Bioinspired Total Synthesis of Penisuloxazin A

The first total synthesis of epidithiodiketopiperazine (ETP) alkaloid penisuloxazin A is described. The key steps of the synthesis involve the La(III)-mediated aldol reaction to construct a benzylic alcohol, which serves as the precursor for rearrangement. Subsequently, a bioinspired Lewis acid-catalyzed rearrangement reaction facilitates sulfur migration, forming the 6/5/6 spiro-benzofuran ring system with an irregular α-β' disulfide skeleton. This synthesis produces penisuloxazin A in 14 steps from inexpensive, available materials. The method could be a general strategy for making irregular α-β' disulfide bridge ETPs, especially those with hydroxamic acids.