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Development of a Kilogram-Scale Process for the Enantioselective Synthesis of 3‑Isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOS-Catalyzed Asymmetric Hayashi Addition Enabled by 1,3-Diol Additives

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journal contribution
posted on 25.08.2017, 00:00 by Eric M. Simmons, Boguslaw Mudryk, Andrew G. Lee, Yuping Qiu, Thomas M. Razler, Yi Hsiao
The development of a scalable process for the Rh-catalyzed asymmetric 1,4-addition of (isopropenyl)­pinacolboronate to 2-cyclohexen-1-one is reported. High-throughput ligand screening and initial optimization studies identified DTBM-SEGPHOS as an effective ligand along with a heptane/MeOH mixed solvent system. An inhibitory effect of the pinacol byproduct was identified, which could be mitigated by the addition of a 1,3-diol such as neopentyl glycol (npg). This process was demonstrated on 1 kg scale with 0.6 mol % Rh, producing (S)-1 in 82% yield and 99.6% ee, and was successfully scaled up at a vendor on 100 kg scale.