Enantioselective Desymmetrization of 1,4‐Dihydropyridines by Oxidative NHC Catalysis

Abstract

The unprecedented desymmetrization of prochiral dialdehydes catalyzed by N-heterocyclic carbenes under oxidative conditions was applied to the highly enantioselective synthesis of 1,4-dihydropyridines (DHPs) starting from 3,5-dicarbaldehyde substrates. Synthetic elaboration of the resulting 5-formyl-1,4-DHP-3-carboxylates allowed for access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates (Hantzsch esters). DFT calculations suggested that the enantioselectivity of the process is determined by the transition state involving the oxidation of the Breslow intermediate by the external quinone oxidant.

Enantioselective N‐Acylation of Biginelli Dihydropyrimidines by Oxidative NHC Catalysis

“…Recycle of Oxidant 8: The alcohol resulting from oxidant 8 reduction (3,3',5,5'‐tetra‐ tert ‐butyl‐[1,1'‐biphenyl]‐4,4'‐diol) was recovered by column chromatography after each run of Table . The subsequent oxidation to 8 was performed stirring the 3,3',5,5'‐tetra‐ tert ‐butyl‐[1,1'‐biphenyl]‐4,4'‐diol (578 mg, 1.41 mmol) with 11 (80 mg, 0.14 mmol) in THF (10 mL) under air atmosphere (1 atm, balloon) for 16 h. Filtration over a pad of Celite and subsequent concentration under reduced pressure afforded 8 as a dark red amorphous solid (572 mg, 88 %) , …”

“…Organocatalytic strategies by N ‐heterocyclic carbene (NHC) catalysis represent a useful tool for the execution of a broad range of asymmetric transformations including benzoin‐type condensations, Stetter reactions, hydroacylations, annulations, and cycloadditions These processes proceed by normal polarity or umpolung reactivity through well‐established activation modes involving key reactive species, namely the Breslow intermediate, homoenolate, and azolium (di)enolate intermediates (Scheme a) . Additionally, the synthetic opportunities given by NHC organocatalysts are further expanded by the application of redox protocols (internal and external oxidation strategies) leading to the acyl azolium intermediate for the acylation of oxygen‐, sulfur‐, and nitrogen‐nucleophiles in challenging kinetic resolution (KR), macrolactonization, desymmetrization,, and polymerization processes. In particular, the N ‐acylation reaction using aldehydes as acylating agents in place of carboxylic acids/derivatives has proven to possess some practical advantages (mild reaction conditions, chemoselectivity, no need of coupling reagents) and it has been successfully applied to the functionalization of alkylamines, anilines, amides, sulfoximines, azomethine imines, and several nitrogen‐containing heterocycles.…”

“…Optically active N3‐acylated DHPMs are typically obtained from the corresponding enantioenriched substrate by treatment with stoichiometric, highly reactive acid chlorides or anhydrides at elevated temperatures in the presence of a base . As part of our studies on oxidative NHC catalysis,, , we herein present the direct asymmetric N ‐acylation of racemic DHPMs with aldehydes through catalytically generated acyl azolium as a mild reaction protocol, tolerant to substitutional variation around the DHPM scaffold (Scheme c).…”

Recent Approaches to Chiral 1,4-Dihydropyridines and their Fused Analogues

“…In 2019, enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5dicarbaldehydes 34 catalysed by chiral N-heterocyclic carbenes (NHC catalyst), an external oxidant, and an alcohol nucleophile leading to the highly enantioselective formation of 5-formyl-1,4-DHP-3carboxylates 37 has been reported [70]. This approach is based on organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 38 but not on the direct construction of the chiral DHP core.…”

“…This approach is based on organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 38 but not on the direct construction of the chiral DHP core. After the search for the best reaction conditions, the following system was selected as an optimal: Desymmetrisation of 3,5-dicarbaldehydes was quinone 35 as oxidant (1 equiv) in the presence of aminoindanol derived pre-catalyst 36, which showed a better In 2019, enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 34 catalysed by chiral N-heterocyclic carbenes (NHC catalyst), an external oxidant, and an alcohol nucleophile leading to the highly enantioselective formation of 5-formyl-1,4-DHP-3-carboxylates 37 has been reported [70]. This approach is based on organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine3,5-dicarbaldehydes 38 but not on the direct construction of the chiral DHP core.…”