Design And Synthesis Of Novel Organocatalysts And Their Application For C-C Bond Forming Reactions

Since List et al. demonstrated that L-proline itself could catalyze the intermolecular direct asymmetric aldol reaction, the concept of small organic molecules as catalysts has received considerable attention. In recent few years, asymmetric organocatalysis has matured into a very powerful, practical and broadly applicable third methodological approach in catalytic asymmetric synthesis.Organocatalysts are purely"organic"molecules, i.e. composed of (mainly) carbon, hydrogen, nitrogen, sulfur and phosphorus. As opposed to organic ligands in transition metal complex, the catalytic activity of organocatalysts resides in the low-molecular- weight organic molecule itself, and no transition metals (or other metals) are required. Organocatalysts have several advantages. They are usually robust, inexpensive and readily available, and non-toxic. Because of their inertness toward moisture and oxygen, demanding reaction conditions, for example inert atmosphere, low temperature, absolute solvents, etc., are, in many instances, not required.Recently, many researchers have focused on the design and synthesis of new and highly efficient organocatalysts due to their widely applications in the field of asymmetric synthesis, especially, enantioselective C-C bond forming reactions,such as aldol reaction, Michael reaction, Henry reaction, etc.So we envision that an appropriate incorporating both prolinamide moieties and nitrogen-containing heterocycles in one molecule could give the potential organocatalysts. In this strategy, based on N-terminal prolyl-dipeptides, we replace C-terminal carboxylic acid by tetrazole and benzoimidazole, which can lead to higher the acidity and solubility of catalysts to improve the reactivity and selectivity of the reaction. Five new organocatalysts 1-5 have been prepared.The organocatalysts 1-5 can be readily prepared from N-carbobenzyloxy-L-proline and correspondingα-amino acid tetrazole orα-aminobenzoimidazole. We seek to use thionyl chloride to chlorinate the N-carbobenzyloxy-L-proline and then reacted without purification with a correspondingα-amino acid tetrazole orα-aminobenzoimidazole in the suitable solvents to give Cbz-protected products in moderate to good yields (28–81%). Finally, hydrogenolysis of the Cbz-protected products in the presence of 5% Pd/C deprotect the N-Cbz group to provide 1-5 in good yield (63–80%).The aldol reaction is one of the most important organic reactions, because it is a carbon-carbon bond forming reaction which produces highly functionalized compounds with a pair of newly generated chiral centers. We first examined the ability of the catalysts 1-5 to promote the direct aldol reaction between acetone and 4-nitrobenzaldehyde under various conditions. Catalysts 2 and 5 are identified as the best catalysts for this reaction which lead to aldol adduct with excellent enantioselectivity and ee value up to 96%.The reactions of different aromatic aldehydes with acetone were studied under the optimized conditions (using 10 mol% of 2 as catalyst, in the presence of 10 mol% Et3N). The reactions of different aromatic aldehydes, which bear an electron-withdrawing group on the benzene ring, proceeded smoothly in excellent enantioselectivities (up to 96%) 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.The C-terminal carboxylic acid of the dipeptides was replaced with benzimidazole in order to improve the solubility of catalyst and new catalysts 4 and 5 were obtained. Next, using 5 as catalyst, we examined the reactions of different aromatic aldehydes with neat acetone. It was found that catalyst 5 show significant catalytic activity in producing the aldol adducts with good yields and excellent enantioselectivities. Furthermore, compared with catalyst 4, 5 could extend the scope of substrates.Finally, we studied direct aldol reaction of different aromatic aldehydes and cyclic ketone donor catalyzed by catalyst 5. In case of catalyst 5, the reaction was carried out in 6 h at room temperature with cyclopentane to afford the desired products in good yield, up to 96% yield. When cyclohexanone was used as nucleophiles, moderate diasteroselectivities (anti : syn up to 97: 3), enantioselectivities (up to 81% ee) and poor to moderate yields (up to 68% yield) were observed using different aromatic aldehydes.The Michael reaction is also an important C-C bond forming reaction in organic synthesis. So we also investigated the application of catalysts 1-5 for the Michael reaction between ketone and trans-β-nitrostyrene in different organic solvents at room temperature. In the presence of 10 mol% catalyst loading, catalysts 2, 3 and 5 gave the product of acetone reacting with trans-β-nitrostyrene in high yield (up to 97% yield), but only in racemic form. Cyclohexanone was also reacted with trans-β-nitrostyrene in high yield (up to 96% yield) and diastereoselectivity (syn : anti up to 99 : 1), but poor to moderate enantioselectivity (up to 53% ee), in the presence of catalysts 2, 3 and 5.Nitro alcohols are known to have potential utility as useful synthetic intermediates for many organic transformations. Then we extended our studies to Henry reaction. Preliminary results showed that catalysts 4, 5 are able to promote the Henry reaction in high yield (up to 94% yield) at room temperature. However, in all cases no enantioselectivity was observed.Via the researching work of this dissertation, suggest a new strategy in the design of new organocatalysts for direct asymmetric aldol reactions and related reactions and make the design and synthesis of catalyst possible to multiple reactions.