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Ti-catalyzed transannular cyclization of epoxygermacrolides. Synthesis of antifungal (+)-tuberiferine and (+)-dehydrobrachylaenolide

Abstract:

We present a divergent strategy for the stereoselective synthesis of both eudesmanolides (+)-tuberiferine and (+)-brachylaenolide starting from the accessible germacrolide (+)-costunolide. The key steps of these syntheses are the Ti-catalyzed transannular cyclization of a 1,4-epoxygermacrolide in the presence or absence of water, respectively. The catalytic cycle operating in the presence of water probably involves the reduction of a tertiary radical by H-atom transfer from aquacomplex Cp2TiIII(OH2)Cl. The catalytic cycle under anhydrous conditions presumably occurs through mixed disproportionation between a tertiary radical and Cp2TiIIICl. Synthetic (+)-tuberiferine and (+)-brachylaenolide displayed an antifungal potency against Phycomyces blakesleeanus comparable or even higher than amphotericin B, the gold standard for antifungal therapy. © 2008 Elsevier Ltd. All rights reserved.