Novel strategies for the synthesis of complex terpenoids and limonoids

The staggering number of distinct, architecturally complex molecules that nature produces from humble prenyl precursors is a testament to the unsurpassed sophistication of its biosynthetic machinery. The high metabolic cost of producing such ornate natural products is indicative of dedicated functions for these compounds, and nature’s reservoir of complex molecules remains one of the most prolific sources of new pharmaceutical leads. Nonetheless, the dazzling complexity of some terpenoids leaves them beyond the reach of synthetic and medicinal chemists. Such daunting structures provide suitable metrics for identifying where the limits of contemporary synthetic approaches and methods break down and inspire efforts to advance the science of synthesis. We were intrigued by several families of inaccessible terpenes for which there appeared to be no suitable existing strategies for their construction, and we embarked upon a campaign for their total synthesis with an aim to bring these compounds within reach of chemical biologists and medicinal chemists. The first chapter of this dissertation describes our synthetic work on the isomalabaricanes, complex marine triterpenoids with remarkably potent and specific anticancer properties. Despite several efforts and calls within the cancer biology literature, such molecules have never been accessed through total synthesis, likely due to the challenge of constructing their characteristic and highly strained trans-syn-trans-perhydrobenz[e]indene scaffold. This stereochemical configuration locks both A- and B-rings into high-energy twist-boat conformations and required an unorthodox sequence and some novel tandem reactions to assemble. The successful asymmetric syntheses of rhabdastrellic acid A, stelletin E, and stelletin A enabled preliminary structure-activity relationship studies wherein the trans-syn-trans scaffold was found to be essential for their potent anticancer activity. The second chapter of this dissertation describes an extension of the technology developed for the synthesis of isomalabaricanes and its application towards the synthesis of a number of perhydrobenz[e]indene natural products. A common structural motif was identified within several hundred polycyclic terpenoids and an efficient synthesis of this fragment and its congeners was achieved in a selective fashion. An unprecedented stereodivergent phenomenon was discovered and optimized into a key transformation for this endeavor. The third chapter of this dissertation presents a powerful convergent strategy towards the phragmalin limonoids, molecules of such complexity that no member has yet to succumb to total synthesis. Central to the synthetic blueprint is a simple fragment coupling that would generate substantial complexity in a single operation, and progress towards the requisite building blocks is described. The versatility of such approach lies in its potential to access a wide range of heavily oxidized limonoids with various patterns of functionality.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Huck, Christopher James

Contributors dc:contributor

• Sarlah, David
• Denmark, Scott E
• Hergenrother, Paul J
• Mitchell, Douglas A

• Organic synthesis
• Natural products
• Terpenoids

Statement dc:rights

• Copyright 2022 Christopher Huck

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115925

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115925