Natural Product Inspired Synthesis of Heterocyclic Systems: Functionalized Dibenzoxepinones and Pyrrolic Compounds
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Authors
Deichert, Julie
Date
Type
thesis
Language
eng
Keyword
Natural Products , Cularine Alkaloids , Palladium-Catalyzed Alpha-Arylation , Dibenzoxepinones , Prodiginines and Tambjamines , Pyrroles , Biosynthetic Enzymes
Alternative Title
Abstract
Plant and microbial alkaloids have a rich history stemming from their structural diversity and
medicinal applications. Accordingly, these natural products and their derivatives continue to pique interest
within the synthetic and biosynthetic communities. Heterocyclic motifs are common among the alkaloids;
the unique chemical transformations and biosynthetic origins of these systems thus present a versatile
platform for the generation of structurally diverse molecules.
Chapter one of this thesis describes the development of an efficient route to key cularine alkaloid
intermediate, Manske’s ketone. Optimization and scope studies were conducted leading to a robust and
general two-step synthesis of functionalized dibenzo[b,f]oxepin-10(11H)-ones via nucleophilic aromatic
substitution (SNAr) and palladium-catalyzed intramolecular α-arylation. We have demonstrated the utility
of these ubiquitous heterocyclic systems by further cross-coupling chemistry. The scope of the α-arylation
methodology was additionally expanded to provide 11-substituted dibenzoxepinones; application to benzofused nitrogen- and sulfur-containing 7-membered heterocycles is also described. Studies into the curious
formation of a trimethoxy-substituted xanthone, the major product under previously described
intramolecular α-arylation conditions, are currently ongoing.
Chapter two describes the evaluation and synthesis of two related classes of bioactive pyrrole-containing alkaloids, the prodiginines and tambjamines. The proton affinity of cyclic tambjamine MYP1
was compared to linear analogue BE-18591 through determination of the apparent pKa values. The
increased basicity of the macrocyclic derivative was rationalized by its structural rigidity. This chapter also
details adjacent investigations into the chemoenzymatic synthesis of prodiginines. The substrate tolerance
of the terminal condensation enzyme involved in prodigiosin biosynthesis, PigC, was demonstrated for a
brominated monopyrrolic substrate. In contrast, the production of this novel analogue was unsuccessful by
a purely synthetic approach. Preliminary studies into the functionalization of related pyrrolic compounds
are also described.
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Attribution 3.0 United States
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.