Study Of Synthesis Of Diphenylprolinol Silyl Ether And Its Application In Asymmetric Michael Additions

(-)-Paroxetine is a potent antidepressant, and some synthetic routs were developed. However, there are few reports on organocatalytic asymmetric synthesis of (-)-paroxetine. Four pathways for synthesis of paroxetine have been designed in this work, and (S)- diphenylprolinol silyl ether was prepared for use as catalyst in the Michael addtions.Michael addition of aldehyde and alkylidene malonates was first tried. Unfortunately, the target material was not achieved owing to the side reactions like condensation and dehydration of the aldehyde. Aza-Michael additions of hydroxylamine andα,β- unsaturated imine with acrolein were then done, and target products were also not obtained though we try to change the conditions, including solvents, additives and Lewis acids.When a mixture of methanol, nitroolefins and acrolein was reacted in the presence of the catalyst, a product of Michael-Michael tandem reaction of the three components was observed. Through optimizing the reaction conditions, we found the optimized conditions were as follows: chloroform as solvent, diphenylprolinol silyl ether as catalyst and benzoic acid as additives (25 mol%). It is able to achieve the product of double-Michael addition at low catalyst loading (5 mol%) and high enantioselectivity (82% ee).To our knowledge, there are still no relevant reports on tandem reaction of the three components: alcohol, nitroolefins and acrolein. Meanwhile, the products can not only be used in synthesis of (-)-paroxetine, but also be applied to synthesis of other biologically active compounds such as peptidomimetic inhibitor Roche-1.