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The molecular architecture of Casdatifan (AB521) from Arcus Biosciences consists of four densely substituted ring systems containing five stereocenters, presenting considerable complexity in the overall synthetic design. 𝐶ℎ𝑒𝑚𝐴𝐼𝑅𝑆 𝑑𝑒𝑣𝑒𝑙𝑜𝑝𝑒𝑑 𝑠𝑒𝑣𝑒𝑟𝑎𝑙 𝑐𝑜𝑛𝑣𝑒𝑟𝑔𝑒𝑛𝑡 𝑠𝑦𝑛𝑡ℎ𝑒𝑡𝑖𝑐 𝑟𝑜𝑢𝑡𝑒𝑠 𝑓𝑜𝑟 𝐴𝐵521, 𝑤ℎ𝑒𝑟𝑒 𝑐𝑟𝑖𝑡𝑖𝑐𝑎𝑙 𝑖𝑛𝑡𝑒𝑟𝑚𝑒𝑑𝑖𝑎𝑡𝑒𝑠 𝑐𝑜𝑢𝑙𝑑 𝑏𝑒 𝑠𝑦𝑛𝑡ℎ𝑒𝑠𝑖𝑧𝑒𝑑 𝑖𝑛 𝑝𝑎𝑟𝑎𝑙𝑙𝑒𝑙 𝑡𝑜 𝑓𝑎𝑐𝑖𝑙𝑖𝑡𝑎𝑡𝑒 𝑡ℎ𝑒 𝑐𝑜𝑛𝑠𝑡𝑟𝑢𝑐𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑓𝑖𝑛𝑎𝑙 𝑡𝑎𝑟𝑔𝑒𝑡 𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑒.

The synthetic route begins with a key coupling reaction between intermediates 10a and 10b, derived from readily accessible commercial precursors such as dibromo benzaldehyde (6b) and bromo indanone (1a) (Scheme 1). The synthesis of 10a follows a four-step sequence as proposed by ChemAIRS, differing from the multistep approach outlined in the corresponding patent. This route initiates with the coupling of fluoroketone 6a and dibromo benzaldehyde 6b, followed by an intramolecular aldol condensation to yield compound 8a. Subsequent steps involve ketone reduction and Pd-catalyzed cyanation, ultimately affording intermediate 10a.

Given the aldehyde functionality in 6b, which poses a potential risk for the coupling reaction, an alternative two-step synthesis of intermediate 7a was developed (Scheme 2). Additionally, our system flagged a risk associated with the synthesis of 10b, as highlighted in Figure 1.

𝐀𝐥𝐭𝐞𝐫𝐧𝐚𝐭𝐢𝐯𝐞 𝐒𝐲𝐧𝐭𝐡𝐞𝐭𝐢𝐜 𝐀𝐩𝐩𝐫𝐨𝐚𝐜𝐡 𝐭𝐨 𝐀𝐁𝟓𝟐𝟏

ChemAIRS also suggested an alternative pathway to AB521, illustrated in Scheme 3. In the first part of the synthesis, intermediate 7a can be obtained as a mixture of isomers post-fluorination, which can be resolved via column chromatography. Importantly, in the latter stages of the synthesis, our system recommended an enantioselective mono-fluorination strategy to prepare compound 3a, as demonstrated in the reference reaction (Figure 2).

In conclusion, ChemAIRS has proven its capability to identify alternative synthetic routes for complex drug molecules, 𝑝𝑟𝑜𝑣𝑖𝑑𝑖𝑛𝑔 𝑢𝑛𝑖𝑞𝑢𝑒 𝑝𝑎𝑡ℎ𝑤𝑎𝑦𝑠 𝑡ℎ𝑎𝑡 ℎ𝑎𝑣𝑒 𝑡ℎ𝑒 𝑝𝑜𝑡𝑒𝑛𝑡𝑖𝑎𝑙 𝑡𝑜 𝑠𝑎𝑣𝑒 𝑟𝑒𝑠𝑒𝑎𝑟𝑐ℎ𝑒𝑟𝑠 𝑡𝑖𝑚𝑒 𝑎𝑛𝑑 𝑒f𝑓𝑜𝑟𝑡, 𝑡ℎ𝑢𝑠 𝑒𝑛𝑎𝑏𝑙𝑖𝑛𝑔 𝑎 𝑚𝑜𝑟𝑒 𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡 𝑒𝑥𝑝𝑙𝑜𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑠𝑦𝑛𝑡ℎ𝑒𝑡𝑖𝑐 𝑠𝑡𝑟𝑎𝑡𝑒𝑔𝑖𝑒𝑠.