Holton Taxol total synthesis
The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol (generic name: paclitaxel).
The Holton Taxol total synthesis is a good example of a linear synthesis starting from commercially available natural compound patchoulene oxide. This epoxide can be obtained in two steps from the terpene patchoulol and also from borneol. The reaction sequence is also enantioselective, synthesizing (+)-Taxol from (−)-patchoulene oxide or (−)-Taxol from (−)-borneol with a reported specific rotation of +- 47° (c=0.19 / MeOH). The Holton sequence to Taxol is relatively short compared to that of the other groups (46 linear steps from patchoulene oxide). One of the reasons is that patchoulene oxide already contains 15 of the 20 carbon atoms required for the Taxol ABCD ring framework.
Other raw materials required for this synthesis include 4-pentenal, m-chloroperoxybenzoic acid, methyl magnesium bromide and phosgene. Two key chemical transformations in this sequence are a Chan rearrangement and a sulfonyloxaziridine enolate oxidation.
It was envisaged that Taxol (51) could be accessed through tail addition of the Ojima lactam 48 to alcohol 47. Of the four rings of Taxol, the D ring was formed last, the result of a simple intramolecular SN2 reaction of hydroxytosylate 38, which could be synthesized from hydroxyketone 27. Formation of the six-membered C ring took place through a Dieckmann condensation of lactone 23, which could be obtained through a Chan rearrangement of carbonate ester 15. Substrate 15 could be derived from ketone 6, which, after several oxidations and rearrangements, could be furnished from commercially available patchoulene oxide 1.
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