A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural Products Spicifernin and Pulvilloric Acid

• Published in: Journal of the American Chemical Society Vol. 131; no. 32; pp. 11350 - 11352
• Main Authors: Bender, Christopher F., Yoshimoto, Francis K., Paradise, Christopher L., Brabander, Jef K. De
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.08.2009; Amer Chemical Soc
• Subjects: Catalysis; Chemistry; Chemistry, Multidisciplinary; Molecular Structure; Penicillium - chemistry; Physical Sciences; Science & Technology; Silver - chemistry; Spiro Compounds - chemical synthesis; Stereoisomerism; ALCOHOLS; ORGANIC-SYNTHESIS; FUNGUS; BIOSYNTHESIS; BIOACTIVE METABOLITES; COCHLIOBOLUS-SPICIFER
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja905387r

We describe a concise synthesis of the structurally novel fungal extremophile metabolite berkelic acid, an effort leading to an unambiguous assignment of C22 stereochemistry. Our synthetic approach was inspired by the recognition that berkelic acid displays structural characteristics reminiscent of two other fungal metabolites, spicifernin and pulvilloric acid. Based on this notion, we executed a synthesis that features a Ag-catalyzed cascade dearomatization−cycloisomerization−cycloaddition sequence to couple two natural product inspired fragments. Notably, a spicifernin-like synthon was prepared with defined C22 stereochemistry in seven steps and three purifications (24−28% overall yield). A potentially useful anti-selective conjugate propargylation reaction was developed to introduce the vicinal stereodiad. An enantioconvergent synthesis of the other coupling partner, the aromatic precursor to pulvilloric acid methyl ester, was achieved in eight steps and 48% overall yield. The total synthesis of berkelic acid and its C22 epimer was thus completed in a 10 step linear sequence and 11−27% overall yield.