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Title page for ETD etd-03072015-135158

Type of Document Dissertation
Author Senter, Timothy James
Author's Email Address tsenter@mit.edu
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
  • Stereoselective Synthesis
  • Azetidine
  • Aziridine
  • Structure based Design
  • Leukemia
  • Menin-MLL
  • Pyrrolizidine
  • Alkaloid
  • Natural Product
  • Sulfinamine
Date of Defense 2014-12-18
Availability unrestricted
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.

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