Annonaceous acetogenins are a class of plant metabolites featuring a long aliphatic chain bearing one, two, or three THF ring(s) with diverse stereochemistry at the middle and an α, β-unsaturated γ-lactone at the end. Considerable attention has been paid to these compounds due to their potent antitumor activity. The antitumor activity and a spectrum of effective tumor cell lines vary depending on the structure of the THF moiety. Therefore, it is very important for development of promising antitumor compounds to construct the THF ring segment with high stereoselectivity and excellent stereodivergency. We have developed a new synthetic method based on Carreira's asymmetric alkynylation using 3-butyne-1,2-diol derivative as a C_4-chiron and stereodivergent THF ring formation. We found that 3-butyne-1,2-diol benzylideneacetal 6 underwent highly stereoselective alkynylation with an α-oxyaldehyde 5, giving both syn- and anti-adducts (7a-b) in good yields and with high optical purities. Furthermore, the adducts 7a-b could be efficiently converted into all four stereoisomers 10a-d of the THF cores by stereodivergent THF ring formation. Next, we planned the asymmetric synthesis of murisolin 13, which was isolated from the seed of annona muricata. It shows potent cytotoxic activity against the human tumor cell lines, A-549, HT-29, and A-498, with potency 10^6 times that of adriamycin. Asymmetric alkynylation of α-tetrahydrofuranic aldehyde 10a, which was prepared by our systematic synthesis, with 1,6-heptadiyne using (1R,2S)-N-methylephedrine as the chiral ligand smoothly proceeded to give the THF ring segment 21 with threo/tarns/threo stereochemistry. γ-Lactone segment 22 was prepared by the coupling reaction of the triflate 18 with the lactone 19 followed by oxidation of sulfide and thermal elimination. Sonogashira coupling of the THF segment 21 and 22 afforded endiyne 23 in good yield. Reduction of 23 with Wilkinson catalyst provided bis-TBS ether 24. Finally, desilylation of 24 gave murisolin 13, whose spectral data were nicely consistent with the reported data of natural product.
