Diastereoselective Synthesis of N-Methylspiroindolines by Intramolecular Mizoroki-Heck Annulations

Jens Lindman; Greeshma Gopalan; Carlos Palo-Nieto; Peter Brandt; Johan Gising; Mats Larhed

doi:10.1021/acsomega.2c04111

Diastereoselective Synthesis of N-Methylspiroindolines by Intramolecular Mizoroki-Heck Annulations

ACS Omega. 2022 Aug 26;7(36):32525-32535. doi: 10.1021/acsomega.2c04111. eCollection 2022 Sep 13.

Authors

Jens Lindman¹, Greeshma Gopalan¹, Carlos Palo-Nieto¹, Peter Brandt¹, Johan Gising¹, Mats Larhed¹

Affiliation

¹ Department of Medicinal Chemistry, Uppsala University, Husargatan 3, SE-751 23 Uppsala, Sweden.

Abstract

Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki-Heck annulation reaction from (+)-Vince lactam-derived cyclopentenyl-tethered 2-bromo-N-methylanilines for the formation of N-methylspiroindolines. A series of 14 N-methylspiroindolines were synthesized in 59-81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected.