Total Synthesis of Mallotusinin

The total synthesis of mallotusinin, which bears a tetrahydroxydibenzofuranoyl (THDBF) bridge between the 2‐oxygen and 4‐oxygen of glucose on corilagin with a 3,6‐O‐(R)‐hexahydroxydiphenoyl (HHDP) bridge, is described. The key features of the total synthesis are: 1) improvements of our previously reported method to synthesize corilagin; 2) establishment of the THDBF skeleton via an unusual intramolecular SNAr reaction of an HHDP analogue, and 3) the application of a two‐step bislactonization strategy for a HHDP bridge construction into the 2,4‐O‐THDBF bridge. Oxidative phenol coupling of 1,2,4‐orthoacetyl‐3,6‐di‐(4‐O‐benzylgalloyl)‐α‐d‐glucopyranose and the orthoester cleavage of the coupling product without the pyranose‐furanose ring transformation are key reactions for the improved synthesis of corilagin, which enabled the adequate supply of a corilagin precursor that was required to develop the mallotusinin synthesis. These established methods are expected to help develop the synthesis of other ellagitannins with a bridge between the two oxygens of corilagin. Synthesis of mallotusinin: The total synthesis of mallotusinin via the second‐generation synthesis of corilagin is described. The key steps are as follows: 1) oxidative phenol coupling of 1,2,4‐orthoacetyl‐3,6‐di‐(4‐O‐benzylgalloyl)‐α‐d‐glucopyranose; 2) orthoester cleavage along with thioglycosylation followed by β‐selective glycosyl esterification; and 3) two‐step bislactonization to construct a 2,4‐O‐tetrahydroxydibenzofuranoyl bridge on corilagin.