Development of an Allenyne-Alkyne [4+2] Cycloaddition and its Application to Total Synthesis of Selaginpulvilin A

Abstract

A new [4+2] cycloaddition of allenyne-alkyne is developed. The reaction is believed to proceed with forming an α,3-dehydrotoluene intermediate. This species behaves as a σπ-diradical to react with a hydrogen atom donor, whereas it displays a zwitterionic reactivity toward weak nucleophiles. The efficiency of trapping α,3-dehydrotoluene depends not only on its substituents but also the trapping agents. Notable features of the reaction are the activating role of the extra alkyne of the 1,3-diyne that reacts with the allenyne moiety and the opposite mode of trapping with oxygen and nitrogen nucleophiles. Oxygen nucleophiles result in the oxygen-end incorporation at the benzylic position of the α,3-dehydrotoluene, whereas with amine nucleophiles the nitrogen-end is incorporated into the aromatic core. Relying on the allenyne-alkyne cycloaddition as an enabling strategy, a concise total synthesis of phosphodiesterase-4 inhibitory selaginpulvilin A is realized.

Keywords: allenyne; cycloaddition; cycloaromatization; selaginpuvilin A; α,3-dehydrotoluene.

Scheme 1

The relationship between the Myers–Saito cyclization and the allenyne‐alkyne [4+2] cycloaddition.

Scheme 2

Reversal of the zwitterionic polarity of α,3‐dehydrotoluene in trapping with oxygen and nitrogen nucleophiles and the diradical reactivity toward a hydrogen donor.

Scheme 3

Total synthesis of selaginpuvilin A.