Metal–Hydrogen Atom Transfer (MHAT)-Initiated Intramolecular Giese Reactions in Total Synthesis

The use of metal–hydrogen atom transfer (MHAT) for olefin hydrofunctionalization has received great attention over the last 20 years, primarily due to its enhanced chemoselectivity and regioselectivity.^[1] The Giese reaction, or the addition of a carbon-centered radical into an electron-deficient alkene, is well-known and has been commonly employed for C–C bond formation over the last 40 years.^[2] More recently, the Baran group coupled these two methodologies to establish a powerful tool for the reductive cross-coupling of electronically-differentiated olefins with propitious application in the context of total synthesis.^[3]

This strategy was used by the Pronin group in 2022 to construct the tricyclic scaffold essential to their synthesis of pleuromutilin.^[4] The Boger group, a pioneer in the MHAT-mediated hydrofunctionalization of olefins, implemented Baran’s conditions late in the enantioselective synthesis of (–)-pseudocopsinine in 2020.^[5] Lastly, the synthesis of (–)-daphnezomines A and B was accomplished by the Li group using this strategy as the penultimate step.^[6]

Overall, the application of this strategy in the context of total synthesis will be emphasized. Its broad scope allows its implementation as a lynchpin at the beginning of a synthesis, while its mild conditions (i.e., functional group tolerance) present it as an option for chemoselective late-stage hydrofunctionalization.

References

^[1] Z. Ma, Org. Chem. Front. 2021, 8, 750

^[2] B. Giese, Angew. Chem. Int. Ed. 1983, 22, 753

^[3] P. Baran, Nature 2014, 516, 343

^[4] S. Pronin, J. Am. Chem. Soc. 2022, 144, 10174

^[5] D. Boger, J. Org. Chem. 2020, 85, 14817

^[6] C. Li, J. Am. Chem. Soc. 2020, 142, 15240