Total Synthesis of (±)-Liphagal via Organic-Redox-Driven Palladium-Catalyzed Hydroxybenzofuran Formation

Abstract

A synthetic route to liphagal, a natural PI3Kα inhibitor isolated from Aka coralliphaga, was established. The present route features an organic redox process where an alkynylquinone undergoes reductive cyclization in the presence of a hydroquinone derivative such as hydroxyquinol (1,2,4-benzenetriol) and catalytic PdCl2 to provide a substituted benzofuran suitable for accessing the natural product. The benzofuran formation takes place via the redox transformation between the alkynylquinone and the electron-rich hydroquinones followed by the concomitant Pd­(II)-catalyzed oxycyclization of the resultant alkynylhydroquinone.

Organic redox cascade cyclization of 2-alkynylquinones by ascorbic acid in combination with a copper catalyst and its application to formal synthesis of liphagal

“…2 We recently reported the synthesis of (±)-liphagal, which features a quinone (Q)-hydroquinone (HQ) organic redox-driven palladium-catalyzed cyclization of alkynylquinone derivative 1 (Scheme 1). 3…”

“…The screening revealed that PdCl 2 (0.1 equiv. ), a suitable catalyst for the Q-HQ redox cascade cyclization in our previous study, 3 provided hydroxybenzofuran 6a 6 in 4% yield (Table 1, entry 1). FeCl 2 , CoCl 2 , NiCl 2 , and ZnCl 2 were incompatible with the present organic redox reaction, leading to low yields of 6a (Table 1, entries 2, 4 and 5) or no cyclized product (Table 1, entry 3).…”

“…Next, we turned our attention to the substrate scope (Table 3). Alkynylquinones 5b to 5i , which were prepared by our previously reported protocol (ESI†), 3 were exposed to CuCl 2 ·2H 2 O (0.1 equiv. ), ascorbic acid (1.2 equiv.…”

“…Upon having established the redox cyclization process using an ascorbic acid/CuCl 2 ·2H 2 O/Cs 2 CO 3 reagent system that enables benzofuran formation, we shifted our attention to its application to the formal synthesis of liphagal (Scheme 5). In this context, because our previous approach required nine steps from homogeraniol to alkynylquinone 1 , 3 we endeavored to design an alternative route with fewer chemical manipulations to access key intermediate 1 . For this purpose, ( E )-geranylacetone ( 8 ) used as the starting material was alkynylated with ethynylmagnesium bromide in THF at −30 °C to furnish propargylic alcohol 9 in 84% yield.…”

“…2 We recently reported the synthesis of (AE)-liphagal, which features a quinone (Q)-hydroquinone (HQ) organic redox-driven palladium-catalyzed cyclization of alkynylquinone derivative 1 (Scheme 1). 3 The key transformation involves a redox cascade reaction of the alkynylquinone, in which a quinone reduction by a hydroquinone derivative such as 1,2,4-benzenetriol (4) is followed by a palladium(II)-catalyzed oxycyclization to produce a hydroxybenzofuran motif (1 -2 -3). This discovery inspired us to further develop a new reagent system that enables the organic redox cascade cyclization of alkynylquinones, thereby expanding the scope of the redox chemistry in organic synthesis.…”