Concise Total Synthesis of Enigmazole A. Issue 4 (10th December 2015)

• Record Type: Journal Article
• Authors: Ahlers, Andreas; de Haro, Teresa; Gabor, Barbara; Fürstner, Alois
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 4(2016)
• Page Start: 1406
• Page End: 1411
• Publication Date: 2015-12-10
• Subjects: alkynes -- gold -- metathesis -- natural products -- transannular reactions; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201510026
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: An efficient entry into the phosphorylated marine macrolide enigmazole A is described. Enigmazole A interferes with c‐Kit signaling by an as yet unknown mode of action and is therefore a potential lead in the quest for novel anticancer agents. Key to success is a gold‐catalyzed cascade comprising a [3, 3]‐sigmatropic rearrangement of a propargyl acetate along the periphery of a macrocyclic scaffold, followed by a transannular hydroalkoxylation of the resulting transient allenyl acetate. This transformation mandated the use of a chiral gold catalyst to ensure a matching double‐asymmetric setting. Other noteworthy steps are the preparation of the oxazole building block by a palladium‐catalyzed C−H activation, as well as the smooth ring‐closing alkyne metathesis of a diyne substrate bearing a propargylic leaving group, which has only little precedent. Abstract : Within reach : A gold‐catalyzed cascade of remarkable complexity paved the way to the parent phosphorylated macrolide of the enigmazole family, which exhibits a highly promising but not yet well‐understood biological profile. Only if the π‐acid itself is chiral, however, was the [3, 3]‐sigmatropic rearrangement complete before the hydroxy group reached across the macrocyclic ring.