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

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.

SUBMITTER: Lindman J

PROVIDER: S-EPMC9476516 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Lindman Jens J Gopalan Greeshma G Palo-Nieto Carlos C Brandt Peter P Gising Johan J Larhed Mats M

ACS omega 20220826 36

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 wa ...[more]

PMID: 36120037

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