Formal Total Synthesis of (−)-Taxol

Abstract

Formal total synthesis of ( ) taxol is described herein. This convergent synthesis was accomplished by utilizing two chiral fragments, both of which were prepared via asymmetric catalysis. A palladium catalyzed reaction was found to afford the eight membered ring effectively, i.e., a B alkyl Suzuki Miyaura coupling reaction and an intramolecular alkenylation of a methyl ketone successfully constructed the B ring of taxol in excellent yield. During the preparation of a substrate for the palladium catalyzed reaction, a unique rearrangement of the epoxy benzyl ether, via a 1,5 hydride shift that generates the C3 stereogenic center and subsequently forms the C1 C2 benzylidene moiety, was observed. Strenuous efforts were required for transformations after the construction of the taxane scaffold to achieve the formal total synthesis of taxol because very few approaches are available for the synthesis of the target compound.

Recent advances in the synthesis of taxoids: 2015-2020

“…Swapping the cyclic acetonide for a cyclic benzylidene acetal, followed by reductive cleavage at the less hindered oxygen and Dess-Martin oxidation gave (+)-8 (R = I). While Nakata's group developed multiple routes to vinylhalides 8, 37,40 the present route gave the highest overall yield and enantioselectivity. Preparation of the C ring fragment 9 commenced with Birch reduction of methyl 2,6dimethoxybenzoate (15); alkylation of the product with LDA followed by methyl iodide gave diene 16 (Scheme 3).…”

“…This approach is relatively unique, as many of the other syntheses create the C1-C2 bond prior to formation of the central eight-membered ring. Precursor The initial steps for preparation of the A ring fragment are similar to those utilized by Nakada 36,37 (c.f. Scheme 2).…”

“…Preparation of the C ring fragment 9 commenced with Birch reduction of methyl 2,6dimethoxybenzoate (15); alkylation of the product with LDA followed by methyl iodide gave diene 16 (Scheme 3). 36,37 Reduction of the ester with DIBAL, protection of the resulting 1 o alcohol as a benzyl ether and acidcatalyzed vinyl ether hydrolysis led to the achiral 1,3-cyclohexadione 17. As was the case for preparation of the A ring fragment, Baker's yeast reduction of 17 proceeded in good yield and excellent enantioselectivity to give (+)-18.…”

“…(+)-9 (94%) Lithium-halogen exchange of (+)-9 and reaction with aldehyde (+)-8 (R = I) gave (+)-7 as a single diastereomer (Scheme 4). 36,37 The stereochemical outcome was rationalized on the basis of a chelationcontrolled addition (see red insert). Sharpless epoxidation of 7 catalyzed with VO(OEt)3 gave epoxide 21 as a single stereoisomer.…”

“…The C4 exocyclic methylene was constructed by deprotection of the C4 silyl ether, Dess-Martin oxidation and a Takai methenylation (Scheme 5). 36,37 Selenium dioxide allylic oxidation of the less substituted exocyclic olefin of 23 proceeded in a stereoselective fashion to give 24. Transformation of 24 to the hydroxyoxetane followed a variation of the methodology utilized in Holton's synthesis.…”