Huang Guanxin, Liu Minjie, Xiong Fangjun, Meng Ge, Tao Yuan, Wu Yan, Peng Haihui, Chen Fener
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, P. R. China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Molecules, Shanghai 200433, P. R. China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, P. R. China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Molecules, Shanghai 200433, P. R. China.
iScience. 2018 Nov 30;9:513-520. doi: 10.1016/j.isci.2018.11.010. Epub 2018 Nov 9.
Chiral syn-1,3-diols are fundamental structural motifs in many natural products and drugs. The traditional Narasaka-Prasad diastereoselective reduction from chiral β-hydroxyketones is an important process for the synthesis of these functionalized syn-1,3-diols, but it is of limited applicability for large-scale synthesis because (1) highly diastereoselective control requires extra explosive and flammable EtBOMe as a chelating agent under cryogenic conditions and (2) only a few functional syn-1,3-diol scaffolds are available. Those involving halogen-functionalized syn-1,3-diols are much less common. There are no reported diastereoselective reactions involving chemical fixation of CO/bromocyclization of homoallylic alcohols to halogen-containing chiral syn-1,3-diols. Herein, we report an asymmetric synthesis of syn-1,3-diol derivatives via direct diastereoselective carboxylation/bromocyclization with both relative and absolute stereocontrol utilizing chiral homoallylic alcohols and CO in one pot with up to 91% yield, > 99% ee, and >19:1 dr. The power of this methodology has been demonstrated by the asymmetric synthesis of statins at the pilot plant scale.
手性顺式 - 1,3 - 二醇是许多天然产物和药物中的基本结构基序。传统的从手性β - 羟基酮进行的 Narasaka - Prasad 非对映选择性还原是合成这些官能化顺式 - 1,3 - 二醇的重要过程，但它在大规模合成中的适用性有限，原因如下：（1）高度的非对映选择性控制需要在低温条件下使用额外的易爆易燃的 EtBOMe 作为螯合剂；（2）仅有少数官能化的顺式 - 1,3 - 二醇支架可用。涉及卤代官能化顺式 - 1,3 - 二醇的情况则更为少见。目前尚无报道涉及将 CO 化学固定/烯丙醇的溴环化反应生成含卤代手性顺式 - 1,3 - 二醇的非对映选择性反应。在此，我们报道了一种通过直接非对映选择性羧化/溴环化反应对顺式 - 1,3 - 二醇衍生物进行不对称合成的方法，该反应在一个反应釜中利用手性烯丙醇和 CO 同时实现了相对和绝对立体化学控制，产率高达 91%，对映体过量值（ee）> 99%，非对映体比例（dr）> 19:1。这种方法的强大之处已在中试规模的他汀类药物不对称合成中得到了证明。
