Total synthesis of phorbaketal A and its analogues

Abstract

Phorbaketal A and derivatives were isolated by Rho et al. in 2009 from the Korean marine sponge Phorbas sp. and it exhibits cytotoxicity against human colorectal, hepatoma, and lung cancer cell lines. Phorbaketal A exhibit positive activity on calcium deposition test such as Alisarin Red assay. Therefore, the Phorbaketal A can be a drug lead for osteophorosis. The total synthesis of Phorbaketal A can contribute to the key pathway of the synthesis of analogues for SAR study. Phorbaketal A possesses an unprecedented structure that is novel spiro[5,5]ketal fused to a hydrobenzopyran ring. Phorbasone A and related compounds were also isolated by Rho et al. in 2011 from the same marine sponge. Since Phorbaketals and Phorbasones have unprecedented structural features through an interesting biosynthetic pathway as well as interesting bio-logical activities, we became interested in the total synthesis of these natural products.We envisioned that the total synthesis of Phorbaketal A can be achieved through Au mediated cy-clization reaction of the precursor readily prepared from (R)-Carvone and Geraniol. The key step of this syn-thesis is Au(I) catalyzed intramolecular cyclization of diol and internal alkyne. The internal alkyne is activat-ed by the Au(I) catalyst and then, an alcohol attacks the alkyne. The resulting enol ether is activated by acid and then, the other alcohol attacks the activated carbon to synthesize spiroketal structure. The alkyne-diol key intermediate was synthesized by coupling of two fragments derived from (R)-Carvone and Geraniol us-ing Cu(I) catalyzed Sonogashira reaction. Another key strategy is selective oxidation of the exo olefin at B ring. This can be achieved by alcohol induced epoxidation after the coupling reaction. The free alcohol from the Carvone fragment is used for this reaction. Through these reactions, we can achieved the first total syn-thesis of Phorbaketal A very efficiently.