Asymmetric synthesis of trisubstituted tetrahydrothiophenes bearing a quaternary stereocenter via double michael reaction involving dynamic kinetic resolution

Article abstract of DOI:10.1021/ol4014975

The stereoselective synthesis of highly functionalized tetrahydrothiophenes bearing three contiguous stereocenters, one of them quaternary, can be achieved by reacting trans-α-cyano-α,β-unsaturated ketones and trans-tert-butyl 4-mercapto-2-butenoate in the presence of a readily available amine thiourea. The products are obtained in high yield, good diastereoselectivity, and excellent enantioselectivity. The overall formation of tetrahydrothiophenes occurs via a cascade double Michael reaction involving a highly efficient process of dynamic kinetic resolution.

Full text of DOI:10.1021/ol4014975

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Synthesis of Trisubstituted
Tetrahydrothiophenes Bearing
a Quaternary Stereocenter via
Double Michael Reaction Involving
Dynamic Kinetic Resolution
Sara Meninno,† Gianluca Croce,‡ and Alessandra Lattanzi*,†
ꢀ
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Giovanni Paolo II,
84084 Fisciano, Italy, and DISIT-Universita del Piemonte Orientale,
ꢀ
Viale T. Michel 11, 15121, Alessandria, Italy
lattanzi@unisa.it
Received May 28, 2013
ABSTRACT
The stereoselective synthesis of highly functionalized tetrahydrothiophenes bearing three contiguous stereocenters, one of them quaternary, can
be achieved by reacting trans-R-cyano-R,β-unsaturated ketones and trans-tert-butyl 4-mercapto-2-butenoate in the presence of a readily available
amine thiourea. The products are obtained in high yield, good diastereoselectivity, and excellent enantioselectivity. The overall formation of
tetrahydrothiophenes occurs via a cascade double Michael reaction involving a highly efficient process of dynamic kinetic resolution.
The development of cascade reactions to synthesize
carbo- and heterocyclic compounds of different ring sizes,
in a single operation, is a topic of intense investigation, in
view of the evident advantages over traditional single-step
less economic procedures.1 The most powerful asymmetric
approaches are organocatalytic, relying on aminocatalysis
and hydrogen bonding catalysis, although the former has
been more extensively applied.2 Organocatalyzed stereo-
selective cascade reactions have been developed to obtain
valuable heterocyclic compounds such as thiochromenes,3
chromenes,4 4-aminobenzopyrans,5 and tetrahydro-
thiophenes,6 via hetero-Michael/Michael, hetero-Michael/
aldol, and hetero-Michael/Henry type reactions. Among the
†
ꢀ
Universita di Salerno.
‡
ꢀ
DISIT-Universita del Piemonte Orientale.
(1) For reviews, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. In
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(b) Enders, D.; Grondal, C.; H€uttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570. (c) Pellissier, H. Chem. Rev. 2013, 113, 442.
(2) For reviews, see: (a) Grondal, C.; Jeanty, M.; Enders, D. Nat.
Chem. 2010, 2, 167. (b) Mayano, A.; Rios, R. Chem. Rev. 2011, 111,
4703.
(4) For selected examples, see: (a) Govender, T.; Hojabri, L.;
Moghaddam, F. M.; Arvidsson, P. I. Tetrahedron: Asymmetry 2006,
ꢁ
17, 1763. (b) Sunden, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.;
ꢁ
Cordova, A. Chem.;Eur. J. 2007, 13, 574. (c) Li, H.; Wang, J.;
E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem. Commun.
(3) For selected examples, see: (a) Wang, W.; Li, H.; Wang, J.; Zu, L.
ꢁ
J. Am. Chem. Soc. 2006, 128, 10354. (b) Rios, R.; Sunden, H.; Ibrahem,
2007, 507. (d) Liu, C.; Zhang, X.; Wang, R.; Wang, W. Org. Lett. 2010,
ꢁ
I.; Zhao, G. L.; Eriksson, L.; Cordova, A. Tetrahedron Lett. 2006, 47,
ꢁ
ꢁ~
12, 4948. (e) Aleman, J.; Nunez, A.; Marzo, L.; Marcos, V.; Alvarado,
C.; Garcia Ruano, J. L. Chem.;Eur. J. 2010, 16, 9453. (f) Wang, X.-F.;
Hua, Q.-L.; Cheng, Y.; An, X.-L.; Yang, Q.-Q.; Chen, J.-R.; Xiao, W.-J.
Angew. Chem., Int. Ed. 2010, 49, 8379. (g) Hou, W.; Zheng, B.; Chen, J.;
Peng, Y. Org. Lett. 2012, 14, 2378. (h) Yang, W.; Yang, Y.; Du, D.-M.
Org. Lett. 2013, 15, 1190.
ꢁ
ꢁ
8547. (c) Rios, R.; Sunden, H.; Ibrahem, I.; Zhao, G. L.; Cordova, A.
Tetrahedron Lett. 2006, 47, 8679. (d) Zu, L. S.; Wang, J.; Li, H.; Xie,
H. X.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (e) Zu, L.;
Xie, H.; Li, H.; Wang, J.; Jiang, W.; Wang, W. Adv. Synth. Catal. 2007,
349, 1882. (f) Dodda, R.; Goldman, J. J.; Mandal, T.; Zhao, C. G.;
Broker, G. A.; Tiekink, E. R. T. Adv. Synth. Catal. 2008, 350, 537.
(g) Wang, J.; Xie, H. X.; Li, H.; Zu, L. S.; Wang, W. Angew. Chem., Int.
Ed. 2008, 47, 4177.
(5) Wang, X.-F.; An, J.; Zhang, X.-X.; Tan, F.; Chen, J.-R.; Xiao,
W.-J. Org. Lett. 2011, 13, 808.
r
10.1021/ol4014975
XXXX American Chemical Society

sulfur containing heterocycles, tetrahydrothiophenes are
particularly interesting due to their important biological
activities, as naturally occurring products, in medicinal
chemistry,7 and as ligands in asymmetric catalysis.8 How-
ever, few methods have been reported for the stereoselective
synthesis of these compounds.9 Among the organocatalytic
cascade reactions, the one-pot double Michael addition
to enantioenriched trisubstituted tetrahydrothiophenes is
a straightforward and convenient process.
trans-4-mercapto-2-butenoates 9 in a one-pot operation.
The process was found to be efficiently catalyzed by a simple
amino thiourea, leading to tetrahydrothiophenes with good
diastereoselectivity and excellent enantioselectivity.
Scheme 2. Noncovalent Organocatalyzed Synthesis of
Trisubstituted Tetrahydrothiophenes Bearing a Quaternary
Stereocenter via Cascade Double Michael Reaction
Scheme 1. Cascade Double Michael Approaches to
Trisubstituted Tetrahydrothiophenes
Up to now, only nitroalkenes and R,β-unsaturated
aldehydes have been successfully used as the Michael accep-
tors for this process under H-bonding catalysis (eq 1)6e or
aminocatalysis (eq 2),6b respectively (Scheme 1). Trisubsti-
tuted tetrahydrothiophenes, bearing tertiary stereocenters,
have been synthesized with excellent stereocontrol.
Our recent work focused on the development of a
noncovalent organocatalyzed cascade double Michael
reaction10 to cyclohexanones and Michael-initiated ring-
closing (MIRC) reactions to three-membered heterocyclic
compounds bearing a quaternary stereocenter.11 Being
interested in expanding the organocatalytic approach
as a tool to access targets of increased complexity, we
now report a study aimed at constructing synthetically
more challenging trisubstituted tetrahydrothiophenes 10,
bearing a quaternary stereocenter (Scheme 2). We envi-
saged a cascade double Michael reaction to compounds 10
catalyzed by a bifunctional organocatalyst, reacting easily
available trans-R-cyano-R,β-unsaturated ketones 8 and
At the outset of our study, trans-R-cyano-R,β-unsatu-
rated ketone8aand trans-ethyl4-mercapto-2-butenoate9a
were reacted in the presence of a variety of bifunctional
organocatalysts at 20 mol % loading (Scheme 2) in toluene
at room temperature (Table 1). Quinine afforded racemic
product 10a in moderate yield and diastereoselectivity
(entry 1), whereas L-diphenyl prolinol 2 gave compound
10a in a better yield, diastereoselectivity, and 19% enan-
tiomeric excess (ee) (entry 2). The use of catalysts with
more effective H-bond donor groups, such as squaramide
3 (entry 3) and the Takemoto thiourea 4 (entry 4), sig-
nificantly improved the enantiocontrol (ee up to 75%).
These results prompted us to investigate other amino
thioureas as catalysts.
Cinchona derived thioureas 5 and 6 behaved similarly to
catalyst 4 in terms of activity and stereoselectivity (entries 5
and 6). Interestingly, catalyst 712 gave the product in good
yield with an inverted diastereoisomeric ratio and 98%
ee for the major diastereoisomer (entry 7). A solvent screen
showed that good results are generally obtained when
working in nonpolar aromatic solvents (entries 8À12), with
toluene being the most effective. The reaction using trans-
methyl 4-mercapto-2-butenoate 9b (entry 13) proceeded with
similar stereocontrol. Pleasingly, more sterically demand-
ing trans-tert-butyl 4-mercapto-2-butenoate 9c enabled the
isolation of the corresponding product 10c in good yield,
improved diastereoisomeric ratio (dr = 9:1), and 99% ee
(entry 14). A comparable result was achieved when the
catalyst loading was reduced to 10 mol % (entry 15).
Under optimized conditions, the scope of the double
cascade Michael reaction was investigated (Table 2).
(6) (a) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am. Chem. Soc.
2006, 128, 14986. (b) Li, H.; Zu, L.; Xie, H.; Wang, J.; Jiang, W.; Wang,
W. Org. Lett. 2007, 9, 1833. (c) Luo, G. S.; Zhang, S. L.; Duan, W. H.;
Wang, W. Tetrahedron Lett. 2009, 50, 2946. (d) Tang, J.; Xu, D. Q.; Xia,
A. B.; Wang, Y. F.; Jiang, J. R.; Luo, S. P.; Xu, Z. Y. Adv. Synth. Catal.
2010, 352, 2121. (e) Yu, C.; Zhang, Y.; Song, A.; Ji, Y.; Wang, W.
Chem.;Eur. J. 2011, 17, 770. (f) Ling, J. B.; Su, Y.; Zhu, H.-L.; Wang,
G.-Y.; Xu, P.-F. Org. Lett. 2012, 14, 1090.
(7) (a) Tsygoanko, V. A.; Blume, Y. B. Biopolim. Kletka 1997, 13,
484. (b) De Clercq, P. J. Chem. Rev. 1997, 97, 1755. (c) Wirsching, J.;
Voss, J.; Adiwidjaja, G.; Balzarini, J.; De Clercq, E. Bioorg. Med. Chem.
Lett. 2001, 11, 1049. (d) Begley, T. P. Nat. Prod. Rep. 2006, 23, 15.
(8) For selected examples, see: (a) Mukaiyama, T.; Asanuma, H.;
Hachiya, I.; Harada, T.; Kobayashi, S. Chem. Lett. 1991, 7, 1209.
(b) Julienne, K.; Metzner, P. J. Org. Chem. 1998, 63, 4532. (c) Zanardi,
J.; Lamazure, D.; Miniere, S.; Reboul, V.; Metzner, P. J. Org. Chem.
2002, 67, 9083.
(9) For a recent review, see: Benetti, S.; De Risi, C.; Pollini, G. P.;
Zanirato, V. Chem. Rev. 2012, 112, 2129.
(10) De Fusco, C.; Lattanzi, A. Eur. J. Org. Chem. 2011, 3728.
(11) (a) Russo, A.; Galdi, G.; Croce, G.; Lattanzi, A. Chem.;Eur. J.
2012, 18, 6152. (b) De Fusco, C.; Fuoco, T.; Croce, G.; Lattanzi, A. Org.
Lett. 2012, 14, 4078.
(12) Catalyst 7 is easily obtained in 60% overall yield over two steps
from (1R,2R)-1,2-diphenylethylenediamine. See the Supporting Infor-
mation for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Reaction Conditionsa
Table 2. Double Michael Reaction of Alkenes 8 and trans-tert-
Butyl 4-Mercapto-2-Butenoate 9c Catalyzed by Thiourea 7a
time
(h)
yieldb
(%)
drc
eed
(%)
time
(h)
yieldb
(%)
drc
eed
(%)
entry
cat.
9
solvent
(%)
entry
R1, R2
Ph,Ph
10
(%)
1
1
2
3
4
5
6
7
7
7
7
7
7
7
7
7
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9c
9c
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
69
70
70
89
70
68
48
74
74
71
72
70
60
36
50
56
76
65
85
80
78
80
69
76
67
74
74
90
84
94
2:1
3:1
3:1
3:1
3:1
2:1
1:4
1:4
1:4
1:3
1:3
1:3
1:4
1:9
1:9
rac
19
1
50
10c
10d
10e
10f
94
70
70
97
98
98
98
85
72
98
96
98
79
9:1
99
2
2
Ph, 4-MeOC6H4
Ph, 4-tBuC6H4
Ph, 4-BrC6H4
Ph, 3-BrC6H4
Ph, 4-CNC6H4
Ph, 4-NO2C6H4
Ph, 2-naphthyl
Ph, 3-furyl
120
150
88
12:1 99
7:1 99
3e
4
3
À39
À75
À83
74
4
12:1 99
10:1 99
5
5
85
10g
10h
10i
6
6
65
9:1
9:1
9:1
9:1
9:1
5:1
1:1
3:1
99
7
98
7
40
>99
>99
99
8
98
8
180
160
78
10j
9
Et2O
94
9
10k
10l
10
11
12
13
14
15e
m-xylene
ClC6H5
CF3C6H5
toluene
toluene
toluene
97
10
11
12
13
4-MeOC6H4, Ph
3-ClC6H4, Ph
Ph, cyclohexyl
(CH2)2Ph, Ph
99
97
70
10m
10n
10o
98
94
69
>99(87)
89
98
96
99
a Reaction conditions: 8 (0.1 mmol), 9c (0.13 mmol), catalyst
(0.01 mmol) in 1 mL of solvent. b Yield of isolated product. c Determined
by 1H NMR analysis of the crude reaction mixture. d Determined by chiral
HPLC analysis of major diastereoisomer. In parentheses the enantiomeric
excess of the other diastereoisomer. e 20 mol % of catalyst 7 was used.
99
a Reaction conditions: 8a (0.1 mmol), 9 (0.12 mmol), catalyst
(0.02 mmol) in 1 mL of solvent. b Yield of isolated product. c Determined
by 1H NMR analysis of the crude reaction mixture. d Determined by
chiral HPLC analysis of major diastereoisomer. e 10 mol % of catalyst 7
and 0.13 mmol of 9c were used.
As expected, compounds 8 bearing electron-donating
substituents on the aryl moiety at the β-position were
less reactive, although the level of stereoselectivity was
maintained (entries 2 and 3). R-Cyano enones bearing
electron-poor substituents gave the product in excellent
yield and enantioselectivity as well as good diastereo-
control (entries 4À7). Other aromatic or heteroaromatic
residues were also well-tolerated (entries 8 and 9).
Substitution on the aryl moiety at the keto position of
compounds 8 had almost no effect on yield and stereo-
selectivity (entries 10 and 11). Although the presence of an
alkyl group at the β-position of enone 8 led to the product
10n as a 1:1 ratio of diastereoisomers, excellent yield and
enantioselectivities were observed (entry 12). Alkyl sub-
stituted enone on the keto moiety afforded the product 10o
in a 3:1 diastereoisomeric ratio, and the major diastereo-
isomer was recovered with 89% ee (entry 13). The absolute
configuration of the major diastereoisomer of compound
10i was determined to be 3S,4R,5S, whereas the relative
configuration of the minor racemic diastereoisomer 10e
was determined to be (3S*,4S*,5R*) by single crystal
X-ray analysis.13
Scheme 3. Suggested Cascade Pathway Involving Dynamic
Kinetic Resolution
a dynamickinetic resolution (DKR)14 was found togovern
the stereochemical outcome via a retro-sulfa Michael/
sulfa-Michael/Michael process.3g Wespeculated thatgiven
the relative acidity of the intermediate adduct 11 R-proton,
a retro-sulfa Michael reaction followed by a selective
sulfa-Michael/Michael process catalyzed by 7 might occur
(Scheme 3). The reaction of 8a and 9c, catalyzed by 7,
was preliminarily monitored by 1H NMR spectroscopy to
check the evolution of adduct 11c over time (Figure 1).
According to the reaction progress profile, adduct 11c
is rapidly formed and consumed. The racemic mixture
of diastereoisomers 11c could be isolated working under
more controlled conditions.13 To verify the hypothesis
illustrated in Scheme 3, adduct 11c was treated under the
same reaction conditions reported in Table 2 (Scheme 4).
Tetrahydrothiophene 10c was obtained in 75% yield,
a 9:1 diastereoisomeric ratio, and 98% ee for the major
diastereoisomer. This result is the same achieved when
reacting enone 8a and thiol 9c directly, thus showing that
In a double asymmetric organocatalytic Michael cas-
cade reaction to thiochromenes starting from nitroalkenes,
(13) See the Supporting Information for details.
(14) For reviews on dynamic kinetic resolution, see: (a) Caddick, S.;
€
Jenkins, K. Chem. Soc. Rev. 1996, 447. (b) Backvall, J.-E. Trends
Biotechnol. 2004, 22, 130. (c) Pellissier, H. Adv. Synth. Catal. 2011,
353, 659.
Org. Lett., Vol. XX, No. XX, XXXX
C

Although the process has not been optimized, a promising
result has been achieved, since product 10c was isolated in
93% yield, with a 60:40 diastereoisomeric ratio and 91% ee
being observed for the major diastereoisomer.
Scheme 5. Stereoselective One-Pot Sequential Knoevenagel/
Double Michael Reaction to Tetrahydrothiophene 10c
Figure 1. Reaction progress profile (entry 1 of Table 2) monitored
by 1H NMR in deuterated toluene.
In conclusion, an effective cascade double Michael
reaction has been developed for the stereoselective con-
struction of trisubstituted tetrahydrothiophenes in a single
operation by using a readily available amino thiourea as
an organocatalyst. These densely functionalized products
are isolated in high yield, good diastereoselectivity, and
excellent enantiocontrol. Notably, one all-carbon quatern-
ary stereocenter was installed, which is a well-known
challenge in asymmetric synthesis.17 A highly efficient
process of DKR is involved in the cascade reaction. The
organocatalyst is able to catalyze a reversible sulfa-Mi-
chael reaction, followed by a highly stereoselective cascade
sulfa-Michael/Michael reaction. Interestingly, it has been
demonstrated that tetrahydrothiophenes can be stereose-
lectively obtained via a sequential one-pot Knoevenagel/
double Michael cascade process.
Scheme 4. Michael Addition of Adduct 11c Catalyzed by
Compound 7
an efficient process of dynamic kinetic resolution is in-
volved. This represents the first example where dynamic
kinetic resolution completely controls the stereochemical
outcome of an asymmetric reaction to access tetrahydro-
thiophenes.15
Given the ever-increasing importance of multicompo-
nent reactions in asymmetric synthesis and medicinal
chemistry to obtain complex scaffolds, starting from sim-
ple reagents,16 we investigated the feasibility of a one-pot
sequential access to tetrahydrothiophenes (Scheme 5).
After treatment of benzaldehyde and benzoyl acetonitrile
under typical Knoevenagel conditions to generate 8a,
catalyst 7 and thiol 9c were added at room temperature.
Acknowledgment. We thank the Italian Ministry of
University and Research (MIUR) for financial support.
A.L. thanks the COST Action CM0905 Organocatalysis
(ORCA). We thank Prof. R. Zanasi (University of Salerno)
for useful discussions.
Supporting Information Available. Experimental pro-
cedures, characterization data, 1H and 13C NMR spectra
for new compounds, X-rays crystal structures, and HPLC
traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) For an example of interplay between DKR and catalyst control
in the stereoselective synthesis of trisubstituted tetrahydrothiophenes,
see ref 6e.
(16) For reviews, see: (a) Bonne, D.; Coquerel, Y.; Constantieux, T.;
Rodriguez, J. Tetrahedron: Asymmetry 2010, 21, 1085. (b) De Graaff, C.;
Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969. (c) Slobbe, P.;
Ruijter, E.; Orru, R. V. A. Med. Chem. Commun. 2012, 3, 1189.
(17) For reviews, see: (a) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295. (b) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX