Synthesis Of Series Organocatalysts Based On Six-membered Ring Aza And Their Application For Asymmetric 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. Therefore, design, synthesis of highly efficient organoctatalysts and their application for asymmetric organic reactions, is a hot research field of asymmetric organic synthesis.With the development of asymmetric organic synthesis in past decade, chiral DMAP derivatives have established themselves as effective enantioselective catalysts for a broad rang of transformation in organic synthesis.In this paper, a novel series of chiral 4-piperidinyl pyridine amide derivatives as potential acyl transfer catalysts and series of based on amino pyridine prolinamides and dipetides have been synthesized which were then applied in asymmetric acyl transfer catalysis(enantioseletivity acylations) and in the direct asymmetric Aldol reaction, separately.As the first part of our work, a series of chiral 4-piperidinyl pyridine amide derivatives as potential acyl transfer catalysts were designed and synthesized based on excellent examples which have been reported. Firstly, the intermediates 4-piperidinyl 2-amino pyridine and 4-piperidinyl 3-amino pyridine were obtained separately from 2-methyl pyridine and 4-chloro 3-nitro pyridine which were then coupled with L-proline and (R)-1,1'-bi (2-naphthol) derivatives to give the target molecules 1a～2c in several steps.The catalytic activity of catalyst 1a was then evaluated in the asymmetric acyl transfer catalysis of (cis)-benzoic acid 2-hydroxy-cyclohexyl ester with acetic anhydride under various conditions including temperature, time, catalyst loading, additive and anhydride. The optimized conditions determined for catalyst la were then extended to other catalysts and the catalytic and enantioselectivities of lb～2c differ significantly. Among the catalytic systems examined, the best catalyst was la, which gave the best result (ee up to 42%. S=2.8).With the optimal conditions in hand, we then examined a variety of second alcohol and acetic anhydride in the presence of la in the enantioselectivity acylations. The cis-cycloheane-1,2-diol derivatives gave the corresponding products in good enantioselectivities(ee up to 42%. S=2.8); the trans-cycloheane-1.2-diol derivatives gave the corresponding products in low enantioselectivities(ee17～29%):the reaction of 1-(naphthalen-2-yl)ethanol with acetic anhydride in high yield but without any enantiselectivity.As another part of our work, a series of prolinamides and dipetides as organocatalysts for the direct asymmetric Aldol reaction have been developed based on pioneering work. First, we obtained the intermediates through coupled reaction of N-Boc-L-Proline with a series of amino pyridine in the presence of DCC. then the prolinamides organocatalyst (1a～1c) were obtained by deprotected in the prence of trifluoroacetic acid. In the similar fashion, we got the dipetides organocatalyst (2a～2c).Initially, the catalytic activity of these new catalysts (1a～2c)was then evaluated in the direct asymmetric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone under various conditions. Catalysts 2a and 2b were identified as the better catalysts for this reaction which lead to aldol adduct in excellent yield of 99%. with high enantioselectivity (ee up to 97%) and perfect diastereoselectivity (dr up to 99:1).We then examined a variety of aromatic aldehydes and ketones in the presence of 2a and 2b in the direct asymmetric aldol reactions under optimized conditions. The benzaldehydes substituted by strong electron-withdrawing nitro- and cyano- groups were converted to the corresponding aldol products in high yields (up to 99%) with high enantioselectivities (up to 97% ee) and diastereoselectivities (up to>99/1. anti/syn). The aldol reactions of cyclohexanone with less reactive benzaldehydes which bearing chloro and fluoro substituents on the benzene ring gave the corresponding aldol products in good yields and enantioselectivities. The reaction with benzaldehyde and 4-methoxybenzaldehyde afforded the products in lower yields and enantioselectivities.The direct asymmetric aldol reactions between various ketones and aldehydes were also examined. The aldol reactions of cyclopentanone with 4-nitrobenzaldehyde and 2-nitrobenzaldehyde gave the corresponding aldol products in good yields (up to 96%) and moderate to good enantioselectivities (ee up to 90%) but with lower diastereoselectivities(30/70. anti/syn). The reaction of acetone with 4-nitro benzaldehyde afforded the aldol product in moderate yield with low enantioselectivity (42% ee).Via the researching work of this dissertation, we hope that we can provide a new methodology to obtain chiral 2-substituted DMAP derivatives, and results serve to illustrate the breadth of the utility of chiral DMAP derivatives, and further progress can be expected.