Chemistry Research Laboratory, Department of Chemistry , University of Oxford , Mansfield Road , Oxford OX1 3TA , United Kingdom.
The Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 151-742 , Korea.
J Org Chem. 2019 May 3;84(9):4971-4991. doi: 10.1021/acs.joc.8b02975. Epub 2019 Apr 12.
Despite numerous advances in spectroscopic methods through the latter part of the 20th century, the unequivocal structure determination of natural products can remain challenging, and inevitably, incorrect structures appear in the literature. Computational methods that allow the accurate prediction of NMR chemical shifts have emerged as a powerful addition to the toolbox of methods available for the structure determination of small organic molecules. Herein, we report the structure determination of a small, stereochemically rich natural product from Laurencia majuscula using the powerful combination of computational methods and total synthesis, along with the structure confirmation of notoryne, using the same approach. Additionally, we synthesized three further diastereomers of the L. majuscula enyne and have demonstrated that computations are able to distinguish each of the four synthetic diastereomers from the 32 possible diastereomers of the natural product. Key to the success of this work is to analyze the computational data to provide the greatest distinction between each diastereomer, by identifying chemical shifts that are most sensitive to changes in relative stereochemistry. The success of the computational methods in the structure determination of stereochemically rich, flexible organic molecules will allow all involved in structure determination to use these methods with confidence.
尽管在 20 世纪后期，光谱方法取得了许多进展，但明确确定天然产物的结构仍然具有挑战性，并且不可避免地，错误的结构会出现在文献中。计算方法可以准确预测 NMR 化学位移，这些方法已经成为确定小分子有机化合物结构的有力工具。在此，我们报告了使用计算方法和全合成的强大组合，对来自大柳珊瑚的小型立体化学丰富的天然产物进行结构确定，以及使用相同方法对诺替尼进行结构确证。此外，我们合成了大柳珊瑚烯炔的另外三个非对映异构体，并证明计算能够将四个合成非对映异构体中的每一个与天然产物的 32 个可能非对映异构体区分开来。这项工作成功的关键是通过识别对相对立体化学变化最敏感的化学位移，来分析计算数据，从而为每个非对映异构体提供最大的区分。计算方法在立体化学丰富、灵活的有机分子结构确定中的成功，将使所有参与结构确定的人员都能够有信心地使用这些方法。
