Chiral Phosphoric Acid Catalyzed Enantioselective Desymmetrization of 1,4‐Dihydropyridines by C(sp³)−H Bromination

Abstract

Described herein is the enantioselective synthesis of Hantzsch‐type 1,4‐dihydropyridines (DHPs), which are frequently contained in pharmaceuticals. Readily available symmetrical 1,4‐DHPs were used as substrates, and the methyl group at the 2‐ or 6‐position of the 1,4‐DHP was selectively monobrominated by desymmetrizing enantioselective bromination. The inert C−H bond was converted into a versatile C−Br bond, which guaranteed the modification of the chiral 1,4‐DHP derivatives with high efficiency. Furthermore, axially chiral 4‐aryl pyridines were accessible by central‐to‐axial chirality conversion.

Enantioselective Synthesis of Atropisomers by Oxidative Aromatization with Central-to-Axial Conversion of Chirality

“…More recently, a different approach for the synthesis of axial chiral 4-arylpyridines was developed by Li and Tang from commercially available symmetrical 1,4-dihydropyridines 24 ( Scheme 9 ) [ 112 ]. The first step of this synthesis relies on an enantioselective desymmetrization by mono-substitution at one of the methyl groups of the 2,6-dimethyl 1,4-dihydropyridines 24 by C3-bromination—[1,3]-Br atom shift.…”

Unexpected Cascade Sequence Forming the C(sp3)–N/C(sp2)–C(sp2) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity

“…The other catalytic annulation reactions were developed by Yan, Vicario, Hui, and co-workers, in which [3 + 3] cycloaddition started with cyclic enamines and α, β-unsaturated ketones with a “head to tail” regioselective reaction through a Michael addition of the enamine moiety (Scheme b) . Based on multistep synthesis, Tang et al provided an enantioselective synthesis of Hantzsch-type 1,4-dihydropyridines (DHPs) for the bioactive molecule of γ-lactam-fused pyridines via bromination of the inert C–H bond (Scheme c) . Pyrrolone or pyridinone intermediates were utilized for the above-mentioned reactions to assemble of γ-lactam-fused pyridones, but their commercial availability is limited. , Therefore, more efficient and practical approaches for bicyclic compounds γ-lactam-fused pyridones are still in high demand.…”

Development of Self-Assembling bis-1,4-Dihydropyridines: Detailed Studies of Bromination of Four Methyl Groups and Bromine Nucleophilic Substitution

“…Bromination of the C–H bond is the first choice to transform it into a flexible synthetic tool, allowing broad reactions through cross-coupling and substitution [ 30 , 31 , 32 ].…”

“…The reaction was reported by two research groups, but no new papers using this reagent have been published since then [ 36 , 37 ]. N-bromophthalimide ( 4 , Figure 1 ), N-bromoacetamide ( 5 , Figure 1 ) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) ( 6 , Figure 1 ) were also utilized as bromine sources for chiral phosphoric acid catalyzed enantioselective desymmetrization of 1,4-DHPs via selective bromination of methyl groups [ 32 ].…”

“…The reaction was reported by two research groups, but no new papers using this reagent have been published since then [36,37]. N-bromophthalimide (4, Figure 1), N-bromoacetamide (5, Figure 1) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (6, Figure 1) were also utilized as bromine sources for chiral phosphoric acid catalyzed enantioselective desymmetrization of 1,4-DHPs via selective bromination of methyl groups [32]. As a part of our studies towards the development of novel self-assembling non-viral delivery systems and establishing the recommendations of structure-activity relationships, we continued the study and development of the original cationic amphiphilic bis-1,4-DHPs connected using [1,1 -biphenyl]-4,4 -dicarbaldehyde in Hantzsch synthesis to create a conjunction between two 1,4-DHP rings.…”