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Title:Total synthesis of marine terpenoids
Author(s):Boyko, Yaroslav
Director of Research:Sarlah, David
Doctoral Committee Chair(s):Sarlah, David
Doctoral Committee Member(s):Denmark, Scott E.; Hergenrother, Paul J.; White, Marie C.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):total synthesis
terpenes
isomalabaricanes
norcembranoids
polyene cyclization
annulation strategy
Abstract:Complex architectures of marine terpenoids and vast assortments of their scaffolds have served as a proving ground for synthetic chemists, inspiring them to develop, assess, and test new methodologies and disconnections. Moreover, besides advancing the field of organic synthesis, marine natural products have also had an immense influence on medicinal chemistry providing new chemical leads for further development to combat life-threatening diseases. Accordingly, several promising families of marine terpenoids were identified to explore their chemistry and biology. The first chapter of this dissertation describes a full account of our synthetic endeavors towards isomalabaricane triterpenoids, natural products discovered 40 years ago in marine sponges of genera Stelleta, Jaspis, Rhabdastrella, and Geodia. Studies showed that these molecules possess valuable biological properties, such as high cytotoxicity, selectivity over non-transformed cells and, hypothetically, a novel mechanism of action. Consequentially, this family of natural products has attracted significant attention from the synthetic community to solve the problem of sustainable supply, and thereby enable further investigation. All attempts however, have failed. Perhaps this is no surprise as the unique structure of isomalabaricanes encompasses highly strained trans-syn- trans perhydrobenz[e]indene core that poses a great challenge. We have been able to develop a series of unconventional transformations to assemble the core architecture in an expedient and enantioselective fashion. To facilitate the development of strategy and completion of the total synthesis, a number of tools at our disposal were utilized, such as computational techniques and a high-throughput screening platform. Enormous strain associated with the core motif manifested itself in various unforeseen reactivities, which could be avoided only upon judicious orchestration of our synthetic manipulations. Finally, our preliminary results reveal non-intuitive importance of the lipophilic core for biological activity, and more in-depth studies will be conducted shortly to assess the therapeutic potential of the isomalabaricane scaffold. In the second chapter, we identified the perhydrobenz[e]indene core as a highly conserved motif in terpene natural products. This observation allowed us to formulate a concept of a privileged molecular recognition moiety. A two-stage general blueprint was envisioned to access those diverse perhydrobenz[e]indene containing natural products under a unified approach. For that, an originally tailored strategy towards isomalabaricanes was expanded upon and rendered divergent with the incorporation of several bifurcation points. This design allowed us to rapidly assemble scaffolds with all the requisite functionalities for further elaboration into natural products and medicinally relevant compounds. The third chapter describes four generations of strategies towards another marine cytotoxic terpenoid, ineleganolide. This diterpenoid has been recognized as a flagship member of norcembranoid family of natural products. Its highly congested, stereochemically-rich structure inspired us to develop an unparalleled approach to this target based on a late-stage ring-expansion transform. The direct precursor for the natural product was synthesized, employing a novel Ni(0)-catalyzed pentanulation, underutilized Se-B bifunctional reagent, and chemoselective aldol cyclization as key steps in the sequence. Additionally, this approach is versatile and can be exploited towards other norcembranoids. Overall, we achieved substantial progress towards the total synthesis of ineleganolide and enabled exploration of the final stage by developing an expedient and convergent route to the advanced intermediates.
Issue Date:2021-02-24
Type:Thesis
URI:http://hdl.handle.net/2142/110771
Rights Information:Copyright 2021 Yaroslav Boyko
Date Available in IDEALS:2021-09-17
Date Deposited:2021-05


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