Research conducted in the Rahaim group is in the area of organic synthesis, specifically focusing on organometallic methodology development directed towards drug discovery applications. The primary goal of the group is the development of reagents, catalysts, and methodology that prepare biologically relevant scaffolds in an economical (atom, redox, step) manner and with diversity. Within the realm of drug discovery natural products1 have been an invaluable source and inspiration with a proven track record.2 Whereas, current high-throughput screening collections are populated with easily synthesized small molecules that have few to no stereocenters, are relatively planar, and have a high aromatic count. Comparative analysis of natural products to drug molecules and library compounds has identified characteristic features of natural products that are under-represented or missing in the latter, namely: a higher degree of structural rigidity and scaffold diversity, more fused, bridged, and spiro ring systems, a higher percentage of sp3- to sp2-carbons, a greater number of chiral centers, and a higher carbon-oxygen bond count in combination with a lower carbon-nitrogen bond count.3 Thus, there is a need for synthetic techniques that can incorporate these characteristic features into drug discovery design strategies for library and probe development. The Rahaim group is looking to address this gap by developing new organometallic methods that can prepare complex molecules with natural product features in a modular manner and amenable to library development. These methods will be applied to the preparation of natural product-mimic libraries, with an emphasis on strategies that also accommodate hit optimization. The objective of which is the development of new pharmacological tools and lead compounds to address unmet medical needs in cancer, infectious, and neurological diseases.
Current research endeavors towards this goal are focusing on new reactions of group IV metallacycles, dual/synergistic catalysis employing temporary tethers, and catalysis with in situ prepared nanoparticles.
New Reactions of Group IV Metallacycles.
A diverse array of three- and five-member ring titanacycles can be prepared from alkynes, alkenes, allenes, carbonyls, imines, and nitriles through reductive coupling intra- and inter-molecularly. These titanium promoted couplings have proven to be a powerful strategy to bond construction. The Rahaim group is interested in leveraging the diacarbanion nature of titanacycles to rapidly and efficiently prepare complex molecules/building blocks/scaffolds, in a modular and economical (atom, step, redox) manner. Investigation in this area is centered around three approaches: 1) sequential one-pot reactions of titanacycles using medicinally (library) relevant electrophiles, 2) the selective transition metal catalyzed iterative cross-coupling of unsymmetrical titanacycles, and 3) nickel catalyzed kinetic dynamic asymmetric umpolung cross-couplings.
Dual/Synergistic Catalysis Employing Temporary Tethers
The use of two metal catalysts in concert allows for bond connections that are not possible with a single catalyst. One of the challenges with this approach to bond construction is overcoming the kinetic barrier of bringing two low concentration intermediates together for reaction. Inspired by nature’s solution to this problem, the Rahaim group will be adopting a temporary tethering strategy. The emphasis of which will be the use to temporary tethers that can be utilized in subsequent functionalization reactions, such as using silicon, boron, and ester tethers. Additionally, investigations into employing carbon dioxide as a traceless tether will be conducted.
Catalysis with In Situ Prepared Transition Metal Nanoparticles
Metal nanoparticles have the advantages of both heterogeneous and homogeneous catalysts. The reactivity and selectivity of metal nanoparticle catalysts can be fine-tuned through the adjustment of the particle size and morphology. While there is high potential for their application the synthetic community, medicinal chemists, especially, have not embraced their use. This is in part due to the lack of commercial availability and the methods for their preparation being laborious and/or requiring specialized equipment. The Rahaim group is developing simple mix and stir procedures to in situ prepare nanoparticle catalysts from readily available bench stable transition metal salts. Application of these nanoparticles in catalysis will emphasize the utilization of renewable feed stock chemicals (CO, CO2,N2) in complex molecule synthesis and the ability to telescope reactions with these nano-catalysts to improve process efficiency.
(1) Ganesan, A. “The impact of natural products upon modern drug discovery” Curr. Opin. Chem. Biol. 2008,12, 306-317.
(2) a) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. “Impact of natural products on developing new anti-cancer agents” Chem. Rev. 2009, 109, 3012-3043. b) Newman, D. J.; Cragg, G. M. “Natural products as sources of new drugs over the last 25 years” J. Nat. Prod. 2007, 70, 461-477. c) Butler, M. S. “Natural products to drugs: natural product-derived compounds in clinical trials” Nat. Prod. Rep. 2008, 25, 475-516. d) Harvey, A. L. “Natural products in drug discovery” Drug Discov. Today 2008, 13, 894-901.
(3) a) Singh, N.; Guha, R.; Giulianotti, M. A.; Pinilla, C.; Houghten, R. A.; Medina-Franco, J. L. “Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries Small Molecule Repository.” J. Chem. Inf. Model 2009, 49, 1010-1024. b) Feher, M.; Schmidt, J. M. “Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry” J. Chem. Inf. Comput. Sci. 2003, 43, 218-227. c) Shelat, A. A.; Guy, R.K. “The interdependence between screening methods and screening libraries” Curr. Opin. Chem. Biol. 2007, 11, 244-251. d) Shelat, A.A.; Guy, R. K. “Scaffold composition and biological relevance of screening libraries” Nat. Chem. Biol. 2007, 3, 442-446. e) Grabowski, K.; Baringhaus, K. H.; Schneider, G. “Scaffold diversity of natural products: inspiration for combinatorial library design” Nat. Prod. Rep. 2008, 25, 892-904. f) Grabowski, K.; Schneider, G. “ Properties and Architecture of Drugs and Natural Products Revisited” Curr. Chem. Biol. 2007, 1, 115-127.
