Ghosh Arun K, Belcher Miranda R
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
J Org Chem. 2020 Aug 21;85(16):10399-10412. doi: 10.1021/acs.joc.0c00390. Epub 2020 Aug 5.
Lewis acid-catalyzed rearrangements of 4,5-dihydro-1,3-dioxepines have been investigated. Rearrangement of vinyl acetals under a variety of conditions resulted in - and 2,3-disubstituted tetrahydrofuran derivatives in a highly stereoselective manner. Rearrangements at lower temperatures typically provided the -2,3-disubstituted tetrahydrofuran carbaldehydes. At higher temperatures, the corresponding -2,3-disubstituted tetrahydrofuran carbaldehydes are formed. The requisite substrates for the vinyl acetal rearrangement were synthesized via ring-closing olefin metathesis of bis(allyoxy)methyl derivatives using Grubbs second-generation catalyst followed by olefin isomerization using a catalytic amount of RuCl(PPh). We examined the substrate scope using substituted aromatic and aliphatic derivatives. Additionally, the rearrangement was utilized in the synthesis of a stereochemically-defined bis-tetrahydrofuran (bis-THF) derivative, which is one of the key structural elements of darunavir, an FDA-approved drug for the treatment of HIV/AIDS.
已对路易斯酸催化的4,5-二氢-1,3-二氧杂环庚烷重排反应进行了研究。在各种条件下，乙烯基缩醛的重排以高度立体选择性的方式生成了α-和β-2,3-二取代的四氢呋喃衍生物。较低温度下的重排通常生成α-2,3-二取代的四氢呋喃甲醛。在较高温度下，则形成相应的β-2,3-二取代的四氢呋喃甲醛。乙烯基缩醛重排所需的底物是通过使用格拉布第二代催化剂对双（烯丙氧基）甲基衍生物进行闭环烯烃复分解反应，然后使用催化量的RuCl(PPh)进行烯烃异构化反应合成的。我们使用取代的芳香族和脂肪族衍生物研究了底物范围。此外，该重排反应还被用于合成一种立体化学定义的双四氢呋喃（双-THF）衍生物，它是达芦那韦的关键结构元素之一，达芦那韦是一种经美国食品药品监督管理局批准用于治疗HIV/AIDS的药物。
