Natural Product Synthesis through the Lens of Informatics

Abstract

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 (C_m/ų) 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, Nuphar 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" Illicium 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-O-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 GABA_AR 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.

Figure 1.

Abstract visualizations of chemical space. a. NPs (•), drugs (•) and commercial building blocks (•) differentiated by ChemGPS using a unique parameterization of chemical space. Adapted with permission from ref. . Copyright 2007 Swiss Chemical Society. b. Different methods to navigate from commercial building blocks to complex molecule space using chemical synthesis.

Figure 2.

Synthetic methods enabled total syntheses, which illuminated biological MOA associated with the asmarines, Nuphar thiaspiranes and isocyanoterpenes.

Figure 3.

Retrosynthetic analysis of SalA identified a common feature (C20 methyl) that destabilized the target, destabilized intermediates and obstructed synthesis; its deletion improved the target and maintained binding.

Figure 4.

Evaluation of 20norSalA, which fulfills the direct goals and fringe benefits of total synthesis.

Figure 5.

Conceptualization of both static and dynamic retrosynthetic analysis as movement through chemical space. A. Viewing NPs as clusters of related structures in chemical space; B. Viewing the relationships between nodes as transforms (Tf.); C. As in traditional retrosynthetic analysis, a Tf. can alter retrosynthetic paths. D. Dynamic analysis constrains the transform by function rather than reactivity.

Figure 6.

Dissection of the Illicium terpenes via an unorthodox attached ring coupling.

Figure 7.

Butenolide heterocoupling: driving forces and applications to cGAS/STING inhibitors and terpenes.

Figure 8.

An alternative hypothesis to explain neurotrophic effects of the Illicium terpenes. Figure of “calcium set-point hypothesis” reproduced with permission from ref . Copyright 1992 Elsevier.

Figure 9.

High oxidation-state building blocks (Gasteiger partial charges in red) merged to access complex antagonists (C_m in black) of GABA_AR, a combinatorial receptor.

Figure 10.

Me-addition to PXN increases complexity (ΔC_m = +12) but shortens the synthetic route, providing a robust supply of a complex GABA_AR antagonist (5MePXN) with improved stability towards hydrolysis.