ORGN 810 |
| Structurally diverse and readily bioavailable libraries of small molecules are envisioned to efficiently discover medicinally useful small molecules. To achieve this vision, diversity-oriented synthesis that aims to create a broad distribution of compounds in the chemical space, emerged as an enabling algorithm. We explore this field by adaptation of phosphine-catalyzed annulations developed in our lab to solid-phase synthesis, generating a library of heterocyclic drug-like small molecules. Using Mukaiyama's reagent and Hunig's base, unsubstituted and γ-substituted allenoic acids were coupled with benzyl alcohol of SynPhase-PS lanterns grafted with Wang resin, forming lantern-bound unsubstituted allenoates and γ-substituted allenoates. These resin-bound allenoates underwent phosphine catalyzed [3 + 2] annulations with imines and maleimides to form dihydropyrroles and bicyclic cyclopentenes, respectively. Phosphine-catalyzed [4 + 2] annulation of lantern-bound α-substituted allenoates with imines generates tetrahydropyridines. Each of the solid-bound heterocycles contains a common reactive functional group, an α,β-unsaturated ester. This enoate group was exploited as lantern-bound tetrahydropyridines, dihydropyrroles and bicyclic cyclopentenes were subjected to Michael additions using aryl and alkyl thiols. The different building blocks–allenoates, imines, maleimides and thiols–were screened and the ones that provided products with high purity and diastereoselectivity by LCMS and 1H NMR analysis were chosen for the synthesis of the library. Upon TFA-mediated cleavage, thousands of heterocyclic compounds were obtained through combinatorial synthesis using split-pool format. The screening of the synthesized heterocyclic compounds resulted in the discovery of several enzyme inhibitors, which could potentially lead to the development of anti-cancer therapeutics. |
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Combinatorial, Parallel and Process Chemistry, Heterocycles, Aromatics, New Reactions and Methodology
8:00 PM-10:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Organic Chemistry |