Natural products have long held societal value as folk medicines, and even in this modern era, many FDA-approved drugs are still being derived from terpenes and alkaloids found in nature. Biomedical research has also benefited from natural products, as previously unknown mechanisms of action have been discovered while studying the unique biochemical pathways that these compounds undergo in the human body. Furthermore, endeavors in the total synthesis of these architecturally diverse compounds have continuously provided chemists with challenges, which in turn have led to the establishement of research programs in both academic and industrial environments. Ever since its inception, our laboratory has been pursuing, and has succeeded in, the total synthesis of iconic natural products in both the terpene and alkaloid families. These syntheses have identified gaps in the chemical literature, which we have subsequently addressed. The products of this research program-new synthetic strategies, unprecedented transformations and novel reagents-have in turn enabled the synthesis of even more natural products and pharmaceutically relevant motifs, thus completing a catalytic cycle of discovery. We seek to replicate this success with the current proposal: the described projects will target complex natural products to identify shortcomings in chemical methodology, while simultaneously devising methods of widespread interest, followed by the assessment of their practicality in the synthesis of complex molecules. This proposal is organized into three parts with the overarching goal of generating chemical knowledge that transcends the original objective of natural product synthesis. The first section delineates plans for late-stage oxidation to efficiently synthesize complex terpene and alkaloid natural products. The second portion of the proposal argues that electrochemistry can be a practical, inexpensive, non-toxic, and scalable solution to a variety of chemistry problems, wherein dimerization of N-H bonds for natural product synthesis, heteroarene fluorination for pharmaceutical development, and allylic oxidation for the functionalization of terpene-type frameworks are presented. Lastly, the third section illustrates the versatile reactivity of olefin-derived, carbon-centered radicals to forge C-C and C-N bonds that are otherwise impractical or impossible to create. The resulting procedures will be utilized in the construction of complex and sterically encumbered pharmaceutical motifs, which will serve to expand chemical space and accelerate discovery in medicinal chemistry. Notably, we have already established numerous collaborations to study the biological properties of the products that will be synthesized, to validate and field-test new methods, and to commercialize reagents for widespread adoption in both academic and industrial settings.
Natural products have traditionally served as platforms for the establishment of medicinal chemistry programs and as sources of inspiration for organic chemistry research. This proposal aims to invent methods in C-C, C-N, C-O and C-F bond formation, enabling the synthesis of terpene and alkaloid scaffolds, as well as other complex molecules of relevance to the pharmaceutical industry. These methods will benefit scientists in a variety of academic and industrial settings owing to their mildness, efficiency, low cost, versatility and practicality.
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| Wang, Jie; Lundberg, Helena; Asai, Shota et al. (2018) Kinetically guided radical-based synthesis of C(sp3)-C(sp3) linkages on DNA. Proc Natl Acad Sci U S A 115:E6404-E6410 |
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| Chu, Hang; Dünstl, Georg; Felding, Jakob et al. (2018) Divergent synthesis of thapsigargin analogs. Bioorg Med Chem Lett 28:2705-2707 |
| Peters, David S; Romesberg, Floyd E; Baran, Phil S (2018) Scalable Access to Arylomycins via C-H Functionalization Logic. J Am Chem Soc 140:2072-2075 |
| Knouse, Kyle W; deGruyter, Justine N; Schmidt, Michael A et al. (2018) Unlocking P(V): Reagents for chiral phosphorothioate synthesis. Science 361:1234-1238 |
| Yan, Ming; Kawamata, Yu; Baran, Phil S (2018) Synthetic Organic Electrochemistry: Calling All Engineers. Angew Chem Int Ed Engl 57:4149-4155 |
| Merchant, Rohan R; Oberg, Kevin M; Lin, Yutong et al. (2018) Divergent Synthesis of Pyrone Diterpenes via Radical Cross Coupling. J Am Chem Soc 140:7462-7465 |
| Kawamata, Yu; Yan, Ming; Liu, Zhiqing et al. (2017) Scalable, Electrochemical Oxidation of Unactivated C-H Bonds. J Am Chem Soc 139:7448-7451 |
| Trammell, Rachel; See, Yi Yang; Herrmann, Aaron T et al. (2017) Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C-H Bonds. J Org Chem 82:7887-7904 |
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