The total synthesis of the spliceosome inhibitor thailanstatin A has been achieved in a longest linear sequence of nine steps from readily available starting materials. A key feature of the developed synthetic strategy is the implementation of a unique, biomimetic asymmetric intramolecular oxa-Michael reaction/hydrogenation sequence that allows diastereodivergent access to highly functionalized tetrahydropyrans, which can be used for the synthesis of designed analogues of this bioactive molecule.