The unique chemistry of small, strained carbocyclic systems has long captivated organic chemists from a theoretical and fundamental standpoint. A resurgence of interest in strained carbocyclic species has been prompted...
Herein, we describe the development of a synthetic strategy towards chiral 3-pyrrolines based on the design principle of iron(III)-catalyzed carbonyl-olefin metathesis. This approach takes advantage of commercially available amino acids as chiral pool reagents and FeCl3 as a Lewis acid catalyst. Our strategy is characterized by its operational simplicity, mild reaction conditions and functional group tolerance. Investigations show that an electron-deficient nitrogen protecting group overcomes limitations arising from competitive binding of the Lewis acid catalyst to unfavorable Lewis basic sites, which ultimately enables catalytic turnover.
The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO 2 Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. HIGHLIGHTSStrain-driven homolysis initiates radical cyclization sequence toward norbornane core Robust functional-group tolerance provides readily modifiable building blocks Unique modes of diastereocontrol afford enantiopure 1aminonorbornanes 1-Aminonorbornanes are shown to offer improved metabolic stability over anilines Staveness et al., Chem 5,[215][216][217][218][219][220][221][222][223][224][225][226] January 10, SUMMARYThis report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp 3 -rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.
Many promising drug candidates and pharmaceutical compounds fail due to idiosyncratic adverse drug reactions (IADRs), often arising from the formation of reactive metabolites. Among the "structural alerts" responsible, anilines are well-known to undergo deleterious metabolic processing, yet isosteric replacement strategies remain limited. Herein we discuss current art and potential new avenues of saturated isosteres to mitigate aniline-related toxicities.
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