Studies On Synthetic Methodology Of Novel Scaffolds With Potential Biological Activities And Its Applications

This dissertation mainly focused on the design and synthesis of potential anti-tumor active small-molecule hydroxamic acid histone deacetylase inhibitors (HDACi). The primary coverage includes three aspects of studies:Beckmann rearrangement and its application; Design and synthesis of indanone-based hydroxamic acid derivatives; Synthetic methodologies for benzothiazole derivatives.1. Beckmann rearrangement and its application:Three highly efficient catalytic systems for Beckmann rearrangement of ketoximes were developed, which includes 10 mol%BF3·Et2O,2 mol%TsCl/2 mol%ZnCl2 and 5 mol% NBS/5 mol%PPh3.Meanwhile, we examined the mechanism of Beckmann rearrangement catalyzed by small organic molecule intensively, and found that newly proposed mechanism by Yamamoto is contradictive to our experiments. As a consequent, we proposed that the Beckmann rearrangement catalyzed by small organic molecules still obeyed the classical well-recognized acid-catalyzed mechanism. Notably, small organic molecule was proposed to react with ketoxime and followed by releasing in-situ equal equivalent of acid, which acts the real catalyst to play the catalytic role. Therefore, small organic molecule actually is the initiator instead of the catalyst. Further study indicated that the degree of acidity of acid-catalysts affected the Beckmann rearrangement significantly. The more acidic, the easier the rearrangement proceeds.In addition, we have developed a facile one-pot strategy for synthesis of N-imidoylbenzotriazoles via sulfonyl chloride mediated Beckmann rearrangement of ketoximes. There are some merits of this newly developed synthetic method, such as easy manipulation, easily available starting materials, high yield and generality of the substrate and so on.2. Design and synthesis of indanone-based hydroxamic acid derivatives:Three hydroxamic acid target compounds Rac-Ⅰ-60a, Rac-Ⅰ-60b and Rac-Ⅰ-60c were prepared via 6 or 7 steps with 6-bromo-l-indanone as starting material with overall yield 18%, 9%and 9%, respectively. In addition, Aldol condensation at position 2 of 6-bromo-l-indanone, then reduction with NaBH4, followed by constructing cinnamyl moiety via Heck reaction and subsequent Pd-mediated isomerization of double bond, afforded the key indanone-based intermediatesⅢ-34a. Finally, another series of target compoundsⅢ-40a,Ⅲ-40b andⅢ-40c were accomplished via 9-10 steps with the overall yield 0.6%,0.4%and 1.0%, respectively.The bioassays of biological activities of these two types of target compounds are ongoing. 3. Synthetic methodologies for benzothiazole derivatives:We found that the mCPBA oxidation of methyl 2-(N-ethyl-2,3-dihydrobenzothiazol-2-yl) acetate gave corresponding product with different structure when compared to that of reported one. On this basis, a facile, mild and highly controllable oxidation method was developed. Two different compounds were obtained when the same substrate were oxidized with different reagents, mCPBA or DDQ. Lastly, the key intermediate ethyl 2-(6-amino-N-methyl-2, 3-dihydrobenzo-thiazol-2-yl)-acetate was synthesized via 4 steps with the overall yield 6.5% using 2-amine-6-nitrobenzothiazole as a starting material.