Natural Product Synthesis through the Lens of Informatics.

Retrosynthetic analysis emerged in the 1960s as a teaching tool with profound implications. Its educational value can be appreciated by a glance at total synthesis manuscripts over 50 years later, most of which contain a retrosynthesis on page one. Its vision extended to computer language-a pioneering idea in the 20th century that continues to expand the frontiers today. The same principles that guide a student to evaluate, expand, and refine a series of bond dissections can be programmed, so that computer assistance can perform the same tasks but at faster speeds.The slow step in the synthesis of complex structures, however, is seldom route design. Compression of molecular information into close proximity (/Å) requires exploration and empiricism, a close connection between theory and experiment. Here, retrosynthetic analysis guides the choice of experiment, so that the most simplifying-but often least assured-disconnection is prioritized: a high-risk, high reward strategy. The reimagining of total synthesis in a future era of retrosynthetic software may involve, counterintuitively, target design, as discussed here.Compared to the 1960s, retrosynthetic analysis in the 21st century finds itself among computers of unimaginable power and a biology that is increasingly molecular. Put together, the logic of retrosynthesis, the insight of structural biology, and the predictions of computation have inspired us to imagine an integration of the three. The synthetic target is treated as dynamic-a constellation of related structures-in order to find the nearest congener with the closest affinity but the shortest synthetic route. Such an approach merges synthetic design with structural design toward the goal of improved access for improved function.In this Account, we detail the evolution of our program from its inception in traditional natural product (NP) total synthesis to its current expression through the lens of chemical informatics: a view of NPs as aggregates of molecular parameters that define single points in a chemical space. Early work on synthesis and biological annotation of apparent metal pool binders and nonselective covalent electrophiles (asmarine alkaloids, isocyanoterpenes, dimers) gave way to NPs with well-defined protein targets. The plant metabolite salvinorin A (SalA) potently and selectively agonizes the κ-opioid receptor (KOR), rapidly penetrates the brain, and represents an important lead for next-generation analgesics and antipruritics. To synthesize and diversify this lead, we adopted what we now call a dynamic approach. Deletion of a central methyl group stabilized the SalA scaffold, opened quick synthetic access, and retained high potency and selectivity. The generality of this idea was then tested against another neuroactive class. As an alternative hypothesis to TrkB channels, we proposed that the so-called "neurotrophic" terpenes may bind to γ-aminobutyric acid (GABA)-gated ion channels to cause weak, chronic excitation. Syntheses of (-)-jiadifenolide, 3,6-dideoxy-10-hydroxypseudoanisatin, (-)-11-debenzoyltashironin, (-)-bilobalide, and (-)-picrotoxinin (PXN) allowed this hypothesis to be probed more broadly. Feedback from protein structure and synthetic reconnaissance led to a dynamic retrosynthesis of PXN and the identification of 5MePXN, a moderate GABAR antagonist with greater aqueous stability available in eight steps from dimethylcarvone. We expect this dynamic approach to synthetic target analysis to become more feasible in the coming years and hope the next generation of scientists finds this approach helpful to address problems at the frontier of chemistry and biology.