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Concept
Wender Taxol total synthesis
Résumé
Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis (one of six to date) by the group of Paul Wender at Stanford University published in 1997. This synthesis has much in common with the Holton Taxol total synthesis in that it is a linear synthesis starting from a naturally occurring compound with ring construction in the order A,B,C,D. The Wender effort is shorter by approximately 10 steps.
Raw materials for the preparation of Taxol by this route include verbenone, prenyl bromine, allyl bromide, propiolic acid, Gilman reagent, and Eschenmoser's salt.
The taxol synthesis started from the terpene verbenone 1 in Scheme 1, which is the oxidation product of naturally occurring α-pinene and forming ring A. Construction of ring B started with abstraction of the pendant methyl group proton by potassium tert-butoxide (conjugated anion is formed) followed by nucleophilic displacement of the bromine atom in prenyl bromide 2 to form diene 3. Ozonolysis of the prenyl group (more electron-rich than the internal double bond) formed aldehyde 4, which, after isomerization or photorearrangement to the chrysanthenone 5, was reacted with the lithium salt (via LDA) of the ethyl ester of propiolic acid 6 in a nucleophilic addition to the alcohol 7. This compound was not isolated but trapped in situ with trimethylsilyl chloride to the silyl ether 9. In the next step, Gilman reagent 8 is a methylating reagent in nucleophilic conjugate addition through the alkyne group to the ketone group, which formed the alcohol 10. The silyl ether protective group was removed by reaction with acetic acid to alcohol 11, which was then oxidized to the ketone 12 with RuCl2(PPh3)3 and NMO as the sacrificial catalyst. The acyloin group in 13 was introduced by KHMDS and Davis’ oxaziridine (see Holton Taxol total synthesis for another use of this system) and its hydroxyl group together with the ester group were reduced by lithium aluminium hydride to tetrol 14.
Source officielle
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