1. Solution-Phase Parallel Synthesis Of 3,5,6-Substituted Indolin-2-ones 2. The Preliminary Research Of Solid-Phase Synthesis Of Indole And Indolin-2-one

Lead compound is the significant foundation of drug discovery. Combinatorialchemistry has been recognized as a powerful tool for the preparation of largenumber of compounds with molecular diversity. It plays an important role in theprocess of lead compound identification and optimization. Combinatorial synthesisis fundamental for the high throughput analysis and screening. Generally,combinatorial synthesis includes solution-phase synthesis and solid-phasesynthesis.Privileged structure, which has become a popular theme in medicinalchemistry recently, presents a class of molecules capable of binding to multiplereceptors with high affinity and demonstrates "drug-like" or "lead-like" properties.Therefore, the exploration of synthesis of privileged structure may provide moreopportunities for discovery of novel lead compound.Experience has shown that compounds with biological activity are often derivedfrom heterocyclic structures. The indole pharmacophore is a fundamentalconstituent of a number of natural and synthetic products with multiple biologicalactivities. Indoles have been designated as privileged structures in medicinalchemistry. Indolin-2-ones belong to this important class of compounds. Because ofthis, interest in indolin-2-ones has grown during the past few years.This thesis is composed of two parts.Part 1: Solution-Phase Parallel Synthesis of 3, 5, 6-SubstitutedIndolin-2-onesA practical and efficient new solution-phase parallel method has beendeveloped for the synthesis of 3-substituted indolin-2-ones with a large variety ofsubstituents at the 5- and 6-positions using 1,5-difluoro-2,4-dinitrobenzene. This 3,5, 6-substituted indolin-2-one skeleton possesses three points of diversification andthus affords new opportunities for identification of hits in drug lead discovery andoptimization.The synthetic procedure includes quantitatively nucleophilic substitution,carbon-carbon bond formation, reduction of aromatic dinitro groups, cyclizationand aldol condensation, yielding three important scaffolds: indolin-2-one, 3-alkyl substituted indolin-2-one, 3-alkyl-3- carboxylate substituted indolin-2-one.The conditions of carbon-carbon bond formation utilizing diethyl malonate orsubstituted diethyl malonate has been explored and optimized. Tin powder inhydrochloric acid under reflux was chose to convert nitroaryl malonate intoindolin-2-one in a one-pot reaction.The configurations of 3-methylene substituted indolin-2-ones may exist as eitherthe Z or E isomer or a mixture, depending on the aldehydes used. The isomers weredetermined by NOE analysis. Generally, the major isomer was obtained asindicated by LC-MS/MS analysis. Compounds containing an alkyl or arylsubstituent at the C-3 position of the 3-substituted indolin-2-ones existed as themajor E isomer forms. Compound analogues containing a pyrrole substituent at theC-3 position of the 3-substituted indolin-2-ones existed as the major Z isomerforms. 3-[(Substituted furanyl)methylidenyl] indolin-2-ones appeared to favor theE isomer form. Indolin-2-ones having a 3-substituted thienyi ring existed as eitherZ or E isomers.Part 2: The Preliminary Research of Solid-Phase Synthesis ofIndole and Indolin-2-oneThe solid-phase synthesis of indole and N-hydroxy indolin-2-one on Knorrresin has been investigated preliminary. A novel C-C bond formation via anucleophilic substitution of the resin-bound 2, 3, 4, 5-tetrafluoro-6-nitrobenzoicacid or 4-fluoro-3-nitrobenzoic acid by diethyl malonate afforded the arylnitroethyl ester, which was reduced with tin (Ⅱ) chloride dihydrate to give the indole orN-hydroxy indolin-2-one.2, 3, 4, 5-tetrafluoro-6-nitrobenzoic acid bound to Knorr resin by Fmocprotectingα-amino acid was converted into N-hydroxy indolin-2-one andquinoxalin-2-one simultaneously via C-C bond formation and reduction. But theyield and purity were poor, and the reaction conditions should be optimized further.