Natural Product Synthesis Enabled by Radical-Polar Crossover Reactions

Abstract

Radical-polar crossover (RPC) chemistry is an emerging field characterized by transformations that involve the coexistence of both radical and ionic species. Since the reactivities of radical and ionic intermediates are orthogonal, applying these two mechanisms in sequence provides significant advantages in the construction of complex molecular architectures. The concept of the RPC approach has become increasingly important in the total synthesis of natural products. This Synopsis presents several examples to showcase recent advancements in this area, including our research on the synthesis of Ganoderma meroterpenoids. In these selected cases, RPC reactions enhance the building of structural complexity and improve overall synthetic efficiency that cannot be achieved by standard synthetic methods.

Figure 1

Radical-polar crossover (RPC) logic.

Scheme 1. Sartillo-Piscil Synthesis of (+)-Cephalosporolide E (2015)

Scheme 2. Inoue Three-Component Cascade (2013)

Scheme 3. Inoue Three-Component Cascade with α-Alkoxyacyl Tellurides (2015)

Scheme 4. Inoue Three-Component Cascade Towards the Cladiellins Ring System (2019)

Scheme 5. Magauer Synthesis of Ganoapplanin (2024)

Scheme 6. Li Collective Synthesis of Macrocalyxoformin A-B and Ludongnin C (2024)

Scheme 7. Pronin Synthesis of (−)-Nodulisporic Acid C (2018)

Scheme 8. Pronin Synthesis of Forskolin (2019)

Scheme 9. Pronin Synthesis of Quassin (2022)

Scheme 10. Vanderwal Annulation Cascade (2023)

Scheme 11. Sartillo-Piscil Synthesis of (+)-Cephalosporolide F (2023)

Scheme 12. Heretsch Synthesis of Abifarine B and Spirochensilide B (2022)

Scheme 13. Magauer Synthesis of Lingzhiol (2024)