The diverse molecular
architectures of terpene natural products are assembled by exquisite
enzyme-catalyzed reactions. Successful recapitulation of these transformations
using chemical synthesis is hard to predict from first principles and therefore
challenging to execute. A means of evaluating the feasibility of such chemical
reactions would greatly enable the development of concise syntheses of complex
small molecules. Herein, we report the computational analysis of the energetic
favorability of a key bio-inspired transformation, which we use to inform our
synthetic strategy. This approach was applied to synthesize two constituents of
the historically challenging indole diterpenoid class, resulting in a concise
route to (–)-paspaline A in 9 steps from commercially available materials and the first pathway
to and structural confirmation of emindole PB in 13 steps. This work highlights
how traditional retrosynthetic design can be augmented with quantum chemical
calculations to reveal energetically feasible synthetic disconnections,
minimizing time-consuming and expensive empirical evaluation.