Drugs are discovered through the biological screening of collections of compounds, followed by optimization toward functional endpoints. The properties of screening collections are often balanced between diversity, physicochemical favorability, intrinsic complexity and synthetic tractability. 1 Whereas natural product (NP) collections excel in the first three attributes, NPs suffer a disadvantage on the last point. Academic total synthesis research has worked to solve this problem by devising syntheses of NP leads, diversifying late-stage intermediates or derivatizing the NP target. This work has led to the discovery of reaction mechanisms, the invention of new methods and the development of FDA-approved drugs. Few drugs, however, are themselves NPs; instead NP-analogs predominate. Here we highlight past examples of NP analog development and successful NP-derived drugs. More recently, chemists have explored how NP analogs alter the retrosynthetic analysis of complex scaffolds, merging structural design and synthetic design. This strategy maintains the intrinsic complexity of the NP but can alter the physicochemical properties of the scaffold, like core instability that renders the NP a poor chemotype. Focused libraries based on these syntheses may exclude the NP but maintain the molecular properties that distinguish NPspace from synthetic space, 2 properties that have statistical advantages in clinical progression. 3,4 Research that expedites synthetic access to NP-motifs can prevent homogeneity of chemical matter available for lead discovery. Easily accessed, focused libraries of NP scaffolds can fill empty but active gaps in screening sets and expand the molecular diversity of synthetic collections.

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A strategy to control the diastereoselectivity of bond formation at a prochiral attached‐ring bridgehead is reported. An unusual stereodivergent Michael reaction relies on basic vs. Lewis acidic conditions and non‐covalent interactions to control re‐ vs. si‐ facial selectivity en route to fully substituted attached‐rings. This divergency reflects differential engagement of one rotational isomer of the attached‐ring system. The successful synthesis of an erythro subtarget diastereomer ultimately leads to a short formal synthesis of merrilactone A.