Asymmetric 5-endo chloroetherification of homoallylic alcohols toward the synthesis of chiral β-chlorotetrahydrofurans

Article abstract of DOI:10.1039/c2cc38436a

An asymmetric 5-endo chloroetherification of homoallylic alcohols is successfully developed that employs an easily available quaternary ammonium salt derived from cinchonine as a conventional organocatalyst. This approach provides ready access to β-chloro

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Asymmetric 5ꢀendo chloroetherification of homoallylic alcohols toward
the synthesis of chiral βꢀchlorotetrahydrofurans
Xianghua Zeng,ac Chengxia Miao, a Shoufeng Wang, a Chungu Xia*a and Wei Sun*a
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
An asymmetric 5ꢀendo chloroetherification of homoallylic
alcohols is successfully developed that employs an easily available
quaternary ammonium salt derived from cinchonine as a
10 conventional organocatalyst. This approach provides a ready
access to βꢀchlorotetrahydrofurans in high enantioselectivities.
Electrophilic halocyclizations of olefins, in which
electrophilichalonium ions are generated from olefins and
open intramolecularly by nucleophilic functional groups, are
15 versatile synthetic transformations with proven applications to
the synthesis of halogenated heterocycles.1,2 In this field, the
use of organocatalysts including chiral ureas, aminoꢀ
thiocarbamate, trisimidazolines and cinchona alkaloid
derivative etc. had made significant contributions towards the
20 halolactonization and haloaminocyclization.2ꢀ4 Compared to
the rapid development in the field of halolactonization and
haloaminocyclization,
the
progress
in
asymmetric
Fig. 2 The organocatalysts used in this study.
haloetherifications is limited,2d,2e although haloetherification
is a highly valuable synthetic method that can produce
25 tetrahydrofuran, tetrahydropyran, and even larger oxacyclic
frameworks.1e
cinchona alkaloid Oꢀether 3b as catalyst gave slightly low
55 yield with an eroded 34% ee (Table 1, entry 2). Subsequent
attempts to improve the enantioselectivity using cinchonine
Oꢀesters as catalyst were also unsuccessful (Table 1, entries 3
and 4). Interestingly, when a catalytic amount of Nꢀbenzylꢀ
cinchoninium bromide 5a was added to the reaction as a
60 catalyst, the ee and yield of the resultant product were
enhanced significantly (Table 1, entry 5).3a,11 Lowering the
In 2003, pioneering work in the iodocyclization of γꢀ
hydroxyꢀcisꢀalkenes catalyzed by chiral salenꢀCo complex has
been reported by Kang et al.5 Recently, Shi and Denmark
30 independently reported the use of chiral phosphoric acid as
catalyst for the highly enantioselective bromoetherifications
of 4ꢀalkeneꢀ1ꢀol substrates.6 In addition, Hennecke et al.
demonstrated chiral BINOLꢀderived compounds could serve
as catalysts for the asymmetric haloetherification reactions on
35 various alkenediol starting materials.7 However, these catalyst
systems generally resulted in 5ꢀexo cyclization with high
enantioselectivities under the optimized conditions. Through
the 5ꢀendo chloroetherification can directly synthetic access to
βꢀchlorotetrahydrofurans, which are useful intermediates or
o
reaction temperature to ꢀ30 C led to the decrease of the yield
and the increase of the ee. On the other hand, inverse results
o
were obtained when the temperature was raised to 0 C (Table
65 1, entries 6 and 7). Of the solvents surveyed, including
chloroform, ethyl ether, and acetonitrile, tetrahydrofuran gave
good isolated yield and ee (Table 1, entries 5 and 8, ESI,
Table S1). This result prompted us to further pursue the
reaction catalyzed by such kinds of catalysts. The
70 chloroetherification of 1a was examined using catalysts 5bꢀi
(Fig. 1) in a 10 mol % catalyst loading. The results indicated
that a further improvement in the enantioselectivity of the
reaction was observed when a 4ꢀtrifluoromethylbenzyl group
was introduced to form the quaternary ammonium salt 5g
75 (Table 1, entry 14). However, Nꢀbenzylꢀcinchoninium
chloride (5b) completely destroyed the stereocontrol (Table 1,
entry 9). In order to further improve the reaction, TsNH2 was
selected as an additive and the yield was increased to 88%
(Table 1, entry 14 vs 17). TsNHCl derived from the chlorine
80 exchange between NCS and TsNH2 has been also observed by
40 important structural motifs in
biologically active
compounds.8,9 As part of our ongoing interest in
functionalization of olefins,10 we herein report the discovery
of highly enantioselective 5ꢀendo chloroetherifications toward
the synthesis of βꢀchlorotetrahydrofurans catalyzed by the
45 cinchonineꢀderived quaternary ammonium salts.
Initially, the chloroetherification of homoallylic alcohol
derivative 1a was selected as a model reaction for screening
the catalysts and reaction conditions. We were encouraged by
the discovery that cinchona alkaloid Oꢀester 3a provided good
50 conversion
and
modest
enantioselectivity
in
the
1
means of H NMR in CDCl3 with the mixture of substrate 1i
chloroetherification of homoallylic alcohol 1a in the presence
of Nꢀchlorosuccinimide (NCS) (Table 1, entry 1). The use of
and the detailed role of the compound is not clear (Fig.
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S1).3c,12 When the solvent and additive effects were combined
(ESI, Table S1), the desired βꢀchlorotetrahydrofuran was
salt catalyst, such as substrate 1h (Table S1, entry 12).
Unfortunately, aliphatic homoallylic alcohols such as 1r or 1s
produced in 88% yield and 86% ee under the optimized 40 were tested and just gave poor results (Table 2, entries 18 and
conditions (Table 1, entry 17).
19).
5
Table 1 Screening the reaction conditions. a
Table 2 Scope of the asymmetric chloroetherification of homoallylic
alcohols. a
Entry Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Temp. (oC) Yield (%) b
ee (%) c
56
34
25
46
75
70
81
82
5
62
10
75
82
85
80
80
86
ꢀ
Entry
1
2
3
4
5
6
7
8
Alcohol
1a
1b
1c
1d
1e
R
Yield (%) b
88
ee (%) c
86
92
90
63
77
75
61
95
95
95
96
52
75
70
76
92
96
11
ꢀ
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
16d
17e
18f
3a
3b
4a
4b
5a
5a
5a
5a
5b
5c
5d
5e
5f
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
78
72
71
80
81
87
52
75
70
89
76
79
84
82
73
52
88
74
2ꢀMeꢀPh
3ꢀMeꢀPh
4ꢀMeꢀPh
4ꢀOHꢀPh
2ꢀMeOꢀPh
3ꢀMeOꢀPh
4ꢀMeOꢀPh
Ph
2ꢀClꢀPh
3ꢀClꢀPh
4ꢀClꢀPh
2,4ꢀdiꢀClꢀPh
4ꢀBrꢀPh
4ꢀFꢀPh
81
78
80
87
90
90
85
85
78
80
87
82
83
75
85
92
1f
ꢀ30
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
9
10
11
12
13
14
15
16
17
18
19
5g
5h
5i
5g
ꢀ
2ꢀCF3ꢀPh
4ꢀCF3ꢀPh
3ꢀNO2ꢀPh
Cy
56
NG
a The reactions were carried out with 1a (0.20 mmol), NCS (0.24 mmol),
catalyst (0.02 mmol, 10 mol %) in solvent (1.0 mL) under argon
atmosphere for 12 h. b Isolated yield. c Determined by chiral HPLC
analysis. d The solubility of catalyst is not good. e TsNH2 (0.1 mmol) was
1s
t-Bu
a The reactions were carried out with homoallylic alcohol 1aꢀs (0.20
45 mmol), NCS (0.24 mmol), TsNH2 (0.10 mmol) and 5g (0.02 mmol, 10
mol%) in THF (1.0 mL) at ꢀ20 oC under argon atmosphere for 12 h. b
Isolated yield. c Determined by chiral HPLC analysis.
10 used as an additive. f The reactions were carried out with substrate 1h
(0.2 mmol), NCS (0.24 mmol), and TsNH2 (0.1 mmol) in solvent (1.0 mL)
under argon atmosphere for 12 h.
To further evaluate the preparative utility of this 5ꢀendo
chloroetherification, the (Z)ꢀconfigured olefin 1t was also
50 investigated. More encouragingly, the 5ꢀendo cyclization
occurred uneventfully and enantioselectivity was only slightly
reduced compared to (E)ꢀconfigured olefin (Scheme 1 and Table
After the optimized conditions were identified, other
substrates were examined, and the scope of the
15 chloroetherification is listed in Table 2. Firstly, the reactions
of substituted phenylbutꢀ3ꢀenꢀ1ꢀol were all performed
smoothly with moderate to excellent yields and ees. As a
whole, the substrates with electronꢀwithdrawing groups gave
slightly better activity. Notably, the highest enantioselectivity
20 of 96% ee was obtained employing aromatic substituted
homoallylic alcohol 1k or 1q as the substrate (Table 2, entries
11 and 17). Homoallylic alcohols bearing monoꢀchloro
substituted phenyl group were converted into desired βꢀ
chlorotetrahydrofuran products in good yield with > 95% ee
25 (Table 2, entries 9ꢀ11). However, enantioselectivities were
greatly reduced for the substrates bearing pꢀF, pꢀBr or 2,4ꢀ
dichloro substituted phenyl group (Table 2, entries 12ꢀ14). In
addition, substrate bearing pꢀCF3 substituted phenyl group
afforded THF product in good yield with a 92% ee (Table 2,
30 entry 16). However, the yield and ee of oꢀCF3 substituted
substrate were only 75% and 76%, probably due to the steric
hindrance (Table 2, entry 15). On the other hand, just
substrates with methyl have about 90% ee (Table 2, entries 1ꢀ
3). And other electronꢀrich aryl substituents gave lower
35 enantioselectivities, which may be ascribed to the enhanced
background reaction (Table 2, entries 4ꢀ7). In fact, the 5ꢀendo
chloroetherification occurs without any quaternary ammonium
2, entry 8). Additionally,
a longerꢀchain alcohol 5ꢀ(4ꢀ
methylphenylꢀ4ꢀpentenꢀ1ꢀol was tested to construct bigger ring
55 system via 6ꢀendo chloroetherification, while poor ee was
obtained (Scheme 1, 1u).
O
5g / NCS
OH
TsNH2 / THF
Cl
1t
2t, 80 % yield, 84 % ee
O
5g / NCS
OH
TsNH2 / THF
Cl
2u, 70 % yield, 13 % ee
1u
Scheme 1
For the 5ꢀendo chloroetherification of (E)ꢀhomoallylic
alcohols, it will result in a transꢀisomer (Scheme 2).6b This
60 phenomenon can be confirmed by NMR experiments (also see
ESI).13 The absolute configuration of 2h was determined as
(2R,3S), by comparing the reported optical rotation and chiral GC
2
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Tan, X. Jiang, F. Chen and Y.ꢀY. Yeung, J. Am. Chem. Soc., 2010,
132, 15474ꢀ15476; (d) W. Zhang, S. Zheng, N. Liu, J. B. Werness, I.
A. Guzei and W. Tang, J. Am. Chem. Soc., 2010, 132, 3664ꢀ3665; (e)
K. Murai, T. Matsushita, A. Nakamura, S. Fukushima, M. Shimura
and H. Fujioka, Angew. Chem., Int. Ed., 2010, 49, 9174ꢀ9177; (f) D.
C. Whitehead, R. Yousefi, A. Jaganathan and B. Borhan, J. Am.
Chem. Soc., 2010, 132, 3298ꢀ3300; (g) R. Yousefi, D. C. Whitehead,
J. M. Mueller, R. J. Staples and B. Borhan, Org. Lett., 2011, 13,
608ꢀ611; (h) C. K. Tan, L. Zhou and Y.ꢀY. Yeung, Org. Lett., 2011,
13, 2738ꢀ2741; (i) M. C. Dobish and J. N. Johnston, J. Am. Chem.
Soc., 2012, 134, 6068ꢀ6071; (j) W. Zhang, N. Liu, C. M.
Schienebeck, K. Decloux, S. Zheng, J. B. Werness and W. Tang,
Chem. Eur. J., 2012, 18, 7296ꢀ7305; (k) J. Chen, L. Zhou, C. K. Tan
and Y.ꢀY. Yeung, J. Org. Chem., 2012, 77, 999ꢀ1009; (l) X. Jiang,
C. K. Tan, L. Zhou and Y.ꢀY. Yeung, Angew. Chem., Int. Ed., 2012,
51, 7771ꢀ7775; (m) C. K. Tan, C. Le and Y.ꢀY. Yeung, Chem.
Commun., 2012, 48, 5793ꢀ5795; (n) D. J. Paull, C. Fang, J. R.
Donald, A. D. Pansick and S. F. Martin, J. Am. Chem. Soc., 2012,
134, 11128ꢀ11131; (o) K. Murai, A. Nakamura, T. Matsushita, M.
Shimura and H. Fujioka, Chem. Eur. J., 2012, 18, 8448ꢀ8453.
(a) L. Zhou, J. Chen, C. K. Tan and Y.ꢀY. Yeung, J. Am. Chem. Soc.,
2011, 133, 9164ꢀ9167; (b) J. Chen, L. Zhou and Y.ꢀY. Yeung, Org.
Biomol. Chem., 2012, 10, 3808ꢀ3811. (c) V. Rauniyar, A. D.
Lackner, G. L. Hamilton and F. D. Toste, Science, 2011, 334, 1681ꢀ
1684; (d) A. Jaganathan, A.Garzan, D. C. Whitehead, R. J. Staples
and B. Borhan, Angew. Chem., Int. Ed., 2011, 50, 2593ꢀ2596; (e)
Y.ꢀM. Wang, J. Wu, C. Hoong, V. Rauniyar and F. D. Toste, J. Am.
Chem. Soc., 2012, 134, 12928ꢀ12931.
analysis of
6
derived from 2h (Scheme 2),3f,14 and the
configurations for all other βꢀchlorotetrahydrofurans were
assigned analogously.
55
60
65
70
75
80
85
90
95
5
Scheme 2
Conclusions
4
In summary, we have developed an enantioselective
chloroetherification of homoallylic alcohols catalyzed by the
chiral quaternary ammonium salts based on cinchonine. This
10 approach represents a successful example of a catalytic, 5ꢀ
endo enantioselective chloroetherification toward the
asymmetric synthesis of βꢀchlorotetrahydrofurans. In this
regard, this reaction is highly practical and the products were
obtained in excellent enantioselectivities. Further studies to
15 expand the substrates scope, improve the selectivity, and
understand the mechanism of this transformation are now
underway.
We thank the Chinese Academy of Sciences and the National
Natural Science Foundation of China (21073210 and
20 21133011). The authors thank Professor Xuegong She for
helpful discussion and NOE measurements.
5
6
(a) S. H. Kang, S. B. Lee and C. M. Park, J. Am. Chem. Soc., 2003,
125, 15748ꢀ15749; (b) H. Y. Kwon, C. M. Park, S. B. Lee, J. H.
Youn and S. H. Kang, Chem. Eur. J., 2008, 14, 1023ꢀ1028.
(a) D. Huang, H. Wang, F. Xue, H. Guan, L. Li, X. Peng and Y. Shi,
Org. Lett., 2011, 13, 6350ꢀ6353; (b) S. E. Denmark and M. T. Burk,
Org. Lett., 2012, 14, 256ꢀ259.
7
8
U. Hennecke, C. H. Müller and R. Fröhlich, Org. Lett., 2011, 13,
860ꢀ863.
(a) M. M. Faul and B. E. Huff, Chem. Rev., 2000, 100, 2407ꢀ2473; (b)
D. C. Braddock and H. S. Rzepa, J. Nat. Prod., 2008, 71, 728ꢀ730;
(c) E. J. Kang and E. Lee, Chem. Rev., 2005, 105, 4348ꢀ4378.
For review on tetrahydrofuran synthesis:(a) J. P. Wolfe and M. B.
Hay, Tetrahedron, 2007, 63, 261ꢀ290; (b) J.ꢀC. Harmange and B.
Figadere, Tetrahedron: Asymmetry, 1993, 4, 1711–1754.
9
Notes and references
10 (a) M. Wu, B. Wang, S.ꢀF. Wang, C.ꢀG. Xia and W. Sun, Org. Lett.,
2009, 11, 3622ꢀ3625; (b) M. Wu, C.ꢀX. Miao, S.ꢀF. Wang, X.ꢀX.
Hu, C.ꢀG. Xia, F. E. Kühn and W. Sun, Adv. Synth. Catal., 2011,
353, 3014ꢀ3022; (c) B. Wang, C.ꢀX. Miao, S.ꢀF. Wang, C.ꢀG. Xia
and W. Sun, Chem. Eur. J., 2012, 18, 6750ꢀ6753; (d) B. Wang, S.ꢀF.
Wang, C.ꢀG. Xia and W. Sun, Chem. Eur. J., 2012, 18, 7332ꢀ7335.
a State Key Laboratory for Oxo Synthesis and Selective Oxidation,
25 Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou,730000, China. Fax: +86-931-8277088; Tel:+86-931-4668278;
E-mail: wsun@licp.cas.cn
b Graduate School of the Chinese Academy of Sciences, Beijing, 100039,
China
100 11 For selected reviews on asymmetric phase transfer catalysts, see: (a)
Asymmetric Phase Transfer Catalysis, ed. K. Maruoka, WileyꢀVCH,
Weinheim, 2008; (b) B. Lygo and B. I. Andrews, Acc. Chem. Res.,
2004, 37, 518ꢀ525; (c) T. Ooi and K. Maruoka, Angew. Chem., Int.
Ed., 2007, 46, 4222ꢀ4266; (d) K. Maruoka and T. Ooi, Chem. Rev.,
30 † Electronic Supplementary Information (ESI) available: Full
experimental details, mechanism studies, product characterization and
reproduction of NMR spectra and HPLC spectra. See
DOI: 10.1039/b000000x/
1
2
(a) S. Ranganathan, K. M. Muraleedharan, N. K Vaish and N.
Jayaraman, Tetrahedron, 2004, 60, 5273ꢀ5308; (b) M. S. Laya, A.
K. Banerjee and E. V. Cabrera, Curr. Org. Chem., 2009, 13, 720–
730; (c) M. D. Dowle and D. I. Davies, Chem. Soc. Rev. 1979, 8,
171–197; (d) A. N. French, S. Bissmire and T. Wirth, Chem. Soc.
Rev., 2004, 33, 354–362; (e) A. M. Montana, C. Batalla and J. A.
Barcia, Curr. Org. Chem., 2009, 13, 919– 938.
For reviews on asymmetric halogenation of olefins: (a) G. Chen and
S. Ma, Angew. Chem., Int. Ed., 2010, 49, 8306ꢀ8308; (b) A.
Castellanos and S. P. Fletcher, Chem. Eur. J., 2011, 17, 5766ꢀ5776;
(c) C. K. Tan, L. Zhou and Y.ꢀY. Yeung, Synlett 2011, 10, 1335ꢀ
1339; (d) S. C. Snyder, D. S. Treitler and A. P. Brucks,
Aldrichimica Acta, 2011, 44, 27ꢀ40; (e) U. Hennecke, Chem. Asian
J., 2012, 7, 456ꢀ465; (f) S. E. Denmark, W. E. Kuester and M. T.
Burk, Angew. Chem., Int. Ed., 2012, 51, 10938ꢀ10953.
105
2003, 103, 3013ꢀ3028; (e) T. Hashimoto and K. Maruoka, Chem.
Rev., 2007, 107, 5656ꢀ5682.
12 (a) Z. Chen, J. Wei, M. Wang, L. Zhou, C. Zhang and X. Shi, Adv.
Synth. Catal., 2009, 351, 2358ꢀ2368. (b) Y. Cai, X. Liu, J. Jiang, W.
Chen, L. Lin and X. Feng, J. Am. Chem. Soc., 2011, 133, 5636ꢀ5639.
35
40
45
50
110 13 (a) L. Crombie and R. D. Wyvill, J. Chem. Soc. Perkin Trans. 1,
1985, 1971ꢀ1981; (b) L. Crombie, and R. D. Wyvill, J. Chem. Soc.
Perkin Trans. 1, 1985, 1983ꢀ1995.
14 E. D. Butova, A. V. Barabash, A. A. Petrova, C. M. Kleiner, P. R.
Schreiner and A. A. Fokin, J. Org. Chem., 2010, 75, 6229ꢀ6235.
3
(a) M. Wang, L. Gao, W. Mai, A. Xia, F. Wang and S. Zhang, J. Org.
Chem., 2004, 69, 2874ꢀ2876; (b) G. E. Veitch and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2010, 49, 7332ꢀ7335; (c) L. Zhou, C. K.
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