Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Magn Reson Chem. 2013 Feb;51(2):82-8. doi: 10.1002/mrc.3909. Epub 2012 Dec 11.
N-Formyl-1-bromo-4-hydroxy-3-methoxymorphinan-6-one (compound 2), an important intermediate in the NIH Opiate Total Synthesis, presumably exists as a mixture of two rotamers (Z and E) in both CHCl(3) and DMSO at room temperature due to the hindered rotation of its N-C18 bond in the amide moiety. By comparing the experimental (1)H and (13)C chemical shifts of a single rotamer and the mixture of compound 2 in CDCl(3) with the calculated chemical shifts of the geometry optimized Z and E rotamers utilizing density functional theory, the crystalline rotamer of compound 2 was characterized as having the E configuration. The energy barrier between the two rotamers was also determined with the temperature dependence of (1)H and (13)C NMR coalescence experiments, and then compared with that from the reaction path for the interconversion of the two rotamers calculated at the level of B3LYP/6-31G*. Detailed geometry of the ground state and the transition states of both rotamers are given and discussed.
N-Formyl-1-bromo-4-hydroxy-3-methoxymorphinan-6-one（化合物 2），NIH 阿片类药物全合成中的一个重要中间体，由于酰胺部分的 N-C18 键的受阻旋转，在室温下，它在 CHCl(3) 和 DMSO 中可能以两种构象（Z 和 E）的混合物形式存在。通过比较化合物 2 在 CDCl(3) 中的单一构象和混合物的实验 (1)H 和 (13)C 化学位移与利用密度泛函理论优化的 Z 和 E 构象的计算化学位移，确定化合物 2 的晶体构象为 E 构型。通过 (1)H 和 (13)C NMR 核各向同性位移实验随温度变化的关系确定了两种构象之间的能垒，然后与从 B3LYP/6-31G*水平计算的两种构象互变反应路径的能垒进行了比较。给出并讨论了两种构象的基态和过渡态的详细几何形状。
