The Construction Of Unsymmetrical Cis-2,5-Disubstituted Pyrrolidines And Their Application For Asymmetric Synthesis

Since the 1970's where the first pyrrolidinic alkaloids with different substituents at 2- and 5- positions of pyrrolidine ring, were found in the Solenopsis ants venom, numerous chemists became involved in the study of these new natural products. 2,5-Disubstituted pyrrolidines play a vital role in biological and pharmaceutical fields as well as organic synthesis. Over the past three decades, the syntheses and utilization of the optically pure symmetrical trans-2,5-disubstituted pyrrolidines were investigated in great detail. However, the preparation and application of enantiopure unsymmetrical cis-2,5-disubstituted pyrrolidines are rarely found in literatures. Recently, some small molecules based on the backbone of unsymmetrical cis-2,5-disubstituted pyrrolidines, were found to be the very potent pharmaceutics for treatment of diabetes, obesity and cancer, and the key issue is how to obtain these pyrrolidine analogues in high availability. Therefore, the exploration of efficient and convenient route to optically pure unsymmetrical cis-2,5-disubstituted pyrrolidines is still a big challenge.This dissertation mainly focuses on five aspects as follows:1. The (+/-)-cis-5-arylcarbamoyl-2-ethoxycarbonylpyrrolidines 42~46 were firstly synthesized in 53-64% yields by using easily available meso-diethyl 2,5-dibromoadipate and (S)-(-)-1-phenylethylamine as starting materials in three steps. This provides a very convenient access to unsymmetrical cis-2,5-disubs- tituted pyrrolidines.2. The new highly hindered amides 47~49 were firstly prepared in the presence of excess amount of N,N-dicyclohexylcarbodiimide (DCC) and 4-N,N-dimethyl- aminopyridine (DMAP) and catalytic (D+)-10-camphorsulfonic acid (10-CSA). This affords a novel route to the highly hindered amides. These highly hindered amides were successfully converted into the corresponding amines by using LiAlH4 as a reductant and 1,4-dioxane as a solvent.3. The enantiopure unsymmetrical cis-2,5-disubstituted pyrrolidines 65 and 66 were prepared by Grignard reaction and separated by a flash column chromatography. The absolute configurations of these optically active pyrrolidines were confirmed by X-ray crystallographic analysis.4. Based on the backbone of enantiopure cis-2-hydroxydiphenylmethyl-5- amino-pyrrolidines 69, the novel precursors of chiral N-Heterocyclic carbenes 71 and thioureas 81 were designed and prepared to be as ligands and organocatalysts. The coordinations of 71 and 81 with Rh, Ru and Pd were firstly investigated, and it was found that neither of them was conformed into sable complex. The catalytic activities of chiral thioureas 81 were researched in the Pd-catalyzed asymmetric allylic alkylation.5. All enantiopure unsymmetrical cis-2,5-disubstituted pyrrolidines containing vicinal diamino orβ-amino alcohol motif we prepared were used as ligands in the Rh-catalyzed asymmetric transfer hydrogenation of acetophenone, and some ligands have shown low catalytic activity, otherwise compounds (+)-69, (-)-69, (+)-96 and (-)-96 exhibit moderate to good catalytic activity for this reaction but low enantioselectivities.