Nuphar Dimers: Crouching Sulfur, Hidden Reactivity

The dimeric Nuphar alkaloids are a structurally unique family of natural products containing an unsymmetrical thiaspirane. These sulfur-containing alkaloids were first isolated from the fresh water plant Nuphar lutea by Achmatowicz in the early 1960s. The most potent member of the Nuphar dimer family (6-hydroxythiobinuphraidine, Figure 1) is a rapid inducer of apoptosis, exhibiting in vivo antitumor activity. The structural basis for the bioactivity of this class of compounds is not well-understood, but it has been shown that the presence of a hemiaminal adjacent to the thioether is required for activity. In the ACS Central Science article by Shenvi and co-workers, the authors propose that activation of a dormant electrophilic sulfur atom embedded in the Nuphar dimers might account for their bioactivity. In 2013, Shenvi described the first total synthesis of a Nuphar dimer via a biomimetic approach involving a dihydroxydimer intermediate. Of note, the dihydroxydimer intermediate itself proved difficult to isolate. The synthesis of the dihydroxydimer was recently accomplished using alternate methods as reported by MacMillan, Eastman and Wu enabling the study of its bioactivity. Shenvi and co-workers suggest that prior isolation difficulties stemmed from S-electrophilicity of the thiaspirane resulting in retrodimerizaton due the use of sulfur-based reagents in the presence of acid. While it is surprising retrodimerization had not previously been reportedespecially in the extensive isolation literatureit is unlikely that dihydroxydimers would have been subjected simultaneously to an acid and thiol concoction during the isolation process. Enlightened by this fortuitous observation, the authors set out to demonstrate their thiol-triggered retrodimerization hypothesis which they believed was also linked to the mechanism of action, and therefore bioactivity, of this class of compounds. Shenvi and co-workers focused their initial proof-ofconcept studies around unadorned monomeric iminium thiaspirane systems in order to cleanly study the reactivity of this pharmacophore with nucleophiles. While the monomers are stable to alcohols such as methanol, they proved reactive to thiophenol. And in the presence of a mild reducing agent, a tertiary amine containing disulfide was obtained. This demonstrated for the first time that the iminium thiaspirane can function as a sulfur electrophile and selectively reacts with thiols over water or alcohol (Figure 2a).