The total syntheses of the alkaloids (-)-histrionicotoxin 259A, 285C and 285E

Abstract

The intramolecular nitrone dipolar cycloaddition of in situ-generated nitrones such as compound 26 has been used for the synthesis of cyclic isoxazolidines XX and XX. The regioselectivity of the intramolecular cycloaddition depends on the nature of the terminal substituent on the dipolarophile. The influence of the substituent on the regioselectivity of the cycloaddition has been examined using several model systems and two methods of nitrone formation. These studies demonstrated that the cyano-substituent plays a special role in favouring the formation of the (6,6,5)-ring fused adduct XX under thermodynamically controlled conditions. The utility of the cyclo-adduct XX9 (see Scheme 16) as a precursor for the naturally occurring histrionicotoxins is illustrated in the synthesis of three “unsymmetrical” (i.e. with each side chain bearing different functional groups) members of the histrionicotoxin family XX, XX and XX