Synthesis of 4-Acetylisocoumarin:  First Total Syntheses of AGI-7 and Sescandelin

Abstract

A practical synthetic route to 4-acetylisocoumarins and the first total synthesis of AGI-7 (5) and sescandelin (4) are described. The readily available homophthalate 8 was transformed to the vinylogous amide ester 13 in high overall yield. Upon treatment of 13 with refluxing aqueous formic acid, the desired 4-acetylisocoumarin (5) and its regioisomer 3-methyl-4-formylisocoumarin (17) were produced in a 3:1 ratio. After separation of the desired product (5) from the unwanted minor isomer, the enantioselective reduction of AGI-7 by borane in the presence of Corey's (S)-oxazaborolidine reagent afforded (+)-sescandelin (4) with a 93% ee.

Biologically Active Metabolites from Fungi, 19: New Isocoumarins and Highly Substituted Benzoic Acids from the Endophytic Fungus,ScytalidiumSP.

“…The alcohol 8 is closely related to the isocoumarin sescandelin B, isolated by Kimura et al [8] and recently synthesized by Kim et al [9], missing only the methyl group at C-5. On the other hand, there is also a close biosynthetic relationship of the hydroxymethyl isocoumarin 8 with the acetyl compound 7, isolated by our group from another endophytic fungus, Mycelia sterila [7].…”

8-Hydroxy-3,4-dimethylisocoumarin

“…It has been widely studied and synthesized as an antifungal and anticancer agent (e.g. Kim et al, 2002;Agata et al, 2000;Sonnenbichler et al, 1993;Singh & Singh, 1988;Nozawa et al, 1981;Chatterjea et al, 1980;Nakajima et al, 1976).…”

Regioselective Synthesis of 4‐(Arylsulfanyl)‐2‐hydroxyhomophthalates by [4+2] Cycloaddition of 3‐(Arylsulfanyl)‐1‐(trimethylsilyloxy)buta‐1,3‐dienes with Dimethyl Penta‐2,3‐dienedioate

“…. This methodology was successfully applied to the synthesis of an analogue of lactonamycin [6], of the N 7 -C 25 fragment of psymberin [7], and of the 4-acetylisocoumarins AGI-7 and sescandelin [8]. Herein, we report what are, to the best of our knowledge, the first [4 þ 2] cycloadditions of 3-(arylsulfanyl)-1-(trimethylsilyloxy)buta-1,3-dienes with dimethyl penta-2,3-dienedioate.…”