Enantioselective Total Synthesis of (−)-Taxol

Abstract

Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde with the aromatic C-ring fragment followed by Lewis acid mediated eightmembered B-ring cyclization gave the desired ABC endo-tricarbocycle. The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene derivative, which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol stereoselectively. For introduction of the C19-methyl, the cyclopropyl ketone was prepared via cyclopropanation of the C-ring allylic alcohol or conjugate addition of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate containing the C19methyl group. Regioselective transformation of three hydroxyl groups of this intermediate, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-oxygen functionality afforded a precursor for D-ring construction. Dihydroxylation of the allyl chloride moiety followed by basic treatment of the resulting diol gave a fully functionalized taxol skeleton. Functional group manipulation of this product including attachment of the C13 side chain provided (-)-taxol.

Synthesis and Antioxidant Activity of Oxygenated Furofuran Lignans

“…After protection of the primary hydroxy group as a tertbutyldimethylsilyl ether by using tert-butyldimethylsilyl chloride and imidazole (97% yield), oxidative cleavage of the olefin by employing osmium-4-methylmorpholine N-oxide and NaIO 4 oxidation gave 14 in 96% yield. Stereoselective -hydroxylation was accomplished by triisopropylsilyl enol etherification, osmium oxidation, and application to silica gel, 10) giving unstablehydroxyaldehyde 15 in 48% yield.…”

Recent Progress in the Chemistry and Biology of Paclitaxel (TaxolTM) and Related Taxanes

“…Chemists have developed several total synthetic approaches and many semisynthetic approaches to obtain paclitaxel chemically, and numerous [39,40], Nicolaou [41], Danishefsky [42], Wender [43,44], and Mukaiyama [45] in the 1990s and also since the "Taxol supply crisis" [46] was solved by the development of successful semisynthetic and biosynthetic approaches to paclitaxel production. The only successful total synthesis of paclitaxel published in the past 10 years is that of Kuwajima and his collaborators (Scheme 8.1), who published their work in 2000 [47].…”

Role of Natural Products in Drug Discovery

“…To allow Taxol to become a commercial drug, a more sustainable access to it was required. Despite many total syntheses [164][165][166][167][168][169][170] it was not feasible to use any of them for large-scale synthetic preparation of paclitaxel. The development by French researchers, Greene, Potier, and coworkers [171] as well as others [172][173][174] offered the possibility to produce Taxol s by semisynthesis.…”