Most such efforts are also accompanied by advances in synthetic organic chemistry, inspiring the development of new synthetic methodology and providing the supernatural products with improved synthetic accessibility. Some such improvements may be regarded by some as iterative enhancements whereas others, we believe, truly live up to their characterization as supernatural products. The design principles and approaches for creating the supernatural products are highlighted with an emphasis on the properties addressed that include those that improve activity or potency, increase selectivity, enhance durability, broaden the spectrum of activity, improve chemical or metabolic stability, overcome limiting physical properties, add mechanisms of action, enhance PK properties, overcome drug resistance, and/or improve in vivo efficacy. In the examples presented, the synthetic efforts provided supernatural products, a term first introduced by our colleague Ryan Shenvi ( Synlett, 2016, 27, 1145–1164), with properties superseding the parent natural product. Select and recent examples are detailed where the key structural changes are designed to improve defined properties or to overcome an intrinsic limitation of the natural product itself. The underlying studies highlight enabling divergent synthetic strategies and methods that permit the systematic medicinal chemistry studies of key analogues bearing deep-seated structural changes not readily accessible by semisynthetic or biosynthetic means.
This review presents select recent advances in the medicinal chemistry of complex natural products that are prepared by total synthesis.
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