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Abstract

The architecture and bioactivity of natural products frequently serve as an embarkation point for the exploration of biologically-relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships (SAR). However, synthetic strategies toward a natural product are not always guided by hypotheses regarding minimal structural features required for bioactivity i.e. a proposed ‘pharmacophore’. Building on Wender’s notions of function-oriented synthesis, we recently developed an approach to natural product total synthesis that we term ‘pharmacophore’-directed retrosynthesis (PDR). In this strategy, a hypothesized, minimal ‘pharmacophore’ of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application for a natural product with an unknown cellular target(s), sequential increases in structural complexity of this minimal ‘pharmacophore’ enables development of an SAR profile throughout the course of the total synthesis effort. Importantly, this approach has the potential to identify simpler congeners retaining bioactivity at a much earlier stage of a total synthesis effort while also informing attachment points for probes for cellular target identification. To date, we have applied this approach to gracilin A, ophiobolin A  and rameswaralide. Selected ongoing examples of PDR in the Romo lab, enabled by fruitful biological collaborations, will be described.