The C-7 Hydroxyl Group

The C-7 hydroxyl group is in many ways the most accessible functional group on the taxane ring system, and is second in reactivity only to the C-2 hydroxyl group in the side chain. For this reason its chemistry has been studied fairly extensively, and many simple derivatives have been prepared. Thus the acetyl derivative 4.1.1.1 (140,141), benzoyl derivative 4.1.1.2 (142), glutaiyl derivative 4.1.1.3 (143), amino acid derivatives 4.1.1.4-4.1.1.6 (144), chloroacetyl derivative 4.1.1.7 (145), and a docosahexaenoic acid derivative 4.1.1.8 (146) have all been prepared and found to have comparable activity to taxol. 

Acyl derivatives at C-7 have been used as probes with the potential for the study of the interaction of taxol and the microtubule. The results stemming from the use of some of these probes will be discussed in section 11. As examples the 7-azidobenzoyl analog 4.1.1.13, (150), the diazirine 4.1.1.14 (757), various aminobenzoyl derivatives such as 4.1.1.15 (752) and the benzophenone derivative 4.1.1.16 (755) have all been prepared. 

The C-7 position has also been used as a place of attachment of cleavable water-solubilizing groups. Simple acyl groups and phosphate groups at C-7 are not readily cleaved under physiological conditions 

Various ether derivatives of taxol have also been prepared. Simple C-7 silyl ethers have poor in vitro cytotoxicity (148 but other ether derivatives sometimes have improved activity. Thus treatment of 2 -protected taxol derivatives with chloromethyl methyl ether followed by deprotection yields the acetal derivative 4.1.1.19 (757), while treatment of baccatin III with dimethyl sulfide in the presence of benzoyl peroxide followed by coupling with side chain gives thiomethyl derivatives such as 4.1.1.20 (158). This latter compound has been selected for development by Bristol-Myers Squibb, and is currently in clinical trials (759). Other ethers such as the amino acid derivative 4.1.1.21 have also been prepared by treatment of 4.1.1.20 with chloroacetic acid, N-iodosuccinimide, and silver triflate followed by N-methylpiperazine (158). 

7-Deoxytaxol and 7,10-dideoxytaxol have also been prepared by a similar route starting from baccatin III 162) this group also prepared 7-epi-lO-deoxytaxol 163). 7-Deoxytaxol has a cytotoxicity comparable to taxol, but 7,10-dideoxytaxol is significantly less cytotoxic to HCT116 cells 162). 

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Regioselective protection of the pentaol 230 with bis-trichloromethyl carbonate and subsequent acetic anhydride treatment affords the C-10 acetoxy C-l, C-2 carbonate compound 231 in good yield. Deprotection of the acetonide function and regioselective silylation of the C-7 hydroxyl group, followed by... 

If we assume that the above dehydration occurs with retention of configuration at C-7, the ready formation of the anhydro derivative from platynecine and the inertness of dihydroxyheliotridane apparently indicate a cis-relationship of the C-7 hydroxyl group with respect to the hydroxymethyl group in platynecine and a Iraws-conformation in dihydroxyheliotridane.1,78 A reversed relationship would follow from the alternative assumption of inversion at C-7. 

Fig. 9. Zanamivir derivatives modified through alkylation of the C-7 hydroxyl group. Values in parentheses reflect IC50 values against influenza A virus in a plaque-reduction assay, and are relative to a reference value of 1.0 for Zanamivir (1).

The final structural proof for guatterine (XVIII) rests upon its conversion by chromium trioxide in pyridine into the alkaloid athero-spermidine (XXI) which was also found in G. psilopus and whose structure was established by its oxidative degradation to 1-azaanthra-quinone-4-carboxylic acid (XXII). It is interesting to note that the relative stereochemistry of the C-7 hydroxyl group in guatterine is opposite to that of the hydroxyl in ushinsunine (XXIII) where the Jea,7 value is only 2.5 cps. The absolute configuration of guatterine has not yet been established. 

Hydroxy THCs, which are major metabolites, are very potent cannabimimetics. Monohydroxylation on other position of the terpene ring also usually leads to active derivatives. Dihydroxylation generally causes loss of activity. Further oxidation of the C-7 hydroxyl group to a carboxyl group causes inactivation. 

In the antibiotic substance, this nine-carbon sugar derivative is attached glycosidically to the C-7 hydroxyl group of 3-[4-hydroxy-3-(3-methyl-2-butenyl)benzamido3-4,7-dihydroxy-8-methylcoumarin (56). 

Direct oxidation of the C-10 hydroxyl group of 10-deacetylbaccatin III was studied by Appendino (42), who found that it could be oxidized with moderate selectivity as compared with the C-13 hydroxyl group by treatment with Mn02 in acetonitrile. Treatment with Cu(OAc)2 oxidized the C-10 hydroxyl group with complete selectivity, but also epimerized the C-7 hydroxyl group. 

Subsequent work from the same group showed that protection as the acetonide was unnecessary as long as the C-7 hydroxyl group was protected as its triethylsilyl derivative 3.2.6, and a variety of 3 -N-acyl analogs 3.2.7 (R = various) (99) and 3 -modified analogs 3.2.7 (R = various) 100) were prepared. The synthesis of additional analogs, including ether derivatives 3.2.8 and 3.2.9, and their cytotoxic activities... 

A C-4 methyl ether derivative of taxol has been made by similar methods. The C-4 deacetylbaccatin III derivative 4.3.1.7 was methylated with LHMDS and methyl triflate to give the protected C-4 methyl ether, which was deprotected to give the ether 4.3.2.7. Interestingly the C-13 hydroxyl group of this compound was more reactive to silylation than the C-7 hydroxyl group, which is the reverse of the normal order due to... 

The C-7 hydroxyl group continues to be a favorite position for deri-vatization. Mastalerz and his colleagues prepared 7/ -thiol derivatives such as A4.1.1-A4.1.3 by displacement of the 7/3-triflate with potassium thioacetate followed by epimerization and alkylation. The analog A4.1.2 was five times more cytotoxic than taxol to the HCT-116 cell line (524). 

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