Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1 S ,6 R )-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1 S ,6 R )-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes ( S )-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E -oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH 4 to afford the monoprotected (1 S ,6 R )-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.