Dissertation
Synthesis of tubuvaline utilizing Mn-mediated radical addition conditions modified for compatibility with heteroaromatics
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.005900
Abstract
The Mn-mediated radical addition reaction developed by our group can synthesize chiral amine substructure with excellent diatereoselectivity. Such methodology was applied in the total synthesis of quinine and tubulysin analogues. Quinine is the well-known anti-malaria drug while tubulysins are a family of natural products with picomolar cytostatic activities. The successful application of our group’s methodology in these total syntheses demonstrated the great value of this radical addition reaction.Aromatic heterocycles are another type of substructures commonly found in biologically active natural products. Quinine contains a quinoline aromatic heterocycle substructure while tubulysins contain a thiazole aromatic heterocycle substructure. Incompatibility of radicals with aromatic heterocycles was observed in the total synthesis of quinine. This incompatibility problem prevented the utilization of our methodology at the late stage of total synthesis where quinoline substructure was present. Consequently, the construction of chiral amine was carried out in the absence of quinoline substructure in the total synthesis of quinine.
Tubuvaline is the most challenging fragment in tubulysins. The thiazole substructure, as well as a chiral amine substructure, are both located on this tubuvaline fragment independently. Because the prior studies showed that our Mn-mediated radical addition method was compromised by incompatibility with quinoline substructure, our radical addition approach to chiral amine synthesis was applied first and the thiazole was constructed later. This order of events added several steps to the sequence, leading to low step-efficiency.
To develop a second-generation tubuvaline synthesis with higher step-economy, as well as to demonstrate the feasibility of applying our methodology at the late stage of total synthesis,
modifications of radical reaction conditions were investigated, and improved compatibility was achieved with our modified condition.
Our second-generation tubuvaline synthesis employed the modified reaction condition and managed to construct chiral amine in the presence of thiazole substructure. Significantly fewer steps were required in our second-generation synthesis.
The excellent diastereoselectivity of our Mn-mediated radical reaction was induced by chiral oxazolidinone auxiliary. This auxiliary is connected to substrates as N-substituents of hydrazone. Influence of stereocenters on other parts of the reactants were not observed previously. In our second-generation tubuvaline synthesis, we observed kinetic resolution in the radical addition reaction: one β-hydrazone diastereomer was preferred by the designed radical addition reaction, while the other diastereomer preferred by side reactions. This unexpected observation indicated complicated transition states in our radical addition reaction when heteroaromatic groups are presented.
Details
- Title: Subtitle
- Synthesis of tubuvaline utilizing Mn-mediated radical addition conditions modified for compatibility with heteroaromatics
- Creators
- Manshu Li
- Contributors
- Gregory K. Friestad (Advisor)Renee S. Cole (Committee Member)Scott R. Daly (Committee Member)Dave Martin (Committee Member)F Christopher Pigge (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.005900
- Publisher
- University of Iowa
- Number of pages
- xix, 269 pages
- Copyright
- Copyright 2021 Manshu Li
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 258-269)
- Public Abstract (ETD)
Chiral amine is the fundamental substructure in proteinogenic amino acids, as well as countless of biologically active natural products and active pharmaceutical ingredients. Therefore, it is very important to develop new methods in synthesizing chiral amines.
Friestad research group developed a chemical reaction that can synthesize chiral amines in excellent efficiency. This reaction has already been applied in the total synthesis of quinine and tubulysin anologues. Quinine is a well-known anti-malaria drug while tubulysins are a family of natural products with remarkable cytostatic activities. These applications demonstrated the great value of this chemical reaction.
Recently, we modified this chemical reaction to expand the versatility of applications. The modified reaction was applied in our second-generation synthesis of tubulysin fragment. Improvement of step-efficiency was achieved. We also discovered unique reactivity in our modified reactions, which can inspire future development of chiral amine synthesis.
- Academic Unit
- Chemistry
- Record Identifier
- 9984096974702771
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