Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

Article abstract of DOI:10.3762/bjoc.12.63

An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes affording the heterocyclic products in good yields and moderate stereoselectivities.

Full text of DOI:10.3762/bjoc.12.63

Stereoselective amine-thiourea-catalysed sulfa-Michael/
nitroaldol cascade approach to 3,4,5-substituted tetrahydro-
thiophenes bearing a quaternary stereocenter
Sara Meninno, Chiara Volpe, Giorgio Della Sala, Amedeo Capobianco
and Alessandra Lattanzi*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 643–647.
Dipartimento di Chimica e Biologia “A. Zambelli”, Via Giovanni Paolo
II, 84084, Fisciano, Italy
doi:10.3762/bjoc.12.63
Received: 14 December 2015
Accepted: 12 March 2016
Published: 05 April 2016
Email:
Alessandra Lattanzi* - lattanzi@unisa.it
*
Corresponding author
This article is part of the Thematic Series "Bifunctional catalysis".
Guest Editor: D. J. Dixon
Keywords:
cascade reaction; tetrahydrothiophenes; aymmetric synthesis; amine
thioureas; organocatalysis
© 2016 Meninno et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-
dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thio-
urea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitro-
styrenes affording the heterocyclic products in good yields and moderate stereoselectivities.
Introduction
The interest toward the development of stereoselective method- covalent organocatalytic cascade sulfa-Michael/Michael [13-15]
ologies to prepare tetrahydrothiophenes bearing multiple chiral and sulfa-Michael/aldol reactions [16-20] enabled the synthesis
centers increased over the last years [1]. Indeed, chiral non- of differently functionalized tetrahydrothiophenes bearing up to
racemic functionalized tetrahydrothiophenes are endowed with three contiguous chiral centers, including quaternary ones, with
different biological activities [2-5] and they are useful ligands good to high control of the diastereo- and enantioselectivity.
in asymmetric catalysis [6]. However, few asymmetric ap-
proaches are available to obtain this class of compounds and Surprisingly, to date there has been one report on a dynamic
only recently organocatalytic stereoselective cascade reactions system combining a 1,1,3,3-tetramethylguanidine (TMG)/ZnI2-
have emerged as the most successful, and straightforward ap- catalyzed diastereoselective cascade sulfa-Michael/nitroaldol
proach to access them [7,8]. Aminocatalytic [9-12] and non- reaction followed by lipases catalyzed kinetic resolution using
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Beilstein J. Org. Chem. 2016, 12, 643–647.
two representative trans-β-methyl-β-nitrostyrenes and 1,4- In the case of trans-β-nitrostyrene (1), a mixture of diastereoiso-
dithiane-2,5-diol as reagents [21]. One diastereoisomer of the mers 5 and 6 were rapidly formed, irrespective of the catalyst
racemic tetrahydrothiophenes, present at the equilibrium, was used, with a poor level of diastereo- and enantioselectivity
preferentially acylated by the enzyme to give the product in (Table 1, entries 1–5). Thiourea catalyst VII afforded the best
high ee.
result, leading to products 5/6 in a ratio of 72/28 although with
low ee values (Table 1, entry 6). Reacting trisubstituted olefin
Different amines such as Et3N, DBU, TMG catalyze the sulfa- 2a with compound 4, led to three isomers with modest dia-
Michael/nitroaldol process of either trans-β-methyl-β-nitro- stereocontrol when using catalysts (I–VII). Among the cata-
styrenes [21] and trans-β-nitrostyrenes [22] with 1,4-dithiane- lysts tested, compound VII proved to be the most active and en-
2
,5-diol. Based on all above considerations and prompted by antioselective, giving the major diastereoisomer 7a with 44% ee
our interest in asymmetric synthesis of functionalized tetra- (Table 1, entry 13). Taking into account that amine thiourea
hydrothiophenes [14], we wondered whether we could use VII, bearing a sterically hindered secondary amine moiety, was
bifunctional organocatalysts to develop a diastereo- and enan- significantly more effective than tertiary amine-based thioureas
tioselective cascade sulfa-Michael/nitroaldol reaction and herein [14,23], catalyst VIII, bearing a sterically demanding neopentyl
we report our preliminary results.
group, was synthesized in order to check its impact on the
stereoselectivity (Scheme 2).
Results and Discussion
According to the literature data, low control of the diastereo- Catalyst VIII was easily obtained in a two-step procedure in
selectivity was observed in the cascade reaction of 1,4-dithiane- fair overall yield. Compound VIII proved to be less active,
2
,5-diol with trans-β-nitrostyrenes, and in the case of (E)-1- affording a comparable level of diastereoselectivity than com-
aryl-2-nitropropene all four diastereoisomeric tetrahydrothio- pound VII, but a lower ee value for major diastereoisomer 7a
phenes were observed when using tertiary amines such Et3N, was measured (Table 1, entry 14). Moreover, the opposite enan-
DBU or TMG [21,22].
tiomer of product 7a was preferentially obtained, thus
suggesting that the nature of the alkyl group on the secondary
At the outset, the sulfa-Michael/nitroaldol reaction was studied amine moiety greatly affects the stereochemical outcome of the
by reacting trans-β-nitrostyrene, (E)-1-phenyl-2-nitropropene process. The relative configuration of diastereoisomers 7a/8a/
and (E)-1-phenyl-2-nitrobutene in toluene at room temperature 9a was established by NOESY and NOE analysis on
with 1,4-dithiane-2,5-diol as precursor of mercaptoacetalde- diastereoisomerically pure 7a and on a diastereoisomeric mix-
hyde, using 10 mol % loading of different bifunctional organo- ture of compounds 8a and 9a (see the Supporting Information
catalysts (Scheme 1, Table 1).
File 1) [24].
Scheme 1: Organocatalysts screened in the cascade reaction.
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Beilstein J. Org. Chem. 2016, 12, 643–647.
Table 1: Asymmetric sulfa-Michael/nitroaldol reaction of nitroalkenes 1–3 with 1,4-dithiane-2,5-diol (4) catalyzed by catalysts I–VIII.
entry
cat.
1–3
time (h)
yield [%]a
drb
ee [%]c
1
2
3
4
5
6
7
8
9
I
1
5.5
2.5
1.5
25
2
75
79
53
52
89
73
77
77
69
59
72
16
90
70
80
58/42 (5/6)
9 (5)/15 (6)
rac (5)/24 (6)
rac (5)/12 (6)
−14 (5)/20 (6)
−3 (5)/−10 (6)
−12 (5)/−24 (6)
19 (7a)
II
1
60/40 (5/6)
III
IV
V
1
44/56 (5/6)
1
50/50 (5/6)
1
38/62 (5/6)
VII
I
1
2
72/28 (5/6)
2a
2a
2a
2a
2a
2a
2a
2a
3
21
17
17
27
18
44
28
40
52
66/28/6 (7a/8a/9a)
66/27/7 (7a/8a/9a)
68/24/8 (7a/8a/9a)
70/23/7 (7a/8a/9a)
68/24/8 (7a/8a/9a)
69/25/6 (7a/8a/9a)
58/30/12 (7a/8a/9a)
65/29/6 (7a/8a/9a)
50/27/23 (11/10/12)
II
13 (7a)
III
IV
V
4 (7a)
10
11
12
13
14
15
2 (7a)
−19 (7a)
VI
VII
VIII
VII
1 (7a)
−44 (7a)
19 (7a)
42 (11)
aIsolated yield of all diastereoisomers after silica gel chromatography. bDetermined by 1H NMR analysis of the crude mixture. cDetermined by chiral
HPLC analysis. Negative values indicate the prevalent formation of the opposite enantiomer.
Scheme 2: Synthesis of catalyst VIII.
Finally, catalyst VII was checked in the reaction of alkene 3 The diastereoselective ratios, determined for tetrahydrothio-
under the same conditions (Table 1, entry 15). After a longer phenes deriving from alkenes 2a and 3, are in line with their
reaction time, diastereoisomers 10–12 were isolated with poor computed thermodynamic stability in toluene (see the Support-
diastereomeric ratio and major isomer 11 was recoverd with ing Information File 1). Indeed, products 8a and 9a were found
4
2% ee [25].
to be 0.7 kcal/mol less stable compared to compound 7a. In the
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Beilstein J. Org. Chem. 2016, 12, 643–647.
case of products 10–12, the predicted relative free energies for Tetrahydrothiophenes, bearing three contiguous stereocenters,
1
0, 11 and 12 fall within a range of 0.1 kcal/mol.
were isolated in good to high yield, moderate diastereo-
selectivity and up to 59% ee.
Pleasingly, a solvent screening for the cascade reaction carried
out on compound 2a with catalyst VII enabled to improve the Conclusion
diastereoselectivity as only 7a/8a were detected in 75:25 ratio In conclusion, we reported a diastereo- and enantioselective
and the enantiocontrol increased to 50% ee for diastereoisomer cascade sulfa-Michael/nitroaldol reaction of (E)-1-aryl-2-
7
a when using chlorobenzene as the solvent at room tempera- nitropropenes with 1,4-dithiane-2,5-diol. The process was
ture (Table 2, entry 5). catalyzed by an easily available amine thiourea to give
,4,5-substituted tetrahydrothiophenes, bearing a quaternary
3
It is worth noting that bifunctional organocatalyst VII appears stereocenter, in good yield and moderate enantiocontrol.
to be more effective in terms of diastereocontrol than previ- It has been demonstrated that a simple bifunctional amine
ously employed Brønsted base/Lewis acid system TMG/ZnI2 thiourea secures a more effective control of the diastereo-
giving four diastereoisomers instead [21].
selectivity than Brønsted base/Lewis acid systems. Data
herein illustrated suggest that fine tuning of the bifunctional
Finally, the sulfa-Michael/nitroaldol cascade reaction was organocatalyst structure and reaction conditions will be re-
applied to other trans-β-methyl-β-nitrostyrenes under the opti- quired for further improvements of the challenging cascade
mized conditions (Table 3).
process.
Table 2: Solvent screening in the asymmetric Michael/nitroaldol reaction of 2a with 1,4-dithiane-2,5-diol (4) catalysed by amine thiourea VII.
entry
solvent
time (h)
yield [%]a
drb
ee 7a [%]c
1
2
3
4
5
CH3CN
21
47
63
63
16
83
93
56
55
69
69/31 (7a/8a)
5
CH3Ot-Bu
CHCl3
72/24/4 (7a/8a/9a)
68/28/4 (7a/8a/9a)
70/30 (7a/8a)
30
51
51
50
ClCH2CH2Cl
C6H5Cl
75/25 (7a/8a)
aIsolated yield of all diastereoisomers after silica gel chromatography. bDetermined by 1H NMR analysis of the crude mixture. cDetermined by chiral
HPLC analysis.
Table 3: Asymmetric sulfa-Michael/nitroaldol reaction of nitroalkenes 2 with 1,4-dithiane-2,5-diol (4) catalysed by amine thiourea VII.
entry
R1
time (h)
yield [%]a
drb
ee 7 [%]c
1
2
3
4
Ph
16
16
40
45
69
66
76
90
75/25 (7a/8a)
50
51
42
59
4-ClC6H4
4-MeC6H4
2-naphthyl
69/31 (7b/8b)
74/26 (7c/8c)
66/26/8 (7d/8d/9d)
aIsolated yield of all diastereoisomers after silica gel chromatography. bDetermined by 1H NMR analysis of the crude mixture. cDetermined by chiral
HPLC analysis.
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Beilstein J. Org. Chem. 2016, 12, 643–647.
2
1.Zhang, Y.; Vongvilai, P.; Sakulsombat, M.; Fischer, A.; Ramström, O.
Adv. Synth. Catal. 2014, 356, 987–992. doi:10.1002/adsc.201301033
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Supporting Information
2
Supporting Information File 1
Experimental procedures, characterization data, NMR
spectra of new compounds and HPLC traces of synthesized
compounds, computational details.
23.Bellavista, T.; Meninno, S.; Lattanzi, A.; Della Sala, G.
Adv. Synth. Catal. 2015, 357, 3365–3373.
doi:10.1002/adsc.201500403
[http://www.beilstein-journals.org/bjoc/content/
2
4.Diastereoisomers 8a and 9a and have the same mobility on TLC.
5.Diastereoisomers 10, 11 and 12 have very similar mobility on TLC. The
relative configurations of diastereoisomers 10/11/12 were assigned by
analogy of chemical shifts observed in the 1H NMR spectra with those
of diastereoisomers 7a/8a/9a.
supplementary/1860-5397-12-63-S1.pdf]
2
Acknowledgements
We thank the Italian Ministry of University and Research
(
MIUR) and University of Salerno for financial support.
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