Synthesis of (-)-Pyrenophorol

Abstract

Macrodiolide antibiotics, which possess interesting structural and biological properties are found in fungi and marine sponges. These macrodiolides are classified into two groups; one includes homodimers that consist of two identical units, and the other includes heterodimers that consist of two different units. Macrodiolides such as pyrenophorol (1), pyrenophorin (2), and vermiculine (3), which have 16membered rings are homodimeric macrodiolides, and macrocylic dilactones such as colletallol (4) and grahamimycin A1, which have 14-membered rings, are heterodimeric macrolides (Fig. 1). Analogs with various degrees of unsaturation such as tetrahydropyrenophorol (5) and dihydropyrenophorin (6), have also been reported. These naturally occurring macrodiolides show antifungal and anthelmintic activities. Pyrenophorol (1) is isolated from the fungi Byssochlamys nivea and Stemphylium radicinum. Pyrenophorin (2), an analog of pyrenophorol (1), is originated from the fungi Pyrenophora avenae and Stemphylium radicinum. These macrodiolides have attracted significant attention of synthetic chemists because of their interesting biological properties and structural features. Kibayashi, Zwanenburg, and, recently, Yadav have reported the synthesis of (–)pyrenophorol. For the preparation of the key intermediate, chiral 4-hydroxy-2-alkenoate, Zwanenburg group exploited the photo-induced rearrangement of the corresponding expoxy diazomethyl ketone. On the other hand, Kibayashi group, synthesized (−)-pyrenophorol using C2 symmetric (R,R)-diepoxide as a chiral building block. Recently, Yadav group synthesized (–)-pyrenophorol employing the hydrolytic kinetic resolution developed by Jacobson and the McMillan α-hydroxylation. In connection with our interests in the synthesis of natural products, we, herein, report the total synthesis of (–)pyenophorol (1). Our synthetic approach is based on the utilization of a chiral building block 8, which was used in our previous synthesis of ophiocerins (Scheme 1). The chiral building block 8, prepared from D-glucose, has the potential to be used as a versatile chiral synthon. As summarized in Scheme 2, the key starting chiral building block 8 was prepared from methyl α-D-glucopyranoside (9), which was prepared from α-D-glucose, in four steps. Regioselective reductive opening of the epoxide ring in 8 was the key step to establish the required stereocenter.