Convergent Synthesis of Fluorescence Labeled Solamin

Abstract

The convergent synthesis of dansyl-labeled solamin, an antitumor Annonaceous acetogenin, has been achieved.The carbon skeleton was assembled from three fragments: the THF ring fragment, the fluorescent fragment, and the γ-lactone fragment, by asymmetric alkynylation.Annonaceous acetogenins are waxy derivatives of long-chain fatty acids (C32 or C34) that are linked by a 2-propanol unit at C-2 position to form a γ-methyl-α,β-unsaturated-γ-lactone. 1 Most acetogenins are characterized by one to three 2,5-disubstituted tetrahydrofuran(s) (THFs) with one or two flanking hydroxyl group(s) at the center of a long carbon chain.Many researchers are engaged in the synthesis of acetogenins 2 and their analogues 3 due to their unique structures and potent antitumor activities.The mechanism of action is considered to involve the inhibition of mitochondrial NADH ubiquinone oxidoreductase (complex I).The inhibition suppresses ATP production, leading to apoptosis of cancer cells. 4However, the structure-activity relationship for complex I inhibition is not completely related to its cytotoxicity.McLaughlin and co-workers suggested that as the mitochondrial assay is cell-free, it does not take into consideration factors such as membrane transport, intracellular transport, and metabolic inactivation. 5In order to visualize cell distribution, Poupon and co-workers synthesized a γ-lactone-free dansyl-labeled squamocin analogue. 6Moreover, Yao and co-workers reported the synthesis of a new fluorescent acetogenin analogue whose THF rings were replaced with acyclic ethers for simplification. 7 living cells, it was suggested that the hydrophilic THF moiety in natural acetogenins is located at the † Dedicated to the late Professor John W. Daly for his outstanding contributions to natural products chemistry.