Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis
Highly diastereoselective synthesis of nucleoside adducts from the carcinogenic benzo[a]pyrene diol epoxide and a computational analysis
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DOI：
10.1021/ja063902u
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发表时间：
2007-01-10
影响因子：
15
通讯作者：
Thomasson, Kathryn A.
中科院分区：
文献类型：
--
作者：
Lakshman, Mahesh K.;Keeler, John C.;Thomasson, Kathryn A.
描述了对应于致癌物（+/-）-7 β，8 α-二羟基-9 α，10 α-环氧-7，8，9，10-四氢苯并[a]芘（BaP DE-2）通过2 ′-脱氧腺苷和2 ′-脱氧鸟苷的顺式开环的核苷加合物的非对映选择性合成。通过高度非对映选择性的二羟基化反应合成了关键中间体（+/-）-10 α-氨基-7 β，8 α，9 α-三羟基-7，8，9，10-四氢苯并[a]芘，其中苯基硼酸是水的替代物。将所得硼酸酯转化为四醇衍生物，其中四个羟基中的两个（反式7，8）被保护为苯甲酸酯，而剩余的两个（顺式9，10）是游离的。然后使顺式二醇实体与乙酸1-氯羰基-1-甲基乙酯反应，得到中间体氯代单乙酰氧基二苯甲酸酯。用叠氮化物取代卤化物，酯完全裂解，叠氮化物催化还原，得到所需的氨基三醇。用氨基三醇从适当保护的核苷衍生物6-氟嘌呤2 '-脱氧核糖核苷和2-氟-2'-脱氧次黄苷置换氟，然后产生二醇环氧化物加合的2 '-脱氧腺苷（dA）和2'-脱氧鸟苷（dG）核苷的非对映体对。分离这些加合物的小等分试样用于表征目的。本方法提供了B a PDE-2与2 '-脱氧鸟苷的顺式加合物的首次非对映选择性合成，以及从共同中间体首次合成dA和dG加合物。的H-1 NMR谱的顺式加合物的合成和比较的反式加合物的信息分析报告。为了深入了解在关键的二羟基化步骤中的非对映选择性，计算分析，包括分子力学（MMFF 94）和半经验AM 1几何优化，产生的结果是相当好的协议与实验观察。
A diastereoselective synthesis of the nucleoside adducts corresponding to a cis ring-opening of the carcinogen (+/-)-7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene (BaP DE-2) by 2'-deoxyadenosine and 2'-deoxyguanosine is described. The key intermediate (+/-)-10 alpha-amino-7 beta, 8 alpha,9 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a] pyrene was synthesized by a highly diastereoselective dihydroxylation wherein phenylboronic acid was a water surrogate. The resulting boronate ester was converted to a tetraol derivative in which two of the four hydroxyl groups (trans 7, 8) were protected as benzoate esters while the remaining two (cis 9, 10) were free. The cis glycol entity was then subjected to a reaction with 1-chlorocarbonyl-1-methylethylacetate to yield an intermediate chloro monoacetoxy dibenzoate. Displacement of the halide with azide, complete cleavage of the esters, and catalytic reduction of the azide yielded the requisite amino triol. Fluoride displacement from appropriately protected nucleoside derivatives, 6-fluoropurine 2'-deoxyribonucleoside and 2-fluoro-2'-deoxyinosine, by the amino triol then yielded diastereomeric pairs of diol epoxide-adducted 2'-deoxyadenosine (dA) and 2'-deoxyguanosine (dG) nucleosides. Small aliquots of these adducts were separated for characterization purposes. The present approach provides the first diastereoselective synthesis of the cis adducts of B a P DE-2 with 2'-deoxyguanosine as well as the first synthesis of both dA and dG adducts from a common intermediate. An informative analysis of the H-1 NMR spectra of the cis adducts synthesized and comparisons to the trans adducts are reported. To gain insight into the diastereoselectivity in the key dihydroxylation step, a computational analysis, including molecular mechanics (MMFF94) and semiempirical AM1 geometry optimizations, yielded results that are in fairly good agreement with the experimental observations.