Condensation of the aryllithium reagents, prepared from the bromides 10 and 11 and tert-butyllithium, with lactone 19 and acid-catalyzed spirocyclization gave the papulacandin spiroketals 14 and 15. Subsequent protection using di-tert-butylsilyl bis(trifluoromethanesulfonate) gave the diols 31 and 30. Isoleucine (37) was converted using a double Wittig reaction sequence and propargylation of the intermediate aldehyde 46 into the alkynol 47. Separation of the C-7 epimers of 47 was achieved using kinetic resolution via Sharpless epoxidation. Both alkynol epimers 53 and 57 were converted into the papulacandin side chain esters 65 and 66 using a hydrozirconation and palladium(0)-catalyzed coupling sequence. Comparisons of Mosher ester derivatives of 65 and 66 with the Mosher ester derivative of the natural papulacandin side chain and further degradation were consistent with the stereochemistry of the natural product being 7S,14S. Esterification of the spiroketals with the mixed anhydride 70 and global deprotection gave papulacandin D (1).