Systematic Synthesis of Diastereomeric THF Ring Cores and Total Synthesis of Anti-Tumor Annonaceous Acetogenins

We have developed a systematic synthesis of the poly-THF ring cores of anti-tumor Annonaceous acetogenins by utilizing asymmetric alkynylation and subsequent stereodivergent THF ring formation as key steps. The asymmetric alkynylation of (alpha)-oxyaldehyde and (alpha)-tetrahydrofuranic aldehyde with an (S)-3-butyne-1,2-diol derivative proceeded in good yield with very high diastereo­selectivity. These adducts were converted into mono- and bis-THF cores by two different methods involving one-pot THF ring formation. The total syntheses of murisolin, 16,19-cis-murisolin, and longimicin D, which show cytotoxic activity against the human ­tumor cell, were accomplished by applying this methodology. 1 Introduction 2 Synthetic Strategy 3 Asymmetric Alkynylation of (alpha)-Oxyaldehyde with a C4-Unit 4 Systematic Synthesis of Mono-THF Segments by Stereo­divergent THF Ring Formation 5 Systematic Synthesis of Bis-THF Segments by an Iterative Process 6 Total Synthesis of Murisolins and Longimicin D 7 Conclusion