Study On The Synthesis Of 4,5-Methano-L-Proline And Its Catalytic Properties For Asymmetric Aldol Reaction

Small organic molecule catalysts have the advantages of easy preparation, high efficiency, low cost, steady performance and environmental friendly, among them, the proline-based catalysts have been widely concerned by researchers at home and abroad in recent years. However, there are still some shortcomings with the proline-based catalysts, such as the difficulty of catalyst synthesis and modification, high catalyst loading and undesirable catalytic effect and so on. Therefore, it is very important to develop a new type of proline-based catalyst with the characteristics of high efficiency, unique structure, and ready availability and successfully apply it to asymmetric catalytic reaction.4,5-methano-L-proline is a key intermediate of antidiabetic medicine saxagliptin, the two isomers cis-4,5-methano-L-proline and trans-4,5-methano-L-proline not only have basic framework of proline, but also have a rigid ternary parallel ring and two chiral bridge hydrocarbons with cis isomer, which are expected to have potential application value in asymmetric catalytic reactions. In this paper, the synthesis of 4,5-methano-L-proline was successfully studied and the catalytic performance in asymmetric aldol reaction was systematically studied. The main research contents were shown as follows:(1) Cis-4,5-methano-L-proline and trans-4,5-methano-L-proline were systematically prepared with L-pyroglutamic acid as raw materials, via esterification, Boc protection, reduction, elimination, cyclopropanation, resolution, ester hydrolysis and deamination protection. The synthetic route makes up the deficiency of the existing preparation method with the advantages of cheap and available raw material, easy separation and purification and environmental friendly. It is very realistic and valuable to carry out this research because that it can not only provide the basis and reference for the synthesis of saxagliptin, but also can be used as an organic small molecule catalyst for asymmetric catalytic reaction.(2) The catalytic effect of 4,5-methano-L-proline for Aldol template reaction of acetone and p-nitrobenzaldehyde was studied. The effects of catalyst isomers, catalyst amount, reaction additives, additive amount, reaction solvent, reaction temperature and other factors on the catalytic performance were studied. The results showed that under the optimum conditions with trans-4,5-methano-L-proline as catalyst (5 mol%), benzoic acid as additive (2 mol%), N,N-dimethylformamide (DMF) as solvent, tempetature-20 ?, the aldol product of acetone and p-nitrobenzaldehyde was obtained in the 99% ee and 85% yield.(3) The universal applicability of 4,5-methano-L-proline for the reactions of acetone and a wide variety of aldehydes was studied with further development of the substrate, mainly including aryl substituted aldehydes, heterocyclic substituted aldehydes and alkyl substituted aldehydes. The research results showed that when aldehydes were aryl substituted aldehyde, the aldol products were obtained in higher yield (81%-95%) and good enantioselectivity (95%-99% ee). Further, the aromatic ring with electron-withdrawing and introduced at the ortho-position, the better catalytic perfoemance was obtained. For heterocyclic substituted aldehyde substrates, the catalytic effect of the catalyst was significantly decreased with 75% yield and 80% ee. For alkyl substituted aldehyde substrates such as isobutylaldehyde substrate, only a trace amount of the aldol adduct could be obtained in the system after 15 h.(4) The catalytic performances of 4,5-methano-L-proline for the reactions of cyclohexanone and a variety of aldehydes including aryl substituted aldehydes, heterocyclic substituted aldehydes were discussed. The results showed that higher yield (86%-92%) and good enantioselectivity (86%-99% ee) were obtained under the optimal reaction conditions. What's more, the applicability of 4,5-methano-L-proline for the reactions of others type of ketone with p-nitrobenzaldehyde through further expanding the ketone substrates was discussed. The results showed that 3,4-dihydronaphthalen-l(2H)-one was also reacted with p-nitrobenzaldehyde under the catalysis of trans-4,5-methano-L-proline to generate the aldol product with high selectivity (91% ee) and 83% yield.2,2-dimethyl-1,3-dioxan-5-one was also reacted with p-nitrobenzaldehyde under the catalysis of trans-4,5-methano-L-proline to generate the aldol product with extremely high selectivity (96% ee) and 80% yield. At last, the possible mechanism of the catalyst-catalyzed Aldol reaction was preliminarily discussed.