Antitumour activity, taxol

The 1,3-dipolar cycloaddition of the carbonyl ylide (31) to the aldimine (32) produces the adduct (33), which has been used to synthesize the taxol C(13) side-chain (34), which is known to be required for the antitumour activity of taxol (Scheme 9).35 The dirhodium tetraacetate-catalysed decomposition of l-diazo-5-phenylpentane-2,5-dione (35) yields the carbonyl ylide (36), which cycloadds to methylenecyclopropanes (37) to produce spirocyclopropanated 8-oxabicyclo[3.2.1]octan-2-ones [(38)-(40)] in 6-75% yields (Scheme 10).36 The 1,3-dipolar cycloadditions of aliphatic or alicyclic thiocarbonyl ylides with thiobenzophenone produce both regioisomeric 1,3-dithiolanes as expected. However, in the case of highly sterically hindered thiocarbonyl ylides, methylene transfer leads to the formation of 4,4,5,5-tetraphenyl-l,3-dithiolane.37,38... 

Epothilones A and B. The discovery that the epothilone family of macrocyclic lactones, isolated from culture extracts of a myxobacterium, had a Taxol -like mechanism of antitumour activity propelled them, almost overnight, to the forefront of both the biological sciences and synthetic chemistry communities. This interest has culminated in several total syntheses of the epothilones and numerous approaches. While the C12-C13 epoxide has been successfully introduced using macrocyclic control, acyclic stereocontrol and, in particular, the aldol reaction have been used to assemble the Ci-C section. Several possible aldol disconnections are shown in Scheme 9-56, and these will be considered in turn. 

T.media possesses antitumour activity (e.g. IL against L1210 murine leukemia cells of 3.6 0.3 nM) higher than that of taxol (e.g. 57.0 3.0 nM) and is also active against adriamycin resistant cells (32). Taxol C possesses selective cytotoxicity in the NCI human cell line screen (33). 10-Deacetyltaxol C, A -methyltaxol C (130) and taxol D (133) also showed activity close to that of taxol in the tubulin assembly assay (32,33). Table 1 lists the different taxanes isolated thus far from different Taxus species. 

Taxol (53) is currently receiving enormous attention from synthetic organic chemists owing to its remarkable antitumour activity [38]. To date, the main source of taxol stems from derivatization of naturally occurring 10-deacetylbaccatin III (54). This compound lacks the C13 side-chain of taxol, a structural unit essential for biological activity [38]. 

There has been intense interest in recent years in selective modification of functionality in baccatin III, 1, the basic diterpenoid core of paclitaxel (Taxol ) which is now established as a clinically active antitumour drug. Given the complexity of 1, rearrangements are common even under mild conditions and attempts to carry out apparently simple transformations are frequently frustrated, as shown by the following example. The 13p-chloro derivative 2 was prepared and fully characterised, then treated with sodium azide in aqueous DMF at 60°C in the expectation that the 13 a azide would be obtained. The product, however, was shown to be the ring cleaved compound 3 (71% yield). 

Oxetanes rarely occur in nature. The diterpene alcohol taxol (paclitaxel ) was isolated in 1971 from the bark of the pacific yew tree (Taxus brevifolia) native to the northwest USA, and its structure elucidated. The compound, which is now marketed, contains an oxetane ring and displays a strong antitumour and antileukaemia activity. Its total synthesis has been achieved [5]. 

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