Type of Document Dissertation Author Senter, Timothy James Author's Email Address email@example.com URN etd-03072015-135158 Title A General and Stereoselective Approach for the Construction of Azabicyclic Compounds: Applications to the Synthesis of (+)-Amabiline and Grandisine D; Structure-based Design of Small Molecule Inhibitors of the Menin-MLL Protein-protein Interaction Degree PhD Department Chemistry Advisory Committee
Advisor Name Title Craig W. Lindsley Committee Chair Gary A. Sulikowski Committee Member Henry C. Manning Committee Member Jeffrey N. Johnston Committee Member Keywords
- Stereoselective Synthesis
- Structure based Design
- Natural Product
Date of Defense 2014-12-18 Availability unrestricted AbstractWe developed a novel approach for the general and enantioselective synthesis of a diverse array of small to large 1-azabicyclo[m.n.0]alkyl ring systems with an embedded olefin handle for further functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated allylation of an Ellman sulfinimine in greater than 9:1 dr, which is readily separable by column chromatography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabicyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent overall yields
Pyrrolizidine, indolizidine, pyrrolo[1,2-a]azepine, and pyrrolo[1,2-a]azocine azabicyclic systems are found in a host of natural products as well as pharmaceutical preparations. The first total synthesis of (+)-amabiline, an unsaturated pyrrolizidine alkaloid from Cynoglossum amabile, was developed. This convergent, enantioselective synthesis proceeds in 15 steps (10-step longest linear sequence) in 6.2% overall yield and features novel methodology to construct the unsaturated pyrrolizidine or (-)-supinidine core. A similar approach was utilized for the concise enantioselective total synthesis of (+)-grandisine D in 16.4% overall yield from commercial materials.
Aziridines and azetidines comprise important classes of nitrogen-containing heterocycles due to both their biological significance and increasing use in medicinal chemistry. A short, high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50-73% overall yields and 88-94% ee, and azetidines in 22-32% overall yields and 84-92% ee.
The protein-protein interaction between menin and MLL (Mixed Lineage Leukemia) plays a critical role in acute leukemias with translocations of the MLL gene. We adopted a structure-guided drug design approach to develop small molecule probes with improved physiochemical properties with the goal of accessing a compound suitable for in vivo studies in animal models of mixed lineage leukemia.
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