Aggarwal Varinder K, Hynd George, Picoul Willy, Vasse Jean-Luc
School of Chemistry, Bristol University, Cantock's Close, UK.
J Am Chem Soc. 2002 Aug 28;124(34):9964-5. doi: 10.1021/ja0272540.
The reaction of an amide-stabilized sulfonium ylide bearing chiral groups on sulfur has been investigated. We have discovered that the camphor-derived amide-stabilized ylide reacts with aldehydes at -50 degrees C in ethanol to give glycidic amides in one step with up to 99% ee and complete diastereoselectivity. From analyzing reactions of different ratios of diastereomers at sulfur it was found that the major diastereomer gave very high enantioselectivity, while the minor one gave much lower selectivity (54% ee). Further mechanistic studies have revealed that enantioselectivity is controlled not in the betaine-forming step (C-C bond formation is reversible) but in the different barriers to bond rotation around the newly formed C-C of the two diastereomeric betaines. Further transformations of epoxyamides were investigated. It was found that epoxyamides could be converted into epoxyketones by reaction with organolithium reagents and that they could be ring-opened by nucleophiles with complete regioselectivity using Yb(OTf)3. The practicality of the process has been exemplified in the synthesis of SK&F 104353, a leukotriene D4 antagonist in the potential treatment of bronchial asthma.
对硫原子上带有手性基团的酰胺稳定的锍叶立德的反应进行了研究。我们发现，樟脑衍生的酰胺稳定叶立德在乙醇中于-50℃与醛反应，一步生成缩水甘油酰胺，对映体过量率高达99%，且具有完全的非对映选择性。通过分析硫原子上不同比例非对映异构体的反应发现，主要非对映异构体具有非常高的对映选择性，而次要非对映异构体的选择性则低得多（对映体过量率为54%）。进一步的机理研究表明，对映选择性不是在形成甜菜碱的步骤中控制的（碳-碳键形成是可逆的），而是在两种非对映异构甜菜碱围绕新形成的碳-碳键旋转的不同势垒中控制的。对环氧酰胺的进一步转化进行了研究。发现环氧酰胺可通过与有机锂试剂反应转化为环氧酮，并且使用Yb(OTf)3时，它们可被亲核试剂以完全的区域选择性开环。该方法的实用性已在潜在治疗支气管哮喘的白三烯D4拮抗剂SK&F 104353的合成中得到例证。
