First Total Syntheses and Biological Evaluation of Both Antipodes 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 α-aminonitrile (a hydrolytically-stable surrogate for its corresponding hemiaminal) with chiral Lewis acid complexes. We have also reassigned the literature structures of (+)->1a–>1b—for those instances in which the NMR spectra were obtained in CD3OD—to their corresponding CD3O– adducts. Our efforts provide for the first time apoptosis data for (−)->3a, (+)->4a, and all five non-natural antipodes prepared. The data indicate high apoptotic activity regardless of the enantiomer or relative stereochemical configuration at C7 and C7′.