Study On The Synthesis Of Zolpidem And The Asymmetric Synthesis Of Phenolic Phenolic Natural Products

This thesis involves two parts of work, including the development of a new synthetic procedure of Zolpidem and the first asymmetric total synthesis of natural product △3-2-Hydroxybakuchiol.1. Zolpidem was the first licensed drug containing the imidazo[1,2-a]pyridine skeleton by FDA, which is widely used to treat insomnia. Interestingly, although the drug patent has expired, the total sale of Zolpidem was up to$ 951 million only in the US market and ranked to 34th in the list of the top 200 brand name drugs by US retail sales in 2010. Nevertheless, the current synthetic process of Zolpidem suffers from a long route, complicated operation, the usage of a large amount of highly toxic reagents and a low overall yield. Thus, the improvement of the synthetic process of Zolpidem is an attractive task.In this thesis, the efficient synthesis of Zolpidem was achieved, through two-step procedure. The first step was the formation of schiff base with 4-methyl-benzaldehyde and 5-methyl-2-aminopyridine catalyzed by TsOH. In the second step, around 260 reaction conditions have been screened and optimized, and the catalytic system of CuI/Binol was finally selected for the tandem reaction to afford Zolpidem in 90% yields (shown in the following scheme).2. The recent research suggested that bakuchiol from ethanol extractive of Psoralen possesses strong estrogenic activity, which can reduce the bone loss of postmenopausal women without the the side effect of uterus hyperplasia by the strong affinity with the estrogen a receptor and the comparable affinity with estrogen β receptor. Compared in structure with bakuchiol, the natural △3-2-Hydroxybakuchiol is more similar to estradiol and diethylstilbestrol, thus it was anticipated to display more potent anti-osteoporosis activities than bakuchiol. However, △3-2-Hydroxybakuchiol was isolated in lower than 0.016% yield from the plant Psoralea corylifolia L.. So far, few biological studies and none of the asymmetric synthesis of △3-2-hydroxybakuchiol have been reported. Therefore, it would be necessary to explore a convenient method for the preparation of △3-2-Hydroxybakuchiol and its analogs.In this thesis, the preparation of the key intermediate 3 bearing chiral quaternary carbon center by asymmetric alkylation of α,β-unsaturated imide induced by Evans chiral auxiliary was developed, by which the first total synthesis of △3-2-Hydroxybakuchiol 1 was achieved in a total yield of 15% through 13 steps including selective reduction, Wittig reaction, Takai-Utimoto reaction, Negishi reaction as key steps (shown in the following scheme).According to the established method,17 analogues of △3-2-Hydroxybakuchiol 1 were synthesized, which could be subjected to the relative pharmacological research in the due course.