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Title page for ETD etd-03252018-034947


Type of Document Dissertation
Author Batiste, Suzanne Marie
URN etd-03252018-034947
Title Rapid Synthesis by Rational Design: An Ion-Templated Macrocyclooligomerization-Based Approach to Prepare Collections of Natural Product-Like Cyclodepsipeptides, Leading to the Discovery of a New Antiarrhythmic Small Molecule
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Björn C. Knollmann Committee Member
Brian O. Bachmann Committee Member
David W. Wright Committee Member
Keywords
  • macrocycle
  • total synthesis
  • ryanodine receptor
  • oligomerization
  • isothermal titration calorimetry
  • chemical biology
  • natural product
  • depsipeptide
Date of Defense 2018-03-08
Availability restricted
Abstract
Fungal cyclooligomeric depsipeptides (CODs) are structurally privileged natural products as demonstrated by their broad spectrum of biological activities, including antibiotic, insecticidal, and antitumor activities. In nature, their synthesis is mediated by fungal-COD-producing nonribosomal peptide synthetases (NRPSs), which recursively condense and then cyclize a series of peptidol monomer units. As selective as this reaction is in nature, its application to the chemical synthesis of oligomeric natural-product like molecules is limited because of its difficulty to control.

A rapid synthesis of CODs was developed, which includes a platform for control over complex structural elements through a hybridization of enantioselective catalysis, Umpolung Amide Synthesis (UmAS), and a Mitsunobu macrocyclooligomerization (MCO). The efficiency and simplicity of this method was illustrated by the shortest synthesis of cyclodepsipeptide natural products (-)-verticilide, (-)-bassianolide, (+)-montanastatin, and (+)-valinomycin, in addition to several other structural, stereochemical, and ring size-diverse analogs. A key feature of this discovery was that ionic salts, which are normally contraindicated in Mitsunobu conditions, can enhance the formation of size-diverse collections of macrocycles or selectivity for a single macrocycle size through an ion-templating effect. Isothermal titration calorimetry (ITC) was implemented as a tool to study macrocycle-template binding interactions, and show that these measurements can be correlated to size-distributions of depsipeptides formed during Mitsunobu-based MCOs. These studies have identified key trends in quantitative metal ion-cyclic depsipeptide binding interactions across discrete collections of macrocycles. Importantly, these behaviors can be elucidated across collections of macrocycles formed from monomers of different sizes, relative stereochemical configuration, and side-chain residues. Finally, this newly accessible area of chemical space that resulted from the rational synthesis of unnatural products led to the discovery of a new inhibitor of ryanodine receptor (RyR2)-mediated calcium leak in a collaborative effort with the Knollmann lab.

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