Attaluri Sivaprasad, Iden Charles R, Bonala Radha R, Johnson Francis
Department of Pharmacological Sciences, and ‡Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Chem Res Toxicol. 2014 Jul 21;27(7):1236-42. doi: 10.1021/tx500122x. Epub 2014 Jun 11.
Plants from the Aristolochia genus have been recommended for the treatment of a variety of human ailments since the time of Hippocrates. However, many species produce the highly toxic aristolochic acids (AAs), which are both nephrotoxic and carcinogenic. For the purposes of extensive biological studies, a versatile approach to the synthesis of the AAs and their major metabolites was devised based primarily on a Suzuki-Miyaura coupling reaction. The key to success lies in the preparation of a common ring-A precursor, namely, the tetrahydropyranyl ether of 2-nitromethyl-3-iodo-4,5-methylendioxybenzyl alcohol (27), which was generated in excellent yield by oxidation of the aldoxime precursor 26. Suzuki-Miyaura coupling of 27 with a variety of benzaldehyde 2-boronates was accompanied by an aldol condensation/elimination reaction to give the desired phenanthrene intermediate directly. Deprotection of the benzyl alcohol followed by two sequential oxidation steps gave the desired phenanthrene nitrocarboxylic acids. This approach was used to synthesize AAs I-IV and several other related compounds, including AA I and AA II bearing an aminopropyloxy group at position-6, which were required for further conversion to fluorescent biological probes. Further successful application of the Suzuki-Miyaura coupling reaction to the synthesis of the N-hydroxyaristolactams of AA I and AA II then allowed the synthesis of the putative, but until now elusive, N-acetoxy- and N-sulfonyloxy-aristolactam metabolites.
自希波克拉底时代起,马兜铃属植物就被推荐用于治疗多种人类疾病。然而,许多物种会产生剧毒的马兜铃酸(AAs),这些酸具有肾毒性和致癌性。为了进行广泛的生物学研究,主要基于铃木-宫浦偶联反应设计了一种通用的合成AAs及其主要代谢物的方法。成功的关键在于制备一种常见的A环前体,即2-硝基甲基-3-碘-4,5-亚甲基二氧基苄醇(27)的四氢吡喃基醚,它是通过肟前体26的氧化以优异的产率生成的。27与各种苯甲醛2-硼酸酯的铃木-宫浦偶联反应伴随着羟醛缩合/消除反应,直接得到所需的菲中间体。苄醇脱保护后,经过两个连续的氧化步骤得到所需的菲硝基羧酸。该方法用于合成AAs I-IV和其他几种相关化合物,包括在6位带有氨丙氧基的AA I和AA II,这是进一步转化为荧光生物探针所必需的。铃木-宫浦偶联反应随后在AA I和AA II的N-羟基马兜铃内酰胺合成中的进一步成功应用,使得合成假定的但迄今为止难以捉摸的N-乙酰氧基和N-磺酰氧基马兜铃内酰胺代谢物成为可能。