Research Of New Organocatalysts For Asymmetric α-Hydroxylation Of β-Keto Esters

The a-hydroxyl-β-keto ester moiety is an important structure in a variety of natural products, Pharmaceuticals and fine chemicals. Asymmetrically oxidizingβ-keto esters is the most effective approach to obtain a-hydroxyl-β-keto esters, however, until now only cinchona alkaloid cinchonine-catalyzed asymmetric a-hydroxylation ofβ-keto esters is raelized in industrial application. It is vitally important both in theoretical study and industrial application to continue developing cheap and efficient chiral organocatalysts with novel frameworks.It is proposed that the recognization process between the chiral organocatalysts and the substrates is similar to the recognization process between the chiral drugs and the targets. The method for the discorvery of lead compounds is applied to the discorvery of novel chiral organocatalyst lead compounds. By establishing the chiral drug molecule library with existed chiral drugs, using asymmetric a-hydroxylation ofβ-keto esters as the model reaction, two types of chiral organocatalyst lead compounds with novel frameworks are screen out from the chiral drug molecule library. Those are chiral organocatalyst lead compounds S-timolol and R-propranolol with a novel framework ofβ-alkyloxylβ-amino alcholol, and lappaconitine with a novle diterpenoid alkaloid framework.Under the optimized reaction conditions, the conversions of the asymmetric a-hydroxylation of methyl 5-chloro-l-indone carboxylate catalyzed by S-timolol and R-propranolol are 92% and 84%, and the enantioselectivitise are 32% ee(R) and 18%ee(S), respectively. The yield of the asymmetric a-hydroxylation of methyl 4-methyloxyl-l-indone carboxylate catalyzed by lappaconitine is 78% and the enantioselectivity reach up to 85% ee(R).Using the priciples of similarity and diversity and the strategy of location directional screening, the structure of the organocatalyst lead compound timolol is modified. The molecular structure of timolol is divided into three parts, a. theβ-alkyloxyl group; b. the hydroxyl group; c. theβ-amino group. According to the division, seventy three timolol analogs B1～B10, N1～N32, BN1～BN3, Q1～Q3, S1～S3, Z1～Z3, U1-U3 and C1～C12 are designed and synthesized. The structure-activity relationship of the organocatalysts is investigated. It is found that the configuration of the chiral carbon atom on part b is the reason for the catalyst to perform enantioselective recognization, and the hydroxyl group is the key group for the catalyst to afford enantioselectivity. The R-configurated catalyst affords S-enanomeric excess product and the S-configurated catalyst affords R-enanomeric excess product. The catalytic performance (activity and enantioselectivity) is affected by the bulk of theβ'-amino group of part c. The catalytic performance of the secondary amine catalyst is generally superior to the primary amine and tertiary amine catalyst. The large steric hindrance group avails to the enantioselectivity, but too much steric hindrance reduces the activity. The electronic effect of the aromatic ring on part a affects the catalytic performance. The electron donating aromatic rings elevate the catalaytic performance; the electron withdrawing aromatic rings reduce the catalaytic performance.The catalytic performance of organocatalyst N6 is found to be the best within the synthesized catalysts. The catalytic system of the catalyst N6 is optimized, and is applied to the synthesis of a key intermediate of the chiral pesticide indoxacarb. It is found that under the optimized reaction conditions, the conversion of the reaction reach to 92% and the enantioselectivity reach to 42% ee, which is comparable with cinchonine-catalyzed asymmetric reaction. The catalyst N6 is easy to synthesize and the price is much lower than cinchonine, showing the potential in industrial scale application.