Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, 200062, China.
Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, Hainan Normal University, Haikou, 571158, China.
Nat Commun. 2021 Apr 8;12(1):2219. doi: 10.1038/s41467-021-22374-y.
1,2-Dihydropyridines are valuable and reactive synthons, and particularly useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. However, the catalytic enantioselective synthesis of structurally diverse 1,2-dihydropyridines is limited to enantioselective addition of nucleophiles to activated pyridines. Here, we report a modular organocatalytic Mannich/Wittig/cycloisomerization sequence as a flexible strategy to access chiral 1,2-dihydropyridines from N-Boc aldimines, aldehydes, and phosphoranes, using a chiral amine catalyst. The key step in this protocol, cycloisomerization of chiral N-Boc δ-amino α,β-unsaturated ketones recycles the waste to improve the yield. Specifically, recycling by-product water from imine formation to gradually release the true catalyst HCl via hydrolysis of SiCl, whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste PhPO from the Wittig step to modulate the acidity of HCl. This approach allows facile access to enantioenriched 2-substituted, 2,3- or 2,6-cis-disubstituted, and 2,3,6-cis-trisubstituted piperidines.
1,2-二氢吡啶是一种有价值且反应性的合成子，特别适合用于合成哌啶和吡啶，而哌啶和吡啶是药物中最常见的结构单元之一。然而，具有结构多样性的 1,2-二氢吡啶的催化对映选择性合成仅限于亲核试剂对活化吡啶的对映选择性加成。在这里，我们报告了一种模块化的有机催化 Mannich/Wittig/环异构化序列，作为一种灵活的策略，使用手性胺催化剂从 N-Boc 亚胺、醛和膦烷中获得手性 1,2-二氢吡啶。该方案中的关键步骤是手性 N-Boc δ-氨基 α,β-不饱和酮的环异构化，通过 SiCl 的水解循环利用废物以提高产率。具体来说，通过水解 SiCl 将亚胺形成过程中的副产物水逐渐释放出真正的催化剂 HCl，同时保持低浓度的 HCl 以抑制副反应，并从 Wittig 步骤中再利用废 PhPO 来调节 HCl 的酸度。这种方法可以方便地获得对映体富集的 2-取代、2,3-或 2,6-顺二取代和 2,3,6-顺三取代的哌啶。
