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Abstract
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 SiCl4, whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste Ph3PO 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.
Highlights
1,2-Dihydropyridines are valuable and reactive synthons, and useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals
We report an organocatalytic strategy for the modular synthesis of chiral 1,2-dihydropyridines from readily available starting materials, namely, a Mannich/Wittig/cycloisomerization sequence (Fig. 1c)[25]
There appears to be only one earlier report on a similar transformation; Donohoe et al utilized a stoichiometric amount of trifluoroacetic acid (TFA) to promote the cycloisomerization of racemic N-tosyl δ-amino enones without a γ-substituent, at 80 °C30
Summary
1,2-Dihydropyridines are valuable and reactive synthons, and useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. Despite intensive studies and significant achievements[5,6,7], the predictable and modular assembly of substituted piperidines in high diastereomeric excess (de) and enantiomeric excess (ee) from readily available starting materials, using inexpensive chiral catalysts, remains a challenge; the tailor-made metal-free synthesis of substituted pyridines with high chemo- and regioselectivity are limited[5] In this context, the 1,2-dihydropyridines are common precursors for the synthesis of piperidines or pyridines, via reduction or oxidation, respectively. We report an organocatalytic strategy for the modular synthesis of chiral 1,2-dihydropyridines from readily available starting materials, namely, a Mannich/Wittig/cycloisomerization sequence (Fig. 1c)[25] This approach takes advantage of the proline-catalyzed Mannich reaction of N-Boc imines and aldehydes, established by List and coworkers[26,27,28], to induce a very high level of asymmetry. Advantages expected from this strategy include the use of inexpensive chiral catalysts, achieving high structural diversity by varying the substituents of each substrate, no contamination from transition metals, and the use of an removable Boc protecting group
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