Total Synthesis of Paspaline A and Emindole PB Enabled by Computational Augmentation of a Transform-Guided Retrosynthetic Strategy

We
report the total syntheses of two indole diterpenoid natural
products, paspaline A and emindole PB. Paspaline A is synthesized
in a 9-step sequence from commercially available materials. The first
total synthesis of emindole PB is accomplished in 13 steps and confirms
a previously ambiguous structural assignment. Density functional theory
calculations are utilized to interrogate the key carbocationic rearrangement
in a predictive capacity to aid in the selection of the most favorable
precursor substrate. This work highlights how retrosynthetic design
can be augmented with quantum chemical calculations to reveal energetically
feasible synthetic disconnections, minimizing time-consuming and expensive
empirical evaluation.