Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO BOX 368, Ridgefield, Connecticut 06877-0368, USA.
J Org Chem. 2013 Apr 19;78(8):3592-615. doi: 10.1021/jo400080y. Epub 2013 Apr 1.
The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.
本文介绍了锌介导和催化的三氟甲基酮与丙炔基硼酸和 N-异丙基-L-脯氨酸配体的不对称丙炔化反应的发展。该方法提供了中等至高的立体选择性，并成功地应用于多公斤规模的糖皮质激素激动剂 BI 653048 的合成。提出了硼-锌与丙炔基硼酸交换的机理，并通过密度泛函理论的建模得到了支持。发现水对锌催化的丙炔化具有加速作用，从而实现了催化过程。反应进度分析支持锌催化的丙炔化主要是受交换限制。提出催化量的水来生成一种中间体，该中间体可以催化交换，从而促进与三氟甲基酮的反应。
