Synthesis of 10b(R)-hydroxypancratistatin, 10b(S)-hydroxy-1-epipancratistatin, 10b(S)-hydroxy-1,2-diepipancratistatin and related isocarbostyrils

Narciclasine (2) was transformed by a series of reactions where Sharpless asymmetric hydroxylations served as the stereochemical controlling step to 10b(R)-hydroxypancratistatin (3), 10b(S)-hydroxy-1-epipancratistatin (13) and 10b(S)-hydroxy-1,2-diepipancratistatin (16). Synthesis of 10b(S)-hydroxy-1,2-diepipancratistatin (16) proceeded from α-triol (11) via cyclic sulfate (14) and inversion of C-2 with cesium benzoate followed by saponification and treatment with a catalytic amount of acid. Compared to pancratistatin (1), these structural modifications led to decreased cancer cell growth inhibition against a minipanel of human cancer cell lines. Narciclasine (2) inhibited the pathogenic yeast Cryptococcus neoformans, and modifications (4, 14 and 15) inhibited growth of the pathogenic bacterium Neisseria gonorrhoeae.