| dc.description.abstract |
<p>Macrocycles have received growing appreciation for their potential in probing a
broader biological space, and there are a significant number of bioactive macrocycles
in nature. In addition, a macrocyclic scaffold provides interesting features, including
high binding affinity and target selectivity due to the pre-organized conformation.
Despite the therapeutic potential and valuable pharmacological characteristics, this
class of scaffolds has been poorly exploited in the field of drug discovery because
of synthetic challenges and incompatibility to the conventional Lipinski’s rule of
five. Therefore, efficient approaches for the generation of diverse and complex macrocycles
are needed to develop novel macrocyclic agents.</p><p>In an attempt to construct a
diverse set of macrocycles, we designed a natural product-like macrocycle library
containing a tetrahydropyran core. Our strategy for the generation of the library
is based on the tandem allylic oxidation/oxa-conjugate addition for the stereoselective
synthesis of a 2,6-cis-tetrahydropyran ring. The incorporation of various building
blocks and the utilization of diverse macrocyclization methods were carried out to
rapidly increase skeletal diversity and complexity. Appendage diversification was
performed to further modulate the physicochemical properties of the macrocycles. Cheminformatic
analyses demonstrated that our macrocycle library covers a distinct chemical space
compared to drug-like space, while significantly overlapping</p><p>with macrocyclic
natural product space. </p><p>We also explored a modular strategy for the synthesis
of a macrocycle from nature, forazoline A, polyketide natural product. Forazoline
A exhibits potent in vivo efficacy against the fungal pathogen Candida albicans displaying
a synergistic effect with amphotericin B. Our approach towards the synthesis of forazoline
A relied on the construction of three major fragments with the desired stereochemistry
and the assembly of those fragments. In the dissertation, the synthetic studies of
cyclohexane, thiazolidine, and alkyl chain fragments were introduced. Construction
of the highly functionalized cyclohexane moiety was efficiently accomplished utilizing
Mukaiyama aldol, Bayer–Villeger reaction, and addition of lithium dimethyl cuprate.
Synthesis of the thiazolidine fragment was investigated via oxa-conjugate addition
and Pummerer-type rearrangements. Finally, the alkyl chain fragment was synthesized
through epoxidation, regioselective ring opening, and β-ketoester formation.</p>
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