Atom-economic synthesis of optically active warfarin anticoagulant over a chiral mof organocatalyst

Article abstract of DOI:10.1002/adsc.201300554

A novel chiral metal-organic framework (MOF) organocatalyst has been developed, based on readily available MIL-101 and the chiral primary diamine (1R,2R)-1,2-diphenylethylenediamine, by the post-synthetic modification. Over the developed chiral heterogeneous catalyst the asymmetric synthesis of (S)-warfarin with high enantioselectivity can be fulfilled on a gram-scale (2.8 g) with excellent yield (92%) at low cost, making the synthesis method an ideal alternative to existing methods. Copyright

Full text of DOI:10.1002/adsc.201300554

COMMUNICATIONS
DOI: 10.1002/adsc.201300554
Atom-Economic Synthesis of Optically Active Warfarin
Anticoagulant over a Chiral MOF Organocatalyst
Tao Shi,a Zhiwei Guo,a Huixian Yu,a Jianwu Xie,a,* Yijun Zhong,a
and Weidong Zhua,*
a
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Institute of Physical Chemistry and
Department of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, Peopleꢀs Republic of China
Fax : (+86)-579-8228-2932; phone: (+86)-579-8228-2932; e-mail: xiejw@zjnu.cn or weidongzhu@zjnu.cn
Received: June 21, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300554.
Abstract: A novel chiral metal-organic framework
(MOF) organocatalyst has been developed, based
on readily available MIL-101 and the chiral primary
diamine (1R,2R)-1,2-diphenylethylenediamine, by
the post-synthetic modification. Over the developed
chiral heterogeneous catalyst the asymmetric syn-
thesis of (S)-warfarin with high enantioselectivity
can be fulfilled on a gram-scale (2.8 g) with excel-
lent yield (92%) at low cost, making the synthesis
method an ideal alternative to existing methods.
and (R)-warfarin, respectively.[1] Due to these very
different anticoagulant activities and half-lives, race-
mic warfarin often leads to many clinical consequen-
ces, such as internal hemorrhages. Different ap-
proaches towards the synthesis of optically active war-
farin have been reported.[2–5] However, most of the re-
ported methods have one or more of the following
drawbacks: tedious separation and recycling of expen-
sive catalysts, low yields of the product, low enantio-
meric excess, and multiple-step synthesis.
Asymmetric reactions catalyzed by homogeneous
organocatalysts have been used as an efficient tool for
the synthesis of enantiopure compounds under mild,
environmentally benign conditions in the past de-
cades.[6] Recently, Halland et al.[3] reported pioneering
work on the one-step synthesis of optically active war-
farin from 4-hydroxycoumarin and benzylideneace-
Keywords: asymmetric synthesis; catalyst design;
heterogeneous catalysis; Michael addition; warfarin
The enantiomers of optically active drugs usually tone in the presence of imidazolidine catalysts. How-
differ, sometimes more than 1000-fold, in their affini- ever, the the nature of the homogeneous catalysis
ty to their biological receptor sites. Furthermore, such makes the separation of the used catalysts from the
enantiomers may be metabolized at different rates in reaction medium difficult. Subsequently, the groups of
the human body, with important clinical consequen- Chin[4] and Chen[5] prepared the optically active war-
ces. Therefore, optically active drugs are becoming in- farin using primary organic amines as homogeneous
creasingly important for the treatment of diseases in catalysts but the gram-scale synthesis of the desired
patients, markets for single-isomer drugs continue to product and the reusability of the used catalysts were
blossom, and both fine chemicals companies and aca- not conducted.
demic chemists are prospecting for new enantioselec-
Presently, metal organic frameworks (MOFs) have
tive technologies to produce single-isomer drugs. An attracted growing attention from both academia and
important and ultimate goal for asymmetric catalysis industry owing to their outstanding features and thus
is to develop new reactions that afford optically specific applications, such as luminescence,[7] magnetic
active compounds that have importantly biological properties,[8] gas storage and adsorptive separation,[9]
and pharmaceutical activities from easily available and catalytic properties.[10] Functionalized MOF mate-
starting materials and catalysts in one step. Warfarin rials can be easily achieved by assembly of designed
has been prescribed as a racemate for more than 40 molecular building blocks or post-synthetic modifica-
years. However, the anticoagulant activity of its S tion (PSM),[11] and MOFs offer great potential in het-
enantiomer is about 5–8 times higher than that of its erogeneous catalysis because of their many catalysis-
R enantiomer and the enantiomers are metabolized friendly features, such as large surface areas, extensive
by different pathways, reflected by the different half- porosity, well-defined cavities and portals, and chemi-
lives in the human body, 21–43 h and 37–89 h, for (S)- cal and composition tunability.[10g,12] In particular,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Tao Shi et al.
COMMUNICATIONS
Figure 1. Schematic representation of the large cage of MIL-101 delimited by the vertex sharing of the super tetrahedron
(ST) (A), the ST cage drawn in polyhedron mode (B), and the m3-O bridged trimeric secondary building unit (SBU) chelated
by six carboxylates (C).
Figure 2. Evolution of the coordinatively unsaturated sites from chromium trimers in the mesoporous cages of MIL-101 after
vacuum treatment at 1508C for 12 h and functionalization of the dehydrated MIL-101 through the selective grafting of the
diamine molecules onto the coordinatively unsaturated sites.
there has been increasing interest in creating chiral class of asymmetric organocatalysts for a range of
porous MOFs for asymmetric heterogeneous cataly- chiral transformations through LUMO-lowering acti-
sis.[12e,13] Recently, a new synthetic strategy for catalyt- vation.[19] These facts suggest that the incorporation of
ically active chiral MOFs, via introduction of privi- a primary amine unit into MIL-101 can create an effi-
À
leged organocatalyst units into achiral frameworks by cient heterogeneous catalyst for organic C C bond
PSM, was demonstrated by Kim and co-workers,[14] forming reactions by activation of carbonyl com-
but unfortunately, their reported ee values (52–81% pounds through the formation of imine intermediates.
ee) were not highly satisfactory in their asymmetric Vicinal diamines were proven to be effective grafting
aldol reactions. Herein we have developed a series of reagents due to their multifunctional chelating groups
novel chiral porous MOF organocatalysts that effec- – two amino groups.[16] As illustrated in Figure 2, if
tively catalyze the Michael reaction of cyclic 1,3-dicar- one amine group of a diamine is coordinated to the
bonyl compounds to a,b-unsaturated ketones with open metal coordination site chromiumACTHNUGRTENUNG(III) of MIL-
good yields and high enantioselectivities. Notably, 101 by direct ligation, the other amine group can act
a chiral anticoagulant drug, (S)-warfarin, was directly as an immobilized base catalyst. Therefore, (1R,2R)-
prepared in 83% ee, and a number of important opti- 1,2-cyclohexanediamine
[(1R,2R)-CHDN]
and
cally, biologically, and pharmaceutically active com- (1R,2R)-1,2-diphenylethylenediamine
[(1R,2R)-
pounds were also obtained on a gram-scale (up to DPEN] were chosen as chiral organic ligands. The
2.8 g) with high enantioselectivities (82–90% ee). chiral MIL-101 organocatalysts were obtained by
MIL-101 (Figure 1) is an ideal MOF for application PSM according to the following two-step procedure
in heterogeneous catalysis due to the following rea- (Figure 2). Firstly, MIL-101 was prepared in a similar
sons:[15,16] on the one hand, its high chemical stability manner as described by Fꢂrey et al.[14] with some
provides a feasibility for ligand PSM; on the other modification. Then the dehydrated MIL-101 was
hand, MIL-101 can be coordinately modified by vari- treated with the chiral ligand (1R,2R)-CHDN or
ous groups such as amino or pyridyl groups to intro- (1R,2R)-DPEN in refluxing anhydrous toluene for
duce NH2 or l-proline catalytic sites as illustrated by 12 h, followed by filtration. The solid was washed
the groups of Ferey,[17] Chang,[18a] Kim,[14] and Shi.[18b] with ethanol and dried at room temperature to afford
In addition, chiral primary amines are an important chiral MIL-101-based catalysts CDMIL-1 and
2
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Atom-Economic Synthesis of Optically Active Warfarin Anticoagulant
Table 1. Screening studies of the Michael addition between
hydroxycoumarin (1a) and benzylideneacetone (2a).[a]
CDMIL-2 incorporating (1R,2R)-CHDN in different
amounts and CDMIL-3 and CDMIL-4 incorporating
(1R,2R)-DPEN in different amounts. All the prepared
MIL-101-based organocatalysts were characterized by
various techniques, including FT-IR, powder X-ray
diffraction (PXRD), thermogravimetric analysis
(TGA), nitrogen adsorption, and elemental analysis,
see the Supporting Information for details. The ele-
mental analysis indicated (Supporting Information,
Table S1) that 1.7 and 1.9 or 1.5 and 1.6 mmol of
(1R,2R)-CHDN or (1R,2R)-DPEN per gram of the
sample were incorporated for CDMIL-1 and CDMIL-
2 or CDMIL-3 and CDMIL-4, respectively. The
PXRD patterns (Supporting Information, Figure S2)
show that almost all the characteristic peaks of the
chiral MIL-101 organocatalysts are maintained but
with some slight variations in the Bragg intensities,
clearly indicating that the structure of the materials is
unchanged during the PSM process. The occurrence
of the characteristic IR absorption bands for all the
MIL-101 organocatalysts demonstrates that Lewis
base sites (NH2) can be retained after following the
PSM process (Supporting Information, Figure S4).
The catalytic performance of CDMILs was firstly
evaluated using the asymmetric Michael addition be-
tween hydroxycoumarin (1a) and benzylideneacetone
(2a) in tetrahydrofuran (THF) at room temperature.
As shown in Table 1, MIL-101 was inactive in the re-
action (Table 1, entry 1). All CDMILs were found to
be highly active at room temperature and clean prod-
uct (S)-warfarin 3aa was obtained with good yield and
enantioselectivity (Table 1, entries 2–5), and the yield
Entry
Solvent
Catalyst
Yield[b] [%]
ee[c] [%]
1
2
3
4
THF
THF
THF
THF
THF
THF
toluene
CHCl3
THF
THF
THF
MIL-101
–
–
CDMIL-1
CDMIL-2
CDMIL-3
CDMIL-4
CDMIL-4
CDMIL-4
CDMIL-4
CDMIL-4
CDMIL-4
CDMIL-4
66
69
68
78
63
52
54
70
25
94
68
63
65
69
61
40
42
83
77
83
5
6[d]
7
8
9[e]
10[f]
11[g]
[a]
Otherwise noted, the reactions were performed with
0.10 mmol of 1a, 0.15 mmol of 2a, 12 mg of catalyst in
1 mL of solvent at room temperature for 2 d.
Isolated yield.
Determined by the chiral HPLC analysis.
6 mg of CDMIL-4 were added.
At 108C for 4 d.
At 08C for 4 d.
The reaction was performed with 4.0 mmol of 1a,
6.0 mmol of 2a, 480 mg of catalyst in 40 mL of tetrahy-
drofuran (THF) at 108C for 4 d.
[b]
[c]
[d]
[e]
[f]
[g]
increased with increases in the incorporated amount scaled up by 40 times (Table 1, entry 11), probably as-
of the chiral organic ligand. Heterogeneous catalyst cribed to the enhanced utilization efficiency of the
CDMIL-4 incorporating (1R,2R)-DPEN was identi- catalyst loaded in the reactor with stirring when
fied as the best catalyst and a 69% ee value was at- scaled up.
tained (Table 1, entry 5), although the origin of the
With the optimal reaction conditions and the
observed difference in the catalytic activity and enan- screened catalyst in hand, the catalytic activities of
tioselectivity between the two incorporated chiral or- heterogeneous catalyst CDMIL-4 and the correspond-
ganic ligands (1R,2R)-CHDN and (1R,2R)-DPEN is ing homogeneous catalyst (1R,2R)-DPEN were fur-
unclear. The yield and ee value were decreased when ther assessed in the asymmetric Michael addition be-
the loading of CDMIL-4 in the reaction system was tween various cyclic 1,3-dicarbonyl compounds and
reduced (Table 1, entry 6). The solvents were a,b-unsaturated ketones under the same conditions.
screened as well, and THF turned out to be optimal Table 2 shows the catalytic results of the asymmetric
to give the product in higher enantioselectivities and Michael addition in the presence of CDMIL-4 or
yields (Table 1, entries 5, 7 and 8). By lowering the re- (1R,2R)-DPEN in THF at 108C, from which the
action temperature to 108C, over CDMIL-4 the yield major conclusions can be drawn as follows: (i) the
was only slightly decreased while a higher enantiose- asymmetric synthesis of chiral drug (S)-warfarin 3aa
lectivity (83% ee) was obtained when the reaction and the related pharmaceutically active compounds
time was extended from 2 to 4 days (Table 1, entry 9). with high yield and enantioselectivity can be fulfilled
However, when the reaction temperature was lowered on a gram-scale (>1 g) at low cost, making the syn-
to 08C, the yield was significantly decreased with thesis method an ideal alternative to existing meth-
a
slight decrease in enantioselectivity (Table 1, ods; (ii) heterogeneous catalyst CDMIL-4 showed re-
entry 10). Notably, the yield was dramatically in- markable catalytic activities in the asymmetric Mi-
creased up to 94% [1.16 g of (S)-warfarin 3aa was ob- chael reactions and the Michael adducts were ob-
tained] when the Michael addition between hydroxy- tained with much higher enantiomeric excesses, com-
coumarin (1a) and benzylideneacetone (2a) was pared to those using the corresponding homogeneous
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Tao Shi et al.
COMMUNICATIONS
Table 2. Asymmetric Michael additions of cyclic 1,3-dicarbonyl compounds (1) to a,b-unsaturated ketones (2).
Entry
1
Ar (2)
3
CDMIL-4[a] yield [%][c]/ee[d,e] [%]
DPEN[b] yield [%][c]/ee[d,e] [%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1b
1e
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3be
3ce
3de
3ee
3ba
3ea
94/83
86/82
91/82
88/83
86/90
81/82
83/85
87/88
86/87
83/85
80/89
91/82
78/86
94/69
85/71
86/70
97/68
88/70
87/72
83/78
89/74
85/70
88/75
76/79
83/67
71/63
p-F-C6H4 (2b)
p-Cl-C6H4 (2c)
m-Cl-C6H4 (2d)
p-Br-C6H4 (2e)
p-Me-C6H4 (2f)
furyl (2g)
p-Br-C6H4 (2e)
p-Br-C6H4 (2e)
p-Br-C6H4 (2e)
p-Br-C6H4 (2e)
Ph (2a)
9
10
11
12
13
Ph (2a)
[a]
The reactions were performed with 4.0 mmol of 1, 6.0 mmol of 2, 480 mg of CDMIL-4 in 40 mL of THF at 108C for 4 d.
The reactions performed with 4.0 mmol of 1, 6.0 mmol of 2, 0.8 mmol of (1R,2R)-DPEN in 40 mL of THF at 108C for
[b]
4 d.
Isolated yield.
Determined by the chiral HPLC analysis.
[c]
[d]
[e]
The absolute configuration was determined to be (S) by the X-ray analysis of 3ac, see the Supporting Information, and
other adducts were assigned accordingly.
catalyst (1R,2R)-DPEN in all cases (Table 2, en- a water/acetone mixture provided enantiopure (>
tries 1–12), and the better enantioselectivity in the 99% ee) warfarin 3aa when starting from a sample
case of the heterogeneous catalyst may originate from with 79% ee. Furthermore, the PXRD data (Support-
the restricted movement of the substrates in the con- ing Information, Figure S2) implied that the used
fined microporous systems in combination with multi- chiral catalyst after the fourth run maintained the
ple chiral induction; (iii) it appeared that the substitu-
entsꢀ electronics had a minimal impact on the yields
(78–94%) and enantioselectivities (82–90% ee); and
Table 3. Reusability of catalyst CDMIL-4 in the asymmetric
Michael addition of hydroxycoumarin (1a) and benzylide-
neacetone (2a).[a]
(iv) the reaction scope was to be quite broad with re-
spect to Michael adducts under the applied condi-
tions. Excellent results were achieved with a,b-unsa-
turated ketones bearing various b-aryl or heteroaryl
substitutions (Table 2, entries 2–7). A few 4-hydroxy-
coumarin derivatives 1b–1d with different substitu-
tions were investigated and remarkable enantioselec-
tivities were achieved (Table 2, entries 8–10). A high
ee value was also received in the case of 5,5-dimethyl-
cyclohexane-1,3-dione (1e) (Table 2, entries 11 and
13).
As heterogeneous catalysis in nature, the catalyst
should be reusable. Therefore, the reusability of chiral
heterogeneous catalyst CDMIL-4 was investigated.
The catalyst can be reused for the asymmetric Mi-
chael addition up to three times without significant
loss of the enantioselectivity (Table 3). Notably, the
yields were excellent (94% and 88%) for the first two
runs. In addition, to improve the enantiomeric purity
of the Michael adduct, a single recrystallization from
Entry Yield
[%]
ee
[%]
N content in the catalyst
(mmolgÀ1)
1
2
3
4
94
88
83
82
3.17 (1.58)[b]
2.98 (1.49)[b]
2.73 (1.37)[b]
1.67 (0.84)[b]
60 (89)[c] 79
31 (93)[c] 73
[a]
The reactions were performed with 4.0 mmol of 1a,
6.0 mmol of 2a, 480 mg of CDMIL-4 in 40 mL of THF at
108C for 4 d.
Numbers in parentheses denote the content of free
amino groups available for the reaction.
Yields in parentheses calculated, based on the recovered
1a.
[b]
[c]
4
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Atom-Economic Synthesis of Optically Active Warfarin Anticoagulant
a single recrystallization. We believe that the strategy
applied in this work may lead to the design and appli-
cation of heterogeneous aminocatalysts in other
asymmetric transformations of a,b-unsaturated ke-
tones as well, which is under way.
Scheme 1. Asymmetric Michael addition over CDMIL-4 was
scaled up by 2.5 times with respect to the reaction shown in
Table 2, entry 1.
Experimental Section
Typical Procedures
MIL-101(Cr) was initially prepared from the hydrothermal
reaction of terephthalic acid with CrACHTUNGTRNEUNG(NO3)3·9H2O, HF, and
ssame tructure as that for the fresh catalyst and the
elemental analysis (Table 3) of the used catalyst also
confirmed the retention of the (1R,2R)-DPEN grafted
on MIL-101, although the amount of the grafted
H2O at 2208C for 8 h. The as-synthesized MIL-101 was fur-
ther purified by a three-step process using filtration, hot eth-
anol, and aqueous NH4F solutions. CDMIL-1, CDMIL-2,
CDMIL-3, and CDMIL-4 were prepared as follows. In a typ-
(1R,2R)-DPEN was slightly decreased after the third ical procedure for preparing CDMIL-4, 0.5 g of the dehy-
drated MIL-101 sample at 1508C for 12 h was suspended in
30 mL of anhydrous toluene. To this suspension, 3.0 mmol
of (1R,2R)-DPEN were added and the mixture was stirred
with heating to reflux for 12 h. Product CDMIL-4 was re-
covered by filtration and washed with ethanol, and then
dried at room temperature for 12 h in an oven to remove re-
sidual water. For CDMIL-1, CDMIL-2, and CDMIL-3, 1.5
and 3.0 mmol of (1R,2R)-CHDN and 1.5 mmol of (1R,2R)-
DPEN, respectively, were used, but the other preparation
conditions were the same. The detailed methods for the
run and significantly decreased from the third to
fourth run.
Finally, in order to investigate the scalability of the
synthesis of (S)-warfarin 3aa over CDMIL-4, as an ex-
ample, the asymmetric Michael addition of hydroxy-
coumarin (1a) and benzylideneacetone (2a) was also
scaled up by 2.5 times with respect to the reaction
shown in Table 2, entry 1 (Scheme 1). The reaction
proceeded effectively and conveniently to prepare
(S)-warfarin 3aa on a gram-scale (up to 2.8 g) with ex- characterization and the textural and physicochemical prop-
erties of the synthesized samples are presented in the Sup-
porting Information.
cellent yield (92%) and enantioselectivity (82% ee).
In summary, a series of novel MOF-based organo-
catalysts CDMILs, which were found to be highly
active in the asymmetric Michael additions, were de-
veloped, based on readily available MIL-101 and
chiral primary diamines [(1R,2R)-CHDN and
(1R,2R)-DPEN]. Among CDMILs, heterogeneous
catalyst CDMIL-4 showed remarkable catalytic activi-
ties in the asymmetric Michael reactions and the Mi-
Before the asymmetric Michael additions, the MIL-101-
based catalysts were treated at 1208C for 12 h in an oven to
remove residual water in the samples. All the catalytic
measurements for the asymmetric Michael additions were
carried out in a glass tube (20 mL) or flask (50 mL or
250 mL), depending on the total volume of the reaction
medium, equipped with a magnetic stirrer. The reactor was
placed in a low constant-temperature trough. After the reac-
chael adducts were obtained with much higher enan- tion, the catalyst was separated by centrifugation. The sol-
vent was removed under reduced pressure and the crude
product was purified by flash chromatography on silica gel
(10% ethyl acetate/petroleum ether) to give solid product 3.
The Michael addition products were found to exist in rapid
equilibrium with a pseudo-diastereomeric hemiketal form in
solution. Therefore, no pseudo-diastereomer was observed
during HPLC analysis using the mixture of hexane/2-propa-
nol containing 0.1% triflouroacetic acid (TFA) as the
eluent. The detailed methods for the catalytic measurements
and product analysis are described in the Supporting Infor-
tiomeric excesses than those using the corresponding
homogeneous catalyst (1R,2R)-DPEN in all cases.
The present development leads to a catalytic enantio-
selective one-step procedure for the formation of one
of the most widely used anticoagulants, warfarin, and
related important compounds. CDMIL-4 can be
reused in the asymmetric Michael addition between
hydroxycoumarin (1a) and benzylideneacetone (2a)
up to three times without significant change of the
enantioselectivity. Notably, the asymmetric synthesis mation.
Crystal data for 3ac: C19H15ClO4 (342.76), orthorhombic,
of chiral drug (S)-warfarin 3aa and the related phar-
maceutically active compounds with high enantiose-
lectivity can be fulfilled on a gram-scale (>1 g) at low
cost, making the synthesis method an ideal alternative
to existing methods. In addition, the asymmetric Mi-
chael addition of hydroxycoumarin (1a) and benzyli-
deneacetone (2a) was scalable and (S)-warfarin 3aa
was obtained on a gram-scale (>2 g) with excellent
yield (92%). Furthermore, it was demonstrated that
space group P2(1)2(1)2(1), a=10.408(3) ꢃ, b=10.566(4) ꢃ,
c=14.982(5) ꢃ, U=1647.6(9) ꢃ3, Z=4, specimen 0.254ꢄ
0.0177ꢄ0.123 mm3, T=296(2) K, SIEMENS P4 diffractome-
ter, absorption coefficient 0.251 mmÀ1, reflections collected
11144, independent 3782 [RACTHNURGTNE(UNG int)=0.1032], refinement by
full-matrix least-squares on F2, data/restraints/parameters
3782/0/219, goodness-of-fit on F2 =1.032, final R indices [I>
2s(I)] R1=0.0444, wR2=0.1144, R indices (all data) R1=
0.0594, wR2=0.1206, largest diff. peak and hole 0.368 and
enantiopure (S)-warfarin could be obtained by À0.172 ꢃÀ3. CCDC 943369 contains the supplementary crys-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Tao Shi et al.
COMMUNICATIONS
tallographic data for this paper (3ac). These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif or on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, U.K. [fax.: (internat.) (+44)-1223/336-033; e-mail: de-
posit@ccdc.cam.ac.uk].
[9] a) S. Kitagawa, R. Kitaura, S. I. Noro, Angew. Chem.
2004, 116, 2388; Angew. Chem. Int. Ed. 2004, 43, 2334;
b) L. Ma, C. Abney, W. Lin, Chem. Soc. Rev. 2009, 38,
1248; c) D. Farrusseng, S. Aguado, C. Pinel, Angew.
Chem. 2009, 121, 7638; Angew. Chem. Int. Ed. 2009, 48,
7502; d) A. Corma, H. Garcia, F. X. L. Xamena, Chem.
Rev. 2010, 110, 4606; e) J. Lee, O. K. Farha, J. Roberts,
K. A. Scheidt, S. T. Nguyen, J. T. Hupp, Chem. Soc.
Rev. 2009, 38, 1450.
Experimental procedures and characterization data are
available in the Supporting Information in detail.
[10] a) N. Stock, S. Biswas, Chem. Rev. 2012, 112, 933;
b) S. M. Cohen, Chem. Rev. 2012, 112, 970.
[11] a) Y. Liu, W. Xuan, Y. Cui, Adv. Mater. 2010, 22, 4112;
b) M. Yoon, R. Srirambalaji, K. Kim, Chem. Rev. 2012,
112, 1196.
[12] a) J. S. Seo, D. Whang, H. Lee, S. I. Jun, J. Oh, Y. Jeon,
K. Kim, Nature 2000, 404, 982; b) W. Lin, MRS Bull.
2007, 32, 544; c) C. D. Wu, A. Hu, L. Zhang, W. Lin, J.
Am. Chem. Soc. 2005, 127, 8940; d) S. H. Cho, B. Ma,
S. T. Nguyen, J. T. Hupp, T. E. Albrecht-Schmitt, Chem.
Commun. 2006, 2563; e) C. D. Wu, W. Lin, Angew.
Chem. 2007, 119, 1093; Angew. Chem. Int. Ed. 2007, 46,
1075.
[13] M. Banerjee, S. Das, M. Yoon, H. J. Choi, M. H. Hyun,
S. M. Park, G. Seo, K. Kim, J. Am. Chem. Soc. 2009,
131, 7524.
[14] G. Fꢂrey, C. Mellot-Draznieks, C. Serre, F. Millange, J.
Dutour, S. Surblꢂ, I. Margiolaki, Science 2005, 309,
2040.
[15] a) P. Serra-Crespo, E. V. Ramos-Fernandez, J. Gascon,
F. Kapteijn, Chem. Mater. 2011, 23, 2565; b) H. X. Yu,
J. W. Xie, Y. J. Zhong, F. M. Zhang, W. D. Zhu, Catal.
Commun. 2012, 29, 101.
[16] Y. K. Hwang, D. Y. Hong, J. S. Chang, S. H. Jhung,
Y. K. Seo, J. Kim, A. Vimont, M. Daturi, C. Serre, G.
Fꢂrey, Angew. Chem. 2008, 120, 4212; Angew. Chem.
Int. Ed. 2008, 47, 4144.
Acknowledgements
We are grateful for the financial support by the Program for
Changjiang Scholars and Innovative Research Team in Chi-
nese Universities (IRT0980), the National Natural Science
Foundation of China (21036006 and 21272214), and Zhejiang
Leading Team of Science and Technology Innovation
(2009R50020).
References
[1] For example, see: a) R. A. OꢀReilly, N. Engl. J. Med.
1976, 295, 354; b) L. B. Wingard, R. A. OꢀReilly, G.
Levy, Clin. Pharmacol. Ther. 1978, 23, 212.
[2] For other reports on stereoselective warfarin synthesis,
see: a) A. S. Demir, C. Tanyeli, V. Gꢅlbeyaz, H.
Akgꢅn, Tur. J. Chem. 1996, 20, 139; b) A. Robinson,
H. Y. Li, J. Feaster, Tetrahedron Lett. 1996, 37, 8321;
c) G. Cravotto, G. M. Nano, G. Palmisano, S. Tagliapie-
tra, Tetrahedron: Asymmetry 2001, 12, 707; d) Y. Tsu-
chiya, Y. Hamashima, M. Sodeoka, Org. Lett. 2006, 8,
4851; optical resolution, see: e) B. D. West, S. Preis,
C. H. Schroeder, K. P. Link, J. Am. Chem. Soc. 1961,
83, 2676.
[3] N. Halland, T. Hansen, K. A. Jørgensen, Angew. Chem.
2003, 115, 5105; Angew. Chem. Int. Ed. 2003, 42, 4955.
[4] H. Kim, C. Yen, P. Preston, J. Chin, Org. Lett. 2006, 8,
5239.
[5] J. W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J. G. Deng,
Y. C. Chen, Org. Lett. 2007, 9, 413.
[17] a) D. Y. Hong, Y. K. Hwang, C. Serre, G. Fꢂrey, J.-S.
Chang, Adv. Funct. Mater. 2009, 19, 1537; b) B. Li, Y.
Zhang, D. Ma, L. Li, G. Li, G. Li, Z. Shi, S. Feng,
Chem. Commun. 2012, 48, 6151.
[18] For selected reviews of organocatalytic asymmetric re-
actions: a) P. I. Dalko, L. Moisan, Angew. Chem. 2001,
113, 3840; Angew. Chem. Int. Ed. 2001, 40, 3726;
b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248; Angew. Chem. Int. Ed. 2004, 43, 5138; c) D. W. C.
MacMillan, Nature 2008, 455, 304; d) J. T. Mohr, M. R.
Krout, B. M. Stoltz, Nature 2008, 455, 323; e) S. Mu-
kherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
2007, 107, 5471; f) Stereoselective Organocatalysis, (Ed.:
R. Rios Torres), Wiley, Hoboken, NJ, 2013; g) Asym-
metric Organocatalysis, Vol. 2 (Eds.: B. List, K. Maruo-
ka), Thieme, Stuttgart, 2012.
[6] M. D. Allendorf, C. A. Bauer, R. K. Bhakta, R. J. T.
Houk, Chem. Soc. Rev. 2009, 38, 1330.
[7] M. Kurmoo, Chem. Soc. Rev. 2009, 38, 1353.
[8] a) K. Sumida, D. L. Rogow, J. A. Mason, T. M. McDo-
nald, E. D. Bloch, Z. R. Herm, T. H. Bae, J. R. Long,
Chem. Rev. 2012, 112, 724; b) M. P. Suh, H. J. Park,
T. K. Prasad, D. W. Lim, Chem. Rev. 2012, 112, 782;
c) J. R. Li, J. Sculley, H. C. Zhou, Chem. Rev. 2012, 112,
869; d) L. J. Murray, M. Dinca, J. R. Long, Chem. Soc.
Rev. 2009, 38, 1294; e) J. R. Li, R. J. Kuppler, H. C.
Zhou, Chem. Soc. Rev. 2009, 38, 1477; f) S. Couck,
J. F. M. Denayer, G. V. Baron, T. Remy, J. Gascon, F.
Kapteijn, J. Am. Chem. Soc. 2009, 131, 6326.
[19] a) Y. C. Chen, Synlett 2008, 1919; b) L. W. Xu, J. Luo,
Y. Lu, Chem. Commun. 2009, 1807.
6
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Atom-Economic Synthesis of Optically Active Warfarin
Anticoagulant over a Chiral MOF Organocatalyst
7
Adv. Synth. Catal. 2013, 355, 1 – 7
Tao Shi, Zhiwei Guo, Huixian Yu, Jianwu Xie,*
Yijun Zhong, Weidong Zhu*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!