Diols epoxide synthesis

Lee H, RG Harvey (1986) Synthesis of the active diol epoxide metabolites of the potent carcinogenic hydrocarbon 7,12-dunethybenz[a]anthacene. J Am Chem Soc 51 3502-3507. 

Synthesis of the Dihydrodiol and Diol Epoxide Metabolites of Carcinogenic Polycyclic Hydrocarbons... 

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

The scope and direction of these biological investigations have been largely determined by the development of methods for the synthesis of the PAH metabolites. The diol epoxides are not isolable as products of metabolism due to their exceptional chemical reactivity. 

Figure 11. Synthesis of the chrysene 1,2- and 3,4-dihydrodiols and the corresponding diol epoxide derivatives from chrysene by Method III (50. Reagents (i) H2,Pd (ii) H2,Pt (iii) DDQ (iv) AgOBZ,I25 (v) NBS A.

Synthesis of 31 by Method I (107,108) and its conversion to the related anti and syn diol epoxide derivatives (32,33) has been reported (108). The isomeric trans-1,lOb-dihydrodiot 37) and the corresponding anti and syn diol epoxide isomers (38,39) have also been prepared (108) (Figure 19). Synthesis of 37 from 2,3-dihydro-fluoranthene (109) could not be accomplished by Prevost oxidation. An alternative route involving conversion of 2,3-dihydrofluoranthene to the i8-tetrahydrodiol (3-J) with OsO followed by dehydration, silylation, and oxidation with peracid gave the Ot-hydroxyketone 35. The trimethylsilyl ether derivative of the latter underwent stereoselective phenylselenylation to yield 36. Reduction of 3 with LiAlH, followed by oxidative elimination of the selenide function afforded 3J. Epoxidation of 37 with t-BuOOH/VO(acac) and de-silylation gave 38, while epoxidation of the acetate of JJ and deacetylation furnished 39. 

Figure 19. Synthesis of the fluoranthene 1,lOb-dihydrodiol (37) and the corresponding anti and syn diol epoxide isomers (38) and 39). Reagents (i) OsO, (ii) H, (iii) Me Sil (iv) m-CPBA (v) Me SiCl (vi) LDA (vii) Me SiCl (viii) PhSeCl (ix) LiAlH, (x) H2325 (xi) K2C03.

Pyrolytic decomposition of cyclic carbonate eaten of 1,2-diols hjus been utilized on occasion for epoxide synthesis. Ethylene Oxide jiml glycidol, for example, have been prepared26 mc from ethylene carbonate and glyceryl carbonate respectively (Eq. 314). 

The Suzuki cross-coupling reaction is recognized as a novel, abbreviated method for the synthesis of 2-hydroxychrysene, 2-hydroxy-5-methylchrysene, and 8-hydroxy-5-methyl-chrysene from easily accessible reactants (Eq. (8)) [23]. These phenolic compounds constitute precursors for the synthesis of dihydrodiol and bay-region diol epoxide derivatives of chrysene and 5-methylchrysene, which are implicated as the active forms of carcinogenic polynuclear aromatic hydrocarbons. 

Rastetter WH, Nachbar RBJ, Russo-Rodriguez S, et al. 1982. Fluoranthene Synthesis and mutagenicity of 4 diol epoxides. J Org Chem 47 4873-4878. 

Dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate continues to be an important reagent in the inverse Diels-Alder reaction, and has been used in the synthesis of ningalin D <05JA10767>, dihydrodiol and diol epoxide of phthalazine <05T1545> and novel pyridazino-psoralen derivatives <05T4805>. 

The hydrolytic kinetic resolution addressed a long-standing problem in enan-tioselective epoxide synthesis. The ability to access almost any terminal epoxide or 1,2-diol in high enantiopurity greatly expanded the chiral pool of compounds available for asymmetric synthesis. Equally important was the demonstration of practicality and efficiency that renders the ARO of a racemic mixture a synthetically viable approach. 

Ruan, Q., Kolbanovskiy, A., Zhuang, P., Chen, J., Krzeminski,)., Amin, S., and Geacintov, N.E. (2002) Synthesis and characterization of site-specific and stereoisomeric fjord dibenzo[a,I]pyrene diol epoxide-JV6)-adenine adducts unusual thermal stabilization of modified DNA duplexes. Chem. Res. Toxicol, 15, 249-261. 

Rechkoblit, O., Zhang, Y., Guo, D., Wang, Z., Amin, S., Krzeminsky,)., Louneva, N., and Geacintov, N.E. (2002) trans-Lesion synthesis past bulky benzo[a]pyrene diol epoxide N -dG and N6-dA lesions catalyzed by DNA bypass polymerases. J. Biol. Chem., 277, 30488-30494. 

Moriya, M., Spiegel, S., Fernandes, A., Amin, S., Liu, T., Geacintov, N., and Grollman, A.P. (1996) Fidelity of translesional synthesis past benzoja] pyrene diol epoxide-2 -deoxyguanosine DNA adducts marked effects of host cell, sequence context, and chirality. Biochemistry, 35, 16646-16651. 

Li, Z., Zhang, H., McManus, T.P., McCormick, J.J., Lawrence, C.W., and Maher, V.M. (2002) hREV3 is essential for error-prone translesion synthesis past UV or benzojajpyrene diol epoxide-induced DNA lesions in human fibroblasts. Mutat. Res., 510, 71-80. 

Remington, K.M., Bennett, S.E., Harris, C.M., Harris, T.M., and Bebenek, K. (1998) Highly mutagenic bypass synthesis by T7 RNA polymerase of site-specific benzo[a]pyrene diol epoxide-adducted template DNA. J. Biol. Chem., ITS, 13170-13176. 

Synthesis and Reactivities of Aromatic Oxides. Much of the work in this area is generated from an interest in the carcinogenicity of many of the fused-ring aromatic oxides. Some syntheses of arene oxides and the chemistry of diol epoxides have been reviewed. 

Dehydrogenation of I -dibenzyloxytetrahydroarenes. In a recent synthesis of diol epoxides of carcinogenic arenes, Fu and Harvey found that 1,2-dibenzyloxytetra-hydroarenes are dehydrogenated in good yield by DDQ in refluxing dioxane. An example is formulated in equation (I). This method is superior to bromination-dehydrobromination the NBS route to 2 from 1 failed completely. 

For many years applications of the Bradsher reaction were restricted due to its limited substrate scope and requirement for harsh reaction conditions. However, after the advancement of the arene oxide concept concerning the metabolism of polycyclic aromatic hydrocarbons, synthesis of all the nuclear monohydroxylated derivatives of 7,12-dimethylbenz[a]-anthracene (DMBA), diol epoxide metabolites of DMBA, and fluoro derivatives of DMBA was undertaken for carcinogenicity and mutagenicity determination studies. " Interest in the Bradsher reaction has increased greatly as a consequence of the need to construct these polycyclic aromatic hydrocarbons. Development of fluoroanthracenylmethyl cinchonidine as an efficient phase-transfer catalyst for asymmetric glycine alkylation also expanded the scope of the Bradsher reaction. ... 

Diol epoxide metabolites of DMBA such as tra 5-3,4-dihydroxy-a //-1,2-epoxy-1,2,3,4-tetrahydro-DMBA (41) or rra 5-3,4-dihydroxy-s y -1,2-epoxy-1,2,3,4-tetrahydro-DMB A (42) has been implicated as the principle active form of DMBA which binds covalently to DNA in vivo. The intermediacy of 41 and 42 was further supported by the development of methods for their synthesis by using the Bradsher cyclization for the construction of the DMBA moiety, coupled with studies of their mutagenicity, tumorigenicity and DNA binding. ... 

Cyclization. A new approach to the synthesis of oxaziridines involves the reaction of tosyl chloride in aqueous alkaline solution with a cyclic nitrone this reaction appears to be mechanistically similar to the cyclization of diol monotosylates in epoxide synthesis. This method has been applied to heterocyclic steroidal nitrones (276). ° Photo-oxidation of cyclohexylamine may... 

Lee H, Luna E, Hinz M, Stezowski 11, Kiselyov AS, Harvey RG (1995) Synthesis of oligonucleotide adducts of the bay region diol epoxide metabolites of carcinogenic polycyclic aromatic hydrocarbons. J Oig Chem 60 5604-5613... 

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