Interplay of direct stereocontrol and dynamic kinetic resolution in a bifunctional amine thiourea catalyzed highly enantioselective cascade michael-michael reaction

Article abstract of DOI:10.1002/chem.201002384

Control is better: A novel chiral amine thiourea catalyzed, highly enantioselective Michael-Michael cascade process serves as a "one-pot" approach to synthetically and biologically significant chiral tetrahydrothiophenes (see scheme). Notably, an unpreced

Full text of DOI:10.1002/chem.201002384

DOI: 10.1002/chem.201002384
Interplay of Direct Stereocontrol and Dynamic Kinetic Resolution in a
Bifunctional Amine Thiourea Catalyzed Highly Enantioselective Cascade
Michael–Michael Reaction
Chenguang Yu,[a, b] Yinan Zhang,[a] Aiguo Song,[a] Yafei Ji,*[a, c] and Wei Wang*[a, c, d]
The success of organocatalysis is perhaps attributed to the
unique activation modes, which render both single- and mul-
tistep cascade reactions to proceed with high efficiency in
terms of reaction yields and selectivity.[1,2] Impressively, capi-
talizing on the reversible iminium–enamine catalysis, chem-
ists have developed a number of synthetically efficient, cata-
lytic, enantioselective cascade processes for the quick con-
struction of complex molecular scaffolds.[2] In contrast, de-
spite the fact that the noncovalent activation modes have
been widely used in single-step asymmetric transforma-
tions,[3] their potential in cascade catalysis remains to be
demonstrated and such examples are relatively rare.[4,5]
Facile assembly of molecular architectures spanning large
tracts of biologically relevant chemical space is a significant,
but challenging task in diversity-oriented synthesis (DOS).[6]
Molecules with highly structural (e.g., functional, stereo-
chemical, and/or scaffold) diversity, a prerequisite for broad
biological activity, are highly valuable in the fields of chemi-
cal biology and drug discovery. Chiral tetrahydrothiophenes
display such an important framework with a wide spectrum
of biological activities.[7] Accordingly, it is highly valuable to
develop efficient methods to create the chiral scaffold with
functional and stereochemical diversities.
Although chiral tetrahydrothiophenes exhibit attractive
biological properties, very few asymmetric synthesis meth-
ods have been reported.[8] Recently, we have disclosed an or-
ganocatalytic, enantioselective thio-Michael–Michel cascade,
affording the functionalized chiral tetrahydrothiophenes
from readily available compounds in an “one-pot” manner
(Scheme 1a).[9] The cascade strategy relies on the use of
[a] C. Yu, Dr. Y. Zhang, A. Song, Prof. Dr. Y. Ji, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, MSC03 2060
Albuquerque, NM 87131-0001 (USA)
Fax : (+1)505-277-2609
E-mail: wwang@unm.edu
[b] C. Yu
State Key Laboratory of Chemical Resources Engineering
Beijing University of Chemical Technology
Beijing 100029 (P. R. China)
Scheme 1. Generation of structurally diverse chiral tetrahydrothiophenes
by organocatalytic thio-Michael–Michael cascade reactions.
[c] Prof. Dr. Y. Ji, Prof. Dr. W. Wang
School of Pharmacy
chiral amine as a catalyst through a covalent bond activation
mode, which, in general, leads to highly enantioenriched
products. In our continuing effort on the construction of the
valuable synthetic target, we disclose herein an alternative
catalytic noncovalent activation strategy to construct the
framework. The “one-pot” thio-Michael–Michael cascade
process was achieved with high enantio- and diastereoselec-
tivity. Notably, the products posses the functional (NO2
group) and stereochemical (trans and cis configuration) di-
East China University of Science and Technology
130 Mei-long Road, Shanghai 200237 (P. R. China)
E-mail: jyf@ecust.edu.cn
[d] Prof. Dr. W. Wang
Shanghai Institute of Materia Medica
Chinese Academy of Sciences
555 Zuchongzhi Road
Shanghai 201203 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002384.
770
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Chem. Eur. J. 2011, 17, 770 – 774

COMMUNICATION
Table 1. Exploration of organocatalyzed enantioselective the thio-Mi-
chael–Michael reaction of trans-ethyl 4-mercapto-2-butenoate (1) with
trans-b-nitrostyrene (2a).[a]
versities (Scheme 1b), which are different from those (CHO
group and trans and trans configuration, Scheme 1a) ob-
tained in the covalent-bond-mediated catalysis. Further-
more, a distinct stereocontrol mode (i.e., direct stereocon-
trol of substrates by a bifunctional chiral catalyst and dy-
namic kinetic resolution in a cooperative manner) was
found to be responsible for high enantioselectivities.[10]
Because a nitro group can be readily transformed into an
amine, a nitrile oxide, a ketone, a carboxylic acid, a hydro-
gen, and so on,[11] nitroolefins, as one of the most active Mi-
chael acceptors, have been intensively investigated in ogano-
catalytic, asymmetric reactions. It is noted that in these
transformations, the general observation is that high enan-
tioselectivity is obtained with asymmetric aminocatalysis.[12]
Nevertheless, the use of a noncovalent hydrogen bonding
activation strategy for an enantioselective thio-Michael ad-
dition to nitroolefins has been elusive. Generally poor enan-
tioselectivities are observed in an organocatalytic,
asymmetric thio-Michael process with nitroolefins as a
result of a high background reaction that results from the in-
herent, highly active, nucleophilic thiols and electrophilic ni-
troolefins.[13] However, recently we have discovered a highly
enantioselective thio-Michael–Michael reaction between ni-
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
d.r.[d]
1
2
3
4
5
6
7
8
9
I
II
III
IV
V
VI
VII
VIII
IX
X
4
4
4
4
4
58
54
54
52
86
66
54
36
64
81
À21
À30
60
À14
À66
84
>30:1
5:1
>30:1
>30:1
8:1
troolefins and the 2-thiol-a, b-unsaturated ester
4
(Scheme 2).[5d] The high enantioselectivities attribute to the
unprecedented dynamic kinetic resolution process. With this
in mind, we decided to apply the novel powerful strategy for
the synthesis of biologically significant chiral tetrahydrothio-
phenes.
4
6:1
3:1
5:1
28
56
4
70
ND[e]
3
22:1
>30:1
10
4
40
[a] Unless specified, see the Experimental Section. [b] Yield of isolated
product. [c] ee=enantiomeric excess; determined by chiral HPLC analy-
sis (Chiralcel OD-H). [d] d.r.=diastereomeric ration; determined by
1H NMR spectroscopy. [e] Not determined.
groups and the strength of the hydrogen donor moiety in
the cinchona alkaloid scaffolds had a significant impact on
the enantio- and diasteroselectivity. The Soꢁs cinchona alka-
loid thiourea catalyst V[15] (Table 1, entry 5) was found to be
the best catalyst in this series. The Takemoto amine thiourea
VI[16] was also an impressive promoter. In this instance, a
good yield (66%) and very encouraging enantio- (84% ee)
and diastereoselectivity (6:1) were achieved. The catalyst
structure–product enantioselectivity relationship study
showed that the dimethyl group in these analogues was opti-
mal for the catalytic activity and the achieved enantioselec-
tivity (Table 1, entries 6–9). Interestingly, the hydrogen-
bond-mediated cascade catalysis gave rise to the product 3a
with cis and trans configuration. Although a good yield
(81%) and excellent d.r. (>30:1) were observed, a poor ee
(40%) (Table 1, entry 10) was obtained with the chiral bi-
naphthyl derived amine thiourea X.
Scheme 2. Hydrogen-bond-mediated highly stereoselective cascade Mi-
chael–Michael process through dynamic kinetic resolution.[5d]
The proof of concept of the proposed cascade reaction
was carried out by a reaction of trans-ethyl 4-mercapto-2-bu-
tenoate (1) with trans-b-nitrostyrene (2a) in CH2Cl2 at room
temperature in the presence of 10 mol% of an organocata-
lyst (Table 1). In light of the fact that bifunctional organo-
ACHTUNGTRENNUNGcatalysts have the capacity of activation of an electrophile
and a nucleophile in a cooperative manner, commonly used
organocatalysts were explored for the process.[3–6,14] The re-
sults revealed that the orientation of the acidic and basic
We then selected the Takemoto catalyst to probe the ef-
fects of the reaction media and the temperature on the cas-
cade process (Table 2). It is known that in the noncovalent
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771

Y. Ji, W. Wang et al.
Table 2. Screening of the solvent and the reaction conditions for a cas-
cade thio-Michael–Michael reaction.[a]
Table 3, the synthetic strategy serves as a general approach
to the highly functionalized, chiral tetrahydrothiophenes
À
À
with a broad substrate scope. Notably, one C S and one C
C bond and three stereogenic centers are formed in a “one-
pot” fashion with high enantioselectivity (92–97% ee) and
good diasteriomeric ratios (6:1 to >30:1). Moreover, the
versatile and densely functionalized, chiral scaffold has a
cis–trans configuration as determined by X-ray crystal struc-
ture analysis of the product (3j) (Figure 1),[17] which is com-
Entry
Solvent
CH2Cl2
t [h]
Yield [%][b]
ee [%][c]
d.r.[d]
1
2
3
4
4
4
66
64
60
77
78
79
79
71
74
48
56
84
84
87
85
88
93
77
84
65
77
72
6:1
6:1
9:1
12:1
12:1
12:1
3:1
5:1
1:1
4:1
6:1
ClACHTUNGTRENNUNG(CH2)2Cl
CHCl3
CHCl3
CHCl3
CHCl3
toluene
xylenes
CH3CN
hexane
Et2O
4[e]
5[e,f]
6[e,g]
7
4
10
72
4
4
4
8
9
10
11
4
4
[a] Unless specified see the Experimental Section. [b] Isolated yield.
[c] Determined by chiral HPLC analysis (Chiralcel OD-H). [d] Deter-
mined by 1H NMR spectroscopy. [e] Catalyst loading 20 mol%. [f] T=
08C. [g] T=À408C.
Figure 1. X-ray structure of 3j.
bond catalysis, nonpolar solvents are generally preferred. It
was found that chloroform was the optimal solvent (60%
yield, 87% ee and d.r.=9:1, Table 2, entry 3). Increasing the
catalyst loading to 20 mol% improved the yield (77%)
(Table 2, entry 4). However, lowering the reaction tempera-
ture (08C and À408C) further enhanced the ee values
(Table 2, entries 5 and 6) without deteriorating the yields.
The established optimal reaction conditions were explored
for examining the scope of the powerful enantioselective
thio-Michael–Michael cascade reaction. As revealed in
plementary to the configuration of the scaffold obtained by
the chiral amine catalyzed process (i.e., trans—trans). The
electronic effect on the enantioselectivity of the cascade re-
action appears limited. Aromatic nitroolefins bearing elec-
tron-neutral
(Table 3,
entry 1),
electron-withdrawing
(Table 3, entries 2–7), and electron-donating groups
(Table 3, entries 8–12) were well tolerated. In all cases, high
ee values were obtained. The steric effect has a certain
impact on the diastereoselectivity. The more hindered sub-
strates (Table 3, entries 4 and 7) resulted in a decrease of
the diastereoselectivity. The heteroaromatic and less re-
Table 3. Cascade thio-Michael–Michael reaction of trans-ethyl 4-mercap-
to-2-butenoate (1) with trans-b-nitrostyrene (2) promoted by catalyst
VI.[a]
AHCTUNGTREGaNNUN ctive alkyl trans-b-nitroolefins (Table 3, entries 13 and 14)
are applicable to the processes as well.
With respect to the mechanism of the asymmetric thio-
Michael–Michael cascade reaction, we initially assumed
that, as we observed in our early studies (Scheme 2),[5d,18]
a
Entry
R
Product t [h] Yield [%][b] ee [%][c]
d.r.[d]
dynamic kinetic resolution (DKR) process to achieve high
enantioselectivity takes place. To verify the hypothesis, we
prepared the racemic form of product of the first Michael
addition rac-6. Treatment of rac-6 in the presence of
10 mol% VI under the same reaction conditions as de-
scribed above gave the desired product 3a in 92% yield.
Nonetheless, lower ee (47%) and d.r. (3:1) (Scheme 3a)
were obtained in comparison with the results that were
achieved by performing the reaction in a cascade manner
(84% ee, d.r.=6:1, Table 1, entry 6). When the reaction was
performed at À408C, an even lower ee (32%, d.r.=4:1,
Scheme 3b) was observed. The studies indicated that a
DKR was involved in the asymmetric cascade process. How-
ever, the ee value and the diastereomeric ratio (84%,
Scheme 3c) were lower than that observed by performing
the reaction in a cascade fashion (Table 2, entry 6, 93% ee,
d.r.=12:1). The results suggested that in addition to the
1
2
3
4
5
6
7
8
Ph
4-FC6H4
4-ClC6H4
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
72
72
96
96
120
96
96
72
72
72
120
120
96
96
120
82
93
73
75
50
62
52
76
60
66
59
51
84
75
51
93
96
96
96
93
97
93
95
96
95
96
92
96
94
95
12:1
14:1
13:1
7:1
16:1
15:1
6:1
15:1
26:1
9:1
2-ClC6H4
2,5-Cl2C6H3
3-BrC6H4
2-CF3C6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
2,4-(MeO)2C6H3
thienyl
9
10
11
12
13
14
15
9:1
10:1
18:1
>30:1
9:1
furanyl
iPr
[a] Unless specified, see the Experimental Section. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis (Chiralcel OD-H or
Chiralpak AS-H). [d] Determined by 1H NMR spectroscopy of the crude
reaction mixture.
772
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Chem. Eur. J. 2011, 17, 770 – 774

Highly Enantioselective Cascade Michael–Michael Reaction
COMMUNICATION
and medicinal chemistry. More significantly, an unprecedent-
ed activation mode of cooperative direct stereocontrol and
dynamic kinetic resolution is identified. Because nonco-
AHCTUNGTREGvNNNU alent bond mediated asymmetric cascade reactions belong
to a much less explored field, the activation mode holds
great potential in developing new synthetically efficient cas-
cade processes with unexpected discoveries. This represents
our future endeavor.
Experimental Section
General procedure (Table 3 entry 1 as an example): Unless specifically
stated, a mixture of trans-ethyl 4-mercapto-2-butenoate (1) (15.7 mL,
0.12 mmol), trans-b-nitrostyrene (2a) (14.9 mg, 0.1 mmol), and catalyst
VI (8.3 mg, 0.02 mmol) in chloroform (0.5 mL) was stirred at À408C for
72 h. The reaction mixture was directly purified by silica gel chromato-
AHCTUNGTRENNUNG
column, hexane/iPrOH 90:10, 0.6 mLminÀ1
, l=210 nm): tminor =16.50,
t
major =17.02 min; [a]2D6:5 =À48.2 (c=1.06, CHCl3).
Acknowledgements
Financial support provided by the National Science Foundation (CHE-
0704015, W.W.), the China “111” project (Grant B07023, W.W.) and the
Chinese Scholarship Council (C.-G.Y.) is gratefully acknowledged.
Scheme 3. Preliminary mechanistic studies of the VI-catalyzed cascade
Michael–Michael reaction.
Keywords: amine thioureas · cascade catalysis · dynamic
kinetic resolution · organocatalysis · tetrahydrothiophenes
DKR effect, the chiral amine thiourea catalyst VI played an
important role in direct controlling the stereoselectivity of
the cascade process. As shown experimentally (Scheme 3c),
an ee value of 84% was obtained at À408C under the same
reaction conditions for the first Michael addition reaction.
Furthermore, an enhancement of the ee value (93%,
Scheme 3d) and the diastereomeric ratio (12:1) was ob-
served when (S)-6 with 84% ee was treated with VI at
À408C.[5d] The discoveries are significant. An interplay of
stereocontrol and DKR in an organocatalytic cascade pro-
cess to govern stereoselectivity is observed.[10] This is a
direct contrast to what we observed in our previously de-
scribed thio-Michael–Michael cascade reaction (Scheme 2),
where DKR is the sole source for governing the stereoselec-
tivity.[5d] Finally, interestingly the treatment of (S)-6
(84% ee) with ent-VI at À408C gave rise to two diastereo-
mers (3a and 7, Scheme 3e). Product 3a was the minor
isomer with lower ee (65%), whereas 7 with a trans–trans
configuration was the major one and an excellent enantiose-
lectivity (96%) was observed.[19]
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À
À
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thiophenes, which are highly valuable in chemical biology
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[17] The structure of 3j was determined by X-ray crystal analysis.
CCDC-788034 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
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data_request/cif.
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sis. CCDC-788035 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
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(Figure S1).
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R. S. Matthews, B. S. Ong, J. B. Press, T. V. Rajan Babu, G. Rous-
Received: August 18, 2010
Published online: December 15, 2010
774
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