The synthesis of phorboxazole B has been accomplished in 27 linear steps and an overall yield of 12.6%. The absolute stereochemistry of the C4−C12, C33−C38, and C13−C19 fragments was established utilizing catalytic asymmetric aldol methodology, while the absolute stereochemistry of the C20−C32 fragment was derived from an auxiliary-based asymmetric aldol reaction. All remaining chirality was incorporated through internal asymmetric induction, with the exception of the C43 stereocenter which was derived from (R)-trityl glycidol. Key fragment couplings include a stereoselective double stereodifferentiating aldol reaction, a metalated oxazole alkylation, an oxazole-stabilized Wittig olefination, and a chelation-controlled addition of the fully elaborated alkenyl metal side chain.