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

Alexander Korotkov, Hui Li, Charles W. Chapman, Haoran Xue, John B. Macmillan, Alan Eastman, Jimmy Wu

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)-6,6′-dihydroxythiobinupharidine (+)-1a, (+)-6-hydroxythiobinupharidine (+)-1-b, (-)-6,6′-dihydroxythionuphlutine (-)-2-a, (-)-6,6′-dihydroxyneothiobinupharidine (-)-3a, and (+)-6,6′-dihydroxyneothionuphlutine (+)-4-a. 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 (+)-1-a-1b - for those instances in which the NMR spectra were obtained in CD<inf>3</inf>OD - to their corresponding CD<inf>3</inf>O-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′. Nuphars are speedy killers: For the first time several of the hydroxylated dimeric nuphar alkaloids and their unnatural enantiomers have been synthesized. First-ever apoptosis data for many of these compounds is provided.

Original languageEnglish (US)
Pages (from-to)10604-10607
Number of pages4
JournalAngewandte Chemie - International Edition
Volume54
Issue number36
DOIs
StatePublished - Sep 1 2015

Fingerprint

Alkaloids
Enantiomers
Cell death
Apoptosis
Lewis Acids
Dimerization
Nuclear magnetic resonance
Acids

Keywords

  • apoptosis
  • cancer
  • caspases
  • nuphar alkaloids
  • total synthesis

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

Cite this

Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids. / Korotkov, Alexander; Li, Hui; Chapman, Charles W.; Xue, Haoran; Macmillan, John B.; Eastman, Alan; Wu, Jimmy.

In: Angewandte Chemie - International Edition, Vol. 54, No. 36, 01.09.2015, p. 10604-10607.

Research output: Contribution to journalArticle

Korotkov, Alexander ; Li, Hui ; Chapman, Charles W. ; Xue, Haoran ; Macmillan, John B. ; Eastman, Alan ; Wu, Jimmy. / Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids. In: Angewandte Chemie - International Edition. 2015 ; Vol. 54, No. 36. pp. 10604-10607.
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