Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




Christopher N. Bobby

Second Advisor

James H. Henderson


DEBS TE, Diels-Alderase, Polyketides, Polyketide thioesterase, Spiculoic Acid A

Subject Categories



Traditionally separate disciplines of a large and broad chemical spectrum, synthetic organic chemistry and biochemistry have found in the last two decades a fertile common ground in the area pertaining to the biosynthesis of natural products. Both disciplines remain indispensable in providing unique solutions on numerous questions populating the field. Our contributions to this interdisciplinary pursuit have been confined to the biosynthesis of polyketides, a therapeutically and structurally diverse class of natural products, where we employed both synthetic chemistry and biochemical techniques to validate complex metabolic processes. One such example pertained to the uncertainty surrounding the regiochemistry of dehydration and cyclization in the biosynthetic pathway of the marine polyketide spiculoic acid A. The molecule's key intramolecular cyclization was proposed to occur through a linear chain containing an abnormally dehydrated polyene system. We synthesized a putative advanced polyketide intermediate and tested its viability to undergo a mild chemical transformation to spiculoic acid A. In addition, we applied a synthetic and biochemical approach to elucidate the biosynthetic details of thioesterase-catalyzed macrocyclizations in polyketide natural products. The outcome of the enzyme's activity is divided between hydrolysis and macrocyclization and limited information is currently available pertaining to its selectivity. We synthesized four enantioenriched NAC-thioester analogs and assayed them with overexpressed DEBS TE, the canonical thioesterase of polyketide natural products, to gain insight into the effect key structural and stereochemical elements of the polyketide substrate have in the macrocyclization selectivity and regioselectivity of the enzyme.


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