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High Resolution Image Download MS PowerPoint Slide 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 R,4 R )-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 IrClH 2 (( S )-3,5- t Bu-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.
Püntener et al. (Mon,) studied this question.