Efficient Single and Dual Iridium-Catalyzed Stereoselective Hydrogenations to Access trans-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 (2R,4R)-4-(4-chlorophenyl)-butane-1,2,4-triol ((R,R)-7a), a key GDC-6599 trans-triol building block, in a one-pot, consecutive reaction sequence. It is based on the use of the single Ir/(S)-SpiroPAP lead catalyst (LC) or rather a rationally designed dual catalyst system comprising Ir/(S)-SpiroPAP and Ir/(R,R)-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((S)-3,5-tBu-SpiroPAP-3-Me)] alone delivered (R,R)-7a 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*((R,R)-Ms-DPEN)]OTf, which promoted the first hydrogenation (3a to (R)-4a) 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*((R,R)-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 (R,R)-7a 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.