The proposed research describes the total synthesis of the drimentines, an indole alkaloid family which have never been synthesized and have only been reported once in their isolation patent. In their sole report, these compounds have shown activity as antibiotics, antifungals, anticancer, and anthelmintic agents. Because of reisolation difficulties, the total syntheses of all five members will offer quick access and sufficient quantities for their further use in SAR and therapeutic studies. The structures have a unique [3.2.1]-bicyclic framework between an indole diketopiperazine derivative and a sesquiterpene. A major synthetic challenge is the construction of the bicyclic framework. One could envision cascade reactions to obtain structural complexity in a single chemical step. This can be achieved through oxidative radical chemistry. First, the synthesis involves the coupling of tryptophan and another amino acid (leucine or proline) and a sesquiterpene derivative through ?-allyl amination chemistry. With all the carbons in place, the key feature to this synthesis is the oxidative radical coupling of two nucleophiles in an intramolecular fashion which converge onto a radical trap, more specifically an olefin tether, affording the [3.2.1] framework in a single step. The oxidation of the indole moiety and the silyl enol ether will be explored with a variety of catalytic oxidants under aerobic conditions. The first oxidants which will be explored are vanadium(V)-oxo complexes. These have been known to perform the umpolung couplings of silyl enol ethers and a variety of nucleophiles. The long-term objectives of the proposal are to provide a new class of bicyclic indole alkaloids which may serve as therapeutics along with other analogs with increased biological activity and offer new methods in the synthesis of complex natural products. Methodology for catalytic tandem oxidative cyclizations provides molecular diversity and complexity without the formation of harmful byproducts known in standard radical cyclizations. These methods will provide new tools to the organic chemist when synthesizing new drug targets of different molecular complexity or new small molecule probes in studying biological mechanisms. Disease and malnutrition have always been socio-economic hardships in many developing countries. The cost-effectiveness of current drugs through long total syntheses remains a bottle-neck for the production cheap therapies in such poor nations. The methods developed in the synthesis of the drimentine family will provide therapeutics in a quick and facile manner which will directly improve public health. ? ? ?
| Schultz, Andrew W; Lewis, Chad A; Luzung, Michael R et al. (2010) Functional characterization of the cyclomarin/cyclomarazine prenyltransferase CymD directs the biosynthesis of unnatural cyclic peptides. J Nat Prod 73:373-7 |
| Luzung, Michael R; Lewis, Chad A; Baran, Phil S (2009) Direct, chemoselective N-tert-prenylation of indoles by C-H functionalization. Angew Chem Int Ed Engl 48:7025-9 |
