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The first total synthesis of ligudentatin A
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Chinese Chemical Letters 19 (2008) 805–806 www.elsevier.com/locate/cclet
The first total synthesis of ligudentatin A Chen Xi Zhang, Fu Qiang Bi, Yu Lin Li * State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000, China Received 4 March 2008
Abstract Ligudentatin A 1, a new phenolic norsesquiterpenes, was first synthesized starting from (+)-perillaldehyde 3 through five steps, successively, in an overall yield of 20.8%. The key steps were the Diels–Alder reaction and aromatization of enone to phenol. # 2008 Yu Lin Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Ligudentatin A; (+)-Perillaldehyde; Diels–Alder reaction; Aromatization
Ligularia dentate Cass. has long been used as a medicinal herb for easing breathing, stimulating blood flow, reducing inflammation, alleviating pain, stopping coughs and getting rid of phlegm [1,2]. In 1998, a new phenolic norsesquiterpenes, ligudentatin A 1, was originally isolated from the L. dentate Cass. by Gao et al., and its structure and absolute configuration were determined by comparison of the spectral data of 1 with liguhodgsonal 2 [3]. As far as we know, the total synthesis of ligudentatin A 1 has not been reported yet. In order to evaluate its biological activities and do further research on the synthesis of phenolic norsesquiterpenes, we explored the total synthesis of compound 1 (Fig. 1). Our synthesis started with (+)-perillaldehyde (Scheme 1). By the published method [4], compound 4 was easily prepared from (+)-perillaldehyde in 87% yield via Wittig reaction. With compound 4 in hand, the next step was Diels– Alder reaction [5]. A mixture of compound 4, propenoic acid methyl ester and a small amount of hydroquinone were heated in a sealed tube under nitrogen atmosphere at 160 8C for 5 h to afford compound 5 in 82% yield. Compound 5 was converted to enone 6 using PDC/t-BuOOH/Celite system [6] at 30 8C for 15 h in 56% yield based on starting material consumed. The last step was aromatization of enone 6 to phenol. In general, DDQ [7], CuBr/LiBr [8] and I2/MeOH [9] are commonly used as the reagents for this reaction. But when we used these reagents, we could not get the anticipated product. At last, aromatization of 6 to give ligudentatin A 1 in 52% yield was accomplished by reaction successively with 1.2 equiv. of LDA in THF at 78 8C and 1.2 equiv. of PhSeBr followed by oxidation of the selenide with 3.5 equiv. 30% H2O2 at 15 8C [10]. The spectroscopic properties of compound 1 are found to be in good agreement with those reported for the natural product [3,11]. In conclusion, an efficient synthetic approach for ligudentatin A 1 has been developed. The advantages of this approach are reasonable yields and the ease with which the reaction can be carried out under mild conditions with
* Corresponding author. E-mail address: [email protected] (Y.L. Li). 1001-8417/$ – see front matter # 2008 Yu Lin Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.04.037
806
C.X. Zhang et al. / Chinese Chemical Letters 19 (2008) 805–806
Fig. 1. Structural of three compounds (1–3).
Scheme 1. Reagents and conditions: (a) n-BuLi, Ph3PCH3I, THF, 50 8C to r.t. 8 h, 87%; (b) propenoic acid methyl ester, hydroquinone, 160 8C, 5 h, 82%; (c) PDC, t-BuOOH, Celite, C6H6, 0–30 8C, 15 h, 56%; (d): (1) LDA, PhSeBr, THF, 78 8C to r.t. 2 h; (2) 30% H2O2, THF, 15 8C, 2 h, 52%.
readily available materials and reagents. It is expected this methodology not only can be used in the synthesis of other phenolic norsesquiterpenes, but also be useful in the synthesis of other complex natural products. Further application of this strategy is underway in our laboratory. Acknowledgments This work was financially supported by the National Natural Science Foundation of China (No. 20272012) and the Special Research Grant for Doctoral Sites in Chinese Universities (No. 20010730001). References [1] Jingsu College of New Medicine, A Dictionary of the Traditional Chinese Medicines, People’s Hygiene Press, Beijing, 1977, p. 2305. [2] Beijing Plant Research Institute of the Academy of Sciences of China, Iconographia Cormophytorum Sinicrum Tomus IV, Science Press, Beijing, 1975, p. 577. [3] K. Gao, Z.J. Jia, Phytochemistry 49 (1998) 167. [4] B. Harirchian, N.L. Bauld, J. Am. Chem. Soc. 111 (1989) 1826. [5] O.P. Vig, S.D. Sharma, G.L. Kad, M.L. Sharma, Indian J. Chem. 13 (1975) 764. [6] N. Chidambaram, S. Chandrasekaran, J. Org. Chem. 52 (1987) 5051. [7] J.A. Robl, Tetrahedron Lett. 31 (1990) 3421. [8] J.E. Baldwin, M.J. Lusch, Tetrahedron 38 (1982) 2939. [9] A.S. Kotnis, Tetrahedron Lett. 32 (1991) 3441. [10] M.I. Al-Hassan, Synth. Commun. 19 (1989) 453. [11] Spectral data of synthetic compound 1: IR (film): 3388, 3053, 2931, 1699, 1649, 1610, 1590, 1466, 1432, 1302, 1211, 1127, 1014, 890 and 777 cm1; EIMS m/z (%): 246 (M+, 67.8), 231 (66.9), 215 (19.9), 203 (61.4), 186 (29.0), 178 (43.5), 171 (100), 163 (34.1), 149 (13.5), 131 (38.1), 115 (46.0), 91 (39.5), 77 (22.8), 65 (13.0), 55 (38.6), 41 (35.2); 1H NMR (300 MHz, CDCl3, d ppm): 6.77 (d, 1H, J = 2.4 Hz, Ar), 7.21 (d, 1H, J = 2.4 Hz, Ar), 6.01 (s, 1H, OH), 4.76 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 3.15 (m, 1H, CH2), 2.85 (m, 2H, CH2), 2.78 (m, 1H, CH2), 2.25 (m, 1H, CH2), 1.90 (m, 1H, CH2), 1.81 (s, 3H, CH3), 1.64 (m, 1H, CH2); 13C NMR (75 MHz, CDCl3, d ppm): 168.64, 152.83, 149.37, 139.31, 130.84, 130.06, 119.53, 115.18, 109.24, 52.07, 41.73, 32.58, 30.24, 27.17, 20.69; ½a14 D +94.5 (c 0.22, CHCl3).
Chinese Chemical Letters 19 (2008) 805–806 www.elsevier.com/locate/cclet
The first total synthesis of ligudentatin A Chen Xi Zhang, Fu Qiang Bi, Yu Lin Li * State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000, China Received 4 March 2008
Abstract Ligudentatin A 1, a new phenolic norsesquiterpenes, was first synthesized starting from (+)-perillaldehyde 3 through five steps, successively, in an overall yield of 20.8%. The key steps were the Diels–Alder reaction and aromatization of enone to phenol. # 2008 Yu Lin Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Ligudentatin A; (+)-Perillaldehyde; Diels–Alder reaction; Aromatization
Ligularia dentate Cass. has long been used as a medicinal herb for easing breathing, stimulating blood flow, reducing inflammation, alleviating pain, stopping coughs and getting rid of phlegm [1,2]. In 1998, a new phenolic norsesquiterpenes, ligudentatin A 1, was originally isolated from the L. dentate Cass. by Gao et al., and its structure and absolute configuration were determined by comparison of the spectral data of 1 with liguhodgsonal 2 [3]. As far as we know, the total synthesis of ligudentatin A 1 has not been reported yet. In order to evaluate its biological activities and do further research on the synthesis of phenolic norsesquiterpenes, we explored the total synthesis of compound 1 (Fig. 1). Our synthesis started with (+)-perillaldehyde (Scheme 1). By the published method [4], compound 4 was easily prepared from (+)-perillaldehyde in 87% yield via Wittig reaction. With compound 4 in hand, the next step was Diels– Alder reaction [5]. A mixture of compound 4, propenoic acid methyl ester and a small amount of hydroquinone were heated in a sealed tube under nitrogen atmosphere at 160 8C for 5 h to afford compound 5 in 82% yield. Compound 5 was converted to enone 6 using PDC/t-BuOOH/Celite system [6] at 30 8C for 15 h in 56% yield based on starting material consumed. The last step was aromatization of enone 6 to phenol. In general, DDQ [7], CuBr/LiBr [8] and I2/MeOH [9] are commonly used as the reagents for this reaction. But when we used these reagents, we could not get the anticipated product. At last, aromatization of 6 to give ligudentatin A 1 in 52% yield was accomplished by reaction successively with 1.2 equiv. of LDA in THF at 78 8C and 1.2 equiv. of PhSeBr followed by oxidation of the selenide with 3.5 equiv. 30% H2O2 at 15 8C [10]. The spectroscopic properties of compound 1 are found to be in good agreement with those reported for the natural product [3,11]. In conclusion, an efficient synthetic approach for ligudentatin A 1 has been developed. The advantages of this approach are reasonable yields and the ease with which the reaction can be carried out under mild conditions with
* Corresponding author. E-mail address: [email protected] (Y.L. Li). 1001-8417/$ – see front matter # 2008 Yu Lin Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.04.037
806
C.X. Zhang et al. / Chinese Chemical Letters 19 (2008) 805–806
Fig. 1. Structural of three compounds (1–3).
Scheme 1. Reagents and conditions: (a) n-BuLi, Ph3PCH3I, THF, 50 8C to r.t. 8 h, 87%; (b) propenoic acid methyl ester, hydroquinone, 160 8C, 5 h, 82%; (c) PDC, t-BuOOH, Celite, C6H6, 0–30 8C, 15 h, 56%; (d): (1) LDA, PhSeBr, THF, 78 8C to r.t. 2 h; (2) 30% H2O2, THF, 15 8C, 2 h, 52%.
readily available materials and reagents. It is expected this methodology not only can be used in the synthesis of other phenolic norsesquiterpenes, but also be useful in the synthesis of other complex natural products. Further application of this strategy is underway in our laboratory. Acknowledgments This work was financially supported by the National Natural Science Foundation of China (No. 20272012) and the Special Research Grant for Doctoral Sites in Chinese Universities (No. 20010730001). References [1] Jingsu College of New Medicine, A Dictionary of the Traditional Chinese Medicines, People’s Hygiene Press, Beijing, 1977, p. 2305. [2] Beijing Plant Research Institute of the Academy of Sciences of China, Iconographia Cormophytorum Sinicrum Tomus IV, Science Press, Beijing, 1975, p. 577. [3] K. Gao, Z.J. Jia, Phytochemistry 49 (1998) 167. [4] B. Harirchian, N.L. Bauld, J. Am. Chem. Soc. 111 (1989) 1826. [5] O.P. Vig, S.D. Sharma, G.L. Kad, M.L. Sharma, Indian J. Chem. 13 (1975) 764. [6] N. Chidambaram, S. Chandrasekaran, J. Org. Chem. 52 (1987) 5051. [7] J.A. Robl, Tetrahedron Lett. 31 (1990) 3421. [8] J.E. Baldwin, M.J. Lusch, Tetrahedron 38 (1982) 2939. [9] A.S. Kotnis, Tetrahedron Lett. 32 (1991) 3441. [10] M.I. Al-Hassan, Synth. Commun. 19 (1989) 453. [11] Spectral data of synthetic compound 1: IR (film): 3388, 3053, 2931, 1699, 1649, 1610, 1590, 1466, 1432, 1302, 1211, 1127, 1014, 890 and 777 cm1; EIMS m/z (%): 246 (M+, 67.8), 231 (66.9), 215 (19.9), 203 (61.4), 186 (29.0), 178 (43.5), 171 (100), 163 (34.1), 149 (13.5), 131 (38.1), 115 (46.0), 91 (39.5), 77 (22.8), 65 (13.0), 55 (38.6), 41 (35.2); 1H NMR (300 MHz, CDCl3, d ppm): 6.77 (d, 1H, J = 2.4 Hz, Ar), 7.21 (d, 1H, J = 2.4 Hz, Ar), 6.01 (s, 1H, OH), 4.76 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 3.15 (m, 1H, CH2), 2.85 (m, 2H, CH2), 2.78 (m, 1H, CH2), 2.25 (m, 1H, CH2), 1.90 (m, 1H, CH2), 1.81 (s, 3H, CH3), 1.64 (m, 1H, CH2); 13C NMR (75 MHz, CDCl3, d ppm): 168.64, 152.83, 149.37, 139.31, 130.84, 130.06, 119.53, 115.18, 109.24, 52.07, 41.73, 32.58, 30.24, 27.17, 20.69; ½a14 D +94.5 (c 0.22, CHCl3).