Synthetic Approaches to Skeletally Diverse Sultams Using Vinyl- and α-Halo Benzenesulfonamides
Jeon, Kyu Ok
University of Kansas
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The development of new chemical methods to generate novel and diverse structures to probe chemical space is an important aspect of early phase drug discovery. Diversity-Oriented Synthesis (DOS) is a powerful strategy that seeks to generate chemical methods capable of delivering an array of molecular scaffolds with structural and functional diversity. Ultimately, these methods can be adapted to produce molecular libraries. It is the purpose of this thesis to highlight a series of new chemical methods that deliver an array of drug-like sultam scaffolds to be screened for broad biological activity in the molecular library program run by the National Institutes of Health. The first project described in chapter one of this dissertation includes the synthesis of a collection of diverse bi- and tricyclic sultams in an overall DOS approach utilizing a ring-opening metathesis / ring-closing metathesis / cross metathesis (ROM-RCM-CM) cascade strategy. A variety of functionalized, tricyclic sultams were generated as precursors derived from a diastereoselective IMDA reaction in good yields and selectivity. The ROM-RCM-CM strategy to produce skeletal and appendage-based diverse sultams is presented. The second project is the generation of diverse sultams utilizing α,β-unsaturated 5- and 6-membered sultams. These 5- and 6-membered sultams were prepared and applied to further diversifications using aza-Michael reactions, cycloadditions, alkylation/benzylations and propargylation-[3+2]-cycloadditions. Utilizing the aza-Michael reaction, we have developed an efficient protocol for the synthesis of a 141-member library collection of isothiazolidine 1,1-dioxide derivatives. The last project outlined in chapter four is the synthesis of novel 7- and 8- membered tricyclic, biaryl sultams using an intramolecular Pd-catalyzed C-arylation reaction. Namely, in the amino ester-derived sultams, remote 1,5- and 1,6-asymmetric induction emanating from the external stereogenic center is operative, whereby a favorable Cα-H/S=O syn pentane interaction, is the source of asymmetric induction for a highly atropdiastereoselective thermodynamic equilibration process yielding a low energy conformer of "like" configuration (S,Sa). In the course of X-ray crystallographic analysis, as well as detailed NMR studies, we uncovered a number of notable and interesting structural features of the 7-membered amino ester-derived sultams in both solid and solution phases that confirm a structure as a single conformer (95:5) containing biaryl axial chirality of "like" configuration (S,Sa) with respect to the stereogenic center in the external side chain. Moreover, variable temperature NMR analysis has indicated that the axis of chirality at the biaryl bond has a relatively small interconversion barrier that allows for this rapid thermodynamic equilibration of the "like" and "unlike" atropdiastereomers. Detailed variable NMR analyses on a number of analogs, vide infra, point to rotamer dynamics (about the N-C bond in the external side chain) and ring size of the corresponding benzothiazepine (n = 1)/benzothiazocine (n = 2) 1,1-dioxides as governing factors in this notable thermodynamic equilibration of atropdiastereomers. Current efforts are focused on the computational calculation for the energy barrier between two atropdiastereomers interconversion, as well as the further development of an "atropdiastereoselective" C-arylation process. In addition, future studies will continue to probe the dynamic factors involved in the origins of atropselectivity. Utilizing this methodology, we are also generating additional libraries of diverse tricyclic, biaryl sultams for high throughput screening of biological activity with our collaborators at the National Institutes of Health.
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