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Enantioselective Total Synthesis of (−)-Taxol
journal contribution
posted on 2000-04-05, 00:00 authored by Hiroyuki Kusama, Ryoma Hara, Shigeru Kawahara, Toshiyuki Nishimori, Hajime Kashima, Nobuhito Nakamura, Koichiro Morihira, Isao KuwajimaEnantioselective 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 eight-membered 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 C19-methyl 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.
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Functional group manipulationBirch conditionsC 13 side chainReductive cleavageRegioselective transformationLewis acidconjugate additionhydroxyl groupsallyl chlorideallyl chloride moietycyano groupintroductionfunctionalized taxol skeletonsinglet oxygenEnantioselectiveABCcyclopropyl ketonecyclopropane ring
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