Methodology Of Tryptamine’s Intramolecular Oxidative Coupling And Study On Alkaloid Pleiocarpamine’s Total Synthesis

Oxidative coupling is a direct C-C bond formation reaction. Extensive studies were devoted to oxidative homocoupling while oxidative heterocoupling received little attention due to competitive homocoupling reaction. Until recent, oxidative coupling of enolates experienced a renaissance due to its applications in alkaloid synthesis by Baran group and Overman group. This paper mainly focused on constructing novel polycyclic indoline derivatives using I2-mediated intramolecular oxidative coupling reaction, and their application in total synthesis of indole-related alkaloids. It includes three parts:intramolecular oxidative coupling of oxindoles, intramolecular oxidative coupling of tryptamine derivatives, and the study on the total synthesis of pleiocarpamine.1. Intramolecular oxidative coupling of oxindoles:Eight analogues of oxindoles with different substituted aromatic ring and protection groups were synthesized. Three of them were linked with tartaric acid part to prepare three coupling precursors, of which, two were used for condition screening, the other was for the synthesis of alkaloid Perophoramidine. After a series of attempts, NaHMDS as a base, I2as an oxidant, THF as solvent, and-78℃to rt was choosed as the best condition for intramolecular oxdative coupling of oxindoles.2. Intramolecular oxidative coupling of tryptamine derivatives:Sixteen tryptamine derivatives were examined under the oxidative coupling condition, only six compounds gave expected results.1,3-dicarbonyl structure was considered to be the most suited to I2-mediated oxidative coupling. An oxidative coupling/cyclization cascade reaction process for preparing polycyclic spiroindolines from simple (3-ketoamides was developed, and twelve derivatives were completed. Then, another similar cascade reaction for polycyclic pyrrolindolines from tryptamine embed malonic diamide was developed. Through generating trianions, two rings and at least one quarternary carbon center, in some cases two or three continuous quarternary carbon centers could be formed in one pot. Twenty two new compounds were designed and synthesized. In addition, four chiral ligands and two chiral bases used in diastereoselective alkylation of enolates were examined in our coupling reaction, but no effect.3. The study on the total synthesis of pleiocarpamine:Known compound4-1did not react under the oxidative coupling condition to give structure of stricatmine. In another route, the oxidative coupling of4-2gave the result not for strictamine but for pleiocarpamine. The unsaturated ester4-7was obtained from Nb-Bn tryptamine by PS reaction, oxidative coupling, decarboxylation and olefination. But the effort to close D-ring failed. Another unsaturated ester4-12was prepared through a similar route. After the deprotection of benzyl, a lengthened side chain was linked with Nb, but the ring-closure still failed. Another attempt of intermolecular Michael addition is still in progress.