Dibohemamines A–C (5–7), three new dimeric bohemamine analogues dimerized through a methylene group, were isolated from a marine-derived Streptomyces spinoverrucosus. The structures determined by spectroscopic analysis were confirmed through the semi-synthetic derivatization of monomeric bohemamines and formaldehyde. These reactions, which could occur under mild conditions, together with the detection of formaldehyde in the culture, revealed that this dimerization is a non-enzymatic process. In addition to the unique dimerization of the dibohemamines, dibohemamines B and C were found to have nm cytotoxicity against the non-small cell-lung cancer cell line A549. In view of the potent cytotoxicity of compounds 6 and 7, a small library of bohemamine analogues was generated for biological evaluation by utilizing a series of aryl and alkyl aldehydes.

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′.

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′.