Highly enantioselective synthesis of warfarin and its analogs by means of cooperative LiClO4/DPEN-catalyzed Michael reaction: Enantioselectivity enhancement and mechanism

Article abstract of DOI:10.1016/j.tet.2010.10.032

The highly enantioselective synthesis of warfarin and its analogs was reported in this manuscript. And a cooperative catalysis was observed in asymmetric primary amine-catalyzed Michael reaction for the enantioselective synthesis of warfarin and its analogs, which led to the finding of several cooperative catalyst systems combined with Lewis acid and primary amine, such as LiClO₄/DPEN. In this Michael reaction of 4-hydrocoumarin, the cooperative catalyst system (LiClO₄/DPEN) resulted in higher levels of stereoselectivity (up to 94%ee). Additionally, the mechanism of the enantioselectivity enhancement in the cooperative catalytic Michael reaction has been investigated by using of ESI-MS and the study of nonlinear effect.

Full text of DOI:10.1016/j.tet.2010.10.032

Tetrahedron 66 (2010) 9708e9713
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective synthesis of warfarin and its analogs by means of
cooperative LiClO4/DPEN-catalyzed Michael reaction: enantioselectivity
enhancement and mechanism
,
a,b,
Hua-Meng Yang a, Li Li a, Ke-Zhi Jiang a, Jian-Xiong Jiang a, Guo-Qiao Lai a , Li-Wen Xu
*
*
a Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, PR China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2010
Received in revised form 12 October 2010
Accepted 15 October 2010
Available online 8 November 2010
The highly enantioselective synthesis of warfarin and its analogs was reported in this manuscript. And
a cooperative catalysis was observed in asymmetric primary amine-catalyzed Michael reaction for the
enantioselective synthesis of warfarin and its analogs, which led to the finding of several cooperative
catalyst systems combined with Lewis acid and primary amine, such as LiClO4/DPEN. In this Michael
reaction of 4-hydrocoumarin, the cooperative catalyst system (LiClO4/DPEN) resulted in higher levels of
stereoselectivity (up to 94%ee). Additionally, the mechanism of the enantioselectivity enhancement in
the cooperative catalytic Michael reaction has been investigated by using of ESI-MS and the study of
nonlinear effect.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
obtained by chemical resolution5 and chiral auxiliary-assisted syn-
thesis strategy.6 Although asymmetric hydrogenation7 and hetereo-
The Michael reaction is one of the most important carbonecarbon
and carboneheteroatom bond-forming processes in organic
synthesis,1 and there is a continuing need for the development
of enantioselective catalytic protocols for this reaction. The use
of asymmetric Michael reactions to generate interesting and
drug-like scaffolds has been actively investigated over the last
decades. One successful example is straightforward production
of chiral warfarin via the well established Michael addition of
4-hydrocoumarin to benzylideneacetone.2
Warfarin and sodium warfarin have been introduced for clinical
use asCoumadinÒ and MarevanÒ tohelpprevent and treatblood clots
in the legs, lungs and those associated with heart-value replacement
oran irregular, rapid heartbeat. It is one of the most widely prescribed
anti-thrombotics in North America over past decades. However, the
active component of CoumadinÒ is a racemic mixture of warfarin,
which results in decreased activity of clotting factors II, VII, IV, and X
by inhibiting vitamin K epoxide reductase and thereby decreasing
blood coagulation by preventing the vitamin K-dependent synthesis
of blood-clotting proteins.3 Further investigation showed consider-
able differences existed in the metabolic disposition of its two en-
antiomers.4 Initially, enantiomerically pure S- or R-warfarin was
DielseAlder cycloaddition reaction8 have been reported as alterna-
tive process, highly enantioselective warfarin synthesis had rarely
been achieved before 2003. Since the first example on the one-step
synthesis of chiral warfarin through Michael addition reported by
Jùrgensen in 2003,2a,b asymmetric organocatalytic Michael addition
of 4-hydrocoumarin to benzylideneacetone has attracted consider-
able attention recently and allowed the straightforward access to
chiral warfarin by using of easily available and inexpensive start
materials. Chiral amines-based organocatalysts, especially primary
amines,9 have been showed to be good efficient in this asymmetric
procedure. However, in most cases, 20 mol % or more catalyst loading
was needed and the reaction time was long.2def
Despite the significant advances in this field, the synthesis of
optically active warfarin and its analogs still represent a consider-
able synthetic challenge. Therefore it is still desirable to develop
novel protocol or strategy for this important transformation. Herein,
we wish to report a novel cooperative catalyst system that using
metal salts and primary amine as combined catalysts in the enan-
tioselective synthesis of chiral warfarin through the Michael re-
action of 4-hydrocoumarin to benzylideneacetone, which leads to
a significant increase in stereoselectivity and novel strategy for the
synthesis of warfarin and its analogs. And in this report, anomalous
nonlinear effects of catalysts provide a coherent mechanistic
rationalization of the role of LiClO4 in the primary amine-catalyzed
Michael reaction.
* Corresponding authors. Tel.: þ86 571 28867756; fax: þ86 571 28865135; e-mail
addresses: licpxulw@yahoo.com (G.-Q. Lai), liwenxu@hznu.edu.cn (L.-W. Xu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.032

H.-M. Yang et al. / Tetrahedron 66 (2010) 9708e9713
9709
Table 1
2. Results and discussion
Effect of metal salts in enantioselective Michael reaction
OH
In an earlier study, we have established that Noyori ligand, Ts-
DPEN, could serve as enantioselective organocatalyst in the Michael
addition of 1,3-dicarbonyl compounds to nitroolefins and indicated
the importance of the primary amine group in controlling the
enantioselectivity in this Michael reaction.10 In an attempt to apply
this catalyst to the asymmetric synthesis of chiral warfarin, how-
ever, only moderate enantioselectivity (64%ee) and low yield is
obtained. As iron salts are convinced with the privileged chelation
effects11 and preparative advantages in the Michael addition of 1,3-
dicarbonyl compounds, such as user-friendly, inexpensive, and
virtually non-toxic metal catalysts, we hypothesized that iron salt
would promote the reaction efficiently with higher enantiose-
lectivity. As revealed in Scheme 1, the addition of catalytic amount
metal salt (5 mol%)
(R,R)-DPEN (5 mol%)
AcOH (10 equiv.)
OH
O
O
∗
O
O
Ph
2a
THF, rt, 24 hr
O
O
Ph
4a
3a
MXn
Yield%a
ee%b
d
47
84c
d
CuF2
CaCl2
<5
<20
NR
NR
50
50
64
29
NR
32
49
25
68
68
<10
<10
<10
NR
<10
NR
NR
72
90
d
Bi(OTf)3
CeCl3$7H2O
AgF
d
88
88
90
88
d
NbCl5
LiClO4$3H2O
SbCl3
Cu(TFA)2
Mg(ClO4)2
Pd(OAc)2
InCl3
OH
O
OH
O
FeCl3/Ts-DPEN
(1:1, 5-10 mol%)
O
∗
Ph
Ph
AcOH (10 eq.),
THF, rt, 24 h
94
87
90
85
49
88
86
90
d
O
4a
O
O
3a
2a
LiCl
LiOAc
CuBr2
CuCl2
Ph
Ph
NHTs
only Ts-DPEN (10mol%):
20% yield, 64%ee
Ts-DPEN (10mol%) and AcOH: 40% yield, 64%ee
FeCl3/Ts-DPEN (5mol%)/AcOH: 60% yield, 81%ee
H2N
1
Ni(NO3)2$6H2O
Ni(OAc)2$4H2O
Co(NO3)2$6H2O
RuCl3
HAuCl4$4H2O
Mn(OAc)2$4H2O
SnCl2$2H2O
Bi(OTf)3
(R,R)-Ts-DPEN
87
d
Scheme 1. Asymmetric synthesis of chiral warfarin catalyzed by cooperative iron/
primary amine catalyst.
d
73
90
92d
92d
90d
80d
73
47
of FeCl3 could improve the yield and enantioselectivity obviously,
and we found that the decrease of catalytic amount of iron and
primary amine to 5 mol %, acceptable yield and higher enantiose-
53
30
<10
83
71
CeCl3$7H2O
NbCl5
ZnCl2
lectivity (81%ee,
D
¼þ17%ee) was achieved in this reaction. Building
on these results, we decided to carry out a first series experiments
using (R,R)-1,2-diphenylethylenediamine (DPEN) as an organo-
catalyst under the optimal conditions,12 while only varying the
metal salts. Interestingly, significant variations in the stereo-
selectivity were observed depending on the nature of metal salts.
The salts of Ca(II), Li(I), Mg(II), Sn(II), and In(III) gave promising
enantioselectivities (>90%ee). When the salts of Bi(III), Cu(II), Ce
(III), Ni(II), Ru(III), and Au(III) were used, no product or only a trace
amount of the Michael adduct was detected even with larger
amount of DPEN (10 mol %). Considering the comprehensive syn-
ergistic effect of metal salt and DPEN in conversion and enantio-
induction, we were pleased to find that LiClO4 led to preferential
enantioselectivity and yield of chiral warfarin. This remarkable
result obtained in THF with LiClO4/DPEN exists a spectacular salt
effect in comparison to that with only DPEN catalyst, which proved
the concept of combining metal catalysis and organocatalysis is
a promising strategy to improve the enantioselectivity (Table 1).13
We then studied the solvent effect in the enantioselective syn-
thesis of chiral warfarin through Michael reaction of 4-hydro-
coumarin to benzylideneacetone. As noted in Table 2, we observed
significant solvent effects on both the overall yields and stereo-
selectivity of the reaction, and 1,4-dioxane provided the product
LiBr
73
92
LiClO4$3H2O/additivee
a
Isolated yields.
b
Enantiomeric excess of warfarin was determined by HPLC analysis using a chiral
phase column.
c
No addition of any metal salts.
DPEN (10 mol %) and metal salt (5 mol %) were used.
The additive is acetophenone (5 mol %). And when the additive is benzaldehyde
d
e
(5 mol %), the isolated yield and enantiomeric excess is 68% and 35%ee, respectively.
Table 2
Solvent effect on the enantioselective synthesis of warfarin
Entrya
Solvent
Yield%b
ee%c
1
2
3
4
5
6
7
8
CHCl3
EtOAc
MeOH
1,4-Dioxane
Toluene
1,2-Dichloroethane
1,4-Dioxane/t-BuOH
THF
55
64
39
61
42
68
54
64
90
89
72
92
82
77
89
90(99)d
a
Under standard conditions: 5 mol % of cocatalysts of LiClO4/(R,R)-DPEN.
Isolated yields.
Enantiomeric excess of warfarin was determined by HPLC analysis using a chiral
b
c
with slight improvement in enantioselectivity (92%ee,
D¼þ8%ee).
phase column.
d
With these findings in hand, we turned our attention to the
general Michael addition of substituted 4-hydrocoumarin to
enones under the optimal reaction conditions. As shown in Table 3,
the warfarin analogs were all obtained with excellent enantiose-
lectivities (90e94%ee) in the presence of the simple cooperative
LiClO4/primary amine catalysts. Interestingly, although NbCl5 gave
a much higher yields than LiClO4 for the examined substrates under
the similar conditions, the enantioselectivities are not enough good
(only 82e90%ee) (see Supplementary data, Table S-3).
Warfarins (99%ee) could be obtained after crystallization.
To gain support for the hypothesis of cooperative effect of metal
salt and primary amine catalysis in this Michael reaction, we made
use of ESI-MS analysis and the nonlinear effect. The direct infusion
eletrospray ionization mass spectrometry (ESI-MS) has been in-
corporated to the set of major techniques for mechanistic studies of
organic reactions.14 Therefore direct evidence of cooperative effect
of LiClO4/primary amine catalyst system was attained by ESI-MS

9710
H.-M. Yang et al. / Tetrahedron 66 (2010) 9708e9713
Table 3
Enantioselective synthesis of warfarin analogs via Michael addition
OH
LiClO4 (5 mol%)
R1
OH
O
(R,R)-DPEN (5 mol%)
∗
O
O
AcOH (10 equiv.)
2
R2
O
1,4-dioxane,
rt, 24 hr
R2
R1
O
O
4: 90-94% ee
3
Entry
R1
R2
Yield%a
ee%b
1
2
3
4
5
6
7
8
H
H
H
H
6-Cl
6-Cl
6-Cl
6-Br
o-OCH3
m-OCH3
p-CH3
p-Cl
4b: 52
4c: 64
4d: 75
4e: 74
4f: 61
4g: 69
4h: 62
4i: 50
91
90
90
90
94
92
91
92
H
o-OCH3
p-CH3
o-OCH3
Fig. 2. ESI-MS spectrum of the Michael reaction mixture under standard conditions:
LiClO4$3H2O (5 mol %), 4-hydrocoumarin (1 equiv), DPEN (5 mol %), benzylideneace-
tone (1.2 equiv), and AcOH (10 equiv) in THF.
a
Isolated yields.
b
Enantiomeric excess of warfarin analogs were determined by HPLC analysis
using a chiral phase column.
results of this nonlinear study, graphically depicted in Fig. 3 clearly
demonstrated the abnormal ‘negative’ nonlinear effect. The ee
value of warfarin was, almost for all eeaux, lower than it should be,
and thus generates the multishaped curve in Fig. 3. It is negative in
part but is positive partially. This abnormal (ꢀ)-NLE is a clear in-
dication of a special behavior of the (R,R)-DPEN even when there
are no LiClO4 and AcOH as additive. The observed asymmetric de-
pletion is interpreted as arising from the presence of two reactive
chiral center of (R,R)-DPEN in the stereochemically determined
transition structure. Additionally, we suggested that the aggrega-
tion of the intermediate of (R,R)-DPEN-based iminium ion is re-
sponsible for this effect, in which more complicated molecule,
some like as ML4 system described by Kagan, is formed. Accord-
ingly, the presence of LiClO4 resulted in the decomposition or re-
striction of such complex and then improved enantioselectivity of
Michael addition.
analysis of the ionic or ionized intermediates directly from the
solutions of reaction mixture. In the cationic ESI spectra of reaction
mixture obtained directly from solution to the gas phase (see Figs. 1
and 2 and Supplementary data), we ‘fished’ several important in-
termediates signals, such as the iminium salts of primary amine
and benzylideneacetone (m/z¼341.16 and 469.13). Thus these po-
tential intermediates in the catalytic cycle showed the role of
lithium salt and (R,R)-DPEN was different as coordinated Lewis acid
and iminium-activated organocatalyst, and their combinational use
resulted in the improved enantioselectivity in the Michael reaction
of 4-hydrocoumarin with enones.
Since the pioneering studies of nonlinear stereochemical effect
of catalyst enantiopurity on product enantiomeric excess by Kagan
et al.,15 observations of this phenomenon have an important di-
agnostic tool mechanistic studies of asymmetric reactions.16 The
Based on aforementioned experimental results and mechanistic
studies, a detailed catalytic cycle for the Michael reaction with 4-
hydrocoumarin andbenzylideneacetone can be proposed in Scheme 2.
ESI-Xlw-YHM100930-024675-2_02 #9-23 RT: 0.16-0.41 AV: 15 NL: 5.34E7
T: + c ESI Full ms [ 50.00-1200.00]
341.16
100
95
90
85
N
Ph
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
+
NH3
MW = 341.2
N
H
N
Ph
MW = 469.26
+
Ph
HN
469.23
N
NH
Li
NH2
557.27
MW = 557.33
213.07
429.13
312.20
301.11
395.29
400
147.10
523.30
500
615.42
106.11
100
0
Fig. 3. Nonlinear effects in LiClO4/DPEN/AcOH (5 mol %/5 mol %/10 equiv) mediated
Michael reaction. Experimental eeprod versus eecat with different catalytic system based
on (R,R)-DPEN: (A) No addition of AcOH ( : diamonds and black line); (B) No addition
200
300
600
m/z
Fig. 1. ESI-MS spectrum of the mixture of LiClO4$3H2O (5 mol %), DPEN (5 mol %),
of LiClO4
( : squares and blue line); (C) Standard conditions with LiClO4/DPEN/AcOH
benzylideneacetone (1.2 equiv), and AcOH (10 equiv) in THF.
(5 mol %/5 mol %/10 equiv)( : uptriangles and red line).

H.-M. Yang et al. / Tetrahedron 66 (2010) 9708e9713
9711
O
samples was operated on an LCQ advantage mass spectrometer
(ThermoFisher Company, USA), equipped with an ESI ion source in
the positive ionization mode, with data acquisition using the Xca-
libur software (Version 1.4).
Ph
Ph
Ph
H2N
NH2
3a
OH
O
O
4.2. General procedure for Michael addition of 4-
hydrocoumarin to benzylideneacetone
2a
Ph
N
Ph
Ph
Ph
N
H
NH2
LiClO4
O
H
N
A catalytic amount of (R,R)-DPEN (5 mol %) and LiClO4 (5 mol %)
were added to a vial containing 4-hydrocoumarin (1 mmol), AcOH
(10 mmol), and benzylideneacetone (1.2 mmol) in THF or 1,4-di-
oxane (2 mL). After vigorous stirring at room temperature for the
times shown in the Table, the reaction mixture was poured into an
extraction funnel containing brine, diluted with distilled water, and
EtOAc. The aqueous phase was extracted with EtOAc. The combined
organic phases were dried with Na2SO4 and the solvent was re-
moved under reduced pressure. The crude product was purified by
silica gel column chromatography to furnish the desired known
warfarin and confirmed by GC/MS, NMR, the ees of the Michael
products were determined by chiral-phase HPLC analysis using
a Chiralcel AD-H column and the indicated eluent systems. The
warfarin and its analogs were found to exist in rapid equilibrium
with a pseudodiastereomeric hemiketal form in solution, which
was determined by 1H NMR spectroscopy. Interestingly, the equi-
librium was so rapid that no pseudodiastereomers were observed
during HPLC analysis. The warfarin and its analogs are known
compounds, and their spectroscopic properties in accordance with
those reported.2
Ph
Ph
i-1 (a)
Ph
i-1 (b)
LiClO4
O
O
O
Ph
i-2
Ph
3a
Ph
H
N
Ph
N
OH
H
H
Ph
H2N
Ph
∗
O
O
NH2
O
O
Ph
O
O
i-3
Scheme 2. Possible catalytic cycle of cooperative catalysis with Lewis acid and orga-
nocatalyst in the combined LiClO4/DPEN-catalyzed Michael reaction.
The 4-hydrocoumarin activated by a lithium-based Lewis acid would
react with chiral iminium intermediate i-1 in situ generated from a,b-
unsaturated ketone and DPEN to provide enantioenriched i-3, in
which the lithium plays positive Lewis acidic activation on the en-
hancement of enantioselectivity and reactivity.
O
O
O
O
Ph
Ph
3. Conclusions
∗
∗
O
O
OH
In summary, we have described a Lewis acidic metal salt effect
with cooperative catalysis when using primary amine as organo-
catalyst in the enantioselective synthesis of warfarin and its analogs
through Michael reaction, which leads to the finding of several
useful metal salts, such as LiClO4, and give an increase in reactivity,
and higher levels of stereoselectivity. Thus, by modifying the re-
action conditions, we were able to obtain the warfarin with an
excellent 94%ee under mild conditions. Finally, present example
showed that further enhancements in the stereoselectivity and
reactivity may be discovered with the novel cooperative strategy, in
which the application of metal complexes or Lewis acid in tuning
the reactivity of organic molecules-promoted reactions would be
an efficient and privileged biomimic catalytic process in asym-
metric catalysis.
HO
4.2.1. Compound 4a. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼1.68 (s,
1.60H, CH3, ketal), 1.72 (s, 1.37H, CH3, ketal), 1.97e2.04 (t, 0.67H,
CH2, ketal), 2.30 (s, 0.46H, CH3, ketal), 2.40e2.60 (m, 1.65H, CH2,
keto), 3.30e3.34 (d, J¼19.2 Hz, 0.29H, CH2, ketal), 3.83e3.39 (dd,
J¼19.2 Hz, 0.22H, CH2, keto), 4.14e4.19 (m, 0.54H, CH, ketal),
4.28e4.30 (m, 0.43H, CH ketal), 4.70e4.72 (d, J¼9.6 Hz, 0.20H, CH,
keto), 7.23e7.30 (m, 7.37H, ArH), 7.50 (t, 0.72H, ArH), 7.80, 7.82 (d,
J¼7.6 Hz, 0.45H), 7.90, 7.91 (d, J¼8, 0.41 Hz), 7.94e7.96 (d, J¼7.6 Hz,
0.16H, ArH), 9.50 (s, 0.21H, OH keto); 13C NMR (100 MHz, CDCl3):
d
(ppm)¼212.318, 171.166, 162.151, 161.384, 159.712, 158.897,
153.023, 152.902, 143.287, 141.410, 132.04, 131.60, 129.27, 128.65,
128.19, 127.99, 127.26, 127.05, 126.97, 126.53, 123.95, 123.65, 123.07,
122.72, 116.69, 116.56, 104.23, 101.13, 100.50, 98.96, 42.51, 39.97,
4. Experimental sections
4.1. General
35.35, 34.13, 28.28, 27.78. IR (film):
n
¼3277.7, 1681.5, 1617.7, 1517.2,
1496.2, 1451.9, 1377.4, 1076.0, 995.9, 763.4, 700.1. GC m/z: 309 (Mþ),
265(bp), 187, 120. HRMS(ESI): calcd for C19H16O4Hþ: [MþH]
309.1121; found 309.1125. HPLC: (Daicel AD-H; 2-propanol/n-hex-
General remarks: all reagents and solvents were used directly
without purification. Flash column chromatography was performed
over silica (200e300 mesh). 1H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively, on Advance (Brucker)
400 MHz Nuclear Magnetic Resonance Spectromer, and were ref-
erenced to the internal solvent signals. Thin layer chromatography
was performed using silica gel; F254 TLC plates and visualized with
ultraviolet light. HPLC was carried out with a Waters 2695 Mil-
lennium system equipped with a photodiode array detector. EI and
CI mass spectra were performed on a Trace DSQ GC/MS spec-
trometer. Data are reported in the form of(m/z). The organo-
catalysts were commercial available and used directly. The Michael
product, warfarin, was known and confirmed by GC/MS, and usual
spectral methods (1H NMR, 13C NMR). The ESI-MS analysis of the
ane, 20:80; flow rate¼1.0 mL/min;
l
¼254 nm): tmajor¼6.3 min
(major), tminor¼16.4 min (minor).
4.2.2. Compound 4b. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼9.13 (s,
0.34H), 7.88e8.01 (m, 1.49H), 7.53e7.83 (m, 1.70H), 7.44e7.49 (m,
0.96H), 7.29e7.36 (m, 1.13H), 6.98e7.07 (m, 1.09H), 6.82e6.98 (m,
2.00H), 4.96 (q, J¼5.2, 8.0 Hz, 0.37H), 4.538 (q, J¼1.6, 6.8 Hz, 0.86H),
3.94 (d, J¼13.2 Hz, 3.18H), 3.701 (s, 0.61H), 3.36e3.42 (m, 0.60H), 2.66
(q, J¼2.0,14.4 Hz, 0.60H), 2.48 (q, J¼6.8,13.6 Hz, 0.35H), 2.30 (q, J¼7.2,
14.4 Hz, 0.58H), 2.18 (s, 0.92H), 2.01e2.10 (m, 0.54H), 1.66 (d,
J¼12.0 Hz, 3.02H); 13C NMR (100 MHz, CDCl3):
d
(ppm)¼208.86,
162.03, 159.83, 157.13, 152.99, 131.87, 130.94, 129.17, 128.86, 128.75,
129.55,126.37,123.87,123.04,121.02,116.643,116.09,115.687,111.283,

9712
H.-M. Yang et al. / Tetrahedron 66 (2010) 9708e9713
110.917, 110.803, 101.187, 100.727, 65.609, 55.358, 36.914, 31.959,
29.730, 29.691, 29.395, 28.193, 22.726. IR (film):
1684.5, 1620.4, 1572.0, 1492.9, 1457.2, 1439.2, 1251.0, 1182.2, 1064.1,
748.2. HRMS(ESI): calcd for C20H18O5Hþ: [MþH] 339.1227; found
339.1226. HPLC (Daicel AD-H; 2-propanol/n-hexane, 20:80; flow
CDCl3):
d
(ppm)¼203.787, 161.684, 160.892, 158.741, 157.904,
n
¼3373.6, 2938.1,
151.313, 151.208, 142.907, 141.284, 131.982, 131.465, 129.563,
129.180, 128.676, 128.259, 127.985, 127.250, 127.085 127.014
126.620, 122.683, 122.336, 118.121, 117.932, 117.103, 116.740, 105.171,
102.211, 100.925, 99.462, 42.506, 40.002, 35.432, 34.438, 29.721,
rate¼1.0 mL/min;
l
¼254 nm): tmajor¼8.53 min, tminor¼14.44 min.
28.044, 27.639, 22.713. IR(film):
n
¼3350.7, 2929.3, 2853.9, 1697.6,
1621.9, 1569.2, 1485.1, 1453.3, 1418.7, 1378.3, 1261.2, 1165.1, 1116.2,
1067.4, 699.7. HRMS(ESI): calcd for C19H15ClO4Hþ: [MþH]
343.0732; found 343.0731. HPLC (Daicel AD-H; 2-propanol/n-hex-
4.2.3. Compound 4c. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼1.64 (d,
J¼7.2 Hz, 3.0H), 1.93e2.03 (m, 0.74H), 2.25 (s, 0.30H), 2.34e2.52 (m,
1.50H), 3.74 (s, 3.05H), 4.11e4.15 (m, 0.56H), 4.20e4.23 (m, 0.38H),
6.72e6.84 (m, 2.87H), 7.18e7.21 (m, 2.12H), 7.51e7.53 (m, 1.19H),
7.57e7.61 (m,1.00H), 7.76e7.79 (q, J¼1.6, 8.4 Hz, 0.48H), 7.86e7.88 (q,
J¼1.2, 8 Hz, 0.46H), 8.08e8.10 (d, J¼7.2 Hz, 0.55H); 13C NMR
ane, 20:80; flow rate¼1.0 mL/min;
l¼254 nm): tmajor¼6.08min,
tminor¼16.44min.
4.2.7. Compound 4g. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼9.25 (s,
(100 MHz, CDCl3):
d
(ppm)¼212.303, 171.033, 162.288, 161.565,
0.33H), 7.64e7.86 (m, 1.48H), 7.38e7.50 (m, 1.26H), 7.13e7.26 (m,
0.94H), 6.98e7.04 (m, 1.00H), 6.82e6.94 (m, 1.88H), 4.94 (d, J¼5.2,
8.4 Hz, 0.28H), 4.50e4.57 (m, 0.78H), 3.90 (d, J¼10.8 Hz, 3.28H),
3.55 (s, 0.68H), 3.38 (q, J¼5.2, 18.8 Hz, 0.33H), 2.62 (q, J¼1.6, 14.4 Hz,
0.48H), 2.46 (q, J¼6.8, 13.6 Hz, 0.31H), 2.29 (q, J¼7.2, 14.4 Hz, 0.51H),
2.19 (s, 0.80H), 2.03 (t, J¼12.4 Hz, 0.41H), 1.67 (d, J¼7.2 Hz, 3.00H);
160.222, 159.832, 152.964, 152.857, 145.059, 143.414, 133.645,
132.024, 131.528, 130.234, 130.162, 129.567, 128.464, 123.964,
123.643,123.095,122.792,119.543,119.050,116.628,116.442,115.958,
115.587, 113.437, 113.220, 112.172, 111.535, 103.995, 101.155, 100.622,
99.187, 55.208, 55.159, 42.615, 40.078, 35.412, 34.403, 31.953, 29.732,
29.384, 27.979, 27.554, 22.717. IR (film):
n¼3377.5, 2923.7, 2852.3,
13C NMR (100 MHz, CDCl3):
d
(ppm)¼208.898, 161.470, 159.933,
1686.3, 1618.8, 1570.7, 1491.1, 1453.9, 1381.3, 1326.3, 1264.8, 1070.7,
903.0, 760.4, 677.0. HRMS(ESI): calcd for C20H18O5Hþ: [MþH]
339.1227; found 339.1226. HPLC (Daicel AD-H; 2-propanol/n-hexane,
158.790, 157.072, 156.919, 155.330, 151.318, 131.804, 131.544,
131.210, 129.199, 128.770, 128.137, 127.660, 126.453, 123.378,
122.651, 122.250, 121.744, 120.976, 120.828, 118.089, 117.908,
117.555, 116.853, 111.303, 110.829, 107.140, 105.414, 102.239,
101.073, 99.604, 56.197, 55.570, 55.392, 45.224, 39.645, 36.955,
30.230, 29.716, 29.289, 28.414, 28.112. HPLC (Daicel AD-H; 2-
20:80; flow rate¼1.0 mL/min;
l¼254 nm): tmajor¼7.88 min,
tminor¼22.24 min.
4.2.4. Compound 4d. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼
propanol/n-hexane, 20:80; flow rate¼1.0 mL/min;
l¼254 nm):
7.795e8.107 (m, 1.59H), 7.468e7.583 (m, 1.51H), 7.292e7.359
(m, 1.15H), 7.18e7.225 (m, 3.96H), 4.251 (q, J¼3.2, 6.8 Hz,
0.50H), 4.132 (q, J¼6.8, 11.2 Hz, 0.55H), 2.306e2.552 (m, 1.30H),
2.83 (d, J¼2.8 Hz, 2.95H), 1.962e2.049 (m, 0.78H), 1.705 (d,
tmajor¼7.56min, tminor¼15.14min.
4.2.8. Compound 4h. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼
7.719e7.888 (m, 1.13H), 7.346e7.483 (m, 1.20H), 7.086e7.226 (m,
5.14H), 4.194e4.219 (m, 0.46H), 4.087e4.132 (m, 0.57H),
2.400e2.521 (m, 1.10H), 2.296 (d, J¼1.6 Hz, 3.05H), 1.918e2.035
(m, 0.94H), 1.647 (d, J¼2.8 Hz, 3.00H); 13C NMR (100 MHz,
J¼14 Hz, 3.04H); 13C NMR (100 MHz, CDCl3):
d
(ppm)¼212.617,
162.204, 101.338, 159.616, 158.723, 153.008, 152.922, 140.149,
138.252, 136.904, 135.957, 131.970, 131.504, 130.024, 129.367,
128.939, 128.471, 129.818, 126.937, 126.820, 123.923, 123.603,
123.078, 116.666, 116.512, 115.951, 115.619, 104.366, 101.320,
100.577, 99.059, 42.661, 39.994, 34.950, 33.752, 31.955, 29.726,
CDCl3):
d
(ppm)¼212.695, 161.743, 160.945, 158.679, 157.849,
151.290, 151.168, 139.875, 138.082, 136.078, 131.926, 131.371,
129.966, 129.394, 129.123, 128.981, 126.969, 126.847, 122.679,
122.299, 118.097, 118.097, 117.884, 117.144, 116.769, 105.316,
102.328, 100.986, 99.532, 42.602, 39.959, 35.016, 33.970, 29.733,
27.956, 27.653, 21.107. HPLC (Daicel AD-H; 2-propanol/n-hex-
28.178, 27.758, 22.721, 21.045. IR (film):
n
¼3375.3, 2921.7,
2851.3, 1685.2, 1607.7, 1564.7, 1512.2, 1489.6, 1452.8, 1384.6,
1376.3, 1248.2, 1070.5, 766.8. HRMS(ESI): calcd for C20H18O4Hþ:
[MþH] 323.1278; found 323.1273. HPLC (Daicel AD-H; 2-prop-
ane, 20:80; flow rate¼1.0 mL/min;
l
¼254 nm): tmajor¼6.57min,
anol/n-hexane, 20:80; flow rate¼1.0 mL/min; ¼254 nm): tma-
l
tminor¼16.51min.
¼6.91min tminor¼17.84min.
jor
4.2.9. Compound 4i. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼
4.2.5. Compound 4e. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼
7.912e8.017 (m, 1.53H), 7.520e7.661 (m, 1.57H), 6.820e7.192 (m,
4.19H), 4.898e5.014 (m, 0.40H), 4.504e4.553 (m, 0.68H), 3.924 (d,
J¼10.8 Hz, 2.99H), 3.330e3.452 (m, 0.43H), 2.614 (q, J¼2, 14.4 Hz,
0.60H), 2.441 (q, J¼6.8,14 Hz, 0.41H), 2.256e2.385 (m, 0.97H), 2.188
(s, 0.91H), 1.960e2.055 (m, 0.68H), 1.688 (d, J¼10.4 Hz, 3.00H); 13C
7.759e7.920 (m, 1.27H), 7.427e7.549 (m, 1.27H), 7.104e7.254 (m,
6.10H), 4.097e4.142 (m, 1.53H), 3.661e3.815 (m, 0.56H),
2.251e2.431 (m, 1.70H), 1.865e1.929 (dd, J¼11.6, 14 Hz), 1.673 (d,
J¼11.2 Hz, 3.00H); 13C NMR (100 MHz, CDCl3):
d
(ppm)¼212.263,
162.287, 162.601, 159.943, 459.323, 152.897, 152.807, 141.931,
140.796, 132.392, 132.099, 132.032, 131.721, 129.459, 128.788,
128.740, 128.496, 128.230, 124.029, 123.782, 123.040, 122.820,
116.632, 116.461, 115.840, 115.564, 103.665, 101.290, 100.409,
99.133, 58.485, 45.200, 42.494, 40.067, 34.879, 34.445, 31.959,
NMR (100 MHz, CDCl3):
d
(ppm)¼208.866,162.233,161.596,161.365,
160.532, 159.811, 158.665, 157.076, 155.333, 151.810, 134.632,
128.805, 128.143, 127.686, 126.430, 125.695, 125.290, 121.750,
121.001, 118.397, 116.735, 111.318, 110.826, 107.161, 102.231, 101.076,
99.568, 56.200, 55.566, 55.388, 45.232, 39.596, 36.935, 30.225,
29.730, 27.999, 27.558, 22.738. IR (film):
n
¼3378.0, 2922.0, 1686.0,
29.713, 19.276, 28.215, 28.151. IR (film):
n
¼3419.5, 2927.7, 1696.4,
1608.5, 1565.6, 1690.5, 1454.2, 1410.8, 1385.8, 1327.6, 1273.2, 1250.0,
1071.6, 763.4. HRMS(ESI): calcd for C19H15ClO4Hþ: [MþH]
343.0732; found 343.0730. HPLC (Daicel AD-H; 2-propanol/n-
1696.4, 1618.9, 1567.1, 1494.0, 1438.3, 1417.6, 1381.1, 1289.0, 1263.5,
1248.0, 1178.7, 1118.6, 1073.0, 751.1. HRMS(ESI): calcd for
C20H17BrO5Hþ: [MþH] 417.0332; found 417.0325. HPLC (Daicel AD-
hexane, 20:80; flow rate¼1.0 mL/min;
l¼254 nm): tmajor¼7.13min,
H; 2-propanol/n-hexane, 20:80; flow rate¼1.0 mL/min;
tmajor¼7.71min, tminor¼17.30min.
l¼254 nm):
tminor¼22.51min.
4.2.6. Compound 4f. 1H NMR (400 MHz, CDCl3):
d
(ppm)¼
Acknowledgements
7.740e7.909 (m, 1.06H), 7.493 (dd, J¼2.4, 8.8 Hz, 0.48H), 7.402 (dd,
J¼2.4, 8.8 Hz, 0.58H), 7.115e7.312 (m, 6.01H), 4.121e4.258 (m,
0.93H), 3.289e3.862 (m, 1.09H), 2.332e2.541 (m, 1.40H), 1.973 (q,
J¼11.6, 14 Hz, 0.63H), 1.671 (d, J¼3.6 Hz, 3.00H); 13C NMR (100 MHz,
This Project was supported by the National Natural Science
Foundation of China (Grant No. 20973051) and Zhejiang Provincial
Natural Science Foundation of China (Y4090139).

H.-M. Yang et al. / Tetrahedron 66 (2010) 9708e9713
9713
9. See recent reviews: (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007,
107, 5416e5470; (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471e5569; (c) Xu, L. W.; Lu, Y. Org. Biomol. Chem. 2008, 6,
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Bertelsen, S.; Jùrgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178e2189; (f) Xu, L. W.;
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10. (a) Ju, Y. D.; Xu, L. W.; Li, L.; Lai, G. Q.; Qiu, H. Y.; Jiang, J. X.; Lu, Y. X. Tetrahedron
Lett. 2008, 49, 6773e6777; (b) Jiang, Z. Y.; Yang, H. M.; Ju, Y. D.; Li, L.; Luo, M. X.;
Lai, G. Q.; Jiang, J. X.; Xu, L. W. Molecules 2010, 15, 2551e2563.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.10.032. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
11. (a) Christoffers, J. Synlett 2001, 723e732; (b) Yang, H. M.; Gao, Y. H.; Li, L.; Jiang,
Z. Y.; Lai, G. Q.; Xia, C. G.; Xu, L. W. Tetrahedron Lett. 2010, 51, 3836e3839.
12. Standard conditions: the enantioselective Michael reactions of 4-hydro-
coumarin (1 mmol) to benzylideneacetone (1.2 mmol) were performed with
5 mol % of metal salt, 5 mol % of organocatalyst, 10 equiv of AcOH in THF (2 mL)
and at room temperature for 24 h.
13. (a) Yang, L.; Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2007, 48, 1599e1603; (b) Shao,
Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745e2755; (c) Zhong, C.; Shi, X. Eur. J.
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