Efficient Single and Dual Iridium-Catalyzed Stereoselective Hydrogenations to Access <i>trans</i> -Butane-1,2,4-triols

Herein, we report a synthetic methodology for the asymmetric hydrogenation of 4-(4-chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester to (2<i>R</i>,4<i>R</i>)-4-(4-chlorophenyl)-butane-1,2,4-triol ((<i>R</i>,<i>R</i>)-<b>7a</b>), a key GDC-6599 <i>trans</i>-triol building block, in a one-pot, consecutive reaction sequence. It is based on the use of the single Ir/(<i>S</i>)-SpiroPAP lead catalyst (LC) or rather a rationally designed dual catalyst system comprising Ir/(<i>S</i>)-SpiroPAP and Ir/(<i>R</i>,<i>R</i>)-Ms-DPEN as the assistant catalyst (AC) as a more efficient alternative to the Genentech protocol involving two ketoreductases. Whereas the best performing LC [IrClH₂((<i>S</i>)-3,5-<i>t</i>Bu-SpiroPAP-3-Me)] alone delivered (<i>R</i>,<i>R</i>)-<b>7a</b> with high enantioselectivity (>99.9%), good diastereoselectivity (trans/cis ratio 7:1), and good yield (71% after crystallization), the diastereoselectivity and yield could be enhanced by adding AC [IrCp*((<i>R</i>,<i>R</i>)-Ms-DPEN)]OTf, which promoted the first hydrogenation (<b>3a</b> to (<i>R</i>)-<b>4a</b>) with higher enantiomeric excess (ee) (96%) than the LC alone (84% ee). Although the AC did not contribute to the successive hydrogenation steps, the higher enantioselectivity in step 1 hydrogenation (90-94% ee), because of both catalysts' contributions, led to an overall higher diastereoselectivity (trans/cis ratio 18:1) and higher yield (77%). The employment of [IrCp*((<i>R</i>,<i>R</i>)-Ms-DPEN)]OTf at a substrate-to-catalyst ratio (S/C) of 1000 made it possible to lower the loading of the costly LC from S/C 1000 to 5000, thus providing the product at significantly lower cost. Finally, the engagement of novel LCs bearing new, easily accessible PNN ligands based on MeOBIPHAN and BINAN motifs furnished (<i>R</i>,<i>R</i>)-<b>7a</b> in comparable quality, the highest yield (81%), and the lowest possible cost. To the best of our knowledge, such a dual catalytic system was utilized for the first time in the stereoselective synthesis of a pharmaceutical intermediate.