1.3- anti-diols

Benzyloxy-2-propenylchromium reagents are formed by the action of iodotrimethylsilane and chromium(II) chloride on 3,3-bis(benzyloxy)-l-propene in the presence of aldehydes, affording derivatives of anti-diols with good diastereoselectivity13. 

Benzo(c)phenanthrene (BcP) is exceptionally weak or inactive as a carcinogen in experimental animals (51). On the other hand, the bay region anti diol epoxide of BcP (14) exhibits high tumor initiating activity on mouse skin (65). 

These hexacyclic hydrocarbons are generally recognized as two of the most potent unsubstituted carcinogenic PAH (38). The 3,4-dihydro-diol of dibenzo(a,i)pyrene (17) and the 1,2-dihydrodiol of dibenzo-(a,h) pyrene (lg) have been synthesized from 4-oxo-l,2,3,4-tetra-hydrodibenzo(a,i)pyrene and 1-oxo-l,2,3,4-tetrahydrodibenzo(a,h)py-rene, respectively, by Method I. (69). Treatment of these dihydro-diols with m-chloroperbenzoic acid gave the corresponding anti diol epoxides (66). 

Epoxidation of the 3,4-dihydrodiol with m-chloroperbenzoic acid afforded stereospecifically the corresponding anti diol epoxide (74). Peracid oxidation of the bay region 1,2-dihydrodiol gave a mixture of the anti and syn diol epoxide diastereomers. Assignment of the major isomer as syn was made through analysis of the NMR spectra of the acetates of the tetraols formed on hydrolysis of the individual diol epoxides (42). Peracid oxidation of the 10,11-dihydrodiol is reported to yield the corresponding anti diol epoxide (12). However, it is likely for steric reasons that the syn isomer is also formed. 

The 9,10-dihydrodiol of 3-MC (24a) was synthesized from 9-hy-droxy-3-MC by Method IV (86). Oxidation of this phenol with Fremy s salt in the presence of Adogen 464, a quaternary ammonium phase transfer catalyst, furnished 3-MC 9,10-dione. Reduction of the qui-none with NaBH -C gave pure 24a in good yield. Treatment of 24a with m-chloroperbenzoic acid was monitored by HPLC in order to optimize the yield of the anti diol epoxide (25 ) and minimize its decomposition. 

Epoxidation of the 1,2- and 7,8-dihydrodiols of 5-MC with m-chloroperbenzoic acid furnished the corresponding anti diol epoxides 26 and J27. Compound 26 was the first diol epoxide bearing a methyl group in the same bay region as the epoxide function to be synthesized. While the diol epoxide 26 is relatively reactive (104), it is more stable than the structurally analogous DMBA 1,2-diol-3,4-epoxide (21) it was obtained as a white crystalline solid. 

Figure 14. (a,b) Views of the structure of an anti-diol epoxide... 

Figure 15. Structures of analogs of the anti-diol epoxide, (a) Klein and Stevens (95), (b) Zacharias, Glusker and Whalen (96).

As described earlier in Chapter 2, B[a]P is metabolized mainly to the 7R 7.8-transdihvdrodiol. However, both enantiomers are further epoxidized on the lower face of the molecule. Thus, while the 7R enantiomer forms mainly the anti-diol epoxide, the 7S enantiomer forms mainly svn-diol epoxide. In some systems, such as human colon (138) or hamster embryo cells (139), significant quantities of svn-diol epoxide adducts are found, including adducts... 

Table I. Relative Yields of Diastereomeric Adducts From Anti-diol Epoxide Plus Polyguanylic Acid Compared to Adducts Generated During Metabolism of BP-7,8-dihydrodiol by Ram Seminal Vesicles in the Presence of Arachidonic Acid...

These findings indicate that PGH synthase in the presence of arachidonate can catalyze the terminal activation step in BP carcinogenesis and that the reaction may be general for dihydrodiol metabolites of polycyclic hydrocarbons. Guthrie et. al. have shown that PGH synthase catalyzes the activation of chrysene and benzanthracene dihydrodiols to potent mutagens (33). As in the case with BP, only the dihydrodiol that is a precursor to bay region diol epoxides is activated. We have recently shown that 3,4-dihydroxy-3,4-dihydro-benzo(a)anthracene is oxidized by PGH synthase to tetrahydrotetraols derived from the anti-diol epoxide (Equation 4) (34). 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

In the hydrogenation of diketones by Ru-binap-type catalysts, the degree of anti-selectivity is different between a-diketones and / -diketones [Eqs (13) and (14)]. A variety of /1-diketones are reduced by Ru-atropisomeric diphosphine catalysts to indicate admirable anti-selectivity, and the enantiopurity of the obtained anti-diol is almost 100% (Table 21.17) [105, 106, 110-112]. In this two-step consecutive hydrogenation of diketones, the overall stereochemical outcome is determined by both the efficiency of the chirality transfer by the catalyst (catalyst-control) and the structure of the initially formed hydroxyketones having a stereogenic center (substrate-control). The hydrogenation of monohydrogenated product ((R)-hydroxy ketone) with the antipode catalyst ((S)-binap catalyst) (mis-... 

Scheme 11.31. The transformation of an ester group in 118 into a vinyl ketone moiety in the preparation of the anti-diol 122 [76],...

Preparation of optically active anti-diol ester (2S,3R)-9... 

The reduction of /1-hydroxy ketones with a tetramethylammonium triace-toxyborohydride-anhydrous acetic acid system yielded the anti diols via the transition state (TA). The stereochemistry of the 1,3-diols was assigned by using H NMR coupling constants after their conversion to the corresponding cyclic acetonide. 

Rodriguez H, Loechler EL. 1993. Mutational specificity of the (+) - anti-diol epoxide of benzo [a] pyrine in a supF gene of an Escherichia coli plasmid DNA sequence context influences hotspots, mutagenic specificity and the extent of SOS enhancements of mutagenesis. Carcinogenesis 14(3) 373-383. 

---