Cirilli Roberto, Ferretti Rosella, La Torre Francesco, Borioni Anna, Fares Vincenzo, Camalli Mercedes, Faggi Cristina, Rotili Dante, Mai Antonello
Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy.
Chirality. 2009 Jun;21(6):604-12. doi: 10.1002/chir.20654.
Chiral 2-(sec-butylthio)-6-[1-(2,6-dichlorophenyl)propyl]-5-methylpyrimidin-4(3H)-one (compound 1) was synthesized to serve as a model compound for structural elucidation of novel S-DABO (dihydroalkoxybenzyloxopyrimidine) derivatives endowed with potential HIV-1 reverse transcriptase inhibitory activity. Stereochemical characterization of four stereoisomers of 1 was achieved by an experimental approach based on the following steps: (a) direct HPLC enantio- and diastereoseparation at semipreparative scale; (b) determination of elution order of stereomeric mixture by using chiroptical detection (polarimeter or circular dichroism (CD)); (c) X-ray crystallography of two diastereoisomers isolated at semipreparative scale. The CD analysis of 1 and its two analogues (compounds 2 and 3), both having a single stereogenic center located in two different alkyl side chains of the dihydropyrimidinone structure, was carried out. The results of this study indicated a correlation between the absolute configuration at C-1 of alkyl side chain of the dihydropyrimidinone structure and the sign of the CD band at around 245 nm.
合成了手性2-(仲丁硫基)-6-[1-(2,6-二氯苯基)丙基]-5-甲基嘧啶-4(3H)-酮（化合物1），作为具有潜在HIV-1逆转录酶抑制活性的新型S-DABO（二氢烷氧基苄氧基嘧啶）衍生物结构解析的模型化合物。通过基于以下步骤的实验方法实现了1的四种立体异构体的立体化学表征：(a) 在半制备规模下直接进行HPLC对映体和非对映体分离；(b) 使用手性光学检测（旋光仪或圆二色性（CD））确定立体异构体混合物的洗脱顺序；(c) 对在半制备规模下分离得到的两种非对映异构体进行X射线晶体学分析。对1及其两种类似物（化合物2和3）进行了CD分析，这两种类似物在二氢嘧啶酮结构的两个不同烷基侧链中均具有单个立体中心。本研究结果表明，二氢嘧啶酮结构烷基侧链C-1处的绝对构型与245 nm左右CD带的符号之间存在相关性。
