Synthesis Of New Cinchona Alkaloid Derivatives And Their Application In The Asymmetric Synthesis Of Chiral Drugs

Osmuim-catalyzed asymmetric dihydroxylation reaction (AD reaction) of olefins, with cinchona alkaloid derivatives as chiral ligands, is the most effective method to obtain chiral vicinal diols. The AD reaction has a wide range of applications in the synthesis of chiral drugs, natural products and fine chemicals. Cinchona alkaloids and their derivatives can also act as organic catalysts to effectively catalyze condensation, addition, as well as substitution reactions, which genderate chiral centers for chemical bonds such as C-C, C-N, C-O and so on, giving highly optical active compounds. Various applications of the cinchona alkaloid derivatives in asymmetric synthesis have been reported in recent years. Our work mainly involves the following two parts:1. Metoprolol is an amino propanol-type selectiveβ1-blocker. It is the most widely prescribed medicine for the treatment of hypertension in the recent years. (S)-enantiomer is the main active isomer. With quinidine as raw material, we synthesized a known ligand 1, 4-bis(9-O-quinindinyl)-phthalazine, and a new ligand 6-nitro-1,4-bis(9-O-quinindinyl)-2, 3-phthalazine. They were applied to catalyze the asymmetric dihydroxylation of allyl [4-(2-methoxyethyl)phenyl] ether to give (2S)-3-[4-(2-methoxyethyl) phenoxy]-1, 2-propanediol, which was further converted into (S)-metoprolol.2.9-(9-deoxy)-epicinchonine and 9-(9-deoxy)-epiquinine were prepared from cinchonine and quinine and then respectively reacted with terephthaloyl chloride and isophthaloyl chloride to give four Cinchona alkaloid derivatives: bis[9-(9-deoxy)-epicinchoninyl]terephthaloyl amide, bis[9-(9-deoxy)-epicinchoninyl]-isophthaloyl amide, bis[9-(9-deoxy)-epiquininyl]terephthaloyl amide and bis[9-(9-deoxy)-epiquininyl]isophthaloyl amide. These cinchona alkaloids derivatives were then applied to catalyze the asymmetric Henry reation of p-methoxybenzaldehyde with nitromethane. The (R)-1-(4-methoxyphenyl)-2-nitroethanol obtained with quinine-derived catalysts was transformed into (R)-2-amino-l-(4-methoxyphenyl)-ethanol upon Pd/C catalyzed hydrogenation. Finally. (R)-2-amino-l-(4-methoxyphenyl)-ethanol was acylated with E-cinnamic acid N-hydroxysuucinamide to give (R)-Aegeline, which is a natural product for blood glucose regulation.