CEPHALOTAXINE SUPPORT STUDIES II
Abstract
Cephalotaxiane and a variety of (alpha)-hydroxysuccinate esters of cephalotaxine known as the harringtonines have been isolated from several Cephalotaxus species. Several harringtonines have been shown to have pronounced antileukemic activity. The cephalotaxine alkaloids are characterized by spiro-fused five membered rings annular to a benzazepine ring system. The goal of this research is the synthesis of cephalotaxine and 11-hydroxycephalotaxine via the appropriately functionalized demethylcephalotaxinone; 11-hydroxycephalotaxine could then be used to synthesize the biologically active harringtonines via an intramolecular transesterification. The synthetic strategy for the construction of the cephalotaxine ring system utilizes a triply convergent tandem conjugate-addition/alkylation reaction of a (gamma),(delta)-dioxygentated vinyl sulfone for the general synthesis of highly functionalized cyclopentanes as potential precursors to cephalotaxine. The one pot synthesis requires: (1) Conjugate addition of hard organometallic reagents (pK(,a) > 25) to a (gamma),(delta)-dioxygentated (alpha),(beta)-unsaturated sulfone in a stereospecific fashion; and (2) Alkylation in situ of the resultant (alpha)-sulfonyl carbanion with one of a variety of electrophilic alkylating agents. The overall yield is dependent upon the nature of the alkylating agent. A number of synthetic approaches to cephalotaxine involving the highly functionalized cyclopentanes prepared have been described and progress detailed. To date, no approach had led to the synthesis of demethylcephalotaxinone, although future potential routes are described.
Degree
Ph.D.
Subject Area
Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.