Expansion and automation of iterative cross-coupling: total synthesis of synechoxanthin and development of a small molecule synthesizer

Sisco, Seiko

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Description

Title

Expansion and automation of iterative cross-coupling: total synthesis of synechoxanthin and development of a small molecule synthesizer

Author(s)

Sisco, Seiko

Issue Date

2014-05-30T17:18:47Z

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

Burke, Martin D.

Doctoral Committee Chair(s)

Burke, Martin D.

Committee Member(s)

• Imlay, James A.
• Katzenellenbogen, John A.
• van der Donk, Wilfred A.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• small molecule
• iterative cross-coupling (ICC)
• reversed-polarity iterative cross-coupling (RP-ICC)
• total synthesis
• carotenoid natural product
• synechoxanthin
• antilipoperoxidant
• automation
• methyliminodiacetic acid (MIDA) boronate

Abstract

Small molecules perform an extraordinary range of important functions. Major advances have been achieved in the laboratory synthesis of small molecules, yet most synthetic efforts are specialized for each target, making synthesis a complex and time-intensive process reserved for specialists. Instead, a general and automated synthesis strategy could provide the broader scientific community rapid access to small molecules for functional studies. To achieve this goal, this dissertation describes the advances toward expanding and automating the iterative cross- coupling (ICC) strategy with N-methyliminodiacetic acid (MIDA) boronate building blocks, an analogous approach to how Nature makes small molecules by iterative assembly of bifunctional building blocks. With the ultimate goal of understanding and optimizing the promising antilipoperoxidant activity of carotenoid natural products, the first total synthesis of synechoxanthin was accomplished. The synthesis was enabled by the development of a new methodology for small molecule synthesis termed reversed-polarity iterative cross-coupling (RP-ICC), in which the polarity of the building blocks is reversed to match the preferred polarity for Suzuki-Miyaura cross-coupling. This strategy expanded the scope and flexibility of ICC by increasing the number of building blocks that can be utilized in the same platform. With an efficient method to access this small molecule, the antilipoperoxidant activity of synechoxanthin was investigated in a chemically-defined liposome system. Preliminary studies indicated that synechoxanthin is an antilipoperoxidant with similar activity to the carotenoid gold standard astaxanthin. To further simplify and generalize the synthesis of small molecules, the ICC strategy was automated through the development of a small molecule synthesizer. Key to this advance was the discovery that MIDA boronates can be purified via a novel type of catch-and-release chromatography. Many different types of small molecules, including materials, pharmaceuticals, and a range of complex natural products and their derivatives were prepared via the fully automated iterative assembly of MIDA boronate building blocks. Contemporaneously with the development of the synthesizer, the ICC platform was expanded to include C-N and Csp3-Csp2 bond formations. Collectively, these advances seek to establish the foundation for a general and automated platform for small molecule synthesis to ultimately help shift the rate-limiting step in small molecule science from synthesis to functional studies.

Graduation Semester

2014-05

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Copyright and License Information

Copyright 2014 Seiko Fujii Sisco

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