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Synthesis of (S)-(+)-tylophorine and its seco analogues using free radical reaction

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Abstract

The synthesis of (S)-(+)-tylophorine and its seco analogues has been accomplished by using free radical reaction. (−)-N-(2,3,6,7-Tetramethoxyphenanthren-9-ylmethyl)-2-bromomethylpyrrolidine (7) and (−)-N-(2,3,6,7-tetramethoxyphenanthren-9-ylcarbonyl)-2-bromomethylpyrrolidine (9) have been obtained for the first time in three and two linear steps from 2,3,6,7-tetramethoxyphenanthrene-9-carboxylic acid (4), respectively. When bromide 7 was subjected to the action of tri-n-butyltin hydride and catalytic amount of azobisisobutyronitrile in acetonitrile at reflux, only a new structural N-((2,3,6,7-tetrame-thoxyphenanthren-9-yl)methyl)piperidine (2) was obtained in excellent yield, without expected (+)- tylophorine. As an alternative route, when bromide 9 was treated with azobisisobutyronitrile and tri-n-butyltin hydride in toluene at reflux, tylophorin-9-one (10) was provided in 33.6% yield. At the same time, a new structural (+)-N-((2,3,6,7-tetramethoxyphenanthren-9-yl)carbonyl)-2-methylpyrrolidine (11) was afforded as the main product in 65% yield. Notably, azobisisobutyronitrile plays dual roles in this reaction, and the possible mechanism has been described. Compounds 10 and 11 were reduced by lithium aluminum hydride to give (+)-tylophorine and (+)-N-((2,3,6,7-tetramethoxyphenanthren-9-yl) methyl)-2-methylpyrrolidine (3), respectively.

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  1. State Key Laboratory of Elemento-Organic Chemistry, Tianjin Key Laboratory of Pesticide Science, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China

    ZiWen Wang, KaiLiang Wang, MingBo Cui & QingMin Wang

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Supported by the National Natural Science Foundation of China (Grant No. 20872072) and the Key Project of Chinese Ministry of Education (Grant No. 106046)

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Wang, Z., Wang, K., Cui, M. et al. Synthesis of (S)-(+)-tylophorine and its seco analogues using free radical reaction. Sci. China Ser. B-Chem. 52, 1288–1299 (2009). https://doi.org/10.1007/s11426-009-0183-z

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