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A new facile synthesis of shikalkin
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Chinese Chemical Letters 19 (2008) 172–174 www.elsevier.com/locate/cclet
A new facile synthesis of shikalkin Qun Lu a,*, Hao Lun Tang a, Yan Qiang Shao a, Jun Chao Cai b a
b
Department of Bioengineering, Southwest Jiaotong University, Chengdu 610031, China Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China Received 8 October 2007
Abstract A short and convergent approach for the synthesis of shikalkin (dl-shikonin) is presented. Stobbe reaction was employed to construct the aromatic skeleton 6. This is followed by a practical method to prepare the key epoxides 9 from aldehydes 8 in high yield. Finally, shikalkin is achieved by Grignard reaction and oxidation. # 2007 Qun Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Synthesis; Shikalkin; Epoxides
Shikonin 1, alkannin 2, are the active ingredients isolated from the roots of the traditional oriental medicinal herb Lithospermium erythrorhizon [1]. They possess extraordinary biological properties, not only of their antiinflammatory, antibacterial, anti-fungal, immunostimulating activities [2], but also of anti-tumor activity [3]. Many studies showed that shikonin and dl-shikonin 3 exerted anti-tumor effects by inhibiting cancer cell growth [3], inducing apoptosis [4] and inhibiting DNA topoisomerase I/II activity [5], antitelomerase activity [6] and antiangiogenesis [7].
The extensive biological activity of shikonin and alkannin coupled with the sensitivity of the molecule drew the attention of synthetic chemists and several approaches were developed for the total synthesis of the molecule [8]. But most of these methods are in low yield, especially the steps of construction of the side chain and development of an effective protecting system for the naphthoquinone core. The efficient synthesis of this apparently simple molecular remained elusive. During the course of our research, we developed a novel route for the formal total synthesis shikonin in which the key intermediate 1,4-bismethoxy-5-hydroxynaphthalene epoxides 9 [9] was obtained in practical method (Scheme 1). 1,4-Dimethoxy-5-hydroxy naphthalene skeleton 6 was prepared by Stobbe type condensation [7] of 4 and 5, followed * Corresponding author. E-mail address: [email protected] (Q. Lu). 1001-8417/$ – see front matter # 2007 Qun Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.11.031
Q. Lu et al. / Chinese Chemical Letters 19 (2008) 172–174
173
Scheme 1. Synthesis of dl-shikonin.
by reduction with LiAlH4 to give naphthol 7 which was oxidated to aldehyde 8 with pyridine-SO3 in high yield. Conversion of aldehyde 8 into key intermediate epoxide 9 was achieved in good yield with standard sulfur yield methodology. The epoxide 9 was opened by treatment with the commercial Grignard reagent 2,2-dimethylvinyl magnesium bromide to afford 10 [10]. Oxidation of naphthol 10 with AgO(II) in THF instead of 1,4-dioxane by one step almost exclusively afforded dl-shikonin 3 [11] in moderate yield. The asymmetric synthesis of 1 and 2 can also use the same strategy by asymmetric epoxidation and are in progress. Reagents and conditions: (a) NaH, diethyl succinate, ethanol, toluene, rt, yield 65%; acetic anhydride, anhydrous sodium acetate, reflux, yield 66%; (b) LiAlH4, THF, rt, yield 90%.; (c) Py-SO3, Et3N, DMSO, 40 8C, 90%, (d) TMSOI, NaH, DMSO, 50 8C, yield 70%; (e) N2, 2,2-dimethylvinylmagnesium bromide, THF, rt, yield 50%; (f) Ag(II)O, 6N HNO3, THF, 0 8C ! rt, yield 30%. Acknowledgment Financial support from the Scientific Research Foundation of State Education Ministry for the Returned Overseas Chinese Scholars is gratefully acknowledged. References [1] [2] [3] [4] [5] [6] [7] [8]
R.H. Thomason, Naturally Occurring Quinones, Recent Advances, Chapman and Hall, New York, 1987, pp. 219. V.P. Papageorgiou, A.N. Assimopoulou, E.A. Couldouros, Angew. Chem. Int. Ed. 38 (1999) 270. X.P. Guo, X.Y. Zhang, S.D. Zhang, Zhongxiyi Jiehe Zazhi1 1 (1991) 598. Y. Yoon, Y.O. Kim, N.Y. Lim, W.K. Jeon, H.J. Sung, Planta Med. 65 (1999) 532. B.Z. Ahn, K.U. Baik, G.R. Kweon, K. Lim, B.D. Hwang, J. Med. Chem. 38 (1995) 1044. Q. Lu, W. Liu, J. Ding, J. Cai, W. Duan, Bioorg. Med. Chem. Lett. 12 (2002) 1375. T. Hisa, Y. Kimura, K. Takada, F. Suzuki, M. Takigawa, Anticancer Res. 18 (1998) 783. (a) Y. Terada, A. Tanoue, A. Hatada, et al. Bull. Chem. Soc. Jpn. 60 (1987) 205; (b) A.M. Moiseenkov, N.N. Balaneva, V.L. Novikov, Dokl. Akad. Bauk. SSSR 295 (1987) 614; (c) M. Braun, C. Bauer, Liebigs Ann. Chem. (1991) 1157; (d) E.A. Couladouros, Z.F. Plyta, A.T. Strongilos, Tetrahedron Lett. 38 (1997) 7263; (e) K.C. Nicolaou, D. Hepworth, Angew. Chem. Int. Ed. 37 (6) (1998) 839.
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Q. Lu et al. / Chinese Chemical Letters 19 (2008) 172–174
[9] The data of compound 9: 1H NMR(400 MHz, CDCl3, d ppm): 3.17(dd, 1H, J = 5.6, 4.0 Hz), 3.87(dd, 2H, J = 5.6,2.8 Hz), 3.94(s, 3H), 4.00(s, 3H), 6.65(s, 1H), 6.66(s, 1H), 6.77(d, 1H, J = 1.6 Hz), 7.01(d, 1H, J = 1.6 Hz), 9.47(s, 1H). [10] The data of compound 10: 1H NMR(400 MHz, CDCl3, d ppm): 1.63(s, 3H), 1.71(s, 3H), 2.15(s, 1H), 2.85–2.87(m, 3H), 3.92(s, 3H), 3.97(s, 3H), 4.64(m, 1H), 5.28(m, 1H), 6.60(s, 1H), 6.60(s, 1H), 6.82(s, 1H) 7.56(d, 1H, J = 0.8 Hz), 9.41(d, 1H, J = 4 Hz). [11] The data of 3: IR (KBr, cm1): 3255 (broad, OH), 1608 (C O); 1H NMR (400 Hz, CDCl3, d ppm): 1.63(s, 3H, CH3), 1.76(s, 3H, CH 3), 2.30– 2.70(m, 3H, CH2 and OH), 4.90(m, 1H, CH(OH)), 5.18(m, 1H, (CH3)2 CH), 7.15–7.20(m, 3H, Ar–H), 12.50(s, 1H, Ar–OH), 12.61(s, 1H, Ar– OH); EIMS (m/z) 288 [M+], 219 [C10H5O4CHOH+], 69 [CH2CH C(CH3)2+]; HRMS: Found: 288.1018. Calcd. for C16H16O5: 288.0998.
Chinese Chemical Letters 19 (2008) 172–174 www.elsevier.com/locate/cclet
A new facile synthesis of shikalkin Qun Lu a,*, Hao Lun Tang a, Yan Qiang Shao a, Jun Chao Cai b a
b
Department of Bioengineering, Southwest Jiaotong University, Chengdu 610031, China Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China Received 8 October 2007
Abstract A short and convergent approach for the synthesis of shikalkin (dl-shikonin) is presented. Stobbe reaction was employed to construct the aromatic skeleton 6. This is followed by a practical method to prepare the key epoxides 9 from aldehydes 8 in high yield. Finally, shikalkin is achieved by Grignard reaction and oxidation. # 2007 Qun Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Synthesis; Shikalkin; Epoxides
Shikonin 1, alkannin 2, are the active ingredients isolated from the roots of the traditional oriental medicinal herb Lithospermium erythrorhizon [1]. They possess extraordinary biological properties, not only of their antiinflammatory, antibacterial, anti-fungal, immunostimulating activities [2], but also of anti-tumor activity [3]. Many studies showed that shikonin and dl-shikonin 3 exerted anti-tumor effects by inhibiting cancer cell growth [3], inducing apoptosis [4] and inhibiting DNA topoisomerase I/II activity [5], antitelomerase activity [6] and antiangiogenesis [7].
The extensive biological activity of shikonin and alkannin coupled with the sensitivity of the molecule drew the attention of synthetic chemists and several approaches were developed for the total synthesis of the molecule [8]. But most of these methods are in low yield, especially the steps of construction of the side chain and development of an effective protecting system for the naphthoquinone core. The efficient synthesis of this apparently simple molecular remained elusive. During the course of our research, we developed a novel route for the formal total synthesis shikonin in which the key intermediate 1,4-bismethoxy-5-hydroxynaphthalene epoxides 9 [9] was obtained in practical method (Scheme 1). 1,4-Dimethoxy-5-hydroxy naphthalene skeleton 6 was prepared by Stobbe type condensation [7] of 4 and 5, followed * Corresponding author. E-mail address: [email protected] (Q. Lu). 1001-8417/$ – see front matter # 2007 Qun Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.11.031
Q. Lu et al. / Chinese Chemical Letters 19 (2008) 172–174
173
Scheme 1. Synthesis of dl-shikonin.
by reduction with LiAlH4 to give naphthol 7 which was oxidated to aldehyde 8 with pyridine-SO3 in high yield. Conversion of aldehyde 8 into key intermediate epoxide 9 was achieved in good yield with standard sulfur yield methodology. The epoxide 9 was opened by treatment with the commercial Grignard reagent 2,2-dimethylvinyl magnesium bromide to afford 10 [10]. Oxidation of naphthol 10 with AgO(II) in THF instead of 1,4-dioxane by one step almost exclusively afforded dl-shikonin 3 [11] in moderate yield. The asymmetric synthesis of 1 and 2 can also use the same strategy by asymmetric epoxidation and are in progress. Reagents and conditions: (a) NaH, diethyl succinate, ethanol, toluene, rt, yield 65%; acetic anhydride, anhydrous sodium acetate, reflux, yield 66%; (b) LiAlH4, THF, rt, yield 90%.; (c) Py-SO3, Et3N, DMSO, 40 8C, 90%, (d) TMSOI, NaH, DMSO, 50 8C, yield 70%; (e) N2, 2,2-dimethylvinylmagnesium bromide, THF, rt, yield 50%; (f) Ag(II)O, 6N HNO3, THF, 0 8C ! rt, yield 30%. Acknowledgment Financial support from the Scientific Research Foundation of State Education Ministry for the Returned Overseas Chinese Scholars is gratefully acknowledged. References [1] [2] [3] [4] [5] [6] [7] [8]
R.H. Thomason, Naturally Occurring Quinones, Recent Advances, Chapman and Hall, New York, 1987, pp. 219. V.P. Papageorgiou, A.N. Assimopoulou, E.A. Couldouros, Angew. Chem. Int. Ed. 38 (1999) 270. X.P. Guo, X.Y. Zhang, S.D. Zhang, Zhongxiyi Jiehe Zazhi1 1 (1991) 598. Y. Yoon, Y.O. Kim, N.Y. Lim, W.K. Jeon, H.J. Sung, Planta Med. 65 (1999) 532. B.Z. Ahn, K.U. Baik, G.R. Kweon, K. Lim, B.D. Hwang, J. Med. Chem. 38 (1995) 1044. Q. Lu, W. Liu, J. Ding, J. Cai, W. Duan, Bioorg. Med. Chem. Lett. 12 (2002) 1375. T. Hisa, Y. Kimura, K. Takada, F. Suzuki, M. Takigawa, Anticancer Res. 18 (1998) 783. (a) Y. Terada, A. Tanoue, A. Hatada, et al. Bull. Chem. Soc. Jpn. 60 (1987) 205; (b) A.M. Moiseenkov, N.N. Balaneva, V.L. Novikov, Dokl. Akad. Bauk. SSSR 295 (1987) 614; (c) M. Braun, C. Bauer, Liebigs Ann. Chem. (1991) 1157; (d) E.A. Couladouros, Z.F. Plyta, A.T. Strongilos, Tetrahedron Lett. 38 (1997) 7263; (e) K.C. Nicolaou, D. Hepworth, Angew. Chem. Int. Ed. 37 (6) (1998) 839.
174
Q. Lu et al. / Chinese Chemical Letters 19 (2008) 172–174
[9] The data of compound 9: 1H NMR(400 MHz, CDCl3, d ppm): 3.17(dd, 1H, J = 5.6, 4.0 Hz), 3.87(dd, 2H, J = 5.6,2.8 Hz), 3.94(s, 3H), 4.00(s, 3H), 6.65(s, 1H), 6.66(s, 1H), 6.77(d, 1H, J = 1.6 Hz), 7.01(d, 1H, J = 1.6 Hz), 9.47(s, 1H). [10] The data of compound 10: 1H NMR(400 MHz, CDCl3, d ppm): 1.63(s, 3H), 1.71(s, 3H), 2.15(s, 1H), 2.85–2.87(m, 3H), 3.92(s, 3H), 3.97(s, 3H), 4.64(m, 1H), 5.28(m, 1H), 6.60(s, 1H), 6.60(s, 1H), 6.82(s, 1H) 7.56(d, 1H, J = 0.8 Hz), 9.41(d, 1H, J = 4 Hz). [11] The data of 3: IR (KBr, cm1): 3255 (broad, OH), 1608 (C O); 1H NMR (400 Hz, CDCl3, d ppm): 1.63(s, 3H, CH3), 1.76(s, 3H, CH 3), 2.30– 2.70(m, 3H, CH2 and OH), 4.90(m, 1H, CH(OH)), 5.18(m, 1H, (CH3)2 CH), 7.15–7.20(m, 3H, Ar–H), 12.50(s, 1H, Ar–OH), 12.61(s, 1H, Ar– OH); EIMS (m/z) 288 [M+], 219 [C10H5O4CHOH+], 69 [CH2CH C(CH3)2+]; HRMS: Found: 288.1018. Calcd. for C16H16O5: 288.0998.