Computer aided Total Synthesis of 25 Picrotoxanes (Li, Shenvi)
The usefulness of the 1,5 Hydrogen Atom Transfer (1,5-HAT) reaction was demonstrated by many total synthesis groups in the last decade. One example is the total synthesis of picrotoxinin in 2020 by the Shenvi group published in JACS. In a follow-up published 2024 in Nature, Ryan Shenvi and Chunyu Li introduced the synthesis of 25 other natural products from this scaffold. It was envisioned that the scaffold would be constructed from a common intermediate using the already established 1,5-HAT reaction. However, this concept was challenged by unproductive β-scission, depending on the electronic and steric environment.
To avoid a risky and lengthy trial-and-error process, Shenvi and Li decided to use in silico DFT calculations based on their experimental data from three previously used intermediates and one example from the literature. This approach guided the scaffold substitution and was then successfully implemented in the synthesis campaign for selected natural products such as coriamytrin and corianin.
A major drawback of this method was the computer resource-demanding nature of DFT calculations. To simplify the calculation load, Shenvi and Li defined parameters such as bond length and bond angles, which were assigned scores based on the initial DFT calculations. These values were then extrapolated onto a heat map, enabling much faster calculations of usable intermediates. This ultimately resulted in the synthesis of a total of 25 natural products accessible via this intermediate.
In conclusion, this work proved how computer-aided calculations can foster total synthesis projects. Although DFT calculations are intensive operations, the Shenvi group demonstrated that while they are necessary at the beginning, they can be avoided through careful use of this data. This concept has been successfully proven and yielded an impressive output of natural products.
Read more: Total synthesis of twenty-five picrotoxanes by virtual library selection 10.1038/s41586-024-08538-y
