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

• Main Author: Senter, Timothy James
• Other Authors: Henry C. Manning
• Format: Others
• Language: en
• Published: VANDERBILT 2015
• Subjects: Chemistry
• Online Access: http://etd.library.vanderbilt.edu/available/etd-03072015-135158/

We 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.