Enantioselective intramolecular Rauhut-Currier reaction catalyzed by chiral phosphinothiourea

Article abstract of DOI:10.1039/c0cc04412a

Chiral organophosphine-catalyzed enantioselective Rauhut-Currier reaction has been disclosed for the first time. With l-valine-derived phosphinothiourea, the intramolecular Rauhut-Currier reaction of bis(enones) was achieved in good yields (up to 99%) wit

Full text of DOI:10.1039/c0cc04412a

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COMMUNICATION
Enantioselective intramolecular Rauhut–Currier reaction catalyzed
by chiral phosphinothioureaw
Jing-Jing Gong,a Tian-Ze Li,a Kun Pana and Xin-Yan Wu*ab
Received 14th October 2010, Accepted 23rd November 2010
DOI: 10.1039/c0cc04412a
Chiral organophosphine-catalyzed enantioselective Rauhut–
Currier reaction has been disclosed for the first time. With
L-valine-derived phosphinothiourea, the intramolecular Rauhut–
Currier reaction of bis(enones) was achieved in good yields (up to
99%) with excellent enantioselectivities (up to 99.4% ee).
organocatalyst for the asymmetric RC reaction. Herein we
report the first organophosphine-catalyzed enantioselective
RC reaction.
Initially, the enantioselective RC reaction of bis(enone) 4a15
was selected as the model reaction to evaluate the natural
amino acid-derived bifunctional organocatalysts (Fig. 1). The
reactions were performed with 20 mol% catalyst in CH2Cl2 at
25 1C, and the results were summarized in Table 1. The results
indicated that phenyl thioureas 1a–1d had low catalytic activity
and the desired products were obtained in poor yields (entries
1–4). However, the enantioselectivity was sensitive to the chiral
backbone, and phosphinothiourea 1d derived from L-valine
gave better result than the corresponding thioureas 1a–1c
(entry 4, 97% ee with 34% yield). To improve the catalytic
activity, L-valine-based organocatalysts with different thiourea
scaffolds were explored and it was found that the aromatic
thioureas provided better enantioselectivity than the aliphatic
thioureas (entries 4–8 vs. 9–11). Among all the screened
phosphinothioureas, none but catalyst 1k showed good
catalytic activity, the RC reaction was accomplished in
3.5 days and a chemical yield of 85% was obtained (entry
The Rauhut–Currier (RC) reaction, also known as vinylogous
Morita–Baylis–Hillman reaction, involves the coupling of one
active alkene/latent enolate to a second Michael acceptor,
creating a new C–C bond between the a-position of one
activated alkene and the b-position of a second alkene under
the influence of a nucleophilic catalyst.1,2 In 1999, Moore and
Erguden revealed an intramolecular transannular Rauhut–
Currier reaction in the synthesis of natural product
waihoensene.3 The pioneering methodological studies of the
intramolecular Rauhut–Currier reaction were demonstrated
by Roush et al.4 and Krische et al.,5 respectively, in 2002. The
first enantioselective version of the intramolecular Rauhut–
Currier reaction was presented by Miller’s group using
N-acetyl cysteine as a catalyst.6 Later on, a chiral rhenium
complex involving phosphine was used as the catalyst by
Gladysz and Seidel for the process.7 Recently Christmann
11). In comparison, the L-valine-derived amide
2 and
sulfonamide 3 were examined. As shown in Table 1, the
thiourea organocatalysts 1d–1k could achieve better
enantioselectivity than the corresponding amide 2 (entries
4–11 vs. 12). Although sulfonamide 3 could provide excellent
and co-workers developed
a
crossed intramolecular
Rauhut–Currier reaction catalyzed by diphenylprolinol silyl
ether via dienamine activation.8 Meanwhile, Wang et al.9 and
Scheidt et al.10 made a progress in the enantioselective
intermolecular RC-type reactions.
It’s well known that tertiary phosphine catalysts are efficient
nucleophiles for the RC reaction.1 However, to the best of our
knowledge, there have been no reports of the enantioselective RC
reaction promoted by the phosphine-based organocatalyst.11,12
We have found that the amino acid-derived phosphinothioureas
were highly efficient in the asymmetric Morita–Baylis–Hillman
reaction.13,14 As a follow-up of our work, we would like
to disclose the application of phosphinothioureas as
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
Shanghai, 200237, P. R. China. E-mail: xinyanwu@ecust.edu.cn;
Fax: +86 21 64252758; Tel: +86 21 64252011
b State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. China
w Electronic supplementary information (ESI) available: Experimental
details, characterization data, NMR spectra for the substrates and
Rauhut–Currier products, HPLC spectra for the Rauhut–Currier
products. See DOI: 10.1039/c0cc04412a
Fig. 1 Structures of the screened phosphine-based organocatalysts.
Chem. Commun., 2011, 47, 1491–1493 1491
c
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Table 1 Screening of the catalysts for the intramolecular Rauhut–
Currier reaction of 4aa
moderate-to-good yields (62%–77%, entries 2–5). In the
protonic polar solvents, such as EtOH and t-BuOH, the
reaction could complete in a shorter time than in other solvents
screened, but the enantioselectivities were unsatisfactory (entries
6 and 7). While in non-protonic polar solvent, such as DMSO,
the catalyst 1k was inefficient (entry 8). Although the highest
enantioselectivity was observed in THF, the reaction was too
sluggish to provide high yield (entry 9, 91% ee and 4% yield).
The solvent survey revealed that CH2Cl2 was the most suitable
solvent for the asymmetric RC reaction (entry 1, 89% ee and
85% yield). Thus the reaction was performed in CH2Cl2 in order
to further optimize the reaction conditions. The results indicated
that the enantioselectivity was constant in different substrate
concentrations, but lower concentration (0.1 M) resulted in
an obvious decrement of the chemical yield (entries 1, 10
and 11). In addition, lower reaction temperature provided
better enantioselectivity. In the context of À30 1C, the desired
product was achieved in 99.4% ee with a comparable yield (entry
15 vs. entries 11–14).
Entry
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
18
28
23
34
23
34
42
20
25
30
85
18
21
75
93
83
97
96
97
95
96
88
94
89e
75
96
9
10
11d
12
13
1j
1k
2
When the optimal reaction conditions were established, a
variety of substrates were investigated and the results were
summarized in Table 3. The results indicated that the reaction
had a wide substrate scope with respect to bis(enones). The
desired products were obtained in excellent enantioselectivity
(90–99.4% ee) in all the cases examined except p-NO2-
substituted substrate 4b. Both the reactivity and the
enantioselectivity were affected by the electronic environment
at the enones. The bis(enones) with an electron-withdrawing
substituent at the phenyl group were more reactive than those
with an electron-donating substituent, whereas the latter could
3
a
Unless stated otherwise, the reactions were performed with 20 mol% of
organocatalyst and 0.2 mmol of 4a in 1 mL CH2Cl2 (0.2 M) at 25 1C for
4 d. Isolated yield. Determined by HPLC using a Chiralpak AD-H
b
c
e
column. d The reaction time is 3.5 days. [a]D14 +26.3 (c 0.4, CHCl3).
enantioselectivity, the chemical yield was unsatisfactory
(entry 13). According to the optical rotation values reported,6
the absolute configuration of the desired product was assigned as
R-configuration.
The survey of solvent was then studied. As shown in Table 2,
the RC reaction was sensitive to the solvent. In toluene,
CHCl3, ether and CH3CN, the products were obtained in
good-to-excellent enantioselectivities (74%–90% ee) with
Table 3 The substrates scope of the intramolecular Rauhut–Currier
reactiona
Table 2 Optimization of the reaction conditionsa
Entry
Ar
Time/d
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5 (a)
4-NO2C6H4 (b)
2-FC6H4 (c)
4.0
0.25
0.4
2.0
2.5
1.0
1.5
3.5
1.0
1.0
5.0
5.0
2.5
5.0
3.0
4.0
80
92
99
93
99
93
98
95
90
91
72
70
85
64
91
74
99.4
81
98
96
93
95
93
90
93
90
99
99
99
99
96
96
Entry Solvent Temp/1C Conc./M Time/d Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
CH2Cl2
Toluene
CHCl3
Ether
CH3CN
EtOH
t-BuOH
DMSO
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
25
25
25
25
25
25
40
0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.3
0.3
0.3
0.3
0.3
3.5
4.0
4.0
3.5
3.5
0.4
2.5
4.5
4.5
4.0
3.5
3.5
3.5
3.5
4.0
85
62
70
72
77
51
74
5
89
75
82
74
90
36
50
48
91
89
89
88
96
99
99.4
4-FC6H4 (d)
2-ClC6H4 (e)
3-ClC6H4 (f)
4-ClC6H4 (g)
2-BrC6H4 (h)
3-BrC6H4 (i)
4-BrC6H4 (j)
3-MeC6H4 (k)
4-MeC6H4 (l)
4-MeC6H4 (l)
4-MeOC6H4 (m)
Naphtha-2-yl (n)
Furan-2-yl (o)
9
10
11
12
13d
14d
15
16
9
4
10
11
12
13
14
15
52
86
87
84
88
80
CH2Cl2 À20
CH2Cl2 À30
a
Unless stated otherwise, the reactions were conducted with 20 mol%
in 0.67 mL CH2Cl2 (0.3 M) at
a
The reactions were performed with 20 mol% of 1k and 0.2 mmol of
of 1k and 0.2 mmol of
4
b
4a. Isolated yield. Determined by HPLC using a Chiralpak AD-H
c
b
c
À30 1C. Isolated yield. Determined by HPLC using a Chiralpak
d
AD-H or AS-H column. 40 mol% of catalyst 1k was used.
column.
c
1492 Chem. Commun., 2011, 47, 1491–1493
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Further investigations of the reaction mechanism and to extend
the scope of this reaction are now in progress.
We are grateful for the financial support from National
Natural Science Foundation of China (20772029), the Program
for New Century Excellent Talents in University (NCET-07-
0286), and the Fundamental Research Funds for the Central
Universities.
Notes and references
Scheme 1 The RC reaction of unsymmetrical bis(enone).
1 For the review, see: C. E. Aroyan, A. Dermenci and S. J. Miller,
Tetrahedron, 2009, 65, 4069.
afford a higher enantioselectivity (entries 2–10 vs. 11–14). The
less reactive substrates could produce a high chemical yield
while increasing the catalyst loading from 20 mol% to 40 mol %
(entries 13 and 14). Comparing with the para- and ortho-
substituted analogues, substrates 4f and 4i bearing the meta-
2 M. M. Rauhut and H. Currier, US Patent 307,499,919,630,122,
American Cyanamid Co., 1963; Chem. Abstr., 1963, 58, 11224a.
3 J. K. Erguden and H. W. Moore, Org. Lett., 1999, 1, 375.
4 S. A. Frank, D. J. Mergott and W. R. Roush, J. Am. Chem. Soc.,
2002, 124, 2404.
substituted aromatic group provided
a slightly higher
5 L.-C. Wang, A. L. Luis, K. Agapiou, H.-Y. Jang and M. J. Krische,
J. Am. Chem. Soc., 2002, 124, 2402.
enantioselectivity probably due to the electronic effect (entry
6 vs. entries 5 and 7, entry 9 vs. entries 8 and 10). The RC
reaction of furan analogue 4o proceeded smoothly providing
74% yield and 96% ee of the corresponding adduct (entry 16).
In addition, the unsymmetrical substrate 6 bearing both a
strong electron-withdrawing group and a strong electron-
donating group was investigated (Scheme 1). Due to the
electronic effect, the bis(enone) 6 provided a regioisomeric
mixture in favor of 7a.16 Compared to the corresponding
symmetrical bis(enones) 4b and 4m, the enantioselectivity
was remarkably decreased (Table 3, entries 2 and 14 vs.
Scheme 1). The results indicated that both the alkene
activation by a nucleophilic catalyst and the coupling of an
activated alkene to a second Michael acceptor had influence on
the RC reaction.
6 (a) C. E. Aroyan and S. J. Miller, J. Am. Chem. Soc., 2007, 129, 256;
(b) C. E. Aroyan, A. Dermenci and S. J. Miller, J. Org. Chem.,
2010, 75, 5784.
7 F. Seidel and J. A. Gladysz, Synlett, 2007, 986.
´
8 E. M. Lopez, R. P. Herrera, T. Marks, W. C. Jacobs, D. Konning,
¨
R. M. de Figueiredo and M. Christmann, Org. Lett., 2009, 11, 4116.
9 J. Wang, H. Xie, L. Zu and W. Wang, Angew. Chem., Int. Ed.,
2008, 47, 4177.
10 T. E. Reynolds, M. S. Binkley and K. A. Scheidt, Org. Lett., 2008,
10, 2449.
11 During the preparation of this manuscript, Miller’s group reported
the chiral phosphine-based amino acid diphenylphosphinoserine as
the catalyst to provide the RC product in 5% conversion, see
ref. 6b. And for other reactions, see: B. J. Cowen and S. J. Miller,
J. Am. Chem. Soc., 2007, 129, 10988.
12 For review on enantioselective phosphine organocatalysis, see:
A. Marinetti and A. Voituriez, Synlett, 2010, 174.
13 (a) J.-J. Gong, K. Yuan and X.-Y. Wu, Tetrahedron: Asymmetry,
2009, 20, 2117; (b) J.-J. Gong, K. Yuan, H.-L. Song and X.-Y. Wu,
Tetrahedron, 2010, 66, 2439.
In summary, we have developed a highly enantioselective
intramolecular Rauhut–Currier reaction of bis(enones) catalyzed
by bifunctional phosphinothiourea derived from natural amino
acid. As the first example of the organophosphine-catalyzed
enantioselective intramolecular Rauhut–Currier reaction, the
catalytic system is highly efficient and it also achieved up to
99% yield with an excellent enantioselectivity (up to 99.4% ee).
14 For phosphinothiourea catalysts, also see: (a) Y.-L. Shi and M. Shi,
Adv. Synth. Catal., 2007, 349, 2129; (b) Y.-Q. Fang and E. N. Jacobsen,
J. Am. Chem. Soc., 2008, 130, 5660; (c) K. Yuan, L. Zhang,
H.-L. Song, Y. Hu and X.-Y. Wu, Tetrahedron Lett., 2008, 49, 6262.
15 P. M. Brown, N. Kapel, P. J. Murphy, S. J. Coles and
¨
M. B. Hursthouse, Tetrahedron, 2007, 63, 1100.
1
16 The isomeric ratio was determined by H NMR.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1491–1493 1493