: 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.
A new method for the total asymmetric synthesis of antitumor agent Taxol is described. Baccatin III, a complex carbon framework, is synthesized by way of B to BC to ABC ring construction. Further, a method of forming Taxol from baccatin III and a β‐amino acid is also demonstrated.
Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.
Synthesis and Antifungal Activity of Novel 14-Membered Benzomacrolides as Galbonolide Analogues. -Asymmetric synthesis of benzene analogues of galbonolide, possessing a benzene ring instead of a conjugated diene structure, is achieved. The synthesis starts from chiral alcohol (III), obtained via enzyme-catalyzed kinetic resolution with high enantioselectivity. Representatively, a method for the introduction of a methylthio and chloride function at the vinyl position is also established. The resulting analogues exhibit only low antifungal activity compared to galbonolide A. -(SAKOH*, H.; SAKURABA, S.; SUGIMOTO, Y.; IMAMURA, H.; JONA, H.; YAMADA, K.; BAMBA-NAGANO, R.; HASHIZUME, T.; MORISHIMA, H.; Chem.
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