Syntheses of 7‐(2‐Hydroxy‐1‐phenylethyl)‐ and 7‐(2‐Hydroxy‐2‐phenylethyl)guanine, DNA Adducts Derived from Styrene 7,8‐Oxide

Abstract

Abstract7‐(2‐Hydroxy‐1‐phenylethyl)‐ and 7‐(2‐hydroxy‐2‐phenylethyl)guanines are important DNA adducts which can be used as markers of exposure to styrene. Two synthetic routes leading to these compounds are presented using allyl‐protected bromohydrins as synthetic equivalents of styrene oxide to alkylate 2‐amino‐6‐chloropurine or 7‐methyl‐10‐oxo‐9,10‐dihydropyrimido[1,2‐a]purine as precursors to guanine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Synthesis of 3‐(2‐hydroxy‐1‐phenylethyl)‐ and 3‐(2‐hydroxy‐2‐phenylethyl)adenine, DNA adducts derived from styrene

“…For guanine derivatives they ranged from 74 -96 % and were slightly better than those previously reported (68-90%) [11] with the catalytic system using ZnCl 2 as an acid. In the palladium complex catalyzed deallylation, coordination of the allylic π-electrons to palladium is essential to enable subsequent reductive cleavage of the allyl group.…”

“…Styrene 7,8-oxide is a weak electrophile reacting with nucleophiles non-selectively at both α-and β-position giving rise to two isomeric products. In our previous work we found that allyl and benzyl protected bromohydrins 2a,b and 3a,b can be used as suitable synthetic equivalents of 1 to achieve selective alkylation (Scheme 1) [10,11]. In addition, benzyl-protected triflate 2benzyloxy-2-phenylethyl triflate (4) [12] was tested as a more reactive alkylating reagent.…”

“…Allylic groups in bromoadenines 9a -12a were resistant to deallylation procedures such as cleavage with NaBH 4 /I 2 [16], SmI 2 [17], DIBAL with [NiCl 2 (dppp)] as a catalyst [18] and PhSiH 3 with Pd(PPh 3 ) 4 as a catalyst [19]. Catalytic deallylation using Pd(PPh 3 ) 4 , ZnCl 2 and poly(methyl)hydrosiloxane (PMHS) [20] which we successfully applied previously to similar allyl-protected guanine derivatives [10,11], gave poor yields (10 % at most) with bromoadenines 9a -12a. However, when ZnCl 2 was replaced by TsOH as a stronger acid, deallylation proceeded smoothly along with reduction of bromine in the position 8 (Scheme 3).…”

“…was prepared by bromination of adenine in aqueous solution [22]. Alkylating reagents, i.e., 2-bromo-1-phenylethanol (2) [23], allyl(2-bromo-1-phenylethyl) ether (2a) [11], allyl(2-bromo-2-phenylethyl) ether (3a) [11], benzyl(2-bromo-1-phenylethyl) ether (2b) [11], benzyl(2-bromo-2-phenylethyl) ether (3b) [24] and 2-benzyloxy-2-phenylethyl triflate (4) [12] were prepared according to published procedures. (3a or 3b).…”

Syntheses of O6‐Alkyl‐ and Arylguanine Derivatives: Nucleobase Adducts Derived from Styrene 7,8‐ and 3,4‐Oxides

“…[5,6] In our previous work we described syntheses of 7-alkylguanines derived from styrene 7,8-oxide (1), a carcinogenic metabolite of styrene. [7] To extend the range of nucleobase adducts that can be used as markers of exposure to styrene, we hereby present synthetic routes leading to O 6 -alkylguanines derived from styrene 7,8-oxide (1) and O 6 -arylguanines derived from arene oxide metabolites of styrene, such as styrene 3,4-oxide (2), 4-(2-hydroxyethyl)benzene 1,2-oxide (3) and 4-carboxymethylbenzene 1,2-oxide (4). A simplified view of the possible formation of O 6 -guanine adducts from styrene metabolites and metabolic intermediates is shown in Scheme 1.…”