Dissertation
Evaluation of β-hydroxy protected aldehyde 1,3-stereoinduction in Mukaiyama aldol reactions and progress towards the total synthesis of bastimolide A
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007177
Abstract
Bastimolide A is a polyhydroxy 40-membered lactone that was isolated off the coast of Bocas del Toro, Panama in 2015. Bioactivity experiments revealed that it possesses potent (IC50 = 80–270 nM) anti-malarial activity against four drug resistant strains of P. falciparum. Bastimolide A does not share the same structural motifs compared to other known anti-malarial active compounds; therefore, it presumably inhibits malaria via an unknown mechanism of action. Coupling this with the fact that it possesses multiple 1,5-diols, which allows for application of our configuration-encoded 1,5-polyol methodology, bastimolide A is a desirable target for our group to pursue and investigate.
We envision a convergent approach that unionizes two fragments, C2–C21 (“Fragment A”) and C22–C43 (“Fragment B”). The northern Fragment A is the main focus of the work presented herein, while my colleague, Jacob Hackbarth, worked towards Fragment B. Fragment A could be accessed from commercially available 1-octenol by applying two prior methods in our group – (1) a detour around our silyl cation-induced ring-opening of enol ester epoxides that includes hydrolysis of a halohydrin ester and (2) configuration-encoded 1,5-polyol synthesis – an iterative approach using Julia Kocienski olefination. These two methods are also the core of the synthesis of Fragment B.
Inspiration from prior work in our group led to a plan for joining Fragments A and B via an asymmetric BF3•OEt2-mediated Mukaiyama aldol reaction with high 1,3-anti stereoinduction. Fragment A is a β-silyloxy aldehyde that lacks branching at the γ-carbon, and is the electrophilic partner of the anti-selective Mukaiyama aldol reaction. The resultant stereocenter produced from the aldol is influenced by 1,3-stereoinduction of the nearby β-silyloxy group. A short study was conducted to identify the optimal β-hydroxy protecting group by performing Mukaiyama aldol reactions with β-silyloxy- and β-alkoxy aldehyde analogs where only the protecting group was changed to measure the effect on 1,3-stereoinduction. Broader impacts of this stereoinduction study include further refinement of Evans 1,3- merged stereoinduction model, aiding in future polyketide (polyacetate) synthesis, and experimental benchmarks for computational studies.
Once C2–C43 of bastimolide A is in-hand, we aim to complete the total synthesis by alkene hydrogenation, Horner-Wadsworth-Emmons (HWE) olefination, and macrolactonization ring-closure. Smith and coworkers completed the first total synthesis of bastimolide A in May 2022, so inspiration will likely be draw upon their work as unforeseen reactivity was observed and optimization was needed for their final steps.
Details
- Title: Subtitle
- Evaluation of β-hydroxy protected aldehyde 1,3-stereoinduction in Mukaiyama aldol reactions and progress towards the total synthesis of bastimolide A
- Creators
- Lucas W. Howell
- Contributors
- Gregory K. Friestad (Advisor)F. Christopher Pigge (Committee Member)David F. Wiemer (Committee Member)Nicole Becker (Committee Member)Scott K. Shaw (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Spring 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007177
- Number of pages
- xix, 274 pages
- Copyright
- Copyright 2023 Lucas W. Howell
- Language
- English
- Date submitted
- 04/19/2023
- Date approved
- 05/24/2023
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 152-164).
- Public Abstract (ETD)
The development of resistance to current malaria drugs is a significant threat to human health and society. To combat this phenomenon, structurally different and other unique antimalarial compounds need to be investigated, like bastimolide A. Bastimolide A falls within a class of compounds called polyols; meaning it is decorated with an array of –OH (alcohol) groups. It has demonstrated potent antimalarial activity, but it is not understood how it attacks and inhibits the malaria parasite Plasmodium falciparum. Therefore, it is essential that efforts are directed towards synthesizing bastimolide A (and medicinally relevant analogues), so that its mechanism of action can be better elucidated.
Polyol natural products, specifically those possessing 1,5-diols, have historically been difficult to make in a convenient manner. Prior work in the Friestad research group has allowed for a cost-efficient way to access 1,5-diols in a selective fashion. We aim to apply this method, alongside other well-known chemical transformations, to synthesize bastimolide A.
Our 1,5-diol strategy is at the core of our synthetic efforts towards making bastimolide A. This strategy is amenable to vast amounts of flexibility and diversification along-the-way to accessing the drug. Specifically, we can easily and rapidly make a variety of different bastimolide A analogues. Making miniscule structural changes to a drug molecule often has profound effects on its bioactivity. Our approach accommodates a variety of structural changes that could potentially have further implications in medicinal chemistry and drug discovery for future malaria therapeutics as we gain insights on its mechanism of action.
- Academic Unit
- Chemistry
- Record Identifier
- 9984425392402771
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