(I)Reductive Decyanation in Organic Synthesis(II)Synthetic Studies on Anti-diabetic 4-Hydroxy-2-furoic acid L-825,373 and It's analogues

• Main Authors: Ting-Yueh Tsai, 蔡廷岳
• Other Authors: Prof. Hsing-Jang Liu
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/51961664220550741586

博士 === 國立清華大學 === 化學系 === 92 === This thesis consists of two chapters, the first of which is further divided into four sections. The first section deals with the use of lithium naphthalenide and other electron transfer reagents in the reductive alkylation and reductive addition of doubly substituted aryl- and heteroarylacetonitriles such as 11 and 41. Using this process, structural motifs whereby a fully substituted methylene carbon adjacent to an aryl (i.e. 16) or heteroaryl ring (i.e. 77) can be readily generated with high yield. These motifs are difficult to achieve with previously described procedures and protocols. The second section details the results of an investigation into the use of disubstituted malononitrile derivatives as substrates for the reductive alkylation/addition reaction as mediated by lithium naphthalenide. In this way, a route towards the high yielding and easy generation of compounds containing a quarternized carbon is achieved (i.e. 84 --> 94). Additionally, by judicious choice of reacting partner (i.e. cyclohexanone), reductive addition across the carbonyl can be followed by an intramolecular reductive elimination reaction to facilitate the formation fully substituted olefins (i.e. 84 --> 154). The third section reports on the use of the reductive addition reaction to allow for the installation of fully substituted acetonitrile derivatives onto the anomeric carbon of carbohydrates with complete stereoselectivity (i.e. 173). The last section of the first chapter in this thesis recounts the results of the use reductive addition and elimination reactions in the establishment of the structural motif. The second chapter delineates the work in establishing a total synthesis route to the antidiabetic natural product L-825,373 and its derivatives. The key step of the envisioned synthetic pathway is a double Claisen-type condensation reaction to form the central furan ring. Indole diglycolate 228 and indole glyoxylate 232 were employed as model substrates to test this reaction, giving rise to furanols 234 and 235. In this way, the central pharmacophore of the natural product consisting of a furan and 2 indole rings was established in 1 step. During the course of this research, it was also established that whereas the condensation reaction was not adversely affected by substitution on the C-7 position of indole diglycolate (i.e. 241), it was highly sensitive to substitution on the C-2 position of indole glyoxylate (i.e. 244). The results of this ongoing total synthesis investigation and the methodological investigations detailed above constitutes this thesis.