Development of Efficient Synthetic Method of Antitamor Annonaceous Acetogenins and Investigation of Highly Potent Derivatives

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Annonaceous acetogenins are class of natural product which exhibit potent cyctotoxicity against human antitumor cell lines. Development of efficient synthetic method of these compounds is required for finding of highly potent derivatives, structure determination of the natural acetogenins, and research of the mode of action. We investigated a novel systematic synthesis of THF cores of acetogenins based on reiterative process, which will be a powerful tool to synthesize various congeners. As a result of the research, we obtained results as follows.1)Asymmetric Alkynylation of α-Oxyaldehydes with a C_4-unitInvestigation for an appropriate C_4-unit to realize high yield and excellent diastereoselectivity revealed that 3-butyne-1,2-diol benzylideneacetal was the best C_4-unit among those we tested. Diastereoselectivity was completely controlled by changing a chiral ligand of alkynylating reagent.2)Stereodivergent Synthesis of THF Ring SegmentFour kinds of diastereomers of mono-THF segment are stereodivergently synthesized by changing the method of THF ring closure.3)Highly Stereocontrolled Synthesis of Poly-THF Ring Segment by Reiterative ProcessSynthesis of poly-THF segment based on reiterative strategy was examined. Eight kinds of bis-THF cores were synthesized in good yield with excellent diastereoselectivity.4)Synthesis of Acetogenin by Assembly with γ-Lactone SegmentTo confirm that our method can be applied to a synthesis of acetogenins, murisolin (mono-THF acetogenin) was synthesized by employing asymmetric alkynylation with diyne as a key step. Thus, the methodology for synthesis of annonaceous acetogenins was established.