AGN192403 (rac-3-exo-isopropylbicyclo[2.2.1]heptan-2-endo-amine), also known as BRD4780, has been shown to selectively clear frameshift Mucin 1 (MUC1), a protein that results in MUC1 Kidney Disease (MKD), in vitro and in vivo. Additionally, in vitro experiments demonstrated a similar effect on other proteinopathies in which aberrant proteins accumulate in the early secretory pathway, including Retinitis Pigmentosa. The literature synthesis of AGN192403 proceeds via a Diels-Alder reaction of (E)-3-methyl-1-nitrobut-1-ene and cyclopentadiene followed by catalytic hydrogenation and salt formation. This pathway may not be suitable for large scale synthesis because the Diels-Alder reaction is conducted at high temperature in a sealed tube, and produces significant amounts of the undesired rac-5-endo-isopropyl-6-exo-nitrobicyclo[2.2.1]hept-2-ene which is challenging to remove. To develop a route suitable for large scale synthesis of BRD4780, we have examined the potential use of commercially available rac-bicyclo[2.2.1]heptan-2-one as a starting material. Our proposed synthesis of BRD4780 proceeds via enolate alkylation followed by reductive amination, deprotection, and salt formation. Critical to the success of this approach is careful investigation of the selectivity of alkylation and reductive amination in this highly sterically hindered system. Our findings show that isopropyl alkylation provides the desired exo product as the major product, and subsequent reductive amination provides the desired endo product as the major product as supported by COSY 1H-NMR. Thus, optimization of this pathway could lead to an efficient way to produce AGN192403/BRD4780 on large scale to meet the demand for further biological studies.

Synthesis of AGN192403/BRD4780 from rac-bicyclo[2.2.1]heptan-2-one

ACS Fall 2020 Virtual Meeting

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