; Gelbrich,
T.; Hursthouse, M. B. Tetrahedron 2001, 57, 7771–7784; (b) Keck, G. E.; Welch,
D. S. Org. Lett. 2002, 4, 3687–3690; (c) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S.
Chem. Commun. 2004, 236–237; (d) Teng, W.-D.; Huang, R.; Kwong, C. K.-W.;
Shi, M.; Toy, P. H. J. Org. Chem. 2006, 71, 368–371.
9. (a) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008, 49,
6262–6264; (b) Yuan, K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron 2009, 65,
8185–8190.
4.2.14. (S)-(4-(Dimethylamino)phenyl)(6-hydroxycyclohex-1-
enyl)methanone 4n14
HPLC analysis (OD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 90/10, flow rate: 0.8 mL/min): tR = 19.4 min (minor),
16.9 min (major); ½a D25
¼ ꢀ55:2 (c 0.30, CHCl3, 98% ee).
ꢁ
10. Gong, J.-J.; Yuan, K.; Song, H.-L.; Wu, X.-Y. Tetrahedron 2010, 66, 2439–2443.
11. (a) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723–4725. and
references cited therein; (b) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am.
Chem. Soc. 2007, 129, 15513–15525.
4.2.15. (S)-(6-Hydroxycyclohex-1-enyl)(thiophen-2-yl)
methanone 4o6,14
HPLC analysis (OD-H column, k = 254 nm, eluent: n-hexane/
i-propanol = 95/5, flow rate: 1.0 mL/min): tR = 18.5 min (minor),
12. Crystallographic data (excluding structure factors) for the structure in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 753478. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
13. (a) Ramirez, F.; Dershowitz, S. J. Org. Chem. 1957, 22, 41–45; (b) Denney, D. B.;
Smith, L. C.; Song, J.; Rossi, C. J. J. Org. Chem. 1963, 28, 778–780; (c) Kuroda, H.;
Hanaki, E.; Izawa, H.; Kano, M.; Itahashi, H. Tetrahedron 2004, 60, 1913–1920.
14. The analytical data of the intramolecular MBH products 4 could be found in our
recent publication; see Ref. 10.
16.7 min (major); ½a D25
¼ ꢀ40:4 (c 0.26, CHCl3, 76% ee).
ꢁ
4.2.16. (S)-(5-Hydroxycyclopent-1-enyl)(phenyl)methanone 4p9a
1H NMR (400 MHz; CDCl3) d 7.78–7.76 (m, 2H), 7.59–7.55 (m,
1H), 7.46 (t, J = 7.6 Hz, 2H), 6.72 (t, J = 2.8 Hz, 1H), 5.30 (s, 1H),
3.21 (br s, 1H), 2.83–2.74 (m, 1H), 2.59–2.34 (m, 2H), 1.97–1.90
(m, 1H); HPLC analysis (AS-H column, k = 254 nm, eluent: n-hex-