The development of free radical-mediated aryl amination and its application toward the total synthesis of ambiguine G nitrile

Free radical-mediated aryl amination was developed as a conceptually unique approach toward the construction of aryl-nitrogen bond. The reaction was optimized to produce indolines in high yields. The scope and generality of this free radical-mediated cyclization was established by applying it to the synthesis of a diverse array of indolines. Aryl amination was found to be a very mild process for the synthesis of an indoline with a highly sensitive functional group. Aryl amination was then applied to the enantioselective synthesis of indoline alpha-amino acids. A modular annulation strategy employing O'Donnell's enantioselective glycine alkylation followed by aryl amination provided access to protected indoline alpha-amino acids in excellent % ee. Absolute configuration of the indoline alpha-amino acid was confirmed by comparison of the specific rotation after appropriate deprotection. This modular annulation approach was then extended to a stereoselective synthesis of substituted indoline alpha-amino acids by replacing the alkylation with a Michael addition step. (+)-ambiguine G is a nitrile-containing indole alkaloid isolated from the cyanobacterium Hapalosiphon delicatulus possessing antifungal activity. (+)-ambiguine G, has a novel pentacyclic framework and, is structurally related to the hapalindoles, fischerindoles and welwitindolinones. However, no synthesis of this natural product has been reported yet. The proposed biosynthetic pathway to the ambiguine family of natural products is discussed. The indole moiety of ambiguine G was constructed using our conceptually unique aryl amination methodology. The stereochemically dense D ring bearing the neo-pentyl chloride was synthesized using a Diels-Alder reaction between Cohen's dime and a beta-chloro-alpha-methyl dienophile. An enolate C-arylation strategy has been attempted for the construction of the C ring. The first A&barbelow;zaC&barbelow;yclopentenyl C&barbelow;arbinyl R&barbelow;adical I&barbelow;somerization (ACCRI) was identified, and documented. This process was found to be operative under aryl amination conditions. The ring-chain isomerization was gated using the steric and electronic aspects of the process. Use of a sterically demanding substrate led to the isolation of the chain isomer constituting a 1,4-imino transfer process. Relevance of ACCRI to biochemical enzyme-mediated isomerization processes is noted.