Stereoselective Total Synthesis of (-)-Spirofungin A by Utilising Hydrogen-Bond Controlled Spiroketalisation

The stereoselective total synthesis of the spiroketal containing Streptomyces metabolite (-)-spirofungin A (1) is described. A key step involved a spiroketalisation controlled by an intramolecular H-bond which favoured the desired spiroketal 4 (13:1 ratio). The presence of the intramolecular H-bond in 4 is possibly due to a 1,5-alkyne-oxygen interaction. Other key steps include an efficient cross-metathesis to form the spiroketal precursor, a tin mediated syn-aldol reaction and a Stille cross-coupling reaction to create the C22-C23 bond. A final Wittig extension followed by deprotection gave (-)-spirofungin A (1).