"選擇性1,3-偶極環加成用於合成帕拉米弗及其類似物"

Abstract

針對近來流感的流行問題，經過多年來眾多科學家的藥物開發，發現神經胺酸酶抑制劑可以用於流感的疫情控制，而在2000年，Babu等人開發出新型克流感藥物：帕拉米弗，它也在2014年被美國食品暨藥物管理局核准使用。這支藥物在合成過程中會經過一個1,3-偶極環加成反應，由於起始物「文斯內醯胺」缺少適當的導引基團，位置與立體選擇性的問題在近二十年來都未能被妥善解決。 在此研究中我們著重在1,3-偶極環加成反應的選擇性。我們一樣選擇以文斯內醯胺為起始物，單純透過適當的分子設計與條件最佳化，特別是使用N-三氟醋醯基來誘導位置選擇性，成功使選擇性大幅提升至94%(根據核磁共振光譜分析)，幾乎比原方法增加30%，經單一次管柱層析分離的產率也提升至77%，與傳統方法相比有將近三倍半的提升，這不僅有效的提升產率，更能大幅降低分離的複雜度。除此之外，我們搭配理論計算來輔佐運用，並且依據實驗結果提出模型來描述高選擇性的成因。這個方法除了改進傳統合成帕拉米弗使用的1,3-偶極環加成反應，同時也提供科學家一個便於在帕拉米弗的側鏈上修飾的方法，以進行結構與活性關係之研究。

Due to the influenza epidemic, many scientists devoted in the drug development and found that the neuraminidase inhibitors could be used for controlling the influenza outbreak. Peramivir, a FDA approved anti-influenza drug, was first synthesized by Babu and coworkers in 2000, and approved by FDA in 2014. The most common synthetic route involved a 1,3-dipolar cycloaddition from Vince lactam derivative. Due to lack of a directing group, the problem in regio- and stereoselectivity could not be solved properly in the past 20 years. In our work, we focused on the selectivity of 1,3-dipolar cycloaddition and modified the dipolarophile to improve the selectivity. In addition, computational analysis was carried out to support this work. We designed a series of Vince lactam derivatives to conduct 1,3-dipolar cycloadditions. After reaction optimization, especially using N-trifluoroacetyl to induce regioselectivity, we greatly improved the selectivity to 94% by NMR analysis, a nearly 30% increase compared to the conventional method. The isolated yield after single column chromatography was 77%, a 3.5-fold increase. This method was not only beneficial to the yield, but substantially reduced the procedure in purification. Furthermore, we did the computational analysis to support this work, and proposed several models to rationalize the causes of high selectivity based on the experimental data. In addition to improve the 1,3-dipolar cycloaddition leading to peramivir synthesis, our method also provides a convenient way to modify the side chain of peramivir, the structure–activity relationship (SAR) study.