The project involves the development of a transition metal catalyzed multicomponent coupling reaction for the preparation of highly substituted benzene rings fused to other aromatic ring systems, which is a substructure frequently encountered in small molecule chemotherapeutics. The method is environmentally friendly and due to its two-component nature can provide a diverse array of structures to support many structure-activity relationship studies. The key reaction has been demonstrated in a simple system. Initial activities involve the development of the optimal conditions and exploring the scope and limit of the process with respect to catalyst and coupling partners, and the examination of variables related to specific target molecules that have demonstrated pharmaceutical relevance. The project culminates with an incredible short total synthesis of clausamine A, a compound that inhibits the tumor initiation capability of the Epstein Barr virus at nanomolar concentrations. The synthesis involves only 6 steps from a readily available monosubstituted indole precursor compound and has tremendous flexibility for the eventual production of structurally similar compounds for the investigation of structure activity relationships. Since the Epstein-Barr virus is a plays a causative role in several lymphatic cancers common in the USA, and since greater than 90% of the USA population carries the Epstein Barr virus without symptoms, discovery of compounds that can inhibit the tumor formation pathway can reduce the incidence of these cancers which disproportionately affect younger people. Successful execution of this research translates to a dramatic increase in the diversity pool for chemotherapeutics that contain fused aromatic ring systems, which are prized for their metabolic and environmental stability, and the ability to serve as a reliable template fo specifically arranging numerous substituent groups. These results will expand the number of readily-available substructures beyond those currently employed, which for many benzene-fused heterocycles is limited to a few substitution commercially available patterns or compounds derived from their limited range of synthetic manipulations.
The project involves the development of a transition metal catalyzed multicomponent coupling reaction that is highly useful for the synthesis of benzene ring systems that frequently appears as substructures in pharmaceutical compounds. The project culminates in a very short total synthesis of clausamine A, a compound that inhibits the tumor initiation capability of the Epstein Barr virus at nanomolar concentrations, and possesses the essential carbon framework of several compounds in exhibit this property. The Epstein-Barr virus is a plays a causative role in several lymphatic cancers common in the USA, and since greater than 90% of the USA population carries the Epstein Barr virus without symptoms, discovery of compounds that can inhibit the tumor formation pathway can reduce the incidence of these cancers which disproportionately affect younger people.
| Dhakal, Bishnu; Gamage, Lalith S R; Zhang, Yanshi et al. (2017) Synthesis of highly substituted benzene ring systems through three-component coupling of enyne imines, Fischer carbene complexes, and electron-deficient alkynes. Tetrahedron Lett 58:1403-1407 |
| Herndon, James W; Dhakal, Bishnu (2016) The [5+5] route to the phenanthrene skeleton. ARKIVOC 2016:276-306 |
