Total synthesis enabled by nickel-catalyzed transformations: Dearomative carboamination and methylenecyclopropane annulation

Hernandez, Lucas William

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Description

Title

Total synthesis enabled by nickel-catalyzed transformations: Dearomative carboamination and methylenecyclopropane annulation

Author(s)

Hernandez, Lucas William

Issue Date

2020-07-08

Director of Research (if dissertation) or Advisor (if thesis)

Sarlah, David

Doctoral Committee Chair(s)

Sarlah, David

Committee Member(s)

• Denmark, Scott E
• Mitchell, Douglas A
• White, Christina

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• total synthesis
• methodology
• dearomatization
• Amaryllidaceae
• alkaloids
• isocarbostyril
• cembranoid
• nickel
• catalysis

Abstract

The use of base metal catalysis is becoming increasingly important, as the sources of transition metals commonly used for the preparation of complex molecules are diminishing. Furthermore, application of these base metal catalysts to the total synthesis of natural products would allow for novel disconnections to be considered. Specifically, nickel catalysis has been emerging as an excellent replacement for traditional palladium-catalyzed transformations, such as Suzuki–Miyaura cross-couplings and Buchwald–Hartwig aminations. However, the use of nickel in asymmetric synthesis, while well established, is still underutilized in the total synthesis of natural products. We sought to develop nickel-catalyzed transformations that would enable unique access to the core scaffolds of natural products with understudied biological activities. To this end, Part 1 of this thesis is based on the development of a divergent synthetic platform to access all the Amaryllidaceae alkaloids using a novel nickel-catalyzed asymmetric dearomative carboamination reaction. This strategy relies on the ability of N-methyl-1,2,4-triazoline-3,5-dione (MTAD) to undergo a [4+2] cycloaddition with benzene to form an intermediary cycloadduct that can then be subjected to a transition metal and nucleophile to form the requisite 1,2-trans-carboaminated product. Chapter 2 describes our efforts to develop this dearomatization reaction, and the subsequent investigations of the synthetic utility of our newly formed diene product to access the cyclitol core. Upon the completion of the synthesis of the 7-deoxypancratistatin and pancratistatin, we then developed a directed cupration/oxidation reaction to create a direct synthetic connection between the two natural products. Chapter 3 delineates how we improved the dearomative carboamination, ultimately providing a glovebox-free protocol by employing Ni(II) salts as the catalyst precursor. We also performed a comprehensive study of the substrate scope of this transformation, as well as further derivatizations of the obtained products. Building on the concepts established in the preceding chapters, Chapter 4 shows how this chemistry was applied to complete the total synthesis of the remaining two alkaloids, narciclasine and lycoricidine. The C-7 cupration reaction was used to synthesize a library of analogs previously inaccessible with other reported sequences. The new analogs were found to be equipotent and significantly more soluble in water than the parent natural products. Part 2 of this dissertation corresponds to the future directions of our base metal catalysis in total synthesis research program. It describes our efforts towards the development of a nickel-catalyzed methylenecyclopropane annulation for the concise preparation of the core scaffold of ineleganolide. The current frontline synthesis towards the norditerpenoid and the final transformations remaining for its completion are described. Towards this end, we developed a novel ring expansion reaction that established a unique connectivity from the starting enone, which is complementary to all previously reported methods.

Graduation Semester

2020-08

Type of Resource

Thesis

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Copyright and License Information

Copyright 2020 Lucas Hernandez

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