Holton Taxol total synthesis

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.

A tandem epoxidation with meta-chloroperbenzoic acid and Lewis acid-catalyzed Grob fragmentation gave ketone 6, which was then protected as the tert-butyldimethylsilyl ether 7 in 94% yield over three steps.

Reduction of the ketone group with 20 equivalents of sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) gave triol 13, which was immediately converted to carbonate 14 by treatment with phosgene.

Reduction of pure ketone 18c using Red-Al followed by basic work-up resulted in epimerization to give the required trans-fused diol 19 in 88% yield.

The terminal alkene group of 20 was next converted to a methyl ester using ozonolysis followed by oxidation with potassium permanganate and esterification with diazomethane.

In the next two steps the MOP protecting group was removed under acidic conditions, and alcohol 27 was reprotected as the more robust benzyloxymethyl ether 28.

At this stage the final missing carbon atom in the Taxol ring framework was introduced in a Grignard reaction of ketone 30 using a 10-fold excess of methylmagnesium bromide to give tertiary alcohol 31.

Allylic alcohol 34, obtained from deprotection of silyl enol ether 33 with hydrofluoric acid, was oxidized with osmium tetroxide in pyridine to give triol 35.

This ketone was deprotonated with potassium tert-butoxide in tetrahydrofuran at low temperature and further oxidized by reaction with benzeneseleninic anhydride to give α-hydroxyketone 44.

Deprotection of the triethylsilyl ether with hydrofluoric acid and removal of the BOM group under reductive conditions gave (−)-Taxol 51 in 46 steps.

Patchoulene oxide (1) could be accessed from terpene patchoulol (52) through a series of acid-catalyzed carbocation rearrangements proceeded by an elimination following Zaitzev's rule to give pathoulene (53).