Enatioselective organocatalytic synthesis of highly functionalized tetrahydrothiophenes by a Michael-aldol cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2009.03.218

A catalytic asymmetric Michael-aldol cascade process for efficient synthesis of trisubstituted tetrahydrothiophenes is reported with high enantio- and diastereo-selectivities. Notably, three consecutive stereogenic centers including one chiral quaternary

Full text of DOI:10.1016/j.tetlet.2009.03.218

Tetrahedron Letters 50 (2009) 2946–2948
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enatioselective organocatalytic synthesis of highly functionalized
tetrahydrothiophenes by a Michael-aldol cascade reaction
a,b,c,
Guangshun Luo a, Shilei Zhang a, Wenhu Duan a,b, , Wei Wang
*
*
a Department of Pharmaceutical Science, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, People’s Republic of China
b Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences,
Shanghai 201203, People’s Republic of China
c Department of Chemistry and Chemical Biology, University of New Mexico, Albuqueruqe, NM 87131-0001, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic asymmetric Michael-aldol cascade process for efficient synthesis of trisubstituted tetrahydro-
thiophenes is reported with high enantio- and diastereo-selectivities. Notably, three consecutive stereo-
genic centers including one chiral quaternary carbon center are efficiently created in the ‘one-pot’
operation.
Received 4 March 2009
Revised 19 March 2009
Accepted 31 March 2009
Available online 5 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reactions
Michael-aldol
Organocatalysis
Tetrahydrothiophenes
The development of new cascade strategies for the efficient con-
struction of biologically important complex molecular architec-
tures remains a challenging goal in modern organic synthesis.1,2
Substituted tetrahydrothiophenes display a broad spectrum of
intriguing biological activities, ranging from the essential enzyme
cofactor,3 potent CCK,4 HIV,5 copper amine oxidase inhibitors,6
hypocholesterolemic agent,7 or plant growth regulators.8 Given
the importance of this scaffold, however, very few asymmetric
methods have been reported.9 In this Letter, we wish to disclose
a recent investigation, which has resulted in a new organocatalytic,
enantioselective cascade Michael-aldol reaction. The process af-
fords highly functionalized tetrahydrothiophenes with high
enantioselectivities (91–97%) and good diastereoselectivity (8:1
to >20:1) from simple achiral substances despite relatively low
yields (25–59%). Significantly, in the cascade sequence, new C–S
and C–C bonds are created with forming a chiral quaternary
carbon.
the synthesis of functionalized chiral tetrahydrothiophenes 3
(Scheme 1, Eq. 1).10f To generate the stereochemical and func-
tional diversity based on the important scaffold, we envisioned
that employing 3-mercapto
a-carbonyl esters 4 instead of ethyl
4-mercapto-2-butenoate 2 could create a novel thia-Michael-al-
dol cascade (Eq. 2). Such cascade would produce products 5
with new structural components. A chiral quaternary carbon
center and a new
a-hydroxy ester group were efficiently assem-
bled in ‘one-pot’ operation. It is noted that the construction of
chiral quaternary carbons has long been a challenge in organic
synthesis.
To explore the possibility of the proposed cascade Michael-al-
dol process, we carried out a model reaction between trans-cin-
namaldehyde 1a and ethyl 3-mercapto-2-oxopropanoate 4 in
toluene at rt in the presence of an organocatalyst (Fig. 1 and Ta-
ble 1). Screening of organocatalysts revealed that (S)-diarylpro-
linol silyl ethers II, III, and VI (Table 1, entries 2, 3, and 6)
afforded promising results in terms of reaction yields (46–71%)
and enantioselectivity (82–87% ee).12 Nevertheless, low catalytic
activities were observed with other pyrrolidine derivatives (en-
tries 1, 4, 5, and 7–10). We decided to choose catalyst VI for fur-
ther optimization of the reaction conditions. Investigation of
solvent effect indicated that the use of a mixture of CH2Cl2
and H2O was the optimal for the process (entry 11). The water
helped to slightly improve the reaction yield (49% yield vs 55%
yield, entries 11 and 12) without compromising ee and dr pre-
sumably owing to the minimization of by-products formed. It
Recently we have developed
a series of organocatalyzed
enantioselective cascade processes for ‘one-pot’ assembly of
complex molecules.10,11 The motivation of this investigation
came from our recent study in exploring double Michael addi-
tion reactions catalyzed by (S)-diphenylprolinol TMS ether for
* Corresponding authors. Tel.: +86 21 5080 6032 (W.D.); tel.: +1 505 277 0756;
fax: +1 505 277 2609 (W.W).
E-mail addresses: wduan@mail.shcnc.ac.cn (W. Duan), wwang@unm.edu (W.
Wang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.218

G. Luo et al. / Tetrahedron Letters 50 (2009) 2946–2948
2947
Table 1
Eq. 1. Michael-Michael cascade
Organocatalytic asymmetric cascade thia-Michael-adol reaction of 3-phenylpropenal
(1a) with ethyl 3-mercapto-2-oxopropanoate (4)a
CO2Et
O
O
OEt
N
H
cat.
CHO
R
H
+
O
cat.
O
OEt
O
OH
EtO2C
CHO
Ph
NaCNBH3
(10 mol %)
R
S
HOAc, THF
1
HS
2
H
+
3
toluene, rt
PhCO2H
(10 mol %)
cat.
S
5a
Ph
SH
2nd Michael
1a
4
OH
EtO2C
CH2OH
Ph
HO
S
O
N
N
O
OEt
S
O
OEt
S
EtO2C
1st Michael
CO2Et
6a
HO
Ph
7
R
R
Entry
Cat
t (h)
Yieldb (%)
eec (%)
drd
S
HS
1
2
3
4
5
6
7
8
I
II
22
3.5
1
96
96
1
3
96
3
96
1
1
1
24
10
46
71
<5
<5
66
<5
<5
53
32
49
55
42
29
0
83
8:1
7:1
Eq. 2. Michael-aldol cascade
III
IV
V
VI
VII
VIII
IX
X
VI
VI
VI
VI
82
9:1
O
O
OEt
O
Nde
Nde
87
Nde
Nde
7:1
OH
EtO2C
CHO
N
H
cat.
H
+
R
Nde
Nde
À6
À32
92
Nde
Nde
10:1
6:1
S
5
R
SH
1
4
9
cat.
aldol
10
11f
12g
13g,h
14g,i
10:1
10:1
11:1
10:1
92
95
95
N
N
S
O
OEt
O
O
OEt
O
Michael
a
Reaction conditions: unless specified, to a mixture of trans-cinnamaldehyde
(1a) (0.135 mmol), 10 mol % catalyst, benzoic acid (0.1 equiv) in toluene (0.5 mL)
was added 3-mercapto-2-oxopropanoate (4) (0.135 mol) in one portion. The reac-
tion mixture was stirred at rt for a specified time. The aldehyde was directly
reduced to alcohol for chiral HPLC analysis.
R
R
SH
Scheme 1. Organocatalytic asymmetric thia-Michael-initiated cascade reactions.
b
Isolated yield for two steps.
Determined by chiral HPLC analysis (Chiralpak AD-H) after reduced by
c
NaCNBH3.
d
Determined by 1H NMR.
Not determined.
CH2Cl2 as a solvent.
CH2Cl2 as a solvent and H2O (10 equiv) added.
5 mol % catalyst used.
1 mol % catalyst used.
e
f
g
Ar
I: Ar = Ph, R = H
IV: Ar = 3,5-(CF3)2C6H3, R = H
h
II: Ar = Ph, R = TMS V: Ar = 3,5-(CF3)2C6H3, R = TMS
III: Ar = Ph, R = TES VI: Ar = 3,5-(CH3)2C6H3, R = TMS
Ar
i
N
H
OR
H
N
H
N
N
N
CO2H
N
N
H
VIII
NHTf
Ph
N
N
H
H
N
H
(8:1 to >20:1 dr) (Table 2). The cascade processes were tolerant
of a variety of Michael acceptors trans-3-arylpropenals 1, which
possess electron-neutral (entry 1), withdrawing (entries 2–7),
donating (entries 8 and 11), a combination of withdrawing-
HN
S
VII
X
IX
Figure 1. Structures of organocatalysts screened.
donating (entries
9 and 10), and heteroaromatic (entry 12)
groups. It appeared that the steric effect imposed by these sub-
stituents (entries 3, 7, and 11) in 1 on the process was also
limited. The limitation of the cascade process was also realized.
A complicated reaction mixture was obtained when aliphatic
was found that the use of 10 equiv of water was optimal.13 The
improvement of both enantioselectivity (95% ee) and diastere-
oselectivity (11:1 dr) (entry 13) was achieved when catalyst
loading was reduced to 5 mol %. No further gain was observed
when the catalyst loading was reduced to 1 mol % (entry 14). It
should be pointed out that the low reaction yield of the Mi-
chael-aldol cascade process resulted from a significant amount
of by-product 7 (10–20%), which was formed from a three-com-
ponent reaction. In addition, unidentified oligomers were found.
It is noteworthy that the reduction of the aldehyde (5a) to alco-
hol (6a) was necessary for convenient chiral HPLC analysis with
good resolution.
a,b-unsaturated aldehydes were employed. The absolute config-
uration of 6b is determined based on X-ray crystal structure
analysis (Fig. 2).14
In conclusion, we have developed a novel and simple organ-
ocatalytic thiol initiated cascade Michael-aldol reaction between
a variety of derivatives of cinnamic aldehydes and 3-mercapto-2-
oxopropanoate. The process, efficiently catalyzed by readily
available (S)-di(3,5-dimethylphenyl)prolinol TMS ether, furnishes
highly functionalized chiral tetrahydrothiophenes with genera-
tion of three new consecutive stereogenic centers including a
chiral quaternary carbon center in high enantioselectivities and
high stereoselectivities in ‘one-pot’ transformation. The reaction
conditions are mild and practical. Further investigation is under-
way to expand the scope and application of this efficient cascade
process.
With the optimized reaction conditions in hand, we next
probed the scope of asymmetric Michael-aldol cascade reaction
promoted by VI. The new methodology provides a facile access
to
a range of trisubstituted tetrahydrothiophenes 6 in high
enantiomeric excess (91–97% ee) and high diastereoselectivities

2948
G. Luo et al. / Tetrahedron Letters 50 (2009) 2946–2948
Table 2
References and notes
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O
O
OEt
O
cat.
OH
EtO2C
CHO NaCNBH3
HOAc
(5 mol %)
H
+
CH2Cl2, rt, 1h
10 eq. H2O
PhCO2H
THF
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Entry
R
Yieldb (%)
eec (%)
drd
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1
2
3
4
5
6
7
8
Ph
4-BrC6H4
2-BrC6H4
4-FC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3,4-(OCH2O)C6H3
2-MeOC6H4
6a, 42
6b, 34
6c, 31
6d, 46
6e, 25
6f, 25
6g, 37
6h, 57
6i, 41
6j, 51
6k, 47
6l, 59
95
93
92
94
94
93
91
97
97
97
97
93e
10:1
12:1
8:1
13:1
>20:1
>20:1
9:1
12:1
>20:1
>20:1
>20:1
>20:1
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9
10
11
12
2-Furanyl
a
Unless stated otherwise, see Supplementary data.
Isolated yield for two steps.
b
c
Determined by chiral HPLC analysis (Chirapak AD, AS or chiralcel OJ-H column).
Determined by 1H NMR.
d
e
Determined by converting to corresponding a,b-unsaturated ester with triethyl
phosphonacetic acid.
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Figure 2. X-ray crystal structure of 6b.
Acknowledgments
We are grateful for the financial support from School of Phar-
macy, East China University of Science and the National Science
Foundation of China (Nos. 03772648 and 30721005), and the Chi-
nese National Programs for High Technology Research and Devel-
opment (Nos. 2006AA020602 and 2007AA02Z147).
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13. One equivalents of water: 49% yield, 90% ee; 10:1 dr; 2.0 equiv of
water: 48% yield, 91% ee; 10:1 dr; 20.0 equiv of water: 42% yield, 91%
ee; 10:1 dr.
14. CCDC 723406 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge via www.ccdc.cam.ac.uk.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.218.