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Leveraging the Reactivity of Photogenerated Quinone Methides from 2H-Chromenes for Target-Directed Synthesis: The Total Synthesis of Piperaduncin A and Alfileramine
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Date
2024Type
ThesisDepartment
Chemistry
Degree Level
Master's Degree
Abstract
In a recent study conducted by the Hitchcock Center of Chemical Ecology focused on analyzing phytochemical diversity of plant species within a specific area of Ecuador, a new 2H-chromene, its prenylated benzoic acid precursor, and its dimer were found within methanolic extracts of the leaves of Piper kelleyi. Due to the structural similarities of the three compounds, it was apparent that a clear biosynthetic relationship was present between them, and research began on 2H-chromenes and their synthetic relationship to complex natural products in cases where they are found concurrently. 2H-chromene compounds represent a natural molecular motif found throughout many different families of plants that has been studied for many years due to their unique photoreactivity. Upon exposure to UV light, chromenes can ring open into the o-quinone methide and its tautomer, resulting in multiple different alkenes and exhibiting a diverse display of reactivity, thus allowing the chromene to act as a manifold in the biosynthesis of a diverse array of complex natural products. One of the most pivotal reactive pathways occurring in nature and stemming from chromene precursors involves Diels Alder type cycloadditions resulting from the generation of multiple alkene intermediates throughout the ring-opening pathway. It was through this mechanism that the existence of chromene dimers in nature were understood to exist, as demonstrated by Jeffrey group collaborators in the total synthesis of dimer 15 isolated from Piper kelleyi and marked by scheme 1.6. Additionally, however, there was found to be HRMS evidence that indicated the existence of another chromene dimer within the original isolate that was unfortunately never fully purified. This compound had remained a mystery and has since been synthetically targeted as a possible chromene dimer made in nature, given the possibility of cycloaddition occurring at different reaction sites about the o-quinone methide intermediates. Despite this apparent possibility, none of the dimers of other isomeric forms were ever successfully synthesized with the method utilized by Jeffrey group collaborators, and largely remained a missing piece of the chromene studies. The presence of these isomeric possibilities has been further evidenced by the findings of different kinds of chromene dimers in nature of different stereochemical makeup, found across several different families of plants and representing at least 4 different isomeric forms resulting from (seemingly) Diels Alder type cycloadditions. Of these cases, the Zanthoxylum alkaloid family discovered by Stermitz et al. will be discussed in detail later on.This thesis will present several different syntheses of 2H-chromenes of varying functionality that would later be used to study the unique reactivity of the o-quinone methide. These model chromenes were then utilized in two major reactive pathways, that of the electrophilic aromatic substitution pathway that would lead to the total synthesis of piperaduncin A, as well as the novel [4+1] dimerization pathway that would lead to the total synthesis of alfileramine. The EAS pathway has been previously established, and involves the trapping of the o-quinone methide by substitution onto a reactive aryl group. The [4+1] pathway represents a new discovery that could uncover the methodology describing how certain chromene dimers are made in nature, featuring the usage of an oxidation catalyst that can generate radical cations upon reactive alkene species to generate highly reactive dienophiles in situ. Through this method, otherwise unfavored Diels Alder type cycloadditions can become thermodynamically favored, thus rapidly producing dimerization products that were previously a synthetic mystery. The specific class of dimers resulting from this pathway can be used to access alfileramine, one of the isomeric forms first discovered by Stermitz et al. Furthermore, the stereochemical findings and subsequent mechanistic analysis performed for this reactive pathway provide evidence for a non-Diels Alder type mechanism that leads to the natural dimers. While this finding is not yet fully understood and is still under investigation, these pieces of evidence will provide further insight into 2H-chromene reactivity and perhaps unlock one of the biosynthetic blueprints that would lead to this specific class of chromene dimers found in nature.
Permanent link
http://hdl.handle.net/11714/12697Additional Information
Committee Member | Tucker, Matthew; Borotto, Nicholas; Dyer, Lee |
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