Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids

摘要

Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)-6,6-dihydroxythiobinupharidine (+)-1a, (+)-6-hydroxythiobinupharidine (+)-1b, (-)-6,6-dihydroxythionuphlutine (-)-2a, (-)-6,6-dihydroxyneothiobinupharidine (-)-3a, and (+)-6,6-dihydroxyneothionuphlutine (+)-4a. The latter two have not been found in nature. We have also made each of their enantiomers (-)-1a-b, (+)-2a, (+)-3a, and (-)-4a. The key step in these syntheses was the dimerization of an -aminonitrile (a hydrolytically stable surrogate for its corresponding hemiaminal) with chiral Lewis acid complexes. We have also reassigned the literature structures of (+)-1a-1bfor those instances in which the NMR spectra were obtained in CD(3)ODto their corresponding CD3O-adducts. Our efforts provide for the first time apoptosis data for (-)-3a, (+)-4a, and all five non-natural enantiomers prepared. The data indicate high apoptotic activity regardless of the enantiomer or relative stereochemical configuration at C7 and C7.