Drawing from our knowledge of the selectivity of these enzymes, our proposed route made the assumption that the first reductive amination step occurs exclusively at the less hindered ketone moiety (Route A, Scheme 8a). To test this hypothesis, we evaluated four ketones (23-26, Scheme 8b) of analogous hindrances and electronic effects to the bulkier side of our diketones. None of the phenyl ketones (24-26) underwent reductive amination (see Supporting Information), strongly implying that for diketone 22 the cascade occurs exclusively through Route A (Scheme 8a). Conversely, amine products were observed when using pentyl ketone 23 as substrate, indicating that Route B could occur simultaneously with Route A for reactions using diketone 21. However, despite the presence of products, low conversions (10-30%) were obtained, which when combined with the fact that the selected IREDs showed high diastero and excellent enantioselectivies (Table ), led us to conclude that Route A is the fastest, and most likely, the sole pathway followed in reactions using diketone 21. Table . Product scope of diketone annulation.