Total synthesis and study of the antilipoperoxidant peridinin, synthesis of versatile MIDA boronate building blocks, and a general strategy for the synthesis of polyenes

Woerly, Eric

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Description

Title

Total synthesis and study of the antilipoperoxidant peridinin, synthesis of versatile MIDA boronate building blocks, and a general strategy for the synthesis of polyenes

Author(s)

Woerly, Eric

Issue Date

2013-05-28T19:19:39Z

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

Burke, Martin D.

Doctoral Committee Chair(s)

Burke, Martin D.

Committee Member(s)

• Moore, Jeffrey S.
• Hartwig, John F.
• Katzenellenbogen, John 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)

• N-methyliminodiacetic acid (MIDA) boronates
• peridinin
• iterative cross coupling

Abstract

Taking advantage of the inherent modularity present in the majority of small molecule natural products, we envision that a building block based approach involving the iterative cross-coupling of MIDA boronate containing molecules can be a universal platform for the preparation of small molecules. Guided by this strategy we completed an efficient, flexible, and fully stereocontrolled synthesis of the carotenoid natural product peridinin. This natural product inspired the development of new methodology, including the stereocontrolled Suzuki-Miyaura cross-coupling of haloallenes and the transesterification of boronic esters to MIDA boronates and MIDA boronates to boronic esters. Utilizing this synthetic material, we probed the antilipoperoxidant activity of peridinin in a chemically defined liposome based system and discovered that peridinin is far more potent than the leading carotenoid gold standard astaxanthin. Detailed mechanistic studies revealed that this superior activity is derived from an early quench of chain propagating lipid peroxyl radicals. Our work with peridinin demonstrated that synthesis is often the rate determining step in studying the function of a molecule. In order to help shift this rate determining step from synthesis to a study of function, we are interested in identifying recurring structural motifs present in small molecule natural products and transforming these motifs into MIDA boronate building blocks. Toward this goal, cis-olefins, 1,1-disubstituted olefins, and the 2-pyridyl moiety are three highly recurring motifs. To gain access to these frameworks, we have developed scalable routes to three MIDA boronate building blocks: (Z)-2-bromovinyl MIDA boronate, 1-bromovinyl MIDA boronate, and 2-pyridyl MIDA boronate. We have demonstrated that these building blocks can be readily functionalized to provide a diverse range of products. Building on this theme, we developed a systematic approach for identifying additional recurring structural motifs present in natural products and transform them to a collection of MIDA boronate building blocks. As a case study for how this can be achieved, we have identified polyene natural products as an excellent opportunity for testing this concept. We identified a collection of just 12 bifunctional haloalkenyl MIDA boronate building blocks would be required to prepare the polyene motifs found in >75% of all polyene natural products that have ever been isolated. Applying this same approach to other classes of small molecule natural products, pharmaceuticals, and materials has the potential to provide a roadmap towards a universal approach to the synthesis of small molecules and expedite access to their functions.

Graduation Semester

2013-05

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Copyright 2013 Eric Woerly

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