Simplified immunosuppressive and neuroprotective agents based on gracilin A

The architecture and bioactivity of natural products frequently serves as an embarkation point for exploration of biologically-relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies toward a natural product are not always guided by hypotheses regarding structural features required for bioactivity. Here we report an approach to natural product total synthesis that we term ‘pharmacophore-directed retrosynthesis’. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in structural complexity of this minimal structure enables development of an SAR profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort as demonstrated herein for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.