Total Synthesis of Anticancer Agent EBC-23

Abstract

Total synthesis of spiroketal EBC-23 has been described by two divergent approaches from three simple building blocks. Gold-catalyzed cycloisomerization of alkynol and acid-mediated spirocyclization of diketalketone were successfully utilized to effect spiroketal formation. A Cu(I)-P(Cy)3-catalyzed protocol for the highly regio- and stereocontrolled hydroboration of internal propargylic alcohol was effectively applied toward the β-hydroxy ketone via vinylboronates.

Gold‐Catalyzed Hydrofunctionalizations and Spiroketalizations of Alkynes as Key Steps in Total Synthesis

“…[90] Methanol turned out to be crucial for the reaction and an equimolar ratio of gold catalyst was applied (Scheme 23). [91] Scheme 20. Gold-catalyzed synthesis of the common intermediate of two natural products.…”

“…The acetonide subunit in precursor 64 enabled the selective formation of spiroketal building block 65 that was further transformed to anticancer agent EBC‐23, isolated in 2007 from the fruit of Cinnamomum laubatii (family Lauraceae) . Methanol turned out to be crucial for the reaction and an equimolar ratio of gold catalyst was applied (Scheme ) …”

Enantioselective Total Synthesis of (+)-EBC-23, a Potent Anticancer Agent from the Australian Rainforest

“…8 Yadav and co-workers recently reported the synthesis of EBC-23 utilizing gold-catalyzed spiroketalization of alkylnol as one of the key steps. 9 As part of our interests in exploration of chemistry and biology of EBC-family of natural products, we sought to develop a practical and convergent synthesis of EBC- one of the key reactions. The spiroketal bearing fused α,βunsaturated δ-lactone structural core was constructed in a onepot reaction from the isoxazoline-derived polyhydroxy ketone intermediate.…”

“…Yamamoto and co-workers reported an efficient synthesis of EBC-23 utilizing a supersilyl-aldol reaction as the key step . Yadav and co-workers recently reported the synthesis of EBC-23 utilizing gold-catalyzed spiroketalization of alkylnol as one of the key steps . As part of our interests in exploration of chemistry and biology of EBC-family of natural products, we sought to develop a practical and convergent synthesis of EBC-23 in an effort to facilitate the synthesis of structural variants.…”

Preparation of benzannulated spiroketals by gold(III) catalyzed spirocyclization of alkynyl diols

“…16 Due to these advantages, gold has been widely used for the synthesis of spiroketal natural products by intramolecular dihydroalkoxylation of alkynyl diols. 4,[17][18][19][20] This transformation has been achieved by simple gold salts such as AuCl [19][20][21] and AuCl3 12 , as well as Au(I) phosphine complexes 4,12,22 , a Au(I) NAC complex 23 and Au(I/III) NHC complexes. 24 As most naturally occurring spiroketals are chiral molecules with a stereogenic spirocentre, the syntheses of chiral spiroketals has attracted attention, targeting at high yields and high diastereo-and enantioselectivities under mild conditions.…”