Allyl-Palladium Catalyzed Dehydrogenation of Carbonyl Compounds and Total Synthesis of (+)-Granatumine A and Clovan-2,9-dione

Date of Award

Spring 2021

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Newhouse, Timothy


Methodology development was motivated by the synthesis of natural products and various biologically active compounds. The direct dehydrogenation of ketones and carboxylic acids are particularly attractive because the corresponding unsaturated products are highly versatile intermediates in organic synthesis and the step-economic approaches may find broad utility in drug discovery. In addition to advance methodologies, computational tools such as DFT calculation and machine learning techniques are also incorporated in retrosynthetic analysis to accelerate the small molecule synthesis process. This thesis herein describes two dehydrogenation methodologies that can be readily applied to the synthesis of pharmaceutically relevant compounds, and two natural product total synthesis that were facilitated by computer-assisted synthetic planning.Chapter 1 describes a highly practical and step-economic a,b-dehydrogenation of carboxylic acids via enediolates through the use of allyl-palladium catalysis. Dianions underwent smooth dehydrogenation when generated using Zn(TMP)2·2LiCl as a base in the presence of excess ZnCl2, thus avoiding the typical decarboxylation pathway of these substrates. Direct access to 2-enoic acids allows derivatization by numerous approaches, and two enoic acid derivatives were investigated to demonstrate moderate 20S proteasome stimulatory activity. Chapter 2 describes the use of allyl-palladium catalysis for the direct α,β-dehydrogenation of cyclic ketones via their zinc enolates. Notably, this transformation operates under basic conditions and tolerates a diverse scope of functional groups. Furthermore, the telescoping of ketone dehydrogenation with organocuprate conjugate addition chemistry allows for the one-step b-functionalization and a,b-vicinal difunctionalization of a wide variety of unactivated ketones. Chapter 3 describes the first total synthesis of (+)-granatumine A, a limonoid alkaloid with PTP1B inhibitory activity, in ten steps. Over the course of this study, two key methodological advances were made: a cost-effective procedure for ketone α,β-dehydrogenation using allyl-palladium catalysis, and a Pd-catalyzed protocol to convert epoxyketones to 1,3-diketones. The central tetrasubstituted pyridine is formed by a convergent Knoevenagel condensation and carbonyl-selective electrocyclization cascade, which was followed by a direct transformation of a 2H-pyran to a pyridine. These studies have led to the structural revision of two members of this family. Chapter 4 describes the 7-step computationally assisted total synthesis of clovan-2,9-dione. A strategic 6-endo radical cyclization was planned as the key step for the concise synthesis, and two machine learning models were developed to evaluate the feasibility of the speculative transformation. Without empirical investigation, the optimal substrate for radical cyclization was identified by high-efficient in silico screening. Our hybrid approach complements the existing computational retrosynthesis planning and have the potential to be applied to complicated natural product total synthesis.

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