Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
J Org Chem. 2011 May 20;76(10):3676-83. doi: 10.1021/jo102114f. Epub 2011 Apr 14.
An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of (19)F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC(50) = 14.12 μM) in drug-resistant MDA-MB-231 breast cancer cells.
报道了一种羰基α-亚甲基化的有效方法，该转化通过在形成烯烃时易于消除三氟乙酸酯来完成。在存在空间位阻的情况下，该方法优于现有方案，我们已经证明了该方法在一系列酮、内酰胺和内酯中的实用性。此外，我们还将该方法应用于天然产物(+)-喇叭茶醇和(-)-eburnamonine 的半合成衍生物的合成，其中羰基靠近大体积的官能团。通过(19)F NMR 的时程还提供了机理见解。对天然产物衍生烯酮的生物学评估导致鉴定出(-)-eburnamonine 的一种衍生物具有显著的细胞毒性(LC(50)=14.12 μM)，在耐药 MDA-MB-231 乳腺癌细胞中。
