Baccatin III as the Precursor of Taxol

The allylalkohol 6 turns out to be the obvious precursor of the protected diol 5, and 6 reasonably arises from a Shapiro coupling of cyclohexadienyllithium 7 with the cyclohexene-4-aldehyde 8 which is the product of oxidation and subsequent diol protection of the bicyclic hydroxylactone 9 the latter emerges from rearrangement of the Diels-Alder cycloadduct 13 of 3-hydroxy-2-pyrone 14 as the diene and 4-hydroxy-2-methyl-2-butenoate 15 as the electron-deficient dienophile. The cyclohexadienyllithium 7 originates from the sulfonylhydrazone of the ketone 10 which is, once again, a Diels-Alder cycloadduct of the protected 3-hydroxymethyl-2,4-dimethyl-l,3-pentadiene 12 and ketene 11 as the dienophile. 

The arylsulfonylhydrazone 18 is a stable precursor of the cyelohexadienyllithium 7. In order to prepare this starting reagent, 3-acetoxymethyl-2,4-dimethyl-1,3-penta-diene 12 is subjected to a Diels-Alder reaction with the ketene equivalent ehloro-acrylnitrile 11a. The cyeloadduct 16 primarily obtained is hydrolyzed to the hyd-roxyketone 17 in i-butyl alcohol. Subsequent reaction with /-butyldimethylsilyl-chloride (TBSCl) and imidazole in dichloromethane serves to protect the primary aleohol function of the intermediate 10 in which the keto carbonyl group is deriva-tized to the required arylsulfonylhydrazone 18 with 2,4,6-triisopropylphenylsul-fonylhydrazide in tetrahydrofuran (THF) as solvent. 

In order to prepare the cyclohexenaldehyde 8, 3-hydroxy-2-pyrone 14 and ethyl 4-hydroxy-2-methyl-2-butenoate 15 are subjected to a Diels-Alder reaction in the presence of phenylboronic acid which arranges both reactants to the mixed boro-nate ester 19 as a template to enable a more efficient intramolecular Diels-Alder reaction with optimal control of the regiochemical course of the reaction. Refluxing in benzene affords the tricyclic boronate 20 as primary product. This liberates the intermediate cycloadduct 21 upon transesterification with 2,2-dimethylpropane-l,3-diol which, on its part, relaxes to the lactone 22. Excessive i-butyldimethyl-silyltriflate (TBSTf) in dichloromethane with 2,6-lutidine and 4-7V,A-dimethyl-aminopyridine (DMAP) as acylation catalysts protects both OH goups so that the primary alcohol 23 is obtained by subsequent reduction with lithiumaluminum-hydride in ether. 

Catalytic amounts of camphor-10-sulfonic acid (CSA) in methanol and dichloro-methane smoothly cleave the orthoester function in 23, giving the intermediate y-lactone-l,3-diol. Subsequent protection of the primary alcohol function with di-methylphenylchlorosilane (TPSCl) in dimethylformamide with imidazole as the base and of the secondary alcohol function via alcoholate with benzylbromide (BnBr) following WiLLlAMSON s ether synthesis yields the y-lactone 24. Its reduction with lithiumaluminumhydride leads to two vicinal primary alcohol groups. Thereafter, camphor-10-sulfonic acid (CSA) in dichloromethane selectively cleaves the TBS ether and catalyzes the transketalization with acetone dimethyUcetal to the precursor 25 of the aldehyde 8. Smooth oxidation of the primary alcohol function in 25 is achieved with tetrapropylammoniumperruthenate (TPAP) and A-methyl-morpholine-A-oxide (NMO) in acetonitrile. 

Shapiro coupling of cyclohexadienyllithium 7, prepared by reacting the sulfonyl-hydrazone 18 with butyllithium in THF, with the cyclohexenaldehyde 8, leads exclusively to the desired stereoisomer 6. The unexpected selectivity probably arises from steric overcrowding of the Si face of the prochiral chelated aldehyde carbonyl in 8 thus enabling the nucleophilic alkenyllithium to approach predominantly from the less-hindered Re face. 

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