Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Abstract

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.

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

“…Perhaps the most significant manipulation was the conversion of C7‐CO 2 Me 1‐aminoNB 2 o to the C7‐methylene 1‐aminoNB 2 v (see Figure B). The C7‐methylene system provides the closest spatial occupancy to the aniline congener, which could prove critical for the execution of our 1‐aminoNB bioisosterism goals (outlined in our prior manuscript). This was achieved through photochemical reductive decarboxylation of a C7‐carboxylic acid species ( 2 u ).…”

“…This work also represents ar are prior example of a1 -aminoNB in the literature;o fn ote,t he majority of prior 1-aminoNB preparations generate the bridgehead amine via aH ofmann or aC urtius rearrangement of terpene-based materials [43][44][45][46] or from downstream products of cyclopentadiene-acrylate Diels-Alder reactions [47][48][49][50] (only one radicalbased closure [51] existed before our work [18] ).…”

“…One example of an imine‐specific rearrangement is the photo‐racemization of dihydropyrazine (−)‐ 3 (see Figure A), facilitated by the non‐classical bond structure available to [2.2.1] bicyclic systems with open‐shell character adjacent to the bridgehead position. This work also represents a rare prior example of a 1‐aminoNB in the literature; of note, the majority of prior 1‐aminoNB preparations generate the bridgehead amine via a Hofmann or a Curtius rearrangement of terpene‐based materials or from downstream products of cyclopentadiene‐acrylate Diels–Alder reactions (only one radical‐based closure existed before our work).…”

Exploiting Imine Photochemistry for Masked N-Centered Radical Reactivity

“…Perhaps the most significant manipulation was the conversion of C7-CO 2 Me 1-aminoNB 2o to the C7-methylene 1-aminoNB 2v (see Figure 6B). TheC 7-methylene system provides the closest spatial occupancytothe aniline congener,which could prove critical for the execution of our 1-aminoNB bioisosterism goals (outlined in our prior manuscript [18] ). This was achieved through photochemical reductive decarboxylation of aC 7carboxylic acid species (2u).…”

Delivering on the Translational Potential of Photochemistry

“…In this issue of Chem, we describe a new photochemical methodology toward 1-aminonorbornanes and provide the preliminary evidence that these systems can serve as aniline bioisosteres. 1 Although we hope that readers will appreciate the unique mechanistic design of our fragmentation-cyclization sequence, we believe that the true value of this work lies in the interdisciplinary prospects implicit to this foundational chemistry. From my perspective, the most intriguing and motivating aspect of this project is our opportunity to deliver a synthesis-centric solution to a translational need.…”