Formal Total Synthesis of (−)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation

• Published in: Chemistry : a European journal 2015-01, Vol.21 (1), p.355-359
• Main Authors: Hirai, Sho, Utsugi, Masayuki, Iwamoto, Mitsuhiro, Nakada, Masahisa
• Format: Article
• Language: English
• Subjects: Catalysis; Crystallography, X-Ray; Cyclization; enantioselectivity; Ethers; Formations; Forming; Ketones; Molecular Conformation; natural products; Paclitaxel - chemical synthesis; Paclitaxel - chemistry; Palladium; Palladium - chemistry; Stereoisomerism; Synthesis; Taxol; total synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201404295

A formal total synthesis of (−)‐taxol by a convergent approach utilizing Pd‐catalyzed intramolecular alkenylation is described. Formation of the eight‐membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd‐catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97 %), indicating the high efficiency of the Pd‐catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5‐hydride shift, generating the C3 stereogenic center and subsequently forming the C1–C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd‐catalyzed reaction. A less taxing route to taxol: The Pd‐catalyzed intramolecular alkenylation of a methyl ketone affords a key cyclized intermediate for the synthesis of (−)‐taxol in excellent yield (97 %) (see scheme; Bn=benzyl; TES=triethylsilyl). Rearrangement of an epoxy benzyl ether through a 1,5‐hydride shift, generating the C3 stereogenic center and subsequently forming the C1–C2 benzylidene, was discovered during the preparation of a substrate for the Pd‐catalyzed reaction.