Some Synthetic Applications of 3 , 4 - disubstituted Indoles Generated via Zirconocene - Stabilized Benzyne Complexes

A method previously developed for the regiospecific synthesis of polysubstituted indolines and indoles has been investigated for its utility in organic synthesis. The method relies on the regiospecific generation of zirconocene-stabilized benzyne complexes from N-allyl-2-bromoaniline derivatives. These complexes undergo an intramolecular olefin insertion to provide 5,5,6-tricyclic indoline zirconacycles, which can be cleaved with iodine to provide regiochemically pure 3-iodomethyl-4-iodoindoline derivatives. These derivatives are then converted into 3-bromomethyl-4-iodoindoles, which have been shown to be versatile synthetic intermediates in the preparation for other polyfunctionalized indole derivatives. Initially, we investigated the utility of 3-bromomethyl-4-iodoindole derivatives for the preparation of enantiomerically pure 4-iodotryptophan compounds. The synthesis involved asymmetric alkylation of Sch6llkopf's bislactim ethers, followed by hydrolysis of the alkylated product to generate the desired chiral tryptophan. In addition we also studied the synthesis of oXsubstituted-4-iodotryptophan derivatives via a double alkylation of the Sch6llkopf's t-butyl bis-lactim ether to generate trisubstituted bis-lactim ethers. The hydrolysis of such ethers, however, proved to be problematic. We have further applied the zirconocene-benzyne method towards the synthesis of two biologically active marine alkaloids, eudistomin D and eudistomidin D. Since these alkaloids contain a 3,4,5-trisubstituted indole fragment of their P-carboline ring systems, we anticipated to form such fragment by an electrophilic cleavage reaction of a 5,5,6-tricyclic zirconacyle intermediate, generated via zirconocene-benzyne complexes. Thesis Supervisor: Stephen L. Buchwald Title : Camille & Henry Dreyfus Professor of Chemistry