Synthetic studies towards the total synthesis of quinolactacin B and its analogues / Putri Nur Arina Mohd Ariff

Quinolactacin 1, was isolated from larvae mulberry pyralid (Margaronia pyloalis Welker) It has a unique N-methyl-quinolone moiety fused to a lactam ring and was found to contribute towards the activity against tumor necrosis factor production. In this study, a short method on synthesizing quinolactacins and their analogues was established by using 2,4-, and 2,3-pyrrolidinediones as the starting materials. In the first part, 2,4-pyrrolidinedione ring 7 which was also known as tetramic acid underwent amination and acylation reactions to produce two types of key lactam intermediates which are intermediates with enamine functionality (79 and 11) and intermediates with enol-ester functionality (87 and 92). The lactam intermediate with enamine functionality, 79 was synthesized from tetramic acid 7 using a stepwise reaction which includes condensation and reduction while enamine 11 was directly synthesized from tetramic acid 7 via amination reaction. Lactam intermediates with enol-ester functionality, 87 and 97 were then synthesized from tetramic acid 7 in the presence of sodium hydride in dry THF with different acyl halides which are 2-florobenzoyl chloride and 2-nitrobenzoyl chloride, respectively. The final part focused on synthesizing quinolactacin analogues using 2,3-pyrrolidinedione ring as the starting material. 2,3-Pyrrolidinediones 95, 96, and 97 were synthesized via a one-pot multicomponent reaction of sodium diethyl oxaloacetate salt, an aldehyde and a primary amine in ethanol. Consequently, 2,3-pyrrolidinedione rings 95, 96, and 97 were used to synthesize quinolactacin analogues via Conrad limpach reaction which consists of thermal condensation of the primary amine and intramolecular cyclization of enamine intermediates. Despite all the challenges and obstacles in synthesizing quinolactacin B, quinolactacin analogues of 101, 102, and 103 were successfully synthesized in short three steps with the yield of 64%, 71% and 70% respectively.