Synthesis of Fluorescent Solamin for Visualization of Cell Distribution

Abstract

Asymmetric synthesis of fluorescent solamin was accomplished by using highly stereoselective asymmetric alkynylation and Williamson etherification as the key steps, wherein the fluorescent acetogenin with all functionality was firstly synthesized.Annonaceous plants produce a polyketide family of natural products, so-called annonaceous acetogenins. 1 They have attracted considerable attention by the interesting biological activity represented by potent cytotoxicity against human cancer cell lines.The mode of action was supposed to be based on its strong inhibitory activity against a mitochondrial complex I.However, the structure-activity relationship against the complex I inhibition was not completely related to its cytotoxicity.McLaughlin suggested that the mitochondrial assay is cell-free and does not take into consideration factors such as membrane transport, intracellular transport, metabolic inactivation, etc. 2 Poupon and co-workers reported the first synthesis of fluorescent squamocin analogue and visualization of its cell distribution. 3Their synthesis is based on degradation of a natural acetogenin.As a result, the γ-lactone moiety was lost by the modification.Recently, Yao and co-workers also reported a new fluorescent acetogenins analogue, 4 in which the THF rings were replaced to acyclic ethers for simplification.These reports prompted us to synthesize a novel fluorescent annonaceous acetogenin, which retains all functionalities.We have developed a systematic and stereoselective synthesis of annonaceous acetogenins. 5By applying this methodology, we planned to synthesize a novel fluorescent annonaceous acetogenin, which possesses all functional groups including the γ-lactone moiety and THF ring flanking by two hydroxy groups.Among the many acetogenin congeners, we selected solamin having a comparatively simple structure, but potent cytotoxicity against a wide range of cancer cell lines. 6,7We planned to introduce the fluorescent tag at the end of the unfunctionalized hydrocarbon chain, because both the γ-lactone, the THF, and hydroxy † Dedicated to the great contribution to organic chemistry of the late professor Ivar Ugi.