Synthesis of Amphidinolide P

Key words

sp-sp² coupling - ruthenium - macrolactonization

Significance

Amphidinolide P is a cytotoxin isolated from the symbiotic dinoflagellates of the genus Amphidinium sp. found in the Okinawan flatworm Amphiscolops sp. Trost and co-workers use a highly chemo- and regioselctive Ru-catalyzed alkene-alkyne coupling reaction to construct the backbone of the natural product and disclose the first example of the use of a β-lactone as a ‘thermodynamic spring’ in macrolactonization.

Comment

The readily available fragments C and D undergo Ru-catalyzed alkene-alkyne coupling to give the 1,4-diene E comprising of the entire backbone of the natural product. A Sharpless asymmetric epoxidation of E gave the epoxide F that underwent macrolactonization upon treatment with Otera’s catalyst 1 to give the adduct G. Treating H with catalyst 1 effected a macrolactonization/hemiacetal forming reaction to give Amphidinolide P.