Enantioselective Morita-Baylis-Hillman reaction organocatalyzed by glucose-based phosphinothiourea

Article abstract of DOI:10.1002/cjoc.201200740

A class of bifunctional phosphinothioureas derived from saccharide was developed as new organocatalysts for the enantioselective Morita-Baylis-Hillman reaction between acrylates and aldehydes. With 10 mol% of glucose-based phosphinothiourea 1d, the allylic alcohols were obtained in up to 96% yield and 83% ee under mild reaction conditions.

Full text of DOI:10.1002/cjoc.201200740

FULL PAPER
DOI: 10.1002/cjoc.201200740
Enantioselective Morita-Baylis-Hillman Reaction
Organocatalyzed by Glucose-based Phosphinothiourea
Yang, Weihong(杨位红)
Sha, Feng(沙风)
Zhang, Xin(张鑫)
Yuan, Kui(袁奎)
Wu, Xinyan*(伍新燕)
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and
Technology, Shanghai 200237, China
A class of bifunctional phosphinothioureas derived from saccharide was developed as new organocatalysts for
the enantioselective Morita-Baylis-Hillman reaction between acrylates and aldehydes. With 10 mol% of glucose-
based phosphinothiourea , the allylic alcohols were obtained in up to 96% yield and 83% ee under mild reaction
1d
conditions.
Keywords asymmetric organocatalysis, Morita-Baylis-Hillman reaction, bifunctional phosphine, chiral phosphi-
nothiourea, acrylate
Introduction
S
S
C12H25
Ph
N
N
H
Morita-Baylis-Hillman (MBH) reaction is well
known as the coupling between the α-position of an ac-
tivated alkenes and an sp2 electrophilic carbon using a
suitable catalyst.[1] Its asymmetric version is an impor-
tant C—C bond-forming avenue to provide enantioen-
riched allylic alcohols, which are useful building blocks
in organic synthesis.[2] Since Hatakeyama[3] developed
the first highly enantioselective MBH reaction, great
progress has been made in the past decade.[4] Up to date,
various chiral organocatalysts, especially bifunctional
phosphines,[4e,5] have evolved to promote the highly
enantioselective catalytic reactions. However, only a
few chiral bifunctional phosphines (Figure 1) are effi-
cient organocatalysts for the asymmetric MBH reaction
of acrylates and carbonyl compounds.[6,7] In our pre-
vious works, we have developed bifunctional phosphi-
nothioureas derived from (1R,2R)-2-amino-1-(diphenyl-
phosphino) cyclohexane and natural amino acids, and
applied them in the enantioselective MBH reaction be-
tween simple acrylates and aromatic aldehydes, provid-
ing up to 83% ee.[7a,7b,8] Very recently, Lu and cowork-
ers[7d] reported this MBH reaction catalyzed by L-threo-
nine-derived phosphine-thiourea, and 69%—90% ee
with 25%—92% yield were obtained. Therefore, the
exploration of highly effective bifunctional phosphine
organocatalysts for this enantioselective transform is
still in great demand.
N
N
H
H
H
PPh2
OTBS
PPh2
F
S
N
H
N
H
PPh2
Figure 1 Typical structures of chiral bifunctional phosphi-
nothioureas.
to develop effective organocatalysts. The saccharide-
based bifunctional thioureas involving primary amine,
secondary amine and tertiary amine are highly efficient
organocatalysts for the enantioselective Michael addi-
tions between nitroalkenes and carbonyl compounds,
such as acetone, acetophenone, cyclohexanone, acety-
lacetone and malonates.[9] As a part of our continuous
efforts to the MBH reaction, we are interested to evalu-
ate whether the chiral phosphinothiourea with additional
chiral scaffold such as sugar can be engineered to en-
hance the catalytic activity as well as enantioselectivity.
Therefore, a series of sugar-based phosphinothiourea
organocatalysts were designed and prepared to catalyze
the asymmetric MBH reaction between acrylate and
aldehyde (Figure 2).
Results and Discussion
The organocatalysts 1a—1f were easily prepared by
condensation of chiral 2-amino-1-(diphenylphosphino)
It has been proved that incorporating carbohydrate
motif to a chiral amino thiourea is a successful approach
*
E-mail: xinyanwu@ecust.edu.cn; Tel.: 0086-21-64252011; Fax: 0086-21-64252758
Received July 18, 2012; accepted August 26, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200740 or from the author.
Chin. J. Chem. 2012, XX, 1—5
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1

Liu et al.
FULL PAPER
Table 1 Screening of the organocatalysts for the MBH reaction
PPh2
PPh2
H
H
N
H
H
N
of methyl acrylate and 4-nitrobenzaldehydea
O
N
O
N
AcO
AcO
AcO
AcO
CHO
S
S
O
OH
OAc
OAc
O
10 mol% 1a - 1f
OAc
1b
OAc
+
MeO
THF, 25 o
C
MeO
1a
NO2
PPh2
PPh2
NO2
H
N
H
N
H
N
H
N
O
O
Yieldb/%
eec/%
－61
－36
－60
79
AcO
AcO
AcO
AcO
Entry
Catalyst
1a
Time/h
S
S
OAc
OAc
1
2
3
4
5
8
97
94
41
90
49
70
OAc
OAc
1b
6
1d
1c
1c
24
24
24
24
PPh2
PPh2
1d
H
N
H
N
H
N
H
N
O
O
AcO
AcO
AcO
AcO
1e
77
S
S
6
1f
73
OAc
OAc
a
OAc
OAc
The reactions were conducted with 10 mol% of organocatalyst,
b
5 equiv. of methyl acrylate in THF (0.2 mol/L) at 25 ℃. Iso-
lated yields. c Determined by chiral HPLC.
1e
1f
Figure 2 Structures of sugar-based phosphinothioureas.
Table 2 The effect of solvent on the MBH reaction between
cyclohexane with the corresponding isothiocyanate de-
rived from different monosaccharide (D-glucose,
D-glactose and D-mannose).
methyl acrylate and 4-nitrobenzaldehydea
CHO
O
OH
O
Initially, the asymmetric MBH reaction of methyl
acrylate and 4-nitrobenzaldehyde in THF at 25 ℃ was
selected as a model reaction to evaluate the organocata-
lysts 1a—1f. The results summarized in Table 1 indi-
cated that the stereoselectivity of the MBH reaction was
controlled by the chiral cyclohexane backbone, and the
bifunctional phosphinothioureas 1d—1f derived from
(1S,2S)-2-amino-1-(diphenylphosphino)cyclohexane
provided higher enantioselectivity than the correspond-
ing diastereoisomers 1a—1c (Entries 4—6 vs. 1—3).
Meanwhile, D-glucose-based phosphinothioureas 1a
and 1d exhibited better catalytic activity and enantiose-
lectivity (Entries 1 and 4). It is obvious that phosphi-
nothiourea 1d was the best catalyst in term of reactivity
and enantioselectivity (Entry 4, 90% yield and 79% ee),
and the results were the same level as our previous re-
ports.[7a,7b] Thus catalyst 1d was selected for further
studies.
Next, the solvent effect on the MBH reaction with
10 mol% organocatalyst 1d was investigated. The re-
sults indicated that the solvent had a significant effect
on the reactivity rather than the enantioselectivity (Ta-
ble 2). When less polar solvents such as toluene,
dichloromethane and chloroform were used as reaction
media, the MBH reactions were sluggish and resulted in
poor chemical yields (27%—35% yield, Entries 1—3).
Among the examined solvents, THF and 1,4-dioxane
provided excellent chemical yields (Entries 5 and 6),
while the use of other aprotic polar solvents led to mod-
erate chemical yields (64%—77% yield, Entries 7—9).
In the case of MeOH, the MBH product was obtained in
low yield due to the side-reaction, and the enantioselec-
tivity was lower than others. Regarding of both chemi-
cal yield and enantioselectivity, THF was selected as
solvent for further optimization of reaction conditions.
10 mol% 1d
solvent, 25 o
+
MeO
MeO
C
NO2
NO2
Entry Solvent
Time/h
48
Yieldb/%
35
eec/%
1
2
3
4
5
6
7
8
9
Toluene
CH2Cl2
CHCl3
Ether
76
70
73
74
77
74
64
68
59
25
48
28
48
27
24
62
THF
24
89
1,4-Dioxane
CH3CN
DMF
24
94
24
64
18
76
DMSO
18
77
10
CH3OH
6
42
a
The reactions were conducted with 10 mol% of organocatalyst
1d, 5 equiv. of methyl acrylate in solvent (0.2 mol/L) at 25 ℃.
b Isolated yields. c Determined by chiral HPLC.
Moreover, the reaction conditions including the ratio
of methyl acrylate to 4-nitrobenzaldehyde (2/3), the re-
action temperature, the substrate concentration and the
loading of catalyst 1d were studied. The results summa-
rized in Table 3 indicated that the chemical yield was
slightly improved when increasing the amount of
methyl acrylate, and the enantioselectivity was change-
less (Entries 1—5. The MBH reaction was sensitive to
the reaction temperature. The higher temperature re-
sulted in better chemical yield but lower enantioselec-
tivity (Entries 4, 6 and 7). In view of chemical yield and
stereoselectivity, the suitable reaction temperature was
25 ℃. When the catalyst loading was reduced to 8
mol%, the reaction rate decreased obviously, and the
2
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Chin. J. Chem. 2012, XX, 1—5

Enantioselective Morita-Baylis-Hillman Reaction Organocatalyzed by Glucose-based Phosphinothiourea
MBH reaction was uncompleted even in 2 d (Entry 8 vs.
4). The lower substrate concentration exhibited positive
effect on the enantioselectivity, but the effect on the
reactivity was irregular (Entries 9—11 and 4). Among
the examined aldehyde concentration, 0.1 mol/L was the
optimal one (Entry 10).
Table 4 The MBH reactions of different arcylates and alde-
hydes catalyzed by 1da
CHO
O
OH
O
10 mol% 1d
THF, 25 oC
+
R'
RO
RO
R'
Table 3 Further optimization of reaction conditions of MBH
reactiona
Entry
1
R
R'
Time/h
28
24
24
24
51
51
51
48
24
24
48
24
24
48
48
48
48
48
48
96
96
Yieldb/% eec/%
Me
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
3-NO2
3-NO2
3-NO2
2-NO2
2-NO2
2-NO2
4-CF3
4-CF3
4-CF3
4-Br
91
90
96
96
35
7
79
75
76
83
29
48
73
79
77
81
72
50
52
77
70
77
72
69
72
68
70
2
Et
CHO
O
OH
O
10 mol% 1d
3
n-Bu
Bn
+
MeO
MeO
THF, 25 o
C
4
2
NO2
5
t-Bu
1-naphthyl
Ph
NO2
3
6
7
6
Entry 2/3 Conc./(mol•L－
)
Time/h
24
Yieldb/% eec/%
1
8
Me
89
91
90
68
77
69
41
80
51
25
31
23
7
1
2
2
4
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.05
0.1
0.3
85
87
89
90
93
63
94
75
78
91
87
77
77
77
77
77
83
74
77
80
79
78
9
n-Bu
Bn
24
10
11
12
13
14
15
16
17
18
19
20
21
3
5
24
Me
4
6
24
n-Bu
Bn
5
10
6
24
6d
7e
8f
9
48
Me
6
24
n-Bu
Bn
6
48
6
24
n-Bu
Me
10
11
6
28
4-Cl
6
24
n-Bu
Me
4-Cl
a Unless stated otherwise, the reactions were performed with 10
c
mol% 1d in THF at 25 ℃. b Isolated yields. Determined by
H
d
e
n-Bu
H
9
chiral HPLC. The reaction was performed at 0 ℃. The reac-
f
a The reactions were performed with 10 mol% of 1d and 6 equiv.
tion was performed at 40 ℃. The loading of organocatalyst 1d
c
of acrylate in THF (0.1 mol/L) at 25 ℃. b Isolated yields. De-
was 8 mol%.
termined by chiral HPLC.
With the optimized reaction conditions in hand (10
mol% 1d, 6 equiv. of acrylate, THF as solvent, 25 ℃),
the substrate scope was surveyed (Table 4). Except the
bulky t-butyl acrylate, the MBH reaction of alkyl acry-
lates with 4-nitrobenzaldehyde exhibited similar level of
enantioselectivities and chemical yields (Entries 1—4 vs.
5). However, the catalytic system was inefficient for
aryl acrylate, and the chemical yield of MBH adducts
was poor (Entries 6 and 7). Therefore, methyl, butyl and
benzyl acrylates were applied as nucleophiles to inves-
tigate the substrate scope of aldehydes. In general, the
benzaldehydes bearing strong electron-withdrawing
group provided good yields (Entries 1—4 and 8—16),
and less active aromatic aldehydes gave low yields (En-
tries 17—21). Regarding the stereoselectivity, except
using 2-substituted benzaldehyde as electrophile (En-
tries 11 — 13), moderate-to-good enantioselectivities
were achieved (68%—83% ee).
OR
H
Ar
O-
O
S
Ph
Ph
OAc
H
N
H
N
P
O
AcO
AcO
OAc
Figure 3 Proposed transition state.
Figure 3. The thiourea scaffold of the bifunctional or-
ganocatalyst forms hydrogen-bond with the aldehyde
carbonyl, and the chiral cyclohexyl backbone causes the
phosphinoyl associated enolate to attack the activated
carbonyl from the si-face to provide the product in the
R-configuration.
Conclusions
The absolute configurations of the MBH reaction
products were assigned as R-configuration by compari-
son of the optical rotation with that of literature re-
port.[3,7,10] The possible mechanism for the asymmetric
MBH reaction is as similar as that in our pervious
work.[7b,8b] The proposed transition state is illustrated in
In summary, we developed a new class of chiral bi-
functional organocatalysts derived from trans-2-amino-
1-(diphenylphosphino)cyclohexane and saccharide,
which showed good catalytic activity and enantio-se-
lectivity in the asymmetric Morita-Baylis-Hillman reac-
tion between alkyl acrylates and aromatic aldehydes.
Chin. J. Chem. 2012, XX, 1—5
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3

Liu et al.
FULL PAPER
Further efforts are underway with a focus on expanding
the application of these bifunctional phosphinothiourea
organocatalyts to other useful transformations.
128.8, 128.4 (d, J＝7.5 Hz), 82.0, 73.0, 72.5, 70.7, 68.4,
62.1, 56.7, 40.6, 33.0, 27.8, 25.5, 24.3, 20.9, 20.8, 20.6,
20.5; 31P NMR (CDCl3, 202 MHz, 85% H3PO4) δ:
－5.68; IR (KBr) ν: 3432, 3071, 2933, 2855, 1754, 1633,
1533, 1434, 1368, 1229, 1038, 908, 745, 699 cm ;
HRMS (EI) calcd for C33H41N2O9PS ([M]＋) 672.2270,
found 672.2271.
－
1
Experimental
General Information
(2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1R,
2R)-2-(diphenylphosphino)cyclohexyl)thioureido)-
tetrahydro-2H-pyran-3,4,5-triyl triacetate (1b)
90% yield, white solid, m.p. 105—107 ℃; [α]D20
Melting points were taken without correction. Opti-
cal rotations were measured on a WZZ-2A digital po-
larimeter at the wavelength of the sodium D-line (589
nm) at 20 ℃. NMR spectra were recorded on Bruker
1
1
－16.0 (c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ:
400 spectrometer. Chemical shifts (δ) of H NMR and
13C NMR spectra were recorded relative to tetramethyl-
silane (δ 0.00). Chemical shifts of 31P NMR spectra
were reported and referenced to 85% H3PO4 (δ 0.0). IR
spectra were recorded on Nicolet Magna-I 550 spec-
trometer. High Resolution Mass spectra (HRMS) were
recorded on Micromass GCT spectrometer with Elec-
tron Ionization resource. HPLC analysis was performed
on Waters equipment with 2487 detector using Daicel
Chiralcel OD-H column, Chiralpak AS-H or AD-H
column.
Toluene, ether and 1,4-dioxane were freshly distilled
from sodium-benzophenone. Dichloromethane, chloro-
form and acetonitrile were distilled from CaH2. DMF
and DMSO were dried over CaH2 and distilled under
reduced pressure. Methanol was distilled from magne-
sium. Thin-layer chromatography (TLC) was performed
on pre-coated silica gel plate. Column chromatography
was performed using silica gel (300—400 mesh) eluting
with ethyl acetate and petroleum ether.
7.68—7.64 (m, 2H), 7.49—7.35 (m, 8H), 5.92 (br, 2H),
5.40 (s, 1H), 5.02 (s, 2H), 4.32 (br, 1H), 4.16—4.08 (m,
2H), 3.81 (s, 1H), 2.44—2.33 (m, 2H), 2.17—2.12 (m,
9H), 2.01 (s, 3H), 1.77—1.66 (m, 4H), 1.48—1.20 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ: 181.8, 171.4,
170.4, 170.2, 169.9, 135.0 (d, J＝14.5 Hz), 134.4 (d,
J＝20.7 Hz), 133.1 (d, J＝18.9 Hz), 129.1, 129.0 (d,
J＝6.5 Hz), 128.7, 128.4 (d, J＝7.5 Hz), 82.3, 71.8,
70.7, 68.2, 67.2, 61.5, 56.9, 40.6, 33.3, 27.9, 25.7, 24.5,
20.9, 20.8, 20.7, 20.6; 31P NMR (CDCl3, 202 MHz, 85%
H3PO4) δ: －5.36; IR (KBr) ν: 3373, 3053, 2932, 2855,
1751, 1533, 1434, 1370, 1229, 1084, 1052, 955, 745,
－
＋
1
699 cm ; HRMS (EI) calcd for C33H41N2O9PS ([M] )
672.2270, found 672.2254.
(2R,3R,4S,5S,6S)-2-(Acetoxymethyl)-6-(3-((1R,
2R)-2-(diphenylphosphino)cyclohexyl)thioureido)-
tetrahydro-2H-pyran-3,4,5-triyl triacetate (1c) 90%
yield, white solid, m.p. 101—103 ℃; [α]D20
＋17.6 (c 0.85, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ:
7.51—7.29 (m, 10H), 7.18 (br, 1H), 6.61 (s, 1H), 5.40—
5.35 (m, 3H), 5.29—5.26 (m, 1H), 4.29—4.16 (m, 4H),
2.37—2.34 (m, 2H), 2.20 (s, 3H), 2.05—2.02 (m, 9H),
1.90—1.65 (m, 3H), 1.32—1.22 (m, 3H), 0.94 (br, 1H);
13C NMR (CDCl3, 100 MHz) δ: 182.4, 170.4, 170.3,
170.0, 169.6, 135.6 (d, J＝11.2 Hz), 135.0 (d, J＝20.3
Hz), 133.8 (d, J＝15.7 Hz), 132.1 (d, J＝16.3 Hz),
129.2, 128.5 (d, J＝5.2 Hz), 128.2 (d, J＝7.5 Hz), 128.0,
81.4, 69.2, 68.8, 68.6, 65.3, 61.3 (d, J＝7.6 Hz), 55.2 (d,
J＝13.7 Hz), 40.2, 33.5, 27.1, 25.5, 24.3, 20.9, 20.8,
20.7, 20.6; 31P NMR (CDCl3, 202 MHz, 85% H3PO4) δ:
－6.86; IR (KBr) ν: 3432, 2932, 2854, 1751, 1538, 1434,
General procedure for the synthesis of catalysts 1a—
1f
To a solution of (R,R)- or (S,S)-1-amino-2-(di-
phenylphosphino)cyclohexane (283 mg, 1.0 mmol) in
3.0 mL CH2Cl2 was added the corresponding sugar-
derived isothiocyanate (428 mg, 1.1 mmol) at room
temperature, and the resulting mixture was stirred at this
temperature until the reaction completed (monitored by
TLC). Then, the solvent was removed under reduced
pressure and the residue was purified by silica gel col-
umn chromatography (2∶1, petroleum ether∶ethyl
acetate) to afford the saccharide-based phosphinothio-
urea compounds 1a—1f.
－
1
1369, 1227, 1054, 745, 699 cm ; HRMS (EI) calcd for
C33H41N2O9PS ([M]＋) 672.2270, found 672.2271.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1S,
2S)-2-(diphenylphosphino)cyclohexyl)thioureido)-
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1R,
2R)-2-(diphenylphosphino)cyclohexyl)thioureido)-
tetrahydro-2H-pyran-3,4,5-triyl triacetate (1a) 92%
yield, white solid, m.p. 93—95 ℃; [α]2D0 －16.3 (c
tetrahydro-2H-pyran-3,4,5-triyl
triacetate
(1d)
92% yield, white solid, m.p. 93—95 ℃; [α]2D0 ＋35.5
1
1
0.8, CH2Cl2); H NMR (CDCl3, 400 MHz) δ: 7.65—
(c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ: 7.47—
7.62 (m, 2H), 7.52—7.35 (m, 8H), 5.82 (br, 2H), 5.26 (t,
J＝9.0 Hz, 1H), 5.02 (t, J＝9.8 Hz, 1H), 4.84—4.80 (m,
1H), 4.58—4.25 (m, 2H), 4.16—4.12 (m, 1H), 3.67 (br,
1H), 2.43—2.31 (m, 2H), 2.15 (s, 3H), 2.08—2.04 (m,
9H), 1.74—1.71 (m, 4H), 1.47—1.14 (m, 4H); 13C
NMR (CDCl3, 100 MHz) δ: 181.8, 171.2, 170.6, 169.9,
169.7, 137.2, 135.0 (d, J＝15.0 Hz), 134.3 (d, J＝20.6
Hz), 133.2 (d, J＝19.3 Hz), 129.1, 128.9 (d, J＝6.7 Hz),
7.36 (m, 10H), 6.14 (br, 2H), 5.83 (t, J＝8.8 Hz, 1H),
5.37 (t, J＝9.6 Hz, 1H), 5.11 (t, J＝9.8 Hz, 1H), 4.90
(br, 1H), 4.38 (d, J＝10.4 Hz, 1H), 4.15 (d, J＝11.2 Hz,
1H), 3.87 (d, J＝10.0 Hz, 1H), 2.33 (br, 1H), 2.07—
2.03 (m, 12H), 1.86—1.64 (m, 5H), 1.38—1.26 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ: 182.4, 171.1, 170.8,
169.9, 169.8, 134.7 (d, J＝20.5 Hz), 134.3 (d, J＝8.9
Hz), 133.6 (d, J＝8.0 Hz), 132.4, 129.8 (d, J＝11.6 Hz),
4
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Chin. J. Chem. 2012, XX, 1—5

Enantioselective Morita-Baylis-Hillman Reaction Organocatalyzed by Glucose-based Phosphinothiourea
129.3 (d, J＝12.1 Hz), 128.6, 128.3, 81.8, 73.8, 73.3,
70.7, 68.3, 61.8, 54.5, 40.4, 33.0, 27.0, 26.0, 24.1, 20.8,
20.7, 20.6, 20.5; 31P NMR (CDCl3, 202 MHz, 85%
H3PO4) δ: －6.14; IR (KBr) ν: 3364, 3053, 2933, 2855,
1752, 1539, 1434, 1368, 1229, 1038, 745, 699 cm ;
HRMS (EI) calcd for C33H41N2O9PS ([M]＋) 672.2270,
found 672.2268.
due was purified by flash column chromatography to
afford the desired product, and the ee value was deter-
mined by HPLC analysis with a chiral column.
－
1
Acknowledgement
We are grateful for the financial support from the
National Natural Science Foundation of China (No.
20772029), the Program for New Century Excellent
Talents in University (No. NCET-07-0286) and the
Fundamental Research Funds for the Central Universi-
ties.
(2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1S,
2S)-2-(diphenylphosphino)cyclohexyl)thioureido)-
tetrahydro-2H-pyran-3,4,5-triyl triacetate (1e) 87%
yield, white solid, m.p. 110—112 ℃; [α]2D0 ＋55.0
1
(c 1.0, CH2Cl2); H NMR (CDCl3, 400 MHz) δ: 7.48—
7.36 (m, 10H), 6.26 (br, 2H), 5.77 (s, 1H), 5.47 (s, 1H),
5.22—5.13 (m, 2H), 4.18—4.07 (m, 3H), 2.34 (br s,
1H), 2.18 (s, 3H), 2.05—2.01 (m, 9H), 1.86—1.64 (m,
5H), 1.31—1.27 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ: 181.9, 171.5, 170.5, 170.1, 169.8, 136.3 (d, J＝9.2
Hz), 134.8 (d, J＝20.3 Hz), 134.4 (d, J＝16.9 Hz),
132.4 (d, J＝14.5 Hz), 129.2, 128.6, 128.3, 128.2, 83.3,
72.4, 70.9, 68.5, 67.3, 61.2, 54.5, 40.5, 33.2, 27.2, 25.4,
24.2, 20.9, 20.8, 20.7, 20.6; 31P NMR (CDCl3, 202 MHz,
85% H3PO4) δ: －6.26; IR (KBr) ν: 3374, 3053, 2933,
2856, 1751, 1539, 1434, 1370, 1227, 1083, 1052, 744,
References
[1] For reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetra-
hedron 1996, 52, 8001; (b) Ciganek, E. Org. React. 1997, 51, 201;
(c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003,
103, 811.
[2] Selected papers on the application of chiral allylic alcohols, see: (a)
Trost, B. M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122,
3534; (b) Iwabuchi, Y.; Furukawa, M.; Esumi, T.; Hatakeyama, S.
Chem. Commun. 2001, 2030; (c) Iwabuchi, Y.; Sugihara, T.; Esumi,
T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867; (d) Trost, B.
M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124, 11616.
[3] Iwabuchi, Y.; Nakatani, M.; Yodoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219.
－
＋
1
699 cm ; HRMS (EI) calcd for C33H41N2O9PS ([M] )
672.2270, found 672.2274.
(2R,3R,4S,5S,6S)-2-(Acetoxymethyl)-6-(3-((1S,
2S)-2-(diphenylphosphino)cyclohexyl)thioureido)-
tetrahydro-2H-pyran-3,4,5-triyl triacetate (1f) 90%
yield, white solid, m.p. 107—109 ℃; [α]2D0 ＋51.5
(c 1.0, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ: 7.62 (t,
J＝7.2 Hz, 2H), 7.54—7.48 (m, 2H), 7.36—7.30 (m,
5H), 7.28—7.23 (m, 1H), 6.55 (d, J＝8.4 Hz, 1H), 6.32
(br s, 1H), 5.23—5.18 (m, 2H), 5.11—5.08 (m, 1H),
4.46 (s, 1H), 4.26—4.12 (m, 3H), 4.01—3.98 (m, 1H),
2.46—2.41 (m, 1H), 2.31—2.28 (m, 1H), 2.20 (s, 3H),
2.11 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.78—1.73 (m,
3H), 1.48—1.38 (m, 1H), 1.31—1.09 (m, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 181.7, 170.6, 170.2, 169.7,
169.5, 137.6 (d, J＝13.8 Hz), 135.6 (d, J＝15.0 Hz),
134.4 (d, J＝20.9 Hz), 133.1 (d, J＝19.2 Hz), 129.0,
128.5 (d, J＝6.6 Hz), 128.4, 128.3 (d, J＝7.7 Hz), 80.3,
69.1, 68.7, 67.9, 65.7, 62.2, 57.2 (d, J＝17.5 Hz), 40.7
(d, J＝15.5 Hz), 33.5, 28.0, 25.6, 24.7, 20.9, 20.8, 20.7,
20.7; 31P NMR (CDCl3, 202 MHz, 85% H3PO4) δ:
－5.84; IR (KBr) ν: 3356, 2932, 2854, 1751, 1539, 1434,
[4] For reviews on the asymmetric Morita-Baylis-Hillman reactions, see:
(a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 4614; (b) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc.
Rev. 2007, 36, 1581; (c) Krishna, P. R.; Sachwani, R.; Reddy, P. S.
Synlett 2008, 2897; (d) Carrasco-Sanchez, V.; Simirgiotis, M. J.;
Santos, L. S. Molecules 2009, 14, 3989; (e) Wei, Y.; Shi, M. Acc.
Chem. Res. 2010, 43, 1005; (f) Wei, Y.; Shi, M. Chin. Sci. Bull.
2010, 1699.
[5] Marinetti, A.; Voituriez, A. Synlett 2010, 174.
[6] For early examples of chiral phosphine-catalyzed MBH reaction
between acrylate and aldehyde, see: (a) Hayase, T.; Shibata, T.; Soai,
K.; Wakatsuki, Y. Chem. Commun. 1998, 1271; (b) Li, W.; Zhang,
Z.; Xiao, D.; Zhang, X. J. Org. Chem. 2000, 65, 3489.
[7] (a) Yuan, K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron 2009, 65,
8185; (b) Gong, J.-J.; Yuan, K.; Wu, X.-Y. Tetrahedron: Asymmetry
2009, 20, 2117; (c) Wang, C.-C.; Wu, X.-Y. Tetrahedron 2011, 67,
2974; (d) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Org. Biomol. Chem.
2011, 9, 6734.
[8] Representative examples of chiral phosphinothiourea organocata-
lysts, see: (a) Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129;
(b) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660;
(c) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.-J.; Wu, X.-Y.
Tetrahedron Lett. 2008, 49, 6262; (d) Zhong, F.; Han, X.; Wang, Y.;
Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837.
[9] (a) Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org.
Lett. 2007, 9, 923; (b) Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A.
Synlett 2008, 3242; (c) Gu, Q.; Guo, X.-T.; Wu, X.-Y. Tetrehedron
2009, 65, 5265; (d) Pu, X.-W.; Li, P.-H.; Peng, F.-Z.; Li, X.-J.;
Zhang, H.-B.; Shao, Z.-H. Eur. J. Org. Chem. 2009, 4622; (e) Lu, A.;
Gao, P.; Wu, Y.; Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem.
2009, 7, 3141; (f) Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.;
Ma, J.-A. J. Org. Chem. 2010, 75, 1402; (g) Pu, X.-W.; Peng, F.-Z.;
Li, X.-J.; Zhang, H.-B.; Shao, Z.-H. Tetrehedron 2010, 66, 3655.
[10] (a) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth. Catal. 2004, 346,
1106; (b) Xu, J.; Guan, Y.; Yang, S.; Ng, Y.; Peh, G.; Tan, C.-H.
Chem.-Asian J. 2006, 1, 724.
－
1
1368, 1225, 1055, 744, 699 cm ; HRMS (EI) calcd for
C33H41N2O9PS ([M]＋) 672.2270, found 672.2274.
General procedure for the asymmetric Morita-
Baylis-Hillman reaction
To a solution of the glucose-based phosphinothio-
urea 1d (0.03 mmol) in THF (3.0 mL) was added the
acrylate (1.8 mmol) at 25 ℃. After stirring for 10 min
at this temperature, the aldehyde (0.3 mmol) was added.
Then the resulting mixture was stirred at 25 ℃ until
the reaction was completed (monitored by TLC). After
removing the solvent under reduced pressure, the resi-
(Lu, Y.)
Chin. J. Chem. 2012, XX, 1—5
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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