Current Research in the Kurth Group

Asymmetric Catalysis: Resin-Bound Hydroxyprolylthreonine Derivatives in Enamine-Mediated Reactions

Proline-derived organocatalysts have been under intense investigation in recent years. When applied to aldol condensations, heterogeneous supported organocatalysts often require high catalyst loading and long reaction times, while delivering varied enantioselectivities. Non-supported organocatalysts often require extended reaction times, have strict solvent requirements, and produce variable yields.

Chromanones are medicinally pertinent heterocycles and the chroman parent system has been found in natural products such as sappone B and robustadial, in addition to being a bioisostere for the hydantoin moiety. Indeed, chromanones have many biomedical applications and, consequently, have received considerable synthetic attention. Current asymmetric preparations of chromanones have modest enantioselectivity, and require advanced precursors.

Clearly, there is a need to develop a practical asymmetric route to optically active chromanones and to advance asymmetric solid-phase catalysts for enamine-mediated reactions. Thus we have developed efficient pyrrolidine TentaGel-bound catalysts that kinetically resolve a variety of substrates at ambient temperatures and with short reaction times. The catalysts are simple to prepare, easily recovered, and can be reused several times. These catalysts have been applied toward the syntheses of optically active chromanones as well as other enamine-derived molecular targets. They demonstrate high facial selectivity and tolerate a variety of functional groups.

Reference: Carpenter, Richard D.; Fettinger, James C.; Lam, Kit S.; Kurth, Mark J.. Asymmetric catalysis: resin-bound hydroxyprolylthreonine derivatives in enamine-mediated reactions. Angewandte Chemie, International Edition (2008), 47(34), 6407-6410.

4'-Methyl-4,5'-bithiazole-based correctors of defective DF508-CFTR cellular processing

Cystic fibrosis (CF), a lethal genetic disease afflicting ~0.04% of caucasian individuals, results in chronic lung infections because mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein fails to confer chloride permeability to epithelial cells in lung and other tissues. ΔF508-CFTR is the most common CF mutation. Functional and biochemical analyses have established methylbithiazoles as particularly promising for further development based on their efficacy in human ΔF508-CFTR airway epithelial cells and their CFTR-specificity.

We have developed two versatile synthetic routes for the reliable preparation of bithiazole derivatives. Corrector potency and efficacy of 148 bithiazoles have been assayed using epithelial cells expressing human ΔF508-CFTR. The resulting structure–activity data establishes that the bithiazole substructure plays a critical function; eight novel methylbithiazole correctors were identified with low micromolar potencies. Ongoing efforts continue to further refine and improve the ΔF508-CFTR corrector activity of bithiazoles.

Reference: Yoo, Choong Leol; Yu, Gui Jun; Yang, Baoxue; Robins, Lori I.; Verkman, A. S.; Kurth, Mark J.. 4'-Methyl-4,5'-bithiazole-based correctors of defective DF508-CFTR cellular processing. Bioorganic & Medicinal Chemistry Letters (2008), 18(8), 2610-2614.

Synthesis of New 5H-Indazolo[3,2-b]benzo[d]-1,3-oxazines via One-Pot Intramolecular Bis-heterocyclizations

The indazolobenzoxazine ring system is a heterocycle comprised of 2H-indazole and dihydrobenzo-1,3-oxazine substructures. Indazoles and benzoxazines are well represented in the chemical literature, and compounds containing these heterocycles are of biological interest. However, the parent indazolobenzoxazine system is unknown and thus a good candidate for the discovery of unique bioactivity.

Previous research in the Kurth group has demonstrated that 3-alkoxy-2H-indazoles can be obtained from o-nitrobenzylamines via an N,N-bond-forming heterocyclization reaction mediated by potassium hydroxide in alcoholic solvent. We have designed an intramolecular variant of this reaction to form two heterocycles in a single step, providing an effective entry into the unique indazolobenzoxazines, and expanding the scope of this heterocyclization. These indazolobenzoxazine heterocycles have been submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening. Pending successful biological screening results, second generation library members will be designed and synthesized for lead optimization.

Reference: Butler, Jeffrey D.; Solano, Danielle M.; Robins, Lori I.; Haddadin, Makhluf J; Kurth, Mark J.. A Facile Synthesis of New 5 H -Indazolo[3,2- b ]benzo[ d ]-1,3-oxazines via One-Pot Intramolecular Bis-heterocyclizations. Journal of Organic Chemistry (2008), 73(1), 234-240.

1,3,5-Triazine-Based Mass Spectral Tagging of One-Bead One-Compound Libraries

Small molecules are ideal tools for probing biological systems and combinatorial chemistry provides the opportunity to synthesize many hundreds of these compounds. One-bead one-compound (OBOC) solid-phase techniques eliminate many of the inherent drawbacks of solution-phase synthesis and additional benefits are derived from the ease of on-bead screening - in both binding and functional assays - of OBOC libraries.

We have developed a triazine-based mass encoding strategy for OBOC libraries. The triazine core accommodates cleavable linker, halogen marker, and diversity receptor moieties and leads to tags which are coupled to bifunctionalized TentaGel resin in a one-pot transformation. These triazine-based tags facilitate decoding by (i) equalizing the ionization potential of liberated tags in single bead MALDI-TOF experiments and (ii) equalizing the reactivity of tags in the bifunctionalized TentaGel resin coupling step.

Reference: Robins, Lori I.; Kurth, Mark J.. 1,3,5-Triazine-Based Mass Spectral Tagging of One-Bead One-Compound Libraries. Organic Letters (2007), 9(2), 171-173.