Design And Synthesis Of Series Novel Organocatalysts Based On Saccharides And Their Application For C-C Bond Forming Reactions

Organic small molecule catalysts, developed rapidly in recent years, are a novel kind of organocatalysts. It is widely used in the field of asymmetric organic synthesis. Because of its feature of environmentally friendly, non-metal and without any modification of the substrate in the reaction process, it received wide attention from researchers. So, design, synthesis of highly efficient organoctatalysts and their application for asymmetric organic reactions, is a hot research field of asymmetric organic synthesis.Asymmetric C-C bond formation reactions are an important class of asymmetric organic synthetic reactions, for example: direct asymmetric Aldol reaction, asymmetric nitro-Michael addition reaction etc. View of the above two types of reaction, researchers have designed and synthesized a large number of excellent organocatalysts. Among of these organocatalysts, prolinamides catalysts and chiral bifunctional thiourea catalysts are two classic types of organocatalysts, and their structural characteristics and catalytic mechanism were intensive studied by researchers. A great deal of theoretical basis of structural characteristics and catalytic mechanism for these two types of organocatalysts was achieved.In this paper, firstly, after we carefully studied the structural characteristics of excellent prolinamides catalysts, which had been reported previously, we designed and synthesized from Boc-L-proline, Boc-4-OH-L-proline respectively with acetylβ-D-glucosamine,β-D-galactosamine andβ-D-xylosamine through the method of mixed-anhydride to obtain target compounds. Then, using trifluoroacetic acid and sodium alcohol to removal of Boc and acetyl protection, we obtained prolinamides catalysts based on saccharids 1a～3b.We first examined the ability of the catalysts 1a～3b to promote the direct aldol reaction between cyclohexanone and 4-nitrobenzaldehyde under various conditions. Catalyst 1b was identified as the best catalyst for this reaction which lead to aldol adduct with excellent enantioselectivity and diastereoselectivity, ee value up to 97%, dr value up to 98:2. ?The reactions of different aromatic aldehydes with cyclohexanone were studied under the optimized conditions (at 0°C,using 10 mol% of 1b as catalyst, in the presence of 10 mol% benzoic acid). The reactions of different aromatic aldehydes, which bear an electron-withdrawing group on the benzene ring, proceeded smoothly in excellent enantioselectivities and diastereoselectivity (yield up to 86%,ee value up to 97%, dr value>99:1) to furnish the aldol adducts. In addition, halogenated benzaldehydes led to decreased yields. Interestingly, the ee values of the products remained at good levels. On the other hand, this catalytic system was proven to be completely ineffective for the aromatic aldehydes with an electron-donating group or without any substitution.Finally, we studied direct aldol reaction of cyclopentanone and 4-nitrobenzaldehyde. In case of catalyst 1b, the reaction was carried out in 24 h under the optimized conditions with cyclopentane to afford the desired products in moderate yield, up to 78% yield, ee value up to 43%, dr value up to 70:30. When acetone was used as nucleophiles, moderate yields (up to 69% yield), and lower enantioselectivities (up to 39% ee) were observed.Then, after we carefully studied the structural characteristics of excellent chiral bifunctional thiourea catalysts, which had been reported previously, we designed and synthesized from 9-amino-deoxy-cinchonine, 9-amino-deoxy-quinine respectively with acetylβ-D-glucose isothiocyanate,β-D-galactose isothiocyanate andβ-D-lactose isothiocyanate to obtain chiral bifunctional cinchonine-thiourea catalysts based on acetyl saccharids 1～6.We first examined the ability of the catalysts 1～6 to promote the nitro-Michael addition reaction between dimethyl malonate and trans-nitrostyrene under various conditions. Catalyst 1 was identified as the best catalyst for this reaction which lead to Michael addition adduct with excellent enantioselectivity and yields (up to 93%), ee value up to 95%. ?Under the optimized conditions (at room temperature, with 15 mol% of catalyst), the reactions of ethyl acetoacetate with trans-nitrostyrene were studied, using catalysts 1 and 2 as catalysts. However, catalyst 2 had shown excellent enantioselectivity, ee value up to 93%, moderate yields and diastereoselectivity (up to 74% yield, dr value up to 64:36).Via the researching work of this dissertation, we hope that we can provide preliminary theoretical basis for design of new organocatalysts based on saccharids, and provide reference for development of catalyst diversity.