Organocatalytic asymmetric michael addition of oxazolones to arylsulfonyl indoles: Facile access to syn-configured α,β-disubstituted tryptophan derivatives

Article abstract of DOI:10.1002/ejoc.201201335

Enantioselective Michael addition of oxazolones to in situ generated vinylogous imine intermediates is reported. A series of optically active 3-alkylindole derivatives with adjacent quaternary and tertiary stereocenters was obtained. The resulting adducts can readily be converted into syn-configured α,β-disubstituted tryptophan derivatives without compromising the stereoselectivities. Organocatalytic asymmetric Michael addition of oxazolones 2 to vinylogous imine intermediates generated in situ from arylsulfonyl indoles 1 is described. This protocol provides facile access to optically active 3-indolyl derivatives with good results. The resulting adducts can be easily converted into syn-α,β-disubstituted tryptophan derivatives without compromising the stereoselectivities. Copyright

Full text of DOI:10.1002/ejoc.201201335

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201335
Organocatalytic Asymmetric Michael Addition of Oxazolones to Arylsulfonyl
Indoles: Facile Access to syn-Configured α,β-Disubstituted Tryptophan
Derivatives
Chang-Wu Cai,[a] Xing-Li Zhu,[a] Song Wu,[a] Zong-Le Zuo,[a] Liang-Liang Yu,[a]
Da-Bin Qin,[a] Quan-Zhong Liu,[a] and Lin-Hai Jing*[a]
Keywords: Organocatalysis / Asymmetric synthesis / Heterocycles / Michael addition / Enantioselectivity
Enantioselective Michael addition of oxazolones to in situ
generated vinylogous imine intermediates is reported. A
resulting adducts can readily be converted into syn-config-
ured α,β-disubstituted tryptophan derivatives without com-
series of optically active 3-alkylindole derivatives with adja- promising the stereoselectivities.
cent quaternary and tertiary stereocenters was obtained. The
lysis. The resulting adducts can be further conveniently con-
Introduction
verted into syn-configured α,β-disubstituted tryptophan de-
rivatives with various substituents at the α- and β-positions
without compromising the stereoselectivities.
Tryptophan, an essential amino acid for many organisms,
is an important structural unit and synthetic intermediate
of various bioactive compounds and natural products.[1]
Likewise, α,β-disubstituted tryptophan structural motifs are
widely found in biologically active molecules and naturally
occurring compounds such as stephacidins,[2a–2d] cycloaply-
sinopsins,[2e,2f] tubastrindoles,[2g] dictazolines,[2g–2i] dict-
azoles,[2i] and waikialoid.[2j] Although this structural scaf-
fold is very important, to the best of our knowledge, only
one asymmetric catalytic version has been reported for the
synthesis of α,β-disubstituted tryptophan derivatives with
methyl or ethyl groups at the β-position.[3] Furthermore,
enantioselective routes to these compounds have been less
explored.[4] Therefore, to explore an efficient approach for
the synthesis of α,β-disubstituted tryptophan derivatives
with various substituents at the α- and β-positions is still
highly desired. In 2006, an innovative solution to the indole
skeleton by using arylsulfonyl indole 1 was developed by
the Petrini group.[5] In that work, compound 1[6] was used
to generate highly active vinylogous imine intermediates
in situ under basic conditions, and these species were then
treated with nucleophiles to afford 3-substituted indole de-
rivatives (Scheme 1).[7,8] Inspired by these elegant studies,
and considering that oxazolone[9] is an excellent masked
amino acid fragment,[3,10] herein we wish to describe the
first stereoselective Michael addition of oxazolones to vin-
ylogous imine intermediates generated in situ from aryl-
sulfonyl-substituted indoles under simple chiral organocata-
Scheme 1. Nucleophilic Michael addition to vinylogous imine in-
termediates generated in situ from arylsulfonyl indoles 1.
Results and Discussion
At the outset of our studies, arylsulfonyl indole 1a and
oxazolone 2a were chosen as model substrates to optimize
the reaction conditions, and the results are listed in Table 1.
The natural cinchona alkaloids quinine (3a), cinchonidine
(3b), and cinchonine (3c) only gave poor yields and enantio-
selectivities and various levels of diastereoselectivities
(Table 1, entries 1–3). Cinchona alkaloid derived Hatakey-
ama catalyst 3d showed unsuccessful results under the reac-
tion conditions (Table 1, entry 4).[11] Subsequently, our at-
tention turned to bifunctional thiourea catalysts.[12] Takem-
oto catalyst 3e provided an excellent ee value, although with
poor diastereoselectivity (Table 1, entry 5).[13] No satisfying
result was achieved when thiourea catalyst 3f bearing a chi-
ral diaminocyclohexane skeleton was used (Table 1, en-
try 6).[13c] Then, we began to investigate cinchona alkaloid
derived thiourea catalysts 3g–j.[14] To our delight, catalyst
3j gave the best dr and ee value (Table 1, entry 10).[14e] To
improve the yield, the reaction concentration was increased
[a] Chemical Synthesis and Pollution Control Key Laboratory of
Sichuan Province, China West Normal University,
1 Shi Da Road, Nanchong 637002, P. R. China
E-mail: cwnujlh@yahoo.com.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201335.
456
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 456–459

Organocatalytic Asymmetric Michael Addition of Oxazolones
Table 1. Optimization of the reaction conditions.[a]
With the optimized reaction conditions in hand, we then
screened a series of arylsulfonyl indoles 1 and oxazolones 2
to establish the general utility of this asymmetric transfor-
mation. As summarized in Table 2, most arylsulfonyl in-
doles and oxazolones underwent the reaction smoothly to
afford syn-selective addition products with good results.
Substrates with a substituent in the para position of the
phenyl ring of R1 gave a slightly higher yield and enantio-
selectivity than did substrates with a substituent in the meta
position. For example, 4-F-substituted 1b gave the product
in 69% yield with 90% ee, whereas 3-F-substituted 1e gave
the product in only 64% yield with 88% ee (Table 2, entry 2
vs. 5). A similar phenomenon was also observed in the reac-
tion of 1c compared with that of 1f (Table 2, entry 3 vs. 6).
However, an even greater difference was achieved when or-
tho-substituted 1q was used (Table 2, entry 17 vs. 19). It is
noteworthy that when 1m was treated with 2a under the
optimized reaction conditions, only 50% ee could be ob-
tained (Table 2, entry 13). This seems to imply that sterics
at the 2-position of the indole core play an important role
in the enantioselectivity of the reaction, which is in line with
previous reports.[8a,8c,8d,8h] Nevertheless, if the R group was
changed from methyl to phenyl, relatively low stereoselecti-
Entry Cat. Base
Solvent
Yield[b]
[%]
dr[c]
ee[d]
[%]
1[e,f]
2[e,f]
3[e,f]
4[e,f]
5[e,f]
6[e,f]
7[e,f]
8[e,f]
9[e,f]
10[e,f]
11[f]
12
13
14
15
16
17
18
19
20
3a K3PO4
3b K3PO4
3c K3PO4
3d K3PO4
3e K3PO4
3f K3PO4
3g K3PO4
3h K3PO4
3i K3PO4
3j K3PO4
3j K3PO4
3j K3PO4
3j Na2CO3
3j K2CO3
3j KF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
30
35
40
29
58
50
64
44
60
52
62
63
45
56
30
45
50
72
31
60
53
50
55
40
40
41
63:37
71:29
50:50
43
36
–19
71:29 Ͻ –5
57:43
62:38
57:43
77:23
69:31
79:21
79:21
82:18
78:22
78:22
70:30
76:24
71:29
70:30
62:38
82:18
73:27
71:29
72:28
73:27
80:20
77:23
94
89
–87
–94
95
97
96
97
91
95
81
90
91
92
49
97
98
96
97
80
95
94
Table 2. Asymmetric Michael addition of oxazolones to arylsul-
fonyl indoles.[a]
3j KF/Al2O3 toluene
3j NaOH
3j KOH
toluene
toluene
toluene
benzene
p-xylene
mesitylene
chlorobenzene
chloroform
DCM
Entry 1: R, R1
2
4
Yield[b] dr[c]
[%]
ee[d]
[%]
3j Et3N
3j K3PO4
3j K3PO4
3j K3PO4
3j K3PO4
3j K3PO4
3j K3PO4
3j K3PO4
21
22
23
24
25
26
1
2
3
4
5
6
7
8
1a: Me, Ph
2a
2a
2a
2a
2a
2a
2a
2a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
63
69
65
70
64
52
81
77
50
65
55
40
60
88
74
51
45
62
71
82:18
81:19
83:17
82:18
79:21
79:21
82:18
82:18
90:10
77:23
67:33
87:13
75:25
58:42
87:13
58:42
87:13
69:31
75:25
97
90
97
96
88
91
84
91
97
89
90
93
50
95
80
91
81
95
86
1b Me, 4-FC6H4
1c: Me, 4-ClC6H4
1d: Me, 4-BrC6H4
1e: Me, 3-FC6H4
1f Me, 3-ClC6H4
1g: Me, 4-MeC6H4
1h: Me, 4-OMeC6H4
DCE
[a] Unless otherwise noted, all reactions were carried out with 1a
(0.11 mmol), 2a (0.1 mmol), catalyst (0.02 mmol), and base
(0.11 mmol) in solvent (1.0 mL) at 30 °C for 2 h. [b] Isolated yield.
[c] Determined by analysis of the crude mixture by 1H NMR spec-
troscopy. [d] Determined by HPLC analysis. [e] Solvent: 2 mL.
[f] Reaction time: 5 h.
9
1i: Me, 3,4-(OMe)2C6H4 2a
10
11
12
13
14[e]
15[e]
16[e]
17[e]
18[e]
19[e]
1j: Me, 3-CF3C6H4
1k: Ph, 4-BrC6H4
1l: Ph, 2-OMeC6H4
1m: H, Ph
1n: Me, 3,4-Cl2C6H4
1o: Me, 1-naphthyl
1p: Me, 3-MeC6H4
1q: Me, 2-OMeC6H4
1c: Me, 4-ClC6H4
1h: Me, 4-OMeC6H4
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
onefold by reducing the volume of solvent, and the product
was obtained in 62% yield (Table 1, entry 11). Further
study showed that the yield did not decrease upon shorten-
ing the reaction time from 5 to 2 h (Table 1, entry 12). To
further optimize the reaction, other parameters such the
base and solvent were examined. Nevertheless, better results
in terms of yield, diastereoselectivity, and enantioselectivity
(Table 1, entries 13–26) were not obtained relative to the re-
sults obtained with K3PO4 and toluene.[8d]
[a] Unless otherwise noted, all reactions were carried out with 1
(0.11 mmol), 2 (0.1 mmol), 3j (0.02 mmol), and K3PO4 (0.11 mmol)
in toluene (1.0 mL) at 30 °C for 2 h. [b] Isolated yield. [c] Deter-
1
mined by analysis of the crude mixture by H NMR spectroscopy.
[d] Measured by using chiral stationary phase HPLC. [e] Reaction
time: 4 h.
Eur. J. Org. Chem. 2013, 456–459
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
457

L.-H. Jing et al.
SHORT COMMUNICATION
vity was observed (Table 2, entry 4 vs. 11), likely because
larger steric hindrance weakens the positive π–π interaction
of the “closed” conformation of the transition state (see the
Supporting Information).[15] As described in the litera-
ture,[16] benzyl-substituted oxazolone 2b gave slightly in-
ferior results compared with methyl-substituted 2a (Table 2,
entry 3 vs. 18 and entry 8 vs. 19).
The absolute configuration of the two contiguous stereo-
centers of Michael addition product 4a was unambiguously
assigned as (10R,11S) by X-ray diffraction analysis (Fig-
ure 1).[17] The absolute configurations of the other products
were assigned by analogy.
Experimental Section
General Procedure: An ordinary test tube equipped with a magnetic
stirring bar was charged with catalyst 3j (0.02 mmol), arylsulfonyl
indole 1 (0.11 mmol), oxazolone 2 (0.1 mmol), K3PO4 (0.11 mmol),
and toluene (1 mL) and then sealed in air. After stirred at 30 °C
for 2 h, the reaction mixture was purified by flash chromatography
on silica gel (ethyl acetate/petroleum ether = 1:5–1:20) to afford
product 4. The product was confirmed by 1H NMR and 13C NMR
spectroscopy. The diastereomeric ratio was determined by analysis
of the crude material by NMR spectroscopy, and the enantiomeric
excess was determined by chiral-phase HPLC analysis.
Supporting Information (see footnote on the first page of this arti-
cle): Analytical data for all prepared compounds with copies of the
1H NMR and 13C NMR spectra and HPLC chromatographs.
Acknowledgments
We are grateful for the financial support of the National Natural
Science Foundation of China (NSFC) (grant number 21102117),
Education Department of Sichuan Province (grant number
10ZA026), Chemical Synthesis and Pollution Control Key Labora-
tory of Sichuan Province (grant number 11CSPC-1-1), Bureau of
Science & Technology and Intellectual Property Nanchong City
(grant number 12A0036), and China West Normal University
(grant number 10B005).
Figure 1. X-ray crystal structure of compound 4a.
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The synthetic versatility of the adducts was illustrated by
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In conclusion, we have developed the first highly stereo-
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graphic data for this paper. These data can be obtained free of
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Received: October 9, 2012
Published Online: November 30, 2012
Eur. J. Org. Chem. 2013, 456–459
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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