Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering , Shanghai Jiao Tong University , 800 Dongchuan Road , Shanghai 200240 , P. R. China.
J Am Chem Soc. 2018 Jun 20;140(24):7587-7597. doi: 10.1021/jacs.8b02865. Epub 2018 Jun 12.
We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C═C double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.
我们开发了一种不对称的氮-对甲苯磺酰基腙封端的四取代烯烃的氮杂-Wacker 型环化反应，能够提供手性的四取代碳中心的手性吡唑啉。在温和的反应条件下，该反应对广泛的底物具有耐受性，能够以高对映选择性得到所需的手性产物。在 C=C 双键上生成两个相邻的立体中心的选择性也很高，这是 Wacker 型反应中很少研究的过程。一项机理研究表明，这种氮杂-Wacker 型环化反应经历顺式-氨基钯化过程。还发现，对于在外烯碳原子上具有两个线性烷基取代基的底物，这两个取代基都大于甲基，与亲核基团处于顺式的烷基取代基更容易进行β-氢消除。当烯烃外碳原子上的两个烷基取代基之一是甲基时，β-氢消除在亚甲基侧选择性进行，因此可以通过改变烯烃的构型来制备两种非对映异构体。此外，产物可以通过三步反应以高产率转化为药物化合物。
