STUDIES DIRECTED TOWARD THE TOTAL SYNTHESIS OF BRUCEANTIN
Abstract
The results of research on a novel approach to the total synthesis of bruceantin, a quassinoidal antileukemia agent, are detailed. The dominant characteristic of the approach is a rapid construction of a major portion of the ring system of the target molecule, incorporating a sulfur atom at a central location in the molecule. Covalent bonding to or electrophilic association with the sulfur atom allows intramolecular delivery of reagents to only one face of the molecule, giving complete control of stereochemistry at several centers. Initial studies showed that early introduction of the diosphenol functionality as present in bruceantin was not feasible. While readily formed, the diosphenol was converted to a suitably protected form only in low yield. With an alternate A-ring functionality, standard synthetic methods led to a 1,2,3,4,4a,9,10,10a-octahydro-4a-mercaptomethyl-7-methoxy-1-methylphenanthrene derivative which showed unusual resistance to Birch reduction. The analogous alcohol also showed anomalous reduction. Consistent with the proposed mechanism, reduction under more vigorous conditions gave the desired 1,4-diene product. The heteroatom substitution was also found to effect the stereochemistry of the center corresponding to C-9 of bruceantin in equilibration of enones and dienol ethers. Assignment of stereochemistries by carbon-13 NMR spectroscopy provided insight into mechanistic details, allowing the choice of the reaction conditions necessary to give intermediates in the epimeric series needed for the total synthesis. Application of light promoted epoxidation methods to a dienol ether allowed formation of a gamma-hydroxyenone without competitive oxidation of a sulfide, as is the case with peracid oxidation of dienol ethers. This allowed stereoselective introduction of the oxygen corresponding to the C-7 oxygen of bruceantin. Finally, intramolecular conjugate addition of an ester enolate bound to the central sulfur atom allowed formation of the C-8 quaternary center with complete control of stereochemistry. A few unsuccessful attempts at formation of the D-ring for bruceantin by this intramolecular conjugate addition, followed by alkylation of the intermediate enolate, are also reported.
Degree
Ph.D.
Subject Area
Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.