| The women's ovulation ceases after menopause result in rapid decline in estrogen levels, which causes a series pathological changes in estrogen target organs such as climacteric symptoms, osteoporosis and the increasing incidence of coronary atherosclerosis, Alzheimer's disease , etc. Estrogen replacement therapy (ERT) was used to maintain normal estrogen level. However, long term ERT would accompany several side effects such as the increase of the risk in the developing endometrial cancer and breast cancer. Phytoestrogen, a kind of non-steroid estrogenic compound derived from plants, is a promising agent for ERT. Phytoestrogens can mimic the effects of estrogen on several target organs. They possess protective effects of estrogen on bone, cardiovascular system, nervous system, ect. They have no cancerous effects on other target organs such as breast and endometria.In the continuation of our efforts in searching for the active extract for the treatment of primary osteoporosis, twenty oligostilbenes have been isolated from Chinese traditional medicine Jin-Que-Gen, the roots of Caragana Sinica in our group. By screening and mechanism study of them, it was found, as the first time, that Pallidol (1) exhibits a more powerful estrogenic activity and might become a promising therapeutic agent for ERT, just like isoflavnones.Due to the scarcity of Pallidol (1) from natural sources, there is of significance in performing the total synthesis of Pallidol and its analogues to meet the demand of the research and clinical application.Structurally, Pallidol (1) is related with some other natural oligostibenes. For example, nature compounds, Leachianol G (3), Leachianol F (4), are the precursors of Pallidol (1), (-)Quadrangularin A (5) and Parthenocissin A (6). So,we have designed methyl derivatives of five natural compounds as our target compounds such as 17e, 29e((, 29e(((, 30e and 30e( .According to structural character of Pallidol (1), the key step involved the construction of 7, 7(, 8, 8(- tetrahydro-7, 7(-diphenylindeno [2, 1, -a] indene and the position of 7, 7(, 8, 8( must be keeped in cis-form. Obviously, it is difficult to overcome angle forces and stereoselectivity in a double cyclization. In the search for methods of double cyclization, our first attempt focused on treatment with one step reaction and was shown as in Scheme I and Scheme II. Our second attempt involved the treatment with two-step reaction and was shown as in Scheme III and Scheme IV. Scheme I, on the bases of references, contained ten-steps reaction sequences in all. We have finished eight-steps to obtain the intermediate, 4, 6, 4(, 6(-tetromethoxyl-2, 2(-ethylenedibenzoly Chloride (15). However it was found of difficulty in getting the expected comformer of Pallidol (1) due to the non-regioselectivity, leading to a mixture of all possible isomers. So we could not isolate them readily. Then, the synthetic route in Scheme II was followed and two model compounds, 17a and 17c, were designed for the study of the construction of 7, 7(, 8, 8(- tetrahydro-7, 7(-diphenylindeno [2,1,-a] indene. At first, the multiaryl-substituted 1, 3-butadienes were obtained from the starting materials of aromatic diketones (18a and 18c) by treatment of 2 equal-mole Wittig reagent. Then, two products such as double-bond position isomers (21a and 21c) and (22a and 22c) were formed by perfect regioselective intermolecular cyclization in the presence of Lewis acid in excellent yields instead of our prospecting model compounds, (17a) and (17c). However, it may be a new regioselective method to synthesis aryl-substituted indenes. Facing the difficulty presented in Scheme I and Scheme II in the synthesis of the structure of double cyclohexane by one step reaction, we turned to use the second strategy for constructing it by twice cyclizations. As the first step, an approach for the preparation of extramolecular double-bond compound should be explored in the second strategy. Thus, we have developed Scheme III to perform extramolecular double–bond com... |
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