Enantioselective synthesis of coumarins catalyzed by a bifunctional amine-thiourea catalyst

Article abstract of DOI:10.1002/chem.201002202

Efficient excess: An efficient and facile enantioselective Michael addition reaction through hydrogen-bonding catalysis for the synthesis of coumarin complexes has been developed (see scheme). A simple bifunctional amine-thiourea small molecule has been discovered to catalyze this process with high yields and high to excellent enantiomeric excesses.

Full text of DOI:10.1002/chem.201002202

DOI: 10.1002/chem.201002202
Enantioselective Synthesis of Coumarins Catalyzed by a Bifunctional
Amine–Thiourea Catalyst
Yaojun Gao, Qiao Ren, Lei Wang, and Jian Wang*[a]
The development of asymmetric methods for the prepara-
tion of functionalized coumarins has been of long-standing
interest to organic chemists. As a result of their broad appli-
cations in organic synthesis they are widely distributed in a
vast array of bioactive molecules.[1] Warfarin (see below) has
been discovered as an anticoagulant, inhibiting Vitamin K
epoxide reductase and thereby decreasing blood coagulation
by preventing the vitamin K dependent synthesis of blood-
clotting proteins.[2] Bromadiolone is a second-generation 4-
hydroxycoumarin derivative, called as a “super-warfarin” for
its added potency and tendency to accumulate in the liver of
the poisoned organism. It was effective against the popula-
tions that had become resistant to the first-generation anti-
coagulants.[3] Phenprocoumon is another anticoagulant drug
for the two enantiomers, one of the enantiomer being more
active than the other.[1f,g,5] For example, warfarin has been
used as a racemate for more than fifty years and it is well
known that the anticoagulant bioactivity of the S enantio-
mer is about several folds higher than that of the R enantio-
mer.[2a] Furthermore, the two enantiomers are metabolized
by different pathways, which are validated by the different
half-lives in living organisms. Due to these different pharma-
cological effects, it may generate a major problem that the
delivery of a high dose might cause internal haemorrhages
in patients. Thus, it is extremely expected that the treatment
of patients with optical pure drug molecule via a low dosage
will significantly reduce the potential pharmacological side
effects. Most importantly, it can also eventually avoid drug–
drug interactions which represent the serious problem with
racemic drug molecules.[1f,g,6]
Therefore, efficient asymmetric syntheses of coumarins
are of great interest.[7] Obviously, great progress has been
made for the synthesis of diversely structured coumarins.
Although asymmetric organocatalysis as a powerful tool in
particular has proven itself a valuable instrument in the
preparation of enantiomerically enriched compounds,[8] the
examples that can produce optical pure enantiomer in an or-
ganocatalytic asymmetric manner are still extremely rare.[9]
Indeed, as early as 2003, Jørgensen reported the first exam-
ple of imidazolidine organocatalyst-promoted asymmetric
Michael reaction of coumarin and a,b-unsaturated ketones
(Scheme 1).[9d] Recently, Chin et al.[9a] and Chen et al.[9b] re-
ported a primary amine catalyzed enantioselective Michael
reaction of coumarin and a,b-unsaturated ketones, respec-
tively. In summary, all these strategies employed iminium
that inhibits coagulation by blocking synthesis of coagula-
tion factors II, VII, IX and X and is frequently used for the
prophylaxis and treatment of thromboembolic disorders.[2b,4]
Although currently most of them are formulated as the
racemate, activity and metabolism are markedly dissimilar
À
catalysis process to promote the key C C bond-forming. Re-
cently, hydrogen-bonding-mediated catalysis that achieve
À
the formation of new C C bond is found as a particularly
[a] Dr. Y. Gao, Q. Ren, L. Wang, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543
Fax : (+65)6516-1691
strategy for the efficient construction of molecular architec-
tures.[10] Especially, there is a remarkable development and
application on chiral bifunctional thiourea catalysis.[11] The
use of inexpensive and readily synthesized chiral thiourea
catalysts has attracted considerable interests and proved to
be effective in several asymmetric transformations. Herein,
E-mail: chmwangj@nus.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002202.
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Chem. Eur. J. 2010, 16, 13068 – 13071

COMMUNICATION
ties (47 and 63% ee, respectively). Further screening of
indane catalyst III and IV (see above), which were recently
developed by our group and have been used to catalyze
some particular reactions with excellent stereo-control,[14]
surprisingly, indane catalyst IV can promote this process to
afford 96% yield and 79% ee in CH2Cl2 (entry 4) and even
give a higher selectivity in toluene (88% ee, entry 4). How-
ever, the further optimization of reaction conditions (such
as solvent and reaction temperature) based on this catalyst
Scheme 1. Organocatalyst-promoted Michael addition of coumarin to
a,b-unsaturated system.
we report a novel strategy for the preparation of chiral cou-
marins through hydrogen-bonding-mediated enantioselec-
tive Michael addition reaction via a new chiral amine thiour-
ea catalyst (Scheme 2). Significantly, this strategy enables
quick construction of diversely functionalized coumarins
with high to excellent enantioselectivity (90–98% ee) from
readily available starting materials under mild reaction con-
ditions.
IV was ineffective for selectivity enhancement. From the
above pre-screened results, we envisioned that the dihedral
angle and the relative crowded two functional groups from
catalyst might play the key role in this case. To investigate
this hypothesis, a series of other amine–thiourea catalysts
V1–4 and VI (see above) has been synthesized. The survey
revealed that we found the new catalyst VI to give the best
selectivity (entry 9, 90% ee) in high yield (97%). Changing
the moiety of R group in catalyst V1–4 framework, the reac-
tion can afford the high yields (Table 1, entries, 5–8, 93–
96%) but without any enhancement on enantiomeric excess
(entries, 5–8, 68–79% ee).
Scheme 2. Strategy for enantioselective synthesis of coumarins.
Table 1. Evaluation of the bifunctional organocatalyst and optimization
of asymmetric cyclization reaction conditions.[a]
To probe the feasibility of the proposed strategy, 4-hy-
droxycoumarin (1a) was treated with b,g-unsaturated a-keto
ester (2a) in the presence of Takemotoꢁs[11d,e] catalyst I (see
below) and Connon et al.,[11m] Deng et al.[10a] and Soꢂs et
al.[12] developed cinchona alkaloid catalyst II (10 mol%).
Herein, b,g-unsaturated a-keto esters are employed as pre-
ferred electrophiles in this kind of process due to their high
reactivity and the easy convertibility of the resultant prod-
ucts to other useful structures.[13] Furthermore, the a-keto
ester functional group can theoretically generate two hydro-
gen bonds with the catalyst to assist the enantioselective Mi-
chael addition process (Scheme 2). As shown in Table 1, in
the presence of catalyst I and II, the process lead to the de-
sired Michael addition product 3a (compound 3a was exist-
ed as a mixture of anomers in CDCl3, see Supporting Infor-
mation for details) in high yields (entries 1 and 2, 91 and
98%, respectively, Table 1) but with only moderate selectivi-
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
I
II
91
98
95
96
96
93
95
96
97
47
63
59
III
IV
V-1
V-2
V-3
V-4
VI
79 (88[d]
72
)
68
75
79
90
[a] Reaction was conducted on 0.1 mmol scale in CH2Cl2 (0.5 mL) cata-
lyzed by 10 mol% catalyst, and the ratio of 1a/2a is 1:1. [b] Yield of iso-
lated product after column chromatography. [c] ee values were deter-
mined by HPLC. [d] Toluene as solvent.
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J. Wang et al.
Table 3. Preliminary substrate scope of the asymmetric synthesis of cou-
Accordingly, catalyst VI was then used for further investi-
gation of solvent and temperature effects in this process. It
was discovered that in general the reactions proceeded well
in less polar solvents with high yields and high enantioselec-
tivities (Table 2, entries 2–10, 95–98% yields, 86–91% ee).
marin derivatives reaction catalyzed by amine–thiourea VI.[a]
Table 2. Influence of solvent and temperature on the enantioselective re-
action.[a]
Entry
X
R’
R
Yield [%][b]
ee [%][c]
1
2
3
4
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Ph (3a)
96
98
98
96
97
98
97
91
95
96
95
95
90
97
97
96
93
96
95
96
95
96
96
95
90
95
96
92
95
93
96
98
94
92
4-FC6H4 (3b)
4-ClC6H4 (3c)
4-MeOC6H4 (3d)
4-MeSC6H4 (3e)
3-MeSC6H4 (3 f)
4-allyloxyC6H4 (3g)
2-allyloxyC6H4 (3h)
4-BnOC6H4 (3i)
4-iPrC6H4 (3j)
2-MeC6H4 (3k)
1-naphthyl (3l)
2-thiophene (3m)
Ph (3n)
5
6[d]
7
Entry
Solvent
DMSO
Yield [%][b]
ee [%][c]
8[d]
9[d]
10
11[d]
12[d]
13[d]
14
15
16
17
1
2
3
4
5
7
8
9
10
11[d]
12[e]
13[f]
95
98
97
95
96
95
96
97
96
96
96
96
6
Cl
N
89
90
87
86
89
86
87
91
93
93
96
CH2Cl2
CHCl3
anisole
Et2O
toluene
xylenes
PhCF3
PhCF3
PhCF3
PhCF3
H
6-Cl
6-CH3
H
Ph (3o)
Ph (3p)
Et (3q)
H
[a] Unless specified, see the Experimental Section for reaction conditions.
[b] Yield of isolated product. [c] Determined by HPLC analysis. [d] Re-
action was performed at À208C.
[a] Unless specified, see the Experimental Section for reaction conditions.
[b] Yield of isolated product after column chromatography. [c] ee values
were determined by HPLC. [d] Reaction was performed at 08C for 3 h.
[e] Reaction was performed at À108C for 5 h. [f] Reaction was per-
formed at À258C for 24 h.
and excellent enantioselectivity (entry 17, 93% yield, 92%
ee). Moreover, the scope of the reaction can be successfully
extended utilizing to 4-hydroxycoumarin analogues 2n and
2o which lead to differently substituted a-keto esters 3n
and 3o with 96 and 98% ee, respectively (entries 14 and 15).
The absolute configuration of product 3c was determined to
be R by using single crystal X-ray diffraction (Figure 1).[15]
Trifluorotoluene was identified as the ideal solvent and af-
forded the best selectivity (entry 10, 91% ee). Lower tem-
perature (À258C) can slightly improve the selectivity with
loss of reaction yield in a reasonable time (entry 13, 96%
yield, 96% ee, 24 h). Meanwhile a convenient and efficient
synthesis of catalyst VI has also been constructed through a
five-step synthesis with an overall 75% yield in our group
(see Supporting Information for details).
Having established the optimal conditions for this Mi-
chael addition reaction, we then investigated the scope of
this process. As shown in Table 3, the process promoted by
catalyst VI serves as a general and atom-economical ap-
proach to construct the chiral coumarins with the formation
À
of one C C bond and one stereogenic center, and the incor-
Figure 1. X-ray crystal structure of compound 3c.
poration of a-keto ester functional group that is available
for further elaboration. A number of a,b-unsaturated a-keto
esters 2a–q that bear alkyl, and aromatic ring as well as het-
eroaromatic ring were involved in the process (entries 1–
17). Notably, in all cases, the reactions promote smoothly to
afford designed Michael adducts 3a–h in high yields (90–
98%) and high to excellent enantioselectivities (90–98%
ee). It appears that the position and electronic properties of
substituents on aromatic rings have a limited effect on the
efficiency and selectivity of this process. Heteroaromatic 2-
thiophene-substituted a-keto ester was also effectively en-
gaged in the process (entry 13, 90% yield, 93% ee). Nota-
bly, g-alkyl-substituted a-keto ester 2q also gave high yield
In conclusion, we have developed an efficient and conven-
ient enantioselective Michael addition reaction for the syn-
thesis of coumarin complex with high yields and excellent
enantioselectivities (up to 98% ee). This protocol proceeded
through a new and simple amine–thiourea-catalyst-promot-
ed conjugated addition strategy. We believe that the catalyt-
ic system and strategy demonstrated here might be applied
to other asymmetric transformations to efficiently assemble
chiral materials with complex structures. Further elaboration
of the products to other types of biologically active com-
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Chem. Eur. J. 2010, 16, 13068 – 13071

Enantioselective Synthesis of Coumarins
COMMUNICATION
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are now ongoing in our group.
[8] For book reviews of asymmetric organocatalysis, see: a) A. Berkes-
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Experimental Section
General procedure: To a solution of 4-hydroxycoumarin (1a; 16.2 mg,
0.1 mmol) in PhCF3 (0.45 mL) was added b,g-unsaturated a-keto ester 2a
(20.4 mg, 0. 1 mmol) at À258C, followed by addition of pre-cooled cata-
lyst VI solution (50 mL; 4.6 mg in 50 mL PhCF3, 0.01 mmol). The reaction
mixture was stirred at À258C for 24 h. The crude product was purified by
column chromatography on silica gel, eluted by hexane/EtOAc 2:1 to
afford (35 mg, 96%) of the desired product 3a as white solid. HPLC
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analysis (Chiralpak IB, isopropanol/hexane 20:80, flow rate 1.0 mLminÀ1
l=254 nm): tmajor =8.8 min, tminor =15.0 min, ee=96%.
,
Acknowledgements
The authors acknowledge the National University of Singapore for finan-
cial support (Academic Research Grant: R143000408133 and
R143000408733).
[11] For selected examples of chiral bifunctional thiourea catalysis, see:
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Keywords: asymmetric catalysis
addition · organocatalysis · thioureas
· coumarins · Michael
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Received: August 1, 2010
Published online: October 28, 2010
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