Efficient Synthesis of Solasodine, O-Acetylsolasodine, and Soladulcidine as Anticancer Steroidal Alkaloids by Xiaoming Zha, Hongbin Sun*, Jia Hao, and Yihua Zhang Center for Drug Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, P.R. China (phone: þ 86-25-85327950; fax: þ 86-25-83271335; email: hbsun2000@yahoo.com) An efficient synthesis of the steroidal alkaloids solasodine (1), O-acetylsolasodine (2), and soladulcidine ( 3) starting from easily available diosgenin and tigogenin in five or six steps (overall yield 25, 24, and 28%, resp.) is described. Moreover, our synthetic route provides a selective modification at C(3) of 1 and related compounds in order to carry out lead optimization on these natural antitumor steroidal alkaloids. Introduction. – Steroidal alkaloids and their glycosides occurring in numerous species of Solanum are known to possess a variety of biological activities including antitumor [1–3][4a,b], antifungal [5], teratogenic [6], antiviral [7], and antiestrogen [8] activities. Solanaceous plants, for example, Solanum nigrum L. and Solanum dulcamara L., are widely used as traditional antitumor drugs in China. Liu reported [9] that solasodine (1) had potent antitumor activity, and its HCl salt was in preclinical trial as an antitumor agent. On the other hand, SBP002 (Coramsine $ ), a proprietary plant preparation containing solasonine and solamargine (both are solasodine glycoalka- loids), is currently in Phase-II clinical trial for treating certain skin cancers [4c][10]. O- Acetylsolasodine (2), extracted from Solanum umbelliferum Eschs, is a natural product with a significant DNA-damaging activity that may be due to the spiro- aminoacetal function group present in the steroidal side chain [11]. Soladulcidine ( 3) (dihydrosolasodine), which is abundant in Solanum dulcamara L. has also been reported to possess antifungal [12] and induction of congenital craniofacial malforma- tion [13] activities. Given the significant biological importance and potential clinical utility of these steroidal alkaloids, it is highly desirable to develop an efficient synthesis of 1 and related compounds, since they are poorly available from plant extraction. For example, 1 usually occurs at ca. 0.0274–0.0426% of the extracts [7]. Surprisingly, little attention was paid to synthetic chemistry of solasodine-family of compounds, and only a few CHEMISTRY & BIODIVERSITY – Vol. 4 (2007) 25 # 2007 Verlag Helvetica Chimica Acta AG, Zürich