Graduate Student Josie Rojo

"Skeletal Editing: Moving atoms in and out of a molecule’s core"

Methods for peripheral modification of a lead compound in drug delivery and other applications have already been well established[1]. However, the methods to edit the core structure of a molecule after it has been fully functionalized are still not well developed[2]. The reactions that afford the modification of skeletal structure of a functionalized molecule are known as skeletal editing. The three major reactions that operate to enable skeletal editing are atom insertion, atom deletion, and atom swapping. Levin’s group was able to develop a method that enabled a one-pot reaction of a secondary amine with an anomeric amide reagent to form an intermediate with a known N2 extrusion activity, consequently forming a product containing one atom less than the starting material. On the other hand, Morandi’s work presented an example that utilizes nitrogen insertion in an indole substrate to promote ring expansion[3]. They proved that protected indole reacts with an electrophilic nitrogen source to form an intermediate that can then undergo ring opening and subsequent elimination to form the ring-expanded product, the quinazoline or quinoxaline. Finally, the group of Li successfully proved for the first time that nonheteroaryl lactones, such as dibenzolactones, can undergo decarbonylative C-O bond-forming reactions to convert lactones into cyclic ether in the presence of a Ni(0) catalyst and a bulky phosphine ligand[4].

References:
[1] Guillemard, L.; Kaplaneris, N.; Ackermann, L.; Johansson, M.J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 2021, 5, 522–545.
[2] Kennedy, S.H.; Dherange, B.D.; Berger, K.J.; Levin, M.D. Skeletal editing through direct nitrogen deletion of secondary amines. Nature. 2021, 593, 223– 227.
[3] Reisenbauer, J.C.; Green, O.; Franchino, A.; Finkelstein, P.; Morandi, B. Late-stage diversification of indole skeletons through nitrogen atom insertion. Science. 2022, 377, 1104–1109.
[4] Luu, Q.H.; Li, J. A C-to-O atom-swapping reaction sequence enabled by Ni-catalyzed decarbonylation of lactones. Chem. Sci. 2022, 13, 1095–1100.