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ChemAIRS explored diverse synthetic approaches to develop a tetrahydrobenzoazepine scaffold, a critical intermediate in the synthesis of BIIB091, Biogen's investigational small-molecule therapy for multiple sclerosis.

Our proposed synthetic routes focused on the construction of the benzazepine core as an N-Boc-protected ketone. Diverging from Biogen's reported synthesis, which utilized an amine transaminase (ATA) biocatalytic approach to establish the benzylic amine stereocenter, 𝐶ℎ𝑒𝑚𝐴𝐼𝑅𝑆 𝑝𝑟𝑜𝑝𝑜𝑠𝑒𝑑 𝑎𝑛 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒 𝑚𝑒𝑡ℎ𝑜𝑑 𝑖𝑛𝑣𝑜𝑙𝑣𝑖𝑛𝑔 𝑟𝑒𝑑𝑢𝑐𝑡𝑖𝑣𝑒 𝑎𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛. This protocol employed ammonium acetate (NH₄OAc) and sodium cyanoborohydride (NaBH₃CN) in isopropanol (𝑖PrOH) as a more conventional synthetic route.

To achieve the key benzazepine framework, ChemAIRS identified three distinct synthetic strategies:

1 𝐅𝐫𝐢𝐞𝐝𝐞𝐥-𝐂𝐫𝐚𝐟𝐭𝐬 (𝐅-𝐂) 𝐀𝐜𝐲𝐥𝐚𝐭𝐢𝐨𝐧 (Schemes 1 and 2):

The F-C acylation served as the critical ring-forming step, though it proved challenging, with modest yields reported by Biogen. ChemAIRS proposed optimized reaction conditions to improve this transformation (Figure 2). Additionally, the algorithm flagged potential side reactions that could compromise the cyclization efficiency (Figure 3), providing insights into reaction optimization.

2 𝐈𝐧𝐭𝐫𝐚𝐦𝐨𝐥𝐞𝐜𝐮𝐥𝐚𝐫 𝐏𝐝-𝐂𝐚𝐭𝐚𝐥𝐲𝐳𝐞𝐝 𝐇𝐞𝐜𝐤 𝐑𝐞𝐚𝐜𝐭𝐢𝐨𝐧 (Scheme 3):

ChemAIRS proposed an alternative cyclization via an intramolecular Heck reaction, utilizing Pd catalysts. The system also identified a range of catalyst options to fine-tune this transformation for improved yield and selectivity (Figure 4).

3 𝐄𝐬𝐭𝐞𝐫-𝐀𝐫𝐲𝐥 𝐇𝐚𝐥𝐢𝐝𝐞 𝐂𝐲𝐜𝐥𝐢𝐳𝐚𝐭𝐢𝐨𝐧 (Scheme 4):

A third approach involved cyclization through the reaction of a corresponding ester with an aryl iodide, offering another viable strategy for the formation of the benzazepine core.

By combining computational insights with chemical expertise, ChemAIRS highlighted these pathways as 𝑣𝑖𝑎𝑏𝑙𝑒 𝑠𝑦𝑛𝑡ℎ𝑒𝑡𝑖𝑐 𝑠𝑡𝑟𝑎𝑡𝑒𝑔𝑖𝑒𝑠, 𝑜𝑓𝑓𝑒𝑟𝑖𝑛𝑔 𝑓𝑙𝑒𝑥𝑖𝑏𝑖𝑙𝑖𝑡𝑦 in addressing the challenges of benzazepine core construction.