The advantages of the "naked carbon skeleton" strategy in the total synthesis of polyoxygenated natural products are demonstrated in the total synthesis of the 18-membered macrolide (+)-aspicilin, 1. This approach employs the easily prepared, nonfunctionalized carbon skeleton of the target molecule, hexadeca-1,3,15-triene, 2. All the required stereogenic carbinol centers are then introduced onto this partially unsaturated hydrocarbon chain using the Sharpless asymmetric dihydroxylation (AD) reaction. Thus, asymmetric synthesis of 1 is achieved in 14 steps and 11% overall yield. Three stereogenic carbinol centers are introduced with very high regio- and enantioselectivity (epimeric excess of 96% at positions 3, 4, and 86% at position 15) by using AD-mix-beta while the fourth is obtained using AD-mix-alpha. This approach is compared with an alternative synthesis of 1 (19 steps and 4.3% overall yield) using chiral building blocks derived from D-arabinose and from the enzymatic reduction of oct-7-yn-2-one, 34, with Thermoanaerobium brockii alcoholdehydrogenase (TBADH).