In the early 1990s, at least thirty separate groups were working on the total synthesis of the chemotherapy medicine paclitaxel (Taxol), culminating with the groups of Robert A. Holton and K. C. Nicolaou publishing nearly simultaneously in 1994. By then, Mukaiyama had retired from the University of Tokyo after reaching the mandatory age of 60 and set up an academic lab at the Tokyo University of Science. The Mukaiyama taxol total synthesis was published between the years of 1997 and 1999 after five years of research, making the Mukaiyama lab the sixth group to report results.
This total synthesis is largely a linear synthesis which forms the four rings of taxol in the order C, B, A, D. It is differentiated from the others from its use of L-serine as a starting material and for being the only total synthesis not to use the Ojima lactam to create the amide tail. Instead, the tail is created from scratch by converting benzyloxyacetic acid into a silyl enol ether, joining it with benzaldehyde with a Mukaiyama aldol addition, and creating the amide from the alcohol via a Mitsunobu reaction followed by benzoylation.
The synthesis also made use of three Swern oxidations during the synthesis of the C ring. This reaction is typically performed at very low temperatures (< -50 °C) to stabilize its activated DMSO intermediate and constantly evolves the strong-smelling DMS, making it very difficult to work with at large scales. The difficulties encountered during their total synthesis prompted Mukaiyama to pursue an alternative method, and in 2001 a room-temperature oxidation involving N-chlorosuccinimide and a catalytic amount of N-t-butylbenzenesulfenamide was developed. The more electronegative nitrogen adjacent to the sulfur in the sulfenamide increased the stability of the intermediate relative to that formed from the sulfur-carbon bond of DMSO and was inspired by his earlier work with sulfenamides while still at the Tokyo Institute of Technology.