Asymmetric Total Synthesis of Taxol.

Abstract

: Asymmetric total syntheses of Taxol and of 8-demethyltaxoids 24-27 from the 8-membered ring compounds 29 and 12 respectively were completed via successive formation of the BC ring system by intramolecular aldol reaction, then the ABC ring system utilizing an intramolecular pinacol cyclization. The conversion of the tricyclic compound 43 to 7-TES baccatin III (49) was carried out by way of a newly devised method of constructing the oxetane ring. The dehydration condensation between a derivative of Nbenzoylphenylisoserine and 49, followed by deprotection afforded the antitumor agent Taxol.Key words : Taxol; 8-demethyltaxoids; 8-membered ring compounds; intramolecular aldol reaction; intramolecular pinacol cyclization; oxetane formation; dehydration.Taxol, substance isolated from the Pacific yew tree, has been found to have an anti-cancer effect, and the synthesis of its complex structure has been a tempting challenge for synthetic chemists over the past decades. 1)In 1994, two groups succeeded in the chemical total synthesis of Taxol: in Holton's strategy, (-)-camphor was used as the starting material, and the synthesis of the complex structure of Taxol was achieved by a,sequence of many highly effective synthetic reactions,2~ whereas in Nicolaou's convergent approach, the key step of B ring closure reaction was carried out after constructing the connected A and C ring systems.3~ In 1995, Danishefsky reported a total synthesis according to a convergent strategy by way of intramolecular Heck cyclization.4~ Recently, Wender accomplished a total synthesis by a linear strategy using fragmentation of an epoxy-alcohol derived from a-pinene.5~In our strategy, the synthesis of the basic skeleton of Taxol was planned to start from the chiral B ring intermediate 29, prepared via optically active polyoxy-unit 8, and to proceed by constructing the A and C ring systems onto this framework (Fig. 2). This novel strategy offers a flexible synthesis of the B ring system of Taxol and its analogues from chiral linear precursors,6),7)Commercially available neopentyl glycol (1) was converted to aldehyde 2 via its benzylideneacetal. An asymmetric aldol reaction between 2 and the requisite ketene silyl acetal promoted by Sn(OTf)2 coordinated with chiral diamine gave the desired optically active ester 3 in good selectivity (anti/syn=79121, anti aldol; 93% ee). The ester 3 was converted to aldehyde 4 as shown in Fig. 3.The chiral aldehyde 4 was also prepared by the Antitumor agent Taxol.

Twenty five years of organic chemistry with diiodosamarium

“…products such as carbohydrates and in the total syntheses. For example, several taxoides and taxol syntheses took advantage of SmI 2 chemistry in a cyclization step or in the reductive removal of a functional group [44][45][46]. Asymmetric synthesis also benefited of samarium diiodide.…”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…The problem was solved by the development of semisynthetic approaches to paclitaxel from (2R,3S)-phenylisoserine and a naturally occurring compound, 10-deacetylbaccatin III (DAB; Figure 6.17) isolated from a renewable source: leaves of the common yew (Taxus baccata) [223]. Several total syntheses of paclitaxel have been reported [224][225][226][227][228][229][230][231][232]. Despite the fact they are state-of-the-art organic chemistry, they are highly laborious, time-consuming and cost-ineffective, and hence completely unattractive as a competitive source of this antitumor agent.…”

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.…”