We seek to continue our investigation of the intramolecular diyl trapping reaction, using specific target molecules or structural units as a means to more clearly focus our efforts, both synthetic and mechanistic. The proposal is divided into three broad sections, the first outlining how the intramolecular diyl trapping reaction might be applied to the construction of taxol-related systems, the second proposing a variety of alternative strategies designed to assemble seven- and eight-membered rings which form an important subunit of a large number of natural products, including the phorbol esters. Phorbol analogs generated in this manner are to be screened for protein kinase C activity by Sphinx Pharmaceuticals. The methodology includes (a) a direct [4+3] cycloaddition between a 1,3-diyl and a 1,3-diene, (b) intramolecular cycloaddition to a cyclobutenone followed by fragmentation of the resulting cycloadduct, and (c) a promising new strategy which proposes to capitalize on our recent discovery that TMM diyls do participate in hydrogen atom abstraction reactions. Following that event, carbon-carbon bond formation ensues to afford either a seven or an eight-membered ring and generate, in quite a direct manner, the bicyclo[5 (or 6).3.0] ring system. The taxol-related chemistry exploits our recently discovered ability to construct the octahydro-4,6-methanoazulene skeleton; isomerization and oxidative cleavage of the pi bond in this system promises to deliver the bicyclo[5.3.1] unit which is required in the target. In addition, the plan allows the facile introduction of oxygen at C1, C2, C9, C10, and C13, and for assembly of the skeleton in a state of high enantiomeric purity. Professor Les Wilson of UCSB will screen our synthetic materials for their microtubule assembly and depolymerization properties. For simplicity, the initial studies are to be conducted on systems devoid of the C15 gem-methyl group found in the taxanes. Whether this unit is important vis a vis its influence on biological activity is, in fact, unknown. Systems devoid of this unit have not been available for screening. It is clear, however, that they significantly affect the conformation of the basic ring system. Acknowledging this, we have devised a plan to introduce them after the diyl trapping reaction. To do so, we propose to examine for the first time, allenes as diylophiles. The last section of the proposal considers the possibility that trimethylenemethane (TMM) related diyls may interact with DNA in a fashion similar to the anticancer agents calicheamicin, neocarzinostatin, dyneamicin, and esperamicin. A detailed investigation of the site(s) of binding, as well as of the chemistry ensuing once the diyl is generated in the presence of DNA plasmid and various 10- or 12-mers is also proposed. Professor David Wemmer of UC Berkeley has agreed to assist us in defining these issues using NMR techniques. In principle, the diyl could cycloadd to one of the bases, or participate in hydrogen atom abstraction to set off a cascade of events similar to those initiated by the natural products and leading to double-stranded cleavage, or it could abstract hydrogen and then participate in C-C bond formation.
| Spielmann, H P; Fagan, P A; Bregant, T M et al. (1995) The binding modes of a rationally designed photoactivated DNA nuclease determined by NMR. Nucleic Acids Res 23:1576-83 |
