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Practical Organic Synthesis Inspired by Nature

Final Report Summary - POSIN (Practical Organic Synthesis Inspired by Nature)

Project Objectives:

The aim of this research is to use Nature as a source of inspiration and direction to improve and develop synthetic organic chemistry. Through targeted total syntheses I will investigate and learn about the highly sophisticated way Nature utilizes dimerizations to rapidly generate molecular complexity. I will demonstrate the power of this biomimetic strategy by synthesizing a wide variety of complex dimeric natural products including phenylethanoids, alkaloids, lignans, and coumarins. The expected outcome will be uniquely efficient synthetic strategies that significantly surpass all previous approaches and new synthetic methodology that will be of broad use in organic synthesis. More generally I will learn how Nature uses relatively simple processes to rapidly generate molecular complexity in a highly efficient manner. In summary the aim of our research is...

1. By mimicking proposed biological processes, devise new synthetic strategies and reactions that will be of broad use in organic synthesis.
2. Improve the science and art of total synthesis by developing short and efficient syntheses of structurally complex natural products.
3. Learn how nature successfully utilizes symmetry to synthesize highly complex molecules that contain no element of symmetry.
4. Provide experimental data that will either support or enable the modification of natural product structures and biosynthetic pathways.
5. Develop a deeper appreciation for the chemistry of life and acquire insight into the origin of natural products and the chemistry of their biosynthetic pathways.

Work Performed Since the Beginning of the Project:

Work has focused on achieving the chemical synthesis of several complex natural products and the development of the required methodology to enable those syntheses. Effort was primarily focused on the synthesis of the ramonanin lignan-dimers, the angiopterlactones, a dimeric thymol derivative, millingtonine, and incargranine A.

Main Results Achieved:

Several biomimetic total syntheses of highly complex natural products have been achieved. The chemical synthesis of the ramonanins A-D was achieved in 9 steps. The results from this purely chemical study supports a proposed spontaneous biosynthetic Diels–Alder dimerization process. This synthesis was published as a communication in Angewandte Chemie International Edition. The total synthesis of angiopterlactone B was achieved in 4 steps and resulted in revision of the proposed configuration of this natural product. This synthesis was published as a communication in Organic Letters, and was ranked as one of the most read papers in the month it was published. The total synthesis of thymarnicol was achieved in 6 steps and validated the biosynthetic proposal made by the isolation chemists. This synthesis was published as a communication in Angewandte Chemie International Edition, and was selected by the editors as a Hot Paper. The total synthesis of millingtonine was achieved in 7 steps, which is significantly shorter than the 12 steps taken in the only other reported synthesis. This synthesis was published as a communication in Angewandte Chemie International Edition, and was highlighted in SynFacts. The total synthesis of incargranine A was achieved in 4 steps and validated our unified biosynthetic proposal for an entire family of phenylethanoid natural products. This synthesis was published as an invited communication for a New Talent issue of Organic and Biomolecular Chemistry, and was selected by the editors as a Hot Paper. Our experience from these projects prompted us to prepare a review on the topic of biosynthetic considerations for natural product structure determination, which was published in Natural Product Reports.