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Concept
Danishefsky Taxol total synthesis
Résumé
The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.
Danishefsky's route to Taxol has many similarities with that of Nicolaou. Both are examples of convergent synthesis with a coupling of the A and the C ring from two precursors. The main characteristic of the Danishefsky variant is the completion of the oxetane D ring onto the cyclohexanol C ring prior to the construction of the 8-membered B ring. The most prominent starting material is the (+) enantiomer of the Wieland-Miescher ketone. This compound is commercially available as a single enantiomer and the single chiral group present in this molecule is able to drive the entire sequence of organic reactions to a single optically active Taxol endproduct. The final step, the tail addition is identical to that of Nicolaou and is based on Ojima chemistry.
In terms of raw material shopping, this taxol molecule consists of the aforementioned Wieland-Miescher ketone, 2-methyl-3-pentanone, lithium aluminium hydride, osmium tetroxide, phenyllithium, pyridinium chlorochromate, the Corey-Chaykovsky reagent and acryloyl chloride. Key chemical transformations are the Johnson-Corey-Chaykovsky reaction and the Heck reaction.
Taxol resulted from the tail addition of the Ojima lactam to alcohol 51, which is baccatin III (the original target molecule of the Danishefsky synthesis). Alcohol 51 was derived from the allylic oxidation of α-acylketone 49. Compound 49 was ultimately derived from the Heck reaction of enol triflate 38, which was used to close the B-ring. Enol triflate 38 resulted from a rearrangement of compound 31 after protection of its hydroxyl group. Compound 31 was derived from the connection of the A and C rings with aldehyde 21 combining with the vinyllithium reagent derived from cyanohydrin 29.
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