Two approaches for the total synthesis of the spiromacrolide retipolide E (5) are described, the first using a modified Mitsunobu reaction as key step for the formation of the strained 14-membered macrolactone, the second a nucleophilic aromatic substitution (S _NAr). In the first approach an α-oxomacrolactone 15 was obtained, which could either be converted into ornatipolide (6) or further transformed into racemic retipolide E [(R,S)-5] by directed aldol condensation with a methyl arylpyruvate. The second approach allowed the synthesis of either racemic or enantiomerically pure retipolide E (5). In the latter case Evans' methodology was used for the introduction of stereogenic center via stereoselective alkylation. The oxazolidinone auxiliary was removed under mild conditions by exchange for 2-arylethanol 22 with Otera's distannoxane catalyst. Synthetic retipolide E allowed the identification of this biosynthetic intermediate in the fruit bodies of the North American mushroom Retiboletus retipes.