TOTAL SYNTHESIS OF THE IONOPHORE ANTIBIOTIC X-14547A (INDANOMYCIN)

The total synthesis of the ionophore antibiotic X-14547A (indanomycin) (1) is described by using a convergent strategy. 2-Ethylvalerolactone was converted into ethyl (E,E,E)-11-[[(.beta.-methoxy)ethoxyl]methoxy]-6-ethyl-2,7,9-undecatrienoate (8) in 8 steps. Intramolecular Diels-Alder reaction of 8 at 110.degree. C followed by deprotection to give the racemic tricyclic lactone 7 proceeded with very high stereoselectivity (> 90%) and in 38% overall yield from 2-ethylvalerolactone. The tricyclic lactone 7 was resolved via the diastereomeric amides 24 and 25 to provide the optically pure lactones 26 and 27. Reaction of 7 with 1-pyrrolylmagnesium bromide gave the pyrrolylcarbonyl derivative 28 whose structure was determined by X-ray crystallography. The optically pure lactone 26 was reacted with 2-lithio-1-[[(.beta.-trimethylsilyl)ethoxy]methyl [SEM group]] pyrrole to give the corresponding N-SEM protected pyrrolylcarbonyl 32. Elaboration of 32 afforded the phenylsulfone 34 which constituted an appropriate right-hand fragment suitable for later coupling. Synthesis of the left-hand tetrahydropyranyl .alpha.,.beta.-unsaturated aldehyde 3 was achieved by using levoglucosan (1,6-anhydro-.beta.-D-glucopyranose) as the starting material. Coupling of 3 with the lithio anion from 34 followed by trapping with benzoyl chloride gave the benzoyloxy phenyl sulfones 57. Reduction of these with sodium amalgam stereoselectively afforded the E,E-diene 58. The synthesis was completed by deprotection and hydrolysis to afford the antibiotic X-14547A (indanomycin).