Chiral N,N′-dioxide - In(OTf)3-catalyzed asymmetric vinylogous Mukaiyama aldol reactions

Article abstract of DOI:10.1039/c4cc09820j

Chiral N,N′-dioxide-In(OTf)₃ complexes were developed as efficient catalysts to catalyze the vinylogous Mukaiyama aldol reaction of the silyl dienol ester with aldehydes. The corresponding δ-hydroxy-α,β-unsaturated esters were obtained in up to

Full text of DOI:10.1039/c4cc09820j

ChemComm
View Article Online
View Journal
COMMUNICATION
Chiral N,N0-dioxide–In(OTf)3-catalyzed
asymmetric vinylogous Mukaiyama aldol
Cite this:DOI: 10.1039/c4cc09820j
reactions†
Received 9th December 2014,
Accepted 2nd January 2015
Kai Fu,a Jianfeng Zheng,a Lili Lin,*a Xiaohua Liua and Xiaoming Feng*ab
DOI: 10.1039/c4cc09820j
www.rsc.org/chemcomm
Chiral N,N0-dioxide–In(OTf)3 complexes were developed as efficient
Despite the enormous success, developing new catalysts for
catalysts to catalyze the vinylogous Mukaiyama aldol reaction of the the VMAR of simple ester-derived dienol ethers is still desirable.
silyl dienol ester with aldehydes. The corresponding d-hydroxy-a,b- In terms of the powerful metal complex catalysis, only copper and
unsaturated esters were obtained in up to 99% yield and 98% ee. titanium complexes have been developed. So, developing other
Moreover, the obtained (R)-3v can be easily transformed to natural metal-based chiral catalysts is greatly meaningful. Indium, which
bioactive products.
is three times as abundant as silver, has been proved to be
particularly effective at activating carbonyl groups.15 On the other
The vinylogous Mukaiyama aldol reaction (VMAR),1 especially the hand, chiral N,N0-dioxides, developed by our group, have been
g-selective aldol process (Fig. 1), belongs to one of the elemental proved to be efficient in various asymmetric transformations by
transformations in organic chemistry. It provides an efficient acting as ligands or organocatalysts.16,17 Herein, we describe a highly
assembly of d-hydroxy-a,b-unsaturated carbonyl compounds and efficient asymmetric VMAR of the methyl crotonate-derived silyl
related polyketide networks, which are attractive targets for biology- dienol ester with aldehydes catalyzed by chiral N,N0-dioxide–indium
driven research.2 There have been considerable efforts towards the complexes to afford optically active g-products in high yield and ee.
catalytic asymmetric VMAR of dioxanone-derived dienol ethers3 What’s the most important is that this method provides an efficient
and simple ester-derived dienol ethers. For the more difficult way to synthesize (R)-d-decalactone, (3R,5R)-valerolactone and
enantioselective VMAR of simple ester-derived dienol ethers,4 chiral (4R,6R,10R,12R)-verbalactone.
oxazaborolidinone,5 bis-phosphoramide6 and disulfonimide7 have
Initial investigations with methyl crotonate-derived silyl dienol
been developed as nonmetallic catalysts to promote the g-adduct ester 1 and cinnamic aldehyde 2a revealed that the addition proceeded
transformation. What’s more, Carreira,8 Campagne,9 Scetti,10 mainly in the g-position of the ketene acetal, providing d-hydroxy-a,b-
Paterson,11 Evans12 and others13 have also developed the chiral unsaturated ester 3a in the presence of the N,N0-dioxide–metal
Cu and Ti complexes for the highly enantioselective g-addition of complex in THF at 35 1C. When a series of metal salts complexed
simple ester-derived dienol ethers to carbonyl compounds, and with L-pipecolic acid-derived N,N0-dioxide L-PiPr2 were detected, com-
some have also demonstrated their application in bioactive pared to lanthanoids Sc(OTf)3 and Yb(OTf)3, In(OTf)3 gave higher yield
natural product synthesis.8,9a,c,11,12,14
(38%) and ee (72%) (Table 1, entries 1–3). The following investigation
of the ligand structure revealed that both the framework and the
steric hindrance of ortho-substituents on the aniline ring of
the N,N0-dioxide affected the activity and enantioselectivity of
the reaction. L-Ramipril-derived L-RiPr2 offered a similar yield
(33%) and ee (69%) with L-PiPr2 (Table 1, entry 4). However,
when L-proline-derived L-PrPr2 was applied, only a trace amount
of the product was obtained and the ee of 3a was decreased to
55% (Table 1, entry 5), which might be caused by less flexibility
and less steric hindrance of the five-membered ring of L-PrPr2.
On the other hand, with a decrease in the steric hindrance of
ortho-substituents on the aniline ring of the N,N0-dioxide from
2,6-diisopropyl to 2,6-diethyl and 2,6-dimethyl, the ee was
decreased from 72% to 63% and 50%, respectively (Table 1, entries
3, 6 and 7). In order to further improve the reactivity and selectivity
Fig. 1 Regioselectivity in the VMAR.
a Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
b Collaborative Innovation Center of Chemical Science and Engineering, Tianjin,
P. R. China
† Electronic supplementary information (ESI) available: Additional experimental
and spectroscopic data. See DOI: 10.1039/c4cc09820j
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Optimization of the reaction conditions
Table 2 Substrate scope of the VMAR of silyl dienol ester 1 with aldehydes 2
Entrya
R
Product
Yieldb (%)
eec (%)
1
2
3
4
PhCHQCH2
3a
3b
3c
3d
91
85
64
70
92(S)
93
90
2-MeOC6H4CHQCH2
4-ClC6H4CHQCH2
2-furylCHQCH2
92
5
3e
99
92
Entrya Ligand Metal
T (1C) Solvent
Yieldb (%) eec (%)
6
7
8
9
10
11
12
13
14
15
16
Ph
3f
90
86
96
93
97
90
99
99
94
96
94
95(S)
86
94
92
95
95
96
87
94
95
96
2-MeC6H4
3-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-PhOC6H4
2-FC6H4
3-FC6H4
4-FC6H4
3-BrC6H4
3g
3h
3i
3j
3k
1
2
3
4
5
6
7
8
L-PiPr2 Sc(OTf)3
L-PiPr2 Yb(OTf)3
L-PiPr2 In(OTf)3
L-RiPr2 In(OTf)3
L-PrPr2 In(OTf)3
L-PiEt2 In(OTf)3
L-PiMe2 In(OTf)3
L-PiPr2 In(OTf)3
L-PiPr2 In(OTf)3
L-PiPr2 In(OTf)3
L-PiPr2 In(OTf)3
35
35
35
35
35
35
35
35
35
35
0
THF
THF
THF
THF
THF
THF
THF
EtOAc
Ethyl caproate 58
Ethyl caproate 76
Ethyl caproate 84
Ethyl caproate 89
Ethyl caproate 91
19
37
59
72
69
55
63
50
75
76
76
81
89
92
27
38
33
3l
Trace
38
3m
3n
3o
3p
16
48
9
10d
11d
12d
13d,e
17
3q
99
98
L-PiPr2 In(OTf)3 ꢀ20
18
19
20
21
22
23
24
25d
26e
3,4-Cl2C6H3
1-Naphthyl
2-Furyl
n-Propyl
n-Pentyl
i-Propyl
t-Butyl
n-Pentyl
n-Pentyl
3r
3s
3t
3u
3v
3w
3x
3v
3v
92
99
96
88
60
65
45
64
65
93
94
L-PiPr2 In(OTf)3 ꢀ20
a
Unless specified, all reactions were performed with the L-metal (10 mol%,
92(S)
83
82(R)
89(S)
98(S)
80(S)
93(R)
2:1), 1 (0.15 mmol), 2a (0.10 mmol) in THF (0.5 mL) at 35 1C for 24 h.
c
b Isolated yields. Determined by HPLC analysis. d The reaction time was
48 h. e 20 mol% of 5-methylsalicylic acid was added.
of the reaction, other reaction conditions were examined. It was
found that the reaction proceeded better in ester solvents. In EtOAc,
higher 48% yield and 75% ee were obtained (Table 1, entry 8). And
in ethyl caproate, 58% yield and 76% ee were obtained (Table 1,
entry 9). The yield could be increased to 76% when the reaction
time was prolonged from 24 h to 48 h (Table 1, entry 10). What’s
more, when the reaction temperature was lowered to 0 1C, the yield
a
Unless specified, all reactions were carried out with 10 mol% L-PiPr2/
In(OTf)3 (2 : 1), 1 (0.15 mmol), 2 (0.10 mmol) and 20 mol% of 5-methyl-
b
salicylic acid in ethyl caproate (0.5 mL) at ꢀ20 1C for 48 h. Isolated
c
d
yields. Determined by HPLC analysis. D-pipecolic acid-derived L-PiPr2
e
was used as the ligand. L-RiPr2 was used as the ligand.
was increased to 84% and the ee was improved to 81% (Table 1, and 15), which might be caused by the steric hindrance of the ortho-
entry 11). By further lowering the temperature to ꢀ20 1C, the yield substituents with the catalyst. Ring-condensed 1-naphthaldehyde
and ee of 3a were both improved to 89% (Table 1, entry 12). Finally, and heteroaromatic 2-furaldehyde were also suitable, affording the
the yield and ee of 3a were further improved to 91% and 92%, corresponding product 3s in 99% yield with 94% ee and 3t in 96%
respectively, by adding 20 mol% of 5-methylsalicylic acid to the yield with 92% ee (Table 2, entries 19 and 20). It is worth pointing
system (Table 1, entry 13).
out that aliphatic aldehydes were also tolerant (Table 2, entries 21–
With the optimized reaction conditions in hand (Table 1, 24). Linear n-butanal and n-hexanal gave the corresponding 3u in
entry 13), the vinylogous Mukaiyama aldol reaction of 1 with 88% yield with 83% ee and (R)-3v in 60% yield with 82% ee (Table 2,
various aldehydes 2 was explored (Table 2). For substituted entries 21 and 22). As expected, a-branched aliphatic aldehydes were
cinnamaldehydes, the electron-donating or electron- beneficial for the enantioselectivity. Isobutyraldehyde could give 3w
withdrawing substituted phenyl group and the heterocyclic with 89% ee and pivaldehyde gave product 3x with 98% ee, albeit
furyl group on the b-position didn’t affect the enantioselectivity with 45% yield (Table 2, entries 23 and 24). What’s more, (S)-3v could
(90–93% ee) (Table 2, entries 1–4). Notably, a-bromo substi- be obtained in 64% yield with 80% ee value when D-pipecolic acid-
tuted cinnamic aldehyde 2e also reacted well, giving 3e in derived L-PiPr2 was used as the ligand (Table 2, entry 25 vs. entry 22),
quantitative yield with 92% ee (Table 2, entry 5). Aromatic which indicated that the configuration of the product was deter-
aldehydes with electron-withdrawing or electron-donating sub- mined by the framework of the ligand.
stituents at different positions on the phenyl ring caused the
Besides, when L-ramipril-derived L-RiPr2 was used as the
reaction to proceed well, providing the corresponding products ligand, the ee of 3v could be further improved to 93% (Table 2,
in 86–99% yields with 86–98% ee (Table 2, entries 6–18). entry 26). The absolute configuration of products 3a, 3f, 3t, 3w
Generally, ortho-substituted aldehydes gave a little lower yields and 3x were determined to be (S)5a and that of product 3v was
and ee values than meta- and para-substituted ones (Table 2, determined to be (R)18d by comparison of the optical rotation
entry 7 vs. entry 8; entry 9 vs. entries 10 and 11; entry 13 vs. entries 14 with that reported in the literature.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
Chem., Int. Ed., 2013, 52, 9097; (g) M. Kalesse, M. Cordes, G. Symkenberg
and H.-H. Lu, Nat. Prod. Rep., 2014, 31, 563; (h) Enantioselective vinylo-
gous Reformatsky-aldol reaction, see: A. Hassan, J. R. Zbieg and
M. J. Krische, Angew. Chem., Int. Ed., 2011, 50, 3493.
2 (a) J. Staunton and K. J. Weissman, Nat. Prod. Rep., 2001, 18, 380;
(b) B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed., 2006, 45, 7506.
3 (a) Y. Shimada, Y. Matsuoka, R. Irie and T. Katsuki, Synlett, 2004, 57;
(b) J. C.-D. Le and B. L. Pagenkopf, Org. Lett., 2004, 6, 4097;
(c) V. B. Gondi, M. Gravel and V. H. Rawal, Org. Lett., 2005, 7, 5657.
4 S. E. Denmark and G. L. Beutner, J. Am. Chem. Soc., 2003, 125, 7800.
5 (a) S. Simsek, M. Horzella and M. Kalesse, Org. Lett., 2007, 9, 5637;
(b) S. Simsek and M. Kalesse, Tetrahedron Lett., 2009, 50, 3485;
(c) M. T. Gieseler and M. Kalesse, Org. Lett., 2014, 16, 548.
6 (a) S. E. Denmark, G. L. Beutner, T. Wynn and M. D. Eastgate, J. Am.
Chem. Soc., 2005, 127, 3774; (b) S. E. Denmark and S. Fujimori, J. Am.
Chem. Soc., 2005, 127, 8971; (c) S. E. Denmark and J. R. Heemstra,
Jr., J. Am. Chem. Soc., 2006, 128, 1038; (d) L. J. Fang, H. R. Xue and
J. Yang, Org. Lett., 2008, 10, 4645; (e) G. Rassu, V. Zambrano,
R. Tanca, A. Sartori, L. Battistini, F. Zanardi, C. Curti and
G. Casiraghi, Eur. J. Org. Chem., 2012, 466.
´
´
7 L. Ratjen, P. Garcıa-Garcıa, F. Lay, M. E. Beck and B. List, Angew.
Chem., Int. Ed., 2011, 50, 754.
Scheme 1 Gram-scale synthesis and synthetic utility.
8 (a) Y. Kim, R. A. Singer and E. M. Carreira, Angew. Chem., Int. Ed.,
1998, 37, 1261; (b) A. Fettes and E. M. Carreira, J. Org. Chem., 2003,
68, 9274.
9 (a) C. J. Brennan and J.-M. Campagne, Tetrahedron Lett., 2001,
42, 5195; (b) G. Bluet and J.-M. Campagne, J. Org. Chem., 2001,
To show the prospect of the methodology in synthesis, a
gram-scale synthesis of (R)-3v was carried out. By treatment of
5 mmol of 2v and 7.5 mmol of 1 in the presence of the L-RiPr2–
In(OTf)3 complex for 48 h, 0.79 g (79% yield) of the isolated (R)-3v
with 94% ee was obtained (Scheme 1). What’s more, the highly
enantiomerically enriched (R)-3v can be easily converted into
(R)-d-decalactone, which has a specific odour and is an impor-
tant constituent of cheese and butter, by simple reduction of the
´
66, 4293; (c) G. Bluet, B. Bazan-Tejeda and J.-M. Campagne, Org.
´
Lett., 2001, 3, 3807; (d) X. Moreau, B. Bazan-Tejeda and J.-M.
Campagne, J. Am. Chem. Soc., 2005, 127, 7288.
10 (a) M. D. Rosa, A. Soriente and A. Scettri, Tetrahedron: Asymmetry,
2000, 11, 3187; (b) A. Soriente, M. D. Rosa, M. Stanzione, R. Villano
and A. Scettri, Tetrahedron: Asymmetry, 2001, 12, 959; (c) M. D. Rosa,
M. R. Acocella, M. F. Rega and A. Scettri, Tetrahedron: Asymmetry,
2004, 15, 3029.
carbon–carbon double bond with 5% Pd/C in CH3OH and the 11 (a) I. Paterson, G. J. Florence, A. C. Heimann and A. C. Mackay,
Angew. Chem., Int. Ed., 2005, 44, 1130; (b) I. Paterson, A. D. Findlay
following cyclization with p-TSA in CH2Cl2. Besides, (R)-3v is also
and G. J. Florence, Org. Lett., 2006, 8, 2131.
a good intermediate to synthesize (3R,5R)-valerolactone 7v,
12 (a) D. A. Evans, E. Hu, J. D. Burch and G. Jaeschke, J. Am. Chem. Soc.,
which is present in mevinolin and compactin and is responsible
for inhibition of cholesterol-induced accumulation of fat, as well
as (4R,6R,10R,12R)-verbalactone 8v, which shows a strong anti-
bacterial activity against three strains of Gram-positive and five
strains of Gram-negative bacteria (Scheme 1).18
In summary, we have developed efficient chiral N,N0-dioxide–
In(III) complexes for the highly enantioselective vinylogous
Mukaiyama aldol reaction of the methyl crotonate-derived silyl
dienol ester with aldehydes. The substrate scope was remarkably
wide, affording the corresponding products in up to 99% yield and
with up to 98% ee. The utility of the methodology is highlighted by
the gram-scale synthesis and the useful conversions. Further
studies of carbonyl compounds with other dienes by the chiral
N,N0-dioxide–metal complex system are ongoing.
2002, 124, 5654; (b) D. A. Evans, P. Nagorny, D. J. Reynolds and
K. J. McRae, Angew. Chem., Int. Ed., 2007, 46, 541; (c) D. A. Evans,
J. D. Burch, E. Hu and G. Jaeschke, Tetrahedron, 2008, 64, 4671.
´
13 (a) P. Remy, M. Langner and C. Bolm, Org. Lett., 2006, 8, 1209;
(b) L. V. Heumann and G. E. Keck, Org. Lett., 2007, 9, 4275; (c) G. W.
Wang, B. M. Wang, S. Qi, J. F. Zhao, Y. H. Zhou and J. P. Qu, Org.
Lett., 2012, 14, 2734.
14 (a) D. L. Aubele, S. Wan and P. E. Floreancig, Angew. Chem., Int. Ed.,
2005, 44, 3485; (b) D. W. Custar, T. P. Zabawa and K. A. Scheidt, J. Am.
Chem. Soc., 2008, 130, 804; (c) K. Fujita, R. Matsui, T. Suzuki and
S. Kobayashi, Angew. Chem., Int. Ed., 2012, 51, 7271; (d) G. J. Florence
and J. Wlochal, Chem. – Eur. J., 2012, 18, 14250; (e) H. Fuwa, T. Muto,
K. Sekine and M. Sasaki, Chem. – Eur. J., 2014, 20, 1848.
15 Selected examples, see: (a) J. Lu, M.-L. Hong, S.-J. Ji, Y.-C. Teo and T.-P.
Loh, Chem. Commun., 2005, 4217; (b) T. Fujimoto, K. Endo, H. Tsuji,
M. Nakamura and E. Nakamura, J. Am. Chem. Soc., 2008, 130, 4492;
(c) U. Schneider, M. Ueno and S. Kobayashi, J. Am. Chem. Soc., 2008,
130, 13824; (d) Z. P. Yu, X. H. Liu, Z. H. Dong, M. S. Xie and X. M. Feng,
Angew. Chem., Int. Ed., 2008, 47, 1308; (e) L. L. Lin, Y. L. Kuang, X. H. Liu
and X. M. Feng, Org. Lett., 2011, 13, 3868.
We appreciate the National Basic Research Program of China
(973 Program: No. 2011CB808600) and the National Natural 16 X. H. Liu, L. L. Lin and X. M. Feng, Acc. Chem. Res., 2011, 44, 574.
17 For recent examples of N,N0-dioxide–metal complexes, see: (a) K. Shen,
Science Foundation of China (No. 21372162 and 21432006) for
financial support.
X. H. Liu, L. L. Lin and X. M. Feng, Chem. Sci., 2012, 3, 327; (b) K. Zheng,
L. L. Lin and X. M. Feng, Acta Chim. Sin., 2012, 70, 1785; (c) Z. Wang,
Z. L. Chen, S. Bai, W. Li, X. H. Liu, L. L. Lin and X. M. Feng, Angew.
Chem., Int. Ed., 2012, 51, 2776; (d) L. Zhou, X. H. Liu, J. Ji, Y. H. Zhang,
X. L. Hu, L. L. Lin and X. M. Feng, J. Am. Chem. Soc., 2012, 134, 17023;
(e) J. Guo, S. X. Dong, Y. L. Zhang, Y. L. Kuang, X. H. Liu, L. L. Lin and
Notes and references
1 (a) G. Casiraghi, F. Zanardi, G. Appendino and G. Rassu, Chem. Rev., 2000,
100, 1929; (b) S. E. Denmark, J. R. Heemstra, Jr. and G. L. Beutner, Angew.
Chem., Int. Ed., 2005, 44, 4682; (c) M. Kalesse, Top. Curr. Chem., 2005,
244, 43; (d) S. V. Pansare and E. K. Paul, Chem. – Eur. J., 2011, 17, 8770;
(e) G. Casiraghi, L. Battistini, C. Curti, G. Rassu and F. Zanardi, Chem.
Rev., 2011, 111, 3076; ( f ) S. B. J. Kan, K. K.-H. Ng and I. Paterson, Angew.
X. M. Feng, Angew. Chem., Int. Ed., 2013, 52, 10245; ( f ) X. H. Liu,
L. L. Lin and X. M. Feng, Org. Chem. Front., 2014, 1, 298.
18 (a) S. Gogoi, N. C. Barua and B. Kalita, Tetrahedron Lett., 2004, 45,
5577; (b) A. Garg and V. K. Singh, Tetrahedron, 2009, 65, 8677;
(c) A. Venkatesham, R. S. Rao and K. Nagaiah, Tetrahedron: Asymmetry,
2012, 23, 381; (d) I. V. Mineeva, Russ. J. Org. Chem., 2013, 49, 979.
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.