The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1–C2 (115), C3–C8 (98), C9–C19 (74), C20–C32 (52), C33–C41 (84) and C42–C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(II)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(II) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(IV)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19–C20 connection was made using a completely stereoselective Wittig–Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33–C46 δ-lactone 3 was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32–C33 linkage was implemented successfully with 83 and C33–C41 lactone 84. The C42–C46 segment of the side chain was then appended via Julia–Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando–Still–Gennari intramolecular (Z)-selective olefination at C2–C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.