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organocatalytic enantioselective formal arylation of azlactones using quinones as aromatic partner Received 00th January 20xx, Accepted 00th January 20xx
Guofeng Li,a,b Wangsheng Sun,b Jingyi Li,b Fengjing Jia,b Liang Hong,*a Rui Wang*a,b
DOI: 10.1039/x0xx00000x www.rsc.org/
A new method for the catalytic enantioselective formal arylation of azlactones using quinones as the aromatic partner was developed for the first time. Under mild conditions, the domino Michael/aromatization/cyclization reaction worked well to afford corresponding products in moderate to high yields and excellent enantioselectivies, some of which have promising cytotoxicity against cancer cells and antibacterial activities.
Azlactones contain three reactive sites at the C2, C4 and C5 positions. The rich reactivity of azlactones enables many transformations, which make them extremely versatile precursors for the synthesis of heterocycles and amino acids.1,2 Take the reactivity of C4 atom for an example, it can undergo alkylation, allylation, benzylation and Michael addition, 1d,3 but arylation has less been reported.4 A limited examples focus on the synthesis of the racemates in harsh conditions. Hartwig et al. developed a Pd-catalyzed arylation using aryl bromides in the presence of a phosphine ligand (Scheme 1a).4a Chai and coworkers reported an arylation using diaryliodonium bromides in combination with silver carbonate (Scheme 1b). 4b Therefore, catalytic enantioselective arylation of azlactones in mild conditions would be still in high demand and challenging. In this paper, we presented the formal arylation of azlactones using quinones as aromatic partner, in which the Michael addition of the azlactones to quinones followed by the subsequent isomerization leading to the formal arylation products (Scheme 1c). Quinones and hydroquinones are an important class of secondary metabolic products with intriguing biological activities. They are well known for their antibacterial, antifungal, antiinflammatory and antitumour activities. 5 Interest in synthesis of diverse hybrid moleculars using
quinones and hydroquinones as raw materials is growing.6 Thus, they have received much attention in asymmetric catalysis.7 Most enantioselective examples focus on the asymmetric synthesis of quinones by Diels-Alder reacrion7a-g and 1,3-dipolar cycloaddition7h-j taking advantage of the fact that quinones can be viewed as electron-deficient alkenes. To obtain hydroquinones, these quinones must undergo a subsequent rearomatization (Scheme 2). In contrast, the direct synthesis of aromatic hydroquinones has been elusive and attractive7k-n.
Scheme 1 Arylation of azlactones.
a. School
of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006 (China). E-mail: [email protected], [email protected] b. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000 (China). † Electronic supplementary information (ESI) available: Experimental procedure, data and NMR spectra of all compounds, and CCDC 1057519. See DOI: 10.1039/x0xx00000x
Scheme 2 Reaction of quinones.
Recently, we found that azlactones could be activated by a thiourea catalyst with a basic site by forming a chiral enolate
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intermediate.8 Taking advantage of C4 nucleophilic and C5 electrophilic properties, we envisioned that the chiral azlactone enolate intermediates could react with quinones to generate chiral hydroquinones, which could be considered as an enantioselective formal arylation of azlactones. The formed hydroquinones could undergo a subsequent domino reaction at C5 to form the final cyclic products (Scheme 3).
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The scope of the azlactone component was next investigated under the optimized reaction conditions (Table 2). In general, the substituents on azlactones had little effect on Scheme 3 Reaction of azlactones with quinones. the enantioselectivies, but in some cases affected the yields.9 At the outset of our study, we conducted the reaction of When R1 was an alkyl group, the reaction proceeded smoothly 1,4-naphthoquinone 1a and azlactone 2a by using a thiourea to give the desired products in moderate to high yield and catalyst 3a in CH2Cl2 at room temperature. The reaction excellent enantioselectivities (Table 2, entries 1-9). Importantly, proceeded efficiently with almost complete conversion and azlactones containing a thioether, amino or alkenyl functional moderate enantioselectivity in 48 h (Table 1, entry 1). group were well tolerated to good results (Table 2, entries 7, 8 Encouraged by this promising result, we then screened several and 9). When R2 was an aryl group, both electron-donating and bifunctional thiourea/squaramide catalysts (Table 1, entries 2– electron-withdrawing substituents on the phenyl ring were 6). The chiral squaramide 3f was the most effective catalyst, accommodated with excellent enantioselectivies (Table 2, giving high conversion and excellent enantioselectivity (Table 1, entries 10-16). Substrate with an alkyl substituent at the C2 entry 6). Further optimization to improve the yield was made position can participate in the reaction with decreased yield by screening of solvents (Table 1, entries 7–12), and (Table 2, entry 17). ClCH2CH2Cl gave the best result (Table 1, entry 12). Thus, we Table 2 Scope of the reaction. carried out the following reactions by the catalysis of squaramide 3f in ClCH2CH2Cl at room temperature. Table 1 Optimization of the reaction.
Entrya
3
Solvent
Conv. (%)b
ee (%)c
1
3a
CH2Cl2
98
66
2
3b
CH2Cl2
98
71
3
3c
CH2Cl2
90
34
4
3d
CH2Cl2
85
81
5
3e
CH2Cl2
82
92
6
3f
CH2Cl2
85
99
7
3f
THF
95
98
8
3f
ether
85
98
9
3f
CHCl3
92
>99
10
3f
toluene
40
97
11
3f
MTBE
90
98
12
3f
ClCH2CH2Cl
99
99
a
All reactions were performed with 1a (0.10 mmol), 2a (0.10 mmol) and 3 (0.02 mmol) in 1.0 mL of the solvent at room temperature. b Determined by 1H NMR spectroscopy of the crude mixture. c The ee value was determined by HPLC on a chiral phase.
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Entrya 1 2
COMMUNICATION R1 Bn
3
R2 C6H5 C6H5 C6H5
4 4a 4b 4c
yield (%)b 96 81 85
ee (%)c 99 99
Table 3 Cytotoxicity and antibacterial activity of compounds 4n and 4j.
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Compounds 4n 4j Juglone
>99
IC50 [μM]a HL-60 Hela 14 14 5 12
a
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4 5
CH3
C6H5 C6H5
4d 4e
86 45
>99 98
6
C6H5
4f
33
>99
7 8 9 10 11 12 13 14 15 16 17
C6H5 C6H5 C6H5 2-Me-C6H4 3-Cl-C6H4 4-Cl-C6H4 4-Br-C6H4 4-NO2-C6H4 4-Me-C6H4 4-MeO-C6H4 (CH3)3
4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q
50 80 89 81 78 95 87 74 95 95 41
87 92 99 98 99 99 97 99 99 99 99
Bn Bn Bn Bn Bn Bn Bn Bn
In conclusion, we have developed the catalytic enantioselective formal arylation of azlactones. Under mild conditions, the domino arylation-cyclization reaction proceeded in moderate to high yields and excellent enantioselectivies. Preliminary activities studies showed that they have promising cytotoxicity against cancer cells and antibacterial activities. Further investigations on these new compounds are ongoing in our laboratories. This work was supported by NSFC (21432003, 21272102 and 21202071); National S&T Major Project of China (2012ZX09504001-003); Program for Changjiang Scholars and Innovative Research Team in University (IRT1137).
Notes and references 1
The generality of this reaction was further evaluated for quinone derivatives (Scheme 4). Benzoquinone 1b could participate in this reaction, affording the final product 4r in 53% yield and up to 99% enantioselectivity. 5-Hydroxy-1,4naphthoquinone (juglone) was also a good reaction partner, 2 and the product 4s was obtained in good yield and enantioselectivity. The absolute configuration of the products was determined by X-ray crystallographic analysis of compound 4k.
Scheme 4 Reaction of azlactone 2a with quinone derivates.
As we mentioned earlier, quinones and hydroquinones have intriguing biological activities.5 We next evaluated their in vitro cytotoxicity and antibacterial activity (For details, see the supporting information). In the control experiment, juglone,10 which has been widely studied for anticancer activity, had an IC50 of 5 μM in HL-60 cells and 12 μM in Hela cells. Among these compounds, 4n showed prominent effects with IC 50 values of 14 μM in HL-60 cells and Hela cells. In addition, 4j showed better antibacterial activity against S. aureus than juglone (32 vs 16 μM).
MIC [μM]b S. aureus B. subtilis 16 16 32 8
Determined by a resazurin reduction assay. b Determined by a standard serial dilution method.
a
All reactions were performed with 1a (0.10 mmol), 2 (0.10 mmol) and 3f (0.02 mmol) in 1.0 mL of ClCH2CH2Cl at room temperature. b Isolated yields. c The ee value was determined by HPLC on a chiral phase.
ChemComm Accepted Manuscript
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For reviews, see: (a) J. S. Fisk, R. A. Mosey and J. J. Tepe, Chem. Soc. Rev., 2007, 36, 1432; (b) N. M. Hewlett, C. D. Hupp and J. J. Tepe, Synthesis, 2009, 2825; (c) R. A. Mosey, J. S. Fisk and J. J. Tepe, Tetrahedron: Asymmetry, 2008, 19, 2755; (d) A.-N. R. Alba and R. Rios, Chem. Asian J., 2011, 6, 720. For selected examples, see: (a) D. Uraguchi, Y. Ueki and T. Ooi, J. Am. Chem. Soc., 2008, 130, 14088; (b) W.-Q. Zhang, L.F. Cheng, J. Yu and L.-Z. Gong, Angew. Chem. Int. Ed., 2012, 51, 4085; (c) M. Terada, H. Tanaka and K. Sorimachi, J. Am. Chem. Soc., 2009, 131, 3430; (d) T. Misaki, G. Takimoto and T. Sugimura, J. Am. Chem. Soc., 2010, 132, 6286; (e) S. Cabrera, E. Reyes, J. Alemán, A. Milelli, S. Kobbelgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2008, 130, 12031; (f) H. Jiang, M. W. Paixão, D. Monge and K. A. Jørgensen, J. Am. Chem. Soc., 2010, 132, 2775; (g) D. Uraguchi, Y. Ueki and T. Ooi, Science, 2009, 326, 120; (h) S. Dong, X. Liu, X. Chen, F. Mei, Y. Zhang, B. Gao, L. Lin and X. Feng, J. Am. Chem. Soc., 2010, 132, 10650; (i) J. Jiang, J. Qing and L.-Z. Gong, Chem. Eur. J., 2009, 15, 7031; (j) M. Terada and H. Nii, Chem. Eur. J., 2011, 17, 1760; (k) A. D. Melhado, M. Luparia and F. D. Toste, J. Am. Chem. Soc., 2007, 129, 12638; (l) A. D. Melhado, G. W. Amarante, Z. J.Wang, M. Luparia and F. D. Toste, J. Am. Chem. Soc., 2011, 133, 3517; (m) S. Dong, X. Liu, Y. Zhu, P. He, L. Lin and X. Feng, J. Am. Chem. Soc., 2013, 135, 10026. For selected recent examples, see: (a) H. Zhou, H. Yang, M. Liu, C. Xia and G. Jiang, Org. Lett., 2014, 16, 5350; (b) B. M. Trost and L, C. Czabaniuk, Chem. Eur. J., 2013, 19, 15210; (c) W. Chen and J. F. Hartwig, J. Am. Chem. Soc., 2013, 135, 2068; (d) D. Uraguchi, Y. Ueki, A. Sugiyama and T. Ooi, Chem. Sci., 2013, 4, 1308; (e) W. Chen and J. F. Hartwig, J. Am. Chem. Soc., 2014, 136, 377; (f) D. Uraguchi, K. Yoshioka, Y. Ueki and T. Ooi, J. Am. Chem. Soc., 2012, 134, 19370. (g) T. Tsubogo, Y. Kano, K. Ikemoto, Y. Yamashita and S. Kobayashi, Tetrahedron: Asymmetry, 2010, 21, 1221. (a) X. Liu and J. F. Hartwig, Org. Lett., 2003, 5, 1915; (b) Z. Chai, B. Wang, J.-N. Chen and G. Yang, Adv. Synth. Catal., 2014, 356, 2714. (c) M. D’Anello, E. Erba, M. L. Gelmi and D. Pocar, Chem. Ber., 1988, 121, 67.
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5
(a) For a review, see: (a) S. Padhye, P. Dandawate, M. Yusufi, A. Ahmad and F. H. Sarkar, Med. Res. Rev., 2012, 32, 1131; for selected recent examples, see: (b) V. Prachayasittikul, R. Pingaew, A. Worachartcheewan, C. Nantasenamat, S. Prachayasittikul, S. Ruchirawat and V. Prachayasittikul, Eur. J. Med. Chem., 2014, 84, 247; (c) P. Dandawate, A. Ahmad, J. Deshpande, K. V. Swamy, E. M. Khan, M. Khetmalas, S. Padhye and F. Sarkar, Bioorg, Med. Chem. Lett., 2014, 24, 2900; (d) D. Belorgey, D. A. Lanfranchi and E. DavioudCharvet, Curr. Pharm. Design., 2013, 19, 2512; (e) F. Lizzi, G. Veronesi, F. Belluti, C. Bergamini, A. López-Sánchez, M. Kaiser, R. Brun, R. L. Krauth-Siegel, D. G. Hall, L. Rivas and M. L. Bolognesi, J. Med. Chem., 2012, 55, 10490; (f) U. V. Mallavadhani, C. V. Prasad, S. Shrivastava and V. G. M. Naidu, Eur. J. Med. Chem., 2014, 83, 84, and references therein. 6 (a) The Chemistry of the Quinoid Compounds (Eds: S. Patai and Z. Rapoport), Wiley, New York, 1988; b) A. Kutyrev, Tetrahedron, 1991, 47, 8043. 7 (a) Ł. Albrecht, C. V. Gómez, C. B. Jacobsen and K. A. Jørgensen. Org. Lett., 2013, 15, 3010; (b) D. Liu, E. Canales and E. J. Corey, J. Am. Chem. Soc., 2007, 129, 1498; (c) E. Canales and E. J. Corey. Org. Lett., 2008, 10, 3271; (d) D. H. Ryu and E. J. Corey, J. Am. Chem. Soc., 2003, 125, 6388; (e) D. A. Evans and J. Wu, J. Am. Chem. Soc., 2003, 125, 10162; (f) D. H. Ryu, G. Zhou and E. J. Corey, J. Am. Chem. Soc., 2004, 126, 4800; (g) Y. A. M. Mohamed, F. Inagaki, R. Takahashi and C. Mukai, Tetrahedron, 2011, 67, 5133; (h) M. Potowski, M. Schürmann, H. Preut, A. P Antonchick and H. Waldmann, Nat. Chem. Biol., 2012, 8, 428; (i) C. Wang, X.-H. Chen, S.-M. Zhou and L.-Z. Gong, Chem. Commun., 2010, 46, 1275; (j) Z. He, T. Liu, H. Tao and C.-J. Wang, Org. Lett., 2012, 14, 6230; (k) W.Y. Siau, W. Li, F. Xue, Q. Ren, M. Wu, S. Sun, H. Guo, X. Jiang and J. Wang, Chem. Eur. J., 2012, 18, 9491; (l) J. Alemán, S. Cabrera, E. Maerten, J. Overgaard and K. A. Jørgensen, Angew. Chem. Int. Ed., 2007, 46, 5520; (m) J. Alemán, B. Richter and K. A. Jørgensen, Angew. Chem. Int. Ed., 2007, 46, 5515; (n) J. Alemán, C. B. Jacobsen, K. Frisch, J. Overgaard and K. A. Jørgensen, Chem. Commun., 2008, 632. 8 (a) W. Sun, G. Zhu, C. Wu, G. Li, L. Hong and R. Wang, Angew. Chem. Int. Ed., 2013, 52, 8633; (b) X. Jiang, H. Zhu, X. Shi, Y. Zhong, Y. Li and R. Wang, Adv. Synth. Catal., 2013, 355, 308; (c) X. Liu, L. Deng, H. Song, H. Jia and R. Wang, Org. Lett., 2011, 13, 1494; (d) X. Liu, L. Deng, X. Jiang, W. Yan, C. Liu and R. Wang, Org. Lett., 2010, 12, 876. 9 The low yields of entries 5-7 and entry 17 were caused by the incomplete conversions. 10 (a) H. Xu, X. Yu, S. Qu and D. Sui, Bioorg. Med. Chem. Lett., 2013, 23, 3631; b) K. B. Aithal, S. M. R. Kumar, N. B. Rao, N. Udupa and S. B. S. Rao, Cell. Biol. Int. 2009, 33, 1039; (c) A. Thakur, J. Med. Plants Res., 2011, 5, 5324.
4 | J. Name., 2012, 00, 1-3
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organocatalytic enantioselective formal arylation of azlactones using quinones as aromatic partner Received 00th January 20xx, Accepted 00th January 20xx
Guofeng Li,a,b Wangsheng Sun,b Jingyi Li,b Fengjing Jia,b Liang Hong,*a Rui Wang*a,b
DOI: 10.1039/x0xx00000x www.rsc.org/
A new method for the catalytic enantioselective formal arylation of azlactones using quinones as the aromatic partner was developed for the first time. Under mild conditions, the domino Michael/aromatization/cyclization reaction worked well to afford corresponding products in moderate to high yields and excellent enantioselectivies, some of which have promising cytotoxicity against cancer cells and antibacterial activities.
Azlactones contain three reactive sites at the C2, C4 and C5 positions. The rich reactivity of azlactones enables many transformations, which make them extremely versatile precursors for the synthesis of heterocycles and amino acids.1,2 Take the reactivity of C4 atom for an example, it can undergo alkylation, allylation, benzylation and Michael addition, 1d,3 but arylation has less been reported.4 A limited examples focus on the synthesis of the racemates in harsh conditions. Hartwig et al. developed a Pd-catalyzed arylation using aryl bromides in the presence of a phosphine ligand (Scheme 1a).4a Chai and coworkers reported an arylation using diaryliodonium bromides in combination with silver carbonate (Scheme 1b). 4b Therefore, catalytic enantioselective arylation of azlactones in mild conditions would be still in high demand and challenging. In this paper, we presented the formal arylation of azlactones using quinones as aromatic partner, in which the Michael addition of the azlactones to quinones followed by the subsequent isomerization leading to the formal arylation products (Scheme 1c). Quinones and hydroquinones are an important class of secondary metabolic products with intriguing biological activities. They are well known for their antibacterial, antifungal, antiinflammatory and antitumour activities. 5 Interest in synthesis of diverse hybrid moleculars using
quinones and hydroquinones as raw materials is growing.6 Thus, they have received much attention in asymmetric catalysis.7 Most enantioselective examples focus on the asymmetric synthesis of quinones by Diels-Alder reacrion7a-g and 1,3-dipolar cycloaddition7h-j taking advantage of the fact that quinones can be viewed as electron-deficient alkenes. To obtain hydroquinones, these quinones must undergo a subsequent rearomatization (Scheme 2). In contrast, the direct synthesis of aromatic hydroquinones has been elusive and attractive7k-n.
Scheme 1 Arylation of azlactones.
a. School
of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006 (China). E-mail: [email protected], [email protected] b. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000 (China). † Electronic supplementary information (ESI) available: Experimental procedure, data and NMR spectra of all compounds, and CCDC 1057519. See DOI: 10.1039/x0xx00000x
Scheme 2 Reaction of quinones.
Recently, we found that azlactones could be activated by a thiourea catalyst with a basic site by forming a chiral enolate
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intermediate.8 Taking advantage of C4 nucleophilic and C5 electrophilic properties, we envisioned that the chiral azlactone enolate intermediates could react with quinones to generate chiral hydroquinones, which could be considered as an enantioselective formal arylation of azlactones. The formed hydroquinones could undergo a subsequent domino reaction at C5 to form the final cyclic products (Scheme 3).
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The scope of the azlactone component was next investigated under the optimized reaction conditions (Table 2). In general, the substituents on azlactones had little effect on Scheme 3 Reaction of azlactones with quinones. the enantioselectivies, but in some cases affected the yields.9 At the outset of our study, we conducted the reaction of When R1 was an alkyl group, the reaction proceeded smoothly 1,4-naphthoquinone 1a and azlactone 2a by using a thiourea to give the desired products in moderate to high yield and catalyst 3a in CH2Cl2 at room temperature. The reaction excellent enantioselectivities (Table 2, entries 1-9). Importantly, proceeded efficiently with almost complete conversion and azlactones containing a thioether, amino or alkenyl functional moderate enantioselectivity in 48 h (Table 1, entry 1). group were well tolerated to good results (Table 2, entries 7, 8 Encouraged by this promising result, we then screened several and 9). When R2 was an aryl group, both electron-donating and bifunctional thiourea/squaramide catalysts (Table 1, entries 2– electron-withdrawing substituents on the phenyl ring were 6). The chiral squaramide 3f was the most effective catalyst, accommodated with excellent enantioselectivies (Table 2, giving high conversion and excellent enantioselectivity (Table 1, entries 10-16). Substrate with an alkyl substituent at the C2 entry 6). Further optimization to improve the yield was made position can participate in the reaction with decreased yield by screening of solvents (Table 1, entries 7–12), and (Table 2, entry 17). ClCH2CH2Cl gave the best result (Table 1, entry 12). Thus, we Table 2 Scope of the reaction. carried out the following reactions by the catalysis of squaramide 3f in ClCH2CH2Cl at room temperature. Table 1 Optimization of the reaction.
Entrya
3
Solvent
Conv. (%)b
ee (%)c
1
3a
CH2Cl2
98
66
2
3b
CH2Cl2
98
71
3
3c
CH2Cl2
90
34
4
3d
CH2Cl2
85
81
5
3e
CH2Cl2
82
92
6
3f
CH2Cl2
85
99
7
3f
THF
95
98
8
3f
ether
85
98
9
3f
CHCl3
92
>99
10
3f
toluene
40
97
11
3f
MTBE
90
98
12
3f
ClCH2CH2Cl
99
99
a
All reactions were performed with 1a (0.10 mmol), 2a (0.10 mmol) and 3 (0.02 mmol) in 1.0 mL of the solvent at room temperature. b Determined by 1H NMR spectroscopy of the crude mixture. c The ee value was determined by HPLC on a chiral phase.
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Entrya 1 2
COMMUNICATION R1 Bn
3
R2 C6H5 C6H5 C6H5
4 4a 4b 4c
yield (%)b 96 81 85
ee (%)c 99 99
Table 3 Cytotoxicity and antibacterial activity of compounds 4n and 4j.
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Compounds 4n 4j Juglone
>99
IC50 [μM]a HL-60 Hela 14 14 5 12
a
Published on 02 June 2015. Downloaded by Karolinska Institutet University Library on 03/06/2015 02:37:01.
4 5
CH3
C6H5 C6H5
4d 4e
86 45
>99 98
6
C6H5
4f
33
>99
7 8 9 10 11 12 13 14 15 16 17
C6H5 C6H5 C6H5 2-Me-C6H4 3-Cl-C6H4 4-Cl-C6H4 4-Br-C6H4 4-NO2-C6H4 4-Me-C6H4 4-MeO-C6H4 (CH3)3
4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q
50 80 89 81 78 95 87 74 95 95 41
87 92 99 98 99 99 97 99 99 99 99
Bn Bn Bn Bn Bn Bn Bn Bn
In conclusion, we have developed the catalytic enantioselective formal arylation of azlactones. Under mild conditions, the domino arylation-cyclization reaction proceeded in moderate to high yields and excellent enantioselectivies. Preliminary activities studies showed that they have promising cytotoxicity against cancer cells and antibacterial activities. Further investigations on these new compounds are ongoing in our laboratories. This work was supported by NSFC (21432003, 21272102 and 21202071); National S&T Major Project of China (2012ZX09504001-003); Program for Changjiang Scholars and Innovative Research Team in University (IRT1137).
Notes and references 1
The generality of this reaction was further evaluated for quinone derivatives (Scheme 4). Benzoquinone 1b could participate in this reaction, affording the final product 4r in 53% yield and up to 99% enantioselectivity. 5-Hydroxy-1,4naphthoquinone (juglone) was also a good reaction partner, 2 and the product 4s was obtained in good yield and enantioselectivity. The absolute configuration of the products was determined by X-ray crystallographic analysis of compound 4k.
Scheme 4 Reaction of azlactone 2a with quinone derivates.
As we mentioned earlier, quinones and hydroquinones have intriguing biological activities.5 We next evaluated their in vitro cytotoxicity and antibacterial activity (For details, see the supporting information). In the control experiment, juglone,10 which has been widely studied for anticancer activity, had an IC50 of 5 μM in HL-60 cells and 12 μM in Hela cells. Among these compounds, 4n showed prominent effects with IC 50 values of 14 μM in HL-60 cells and Hela cells. In addition, 4j showed better antibacterial activity against S. aureus than juglone (32 vs 16 μM).
MIC [μM]b S. aureus B. subtilis 16 16 32 8
Determined by a resazurin reduction assay. b Determined by a standard serial dilution method.
a
All reactions were performed with 1a (0.10 mmol), 2 (0.10 mmol) and 3f (0.02 mmol) in 1.0 mL of ClCH2CH2Cl at room temperature. b Isolated yields. c The ee value was determined by HPLC on a chiral phase.
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