Synthesis Of A New Diphosphine Ligand And Catalytic Asymmetric Hydrogrntion Of Two Classes Of β-Keto Enanmines

Catalytic asymmetric hydrogenation is not only one of the hot areas of asymmetric synthesis, but also the main method to prepare optically pure compounds. Catalytic asymmetric hydrogenation includes the designs and syntheses of new ligands and novel prochiral substrates. Although more than two thousand phosphorous ligands have been developed, no one ligand can catalyze the whole prochiral substrates. It is inevitable to explore novel and efficient ligand so that we can catalyze all developed prochiral by asymmetric hydrogenation. Prochiral substrates can be transferred to various optically pure compounds, such as chiral amino acids, chiral amines and chiral alcohols, which are key intermediates for synthesis of pesticide, medicine and natural products. For instance, the chiral center of Metolachlor is induced by the catalytic asymmetric hydrogenation of the corresponding prochiral substrates, consequently, the development of new prochiral substrates have received great attention. Based on the above mentioned aims, we not only developed a new ligand and two classes of new substrates, but also explored their asymmetric hydrogenation.1. Starting from the 3-bromo-phenol, the hydroxyl group was protected to afford carbamate 19. We used trichloride ion to run the cross coupling reaction and got the backbone of biphenyl 24. Mitsunobu reaction of the deprotected biphenyl structure 25 with chiral C3-diol gave the dibromide structure 23. For this step, we got two diastereomers with different biphenyl configurations. Product 23 was obtained after column chromatography in 22% yield. The new ligand was obtained by quenched the dibromide structure 23 with dicylcohexylphine chloride.Investigating of its application in asymmetric hydrogenation ofα-dehydro-amino acid esters and dimethyl itaconate, excellent enantioselectivities (ee > 99%) forα-dehydro-amino acid esters and good enantioselectivities (up to 90% ee) for dimethyl itaconate were achieved. This ligand has excellent performance in asymmetric hydrogenation. Its prominent advantage is that it is not allergic to the air. 2. A series of well-definedβ-keto enamides were prepared in moderate to good yield (up to 90%) by direct condensation of readily accessible 1, 3-diketones with an acetamide under a Dean-Stark condition. In each case, only (Z)-enamide was observed probably due to the intramolecular hydrogen bond.After having optimized the reaction conditions of asymmetric hydrogenation, we selected Rh-DuanPhos as the ideal catalyst to reduce a class ofβ-keto enamides (15 examples). Under optimized reaction conditions, a series of optically pureβ-amino ketones were firstly afforded with excellent enantioselectivities (ee > 99%) through reduction of the C=C bonds ofβ-keto enamides with Rh-DuanPhos. Furthermore, we also firstly achieved a variety of chiral anti-1, 3-amino alcohols with high enantioselectivities (ee > 99%) and diastereoselectivites (d.r. < 1:99) by reduction of the C=C bonds and C=O bonds ofβ-keto enamides with Rh-DuanPhos under more stern reaction conditions. Fortunately, we developed a facile method to synthesize variousγ-aryl amines with excellent ee's (ee > 99%) through a coupled sequential reduction, that was we first reducedβ-keto enamides with Rh-DuanPhos, and followed by Pd/C hydrogenolysis. Chiralβ-amino ketones, anti-1, 3-amino alcohols andγ-aryl amines play an important role in the bioactive natural products and synthesis of pharmaceuticals.3. A series ofβ-keto enamines were readily prepared with good yields via a one-pot reaction according to the reported literature. In the presence of sodium ethoxide, substituted acetophenone reacted with ethyl formate for 12 h, and then methylamine hydrochloride solution was added to the resulting suspension in situ.Under the optimized reaction conditions, a range of enantiomerically pureγ-amino alcohols were readily prepared with very high enantioselectivities via trans-[RuCl2{(S)-xyl binap}-{(S)-daipen}] catalyzed asymmetric hydrogenation of a family of unprotectedβ-enamines. In all cases, the ee's value was up to 99%. It is noteworthy that this catalytic system can catalyze the mixture of Z isomer and E isomer substrates for a great number of catalysts fails in the hydrogenation of E isomer substrates.The development of the new ligand adds a new member to the family of diphosphine ligands, and provides new method for synthesis of chiral amino acids as well.The success of preparation of two kinds ofβ-enamines and their asymmetric hydrogenation enrich the protocol for the synthesis of chiralβ-amino ketones, anti-1,3-amino alcohols,γ-arylisobutylamines andγ-amino alcohols. It is the first time to get high optically pure these four kinds of chiral products.On the one hand, it offers an economical pathway for the preparation of enantiomerically pure amino alcohols and chiral isobutyl amine pesticides and drugs. On the other hand, it also set the fundamental theory for the transformation of functional groups in organic synthesis. It is obvious that the above results own very important value in scientific theory and industrial application.