Synthesis And Application Of Chiral Oxazoline-Phosphoramidites In The Substitution,Hydrogenation And Synthesis Of Optical Purity Ibutilide Fumatate

The dissertation consists of two parts: Part 1. Synthesis and application of chiral oxazoline-phosphoramidite ligands in the substitution and hydrogenation. Part 2. Synthesis of optical purity Ibutilide Fumatate.Part 1. A series of BINOL-based oxazoline-phosphoramidite ligands (9a-9h, 10a-10b) were prepared with L-proline, chiral amino alcohols and BINOL as the starting materials. Condensation of N-Cbz-Z-proline and different amino alcohols gave amides in high yields, After deprotection of Cbz with hydrolysis, the amino-oxazoline further reacted with PCl₃ and chiral BINOL to provided ligands. The Pd-complexes formed in situ were tested in the asymmetric allylic alkylation of 1, 3-diphenyl-2-propenyl acetate. The results showed that the complexes were effective catalysts in the alkylation of 1, 3-diphenyl-2-propenyl acetate with CH₂(CO₂Me)₂ as a nucleophile. The catalyst 9f was given the best result with conditions: 6mol% ligands, 2.5mol% [Pd(η³-C₃H₅)Cl]₂, BSA/KOAc in CH₂Cl₂. The yield and enantiometric excess were up to 90% and 91% ee. Further, the ligands were reaction [Ir(COD)Cl]₂ and NaBArF to equipped Ir-catalysts. The Ir-complexes were checked as asymmetric hydrogenations of functional and unfunctional olefins. The catalysts 11a-11d showed higher catalytic activities and enantioselectivities (100% conversion, 83-93%ee) than 11e-11h (26-95% conversion, 9-57%ee) in the hydrongenation of unfunctional olefin (E)-1,2-diphenyl-1-propene. The best result (100% conversion, 93% ee) was provided with 11a as catalyst in the hydrongenation of unfunctional olefin. All catalysts showed high catalytic activities in the hydrongenation of functional olefins allyl alcohols or its acetate (100% conversion). But all the catalysts showed moderate enantioselectivities in the hydrongenation of functional olefins. The best results (100% conversion, 70% ee) were obtained in the hydrongenation of allyl acetates with 11a as catalyst. The results showed that catalysts 11c and 12a (100% yield and 74% ee) were the best catalysts of choice in the hydrongenation of allylalcohols. The best results (100% yield and 96% ee) were obtained in the hydrongenation of (Z)-1,2-diphenyl-1-propene with 11a as catalyst.Part 2. The prochiral ketone 4 was synthesized from aniline by methylsulfonylation, Friedel-Crafts reaction and condensation. Reduction of 4 was carried out with five different ways, including asymmetric CBS reduction, asymmetric transfer hydrogenation and asymmetric hydrogenation. The CBS reduction provided intermediate (S)-5 in 45% yield in the presence of 10mol% CBS as catalyst. The absolute configuration was established by the optical rotation (-12.5, c 1.1, EtOH) based the literature. The transfer hydrogenation reaction of 4 in the presence of 5mol% RuCl[(S,S)-Tsdpen(p-cymene)] as catalyst and HCOOH/Et₃N as hydrogen donor. The product (S)-5 was obtained with 60% yield and the optical rotation was -12.7 (c 1.5, EtOH). The hydrogenation of the prochiral ketone 4 with catalyst 5mol% (S)-BINAP-Ru(â…¡) gave (R)-5 with 30% yield and the optical rotation was +11.2 (c 1.1, EtOH). Attempts reduction of 4 with chiral BINAL-H and chiral salen-Co-NaBH₄ system were failed. The target product optical Ibutilide Fumatate was synthesized after the reduction of the intermediate 5 with LiAlH₄, and then salinification the product with fumaric acid.