Ru-SunPhos Catalyzed Asymmetric Hydrogenation In The Synthesis Of Optically Pure Ethyl2-Hydroxy-4-Arylbutyrate

For the application of Ru-SunPhos catalyzed asymmetric hydrogenation technology in the future, firstly the importance of chirality, the protocols of obtaining chiral compounds were briefly reviewed, and the recent important progress in asymmetric synthesis of ethyl (/?)-2-hydroxy-4-phenylbutanote, a key intermediate for the syntheses of angiotensin-converting enzyme inhibitors (ACEI) was also summarized. Secondly, a class of C2axial chiral bidentate phosphine ligands-SunPhos series were synthesized by optimization synthetic rute. And, the SunPhos ligands were applied to the asymmetric hydrogenation of functionalized ketones to get chiral ethyl2-hydroxy-4-arylbutyrate. Finally, based on the study results, three strategies to preparation optical pure ethyl2-hydroxy-4-phenylbutyrate have been developed.The main contents include:1. After optimizing the original synthetic rute, the ligands such as SunPhos series were synthesized by Arbuzov reaction catalyzed by anhydrous NiCl2, lithiation of the ethyl phosphate with LDA, oxidative coupling with anhydrous FeCl3, chlorination the diphosphate with SOCl2, reaction with Grignard reagent, optical resolution with (-)-DBTA or (-)-DTTA as resolving agent, and reduction with HSiCl3. Then, the ligand SunPhos was produced successfully at100g-scale.2. The hydrogenation of (E)-ethyl2-oxo-4-arylbut-3-enoate with [NH2Me2]+[{RuCl [(S)-SunPhos]}2(μ-Cl3)] in the presence of the1M HCl gave ethyl2-hydroxy-4-arylbutyrate with93.7%-95.7%ee. Further investigation has proved that the hydrogenation proceeds via a sequential hydrogenation of C=O and C=C bonds.3. A challenging direct asymmetric hydrogenation of2-oxo-4-arylbut-3-enoic acids to give2-hydroxy-4-arylbutanoic acids (85.4%～91.8%ee) were achieved with a Ru-catalyst based on SunPhos as chiral ligand. Further investigation of the reaction revealed that partial isomerization of2-hydroxy-4-arylbutenoic acids was involved in the hydrogenation process.4. The asymmetric hydrogenation of saturate2-oxo-4-arybutanoic acids were accomplished by employing [RuCl(benzene)(5)-SunPhos]Cl as catalyst and trace1M HBr as additive. The high enantioselectivities (88.4%～92.6%ee) and efficiency (TON=10,000, TOF=300h-1) make this method efficient for the synthesis of an important intermediate,(R)-2-hydroxy-4-phenylbutanoic acid, for ACE inhibitors.In conclusion, according to the research results, a convenient protocol for preparation of SunPhos series ligands have been developed, and an efficient strategy for the conversion of inexpensive functionalized ketones into optically active ethyl2-hydroxy-4-arylbutyrate by asymmetric hydrogenation have been presented also. The applications of this procedure for the large scale preparation of SunPhos series ligands and ethyl2-hydroxy-4-arylbutyrate are m progress.