Total Synthesis of Piericidin A1. Application of a Modified Negishi Carboalumination-Nickel-Catalyzed Cross-Coupling

Abstract

A total synthesis of the mitochondrial complex I inhibitor piericidin A1 is described. It features a unique strategy for the key disconnection, highlighting a modified Negishi carboalumination/Ni-catalyzed cross-coupling on a polyenyne precursor.

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress

“…This chemistry, for example, was independently exploited by Lipshutz 65 and Hosokawa and Tatsuta, 66 targeting piericidin A1 (123) and actinopyrone A (124), respectively (Scheme 21). In particular, both authors focused on preparation of intermediary polypropionate anti-aldol 122, which was accessed via TiCl 4 -promoted VMAR between ketene acetal ent-94 and tiglic aldehyde 121.…”

Carboalumination/Ni-catalyzed couplings. A short synthesis of verticipyrone

“…7 Coupling partners 4 and 5 are subsequently joined by a Ni-catalyzed cross-coupling. This approach mirrors our recent synthesis of piericidin A1 (3), 8 expanding the scope of this onepot coupling reaction to include chloromethylated pyrones. 9 The heterocyclic chloromethyl-c-pyrone coupling partner 4 was prepared in four steps from known diketoester 6 (Scheme 2).…”

The unique chemistry and biology of the piericidins

“…A vinylogous Mukaiyama aldol reaction generated the eight-carbon vicinal methyl/hydroxyl side chain framework. 44 This route, to the synthesis of piericidin A (1) in a total of 18 steps from commercial material, involves a longest linear sequence of 11 steps Piericidins from actinomycetes X Zhou and W Fenical from the N,O-silyl ketene acetal (Figure 10), which overall compares very favorably with the previous synthesis of piericidin A (1). [39][40][41] The total syntheses of the piericidin related natural products Mer-A2026B (22) and JBIR-02 (25) were reported in 2013 by Gademann's group.…”