title: Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids.
abstract: Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)-6,6'-dihydroxythiobinupharidine (+)-1 a, (+)-6-hydroxythiobinupharidine (+)-1 b, (-)-6,6'-dihydroxythionuphlutine (-)-2 a, (-)-6,6'-dihydroxyneothiobinupharidine (-)-3 a, and (+)-6,6'-dihydroxyneothionuphlutine (+)-4 a. The latter two have not been found in nature. We have also made each of their enantiomers (-)-1 a-b, (+)-2 a, (+)-3 a, and (-)-4 a. 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 (+)-1 a-1 b—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 (-)-3 a, (+)-4 a, 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'.
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 (United States).
authors.forename: Alexander
authors.initials: A
authors.lastname: Korotkov
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 (United States).
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Lebanon, New Hampshire 03756 (United States).
authors.forename: Charles W
authors.initials: CW
authors.lastname: Chapman
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 (United States).|Natural Products LINCHPIN Laboratory, Texas A&M University, College Station, Texas, 77840 (United States).
authors.forename: Haoran
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, 75390 (United States). john.macmillan@utsouthwestern.edu.
authors.forename: John B
authors.initials: JB
authors.lastname: MacMillan
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Lebanon, New Hampshire 03756 (United States). alan.r.eastman@dartmouth.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 (United States). jimmy.wu@dartmouth.edu.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Wu
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D019281:Dimerization; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids
keywords: apoptosis; cancer; caspases; nuphar alkaloids; total synthesis