Synthesis Of Planar Chiral [2.2]Paracyclophane Triazolium Salts And Their Applications In Asymmetric Catalysis

Efficient methods to take chiral compounds from racemic starting materials are in high demanding, especially in the pharmaceutical and biochemical industry. The most important access to the enantiopure compounds was enantioselective catalysis from pro-chiral starting materials. Besides the ligands incorporating central chirality, the ligands used in asymmetric catalysis also can include axial chirality, planar chirality as well as combination of them. Since the end of last century, more and more literatures about planar chiral substituted [2.2]paracyclophane used as ligands in asymmetric catalysis were reported. The planar chirality plays more important role in organometallic catalysis. Since the first report of isolation of stable carbenes in1991, because of their good electron-donating and readily modification of the structure, N-heterocarbenes(NHCs) concentrated the interest of a lot of chemists in the area of catalysis and organocatalysis. The most famous application is the Grubbs catalysts in the olefin metathesis. The first successful application of chiral NHCs in asymmetric catalysis was reported at the beginning of21st century, since then, the literatures of design, synthesis and application of chiral NHCs were reported explosively.Catalysis mediated by NHCs and their metal complexes has emerged as a powerful tool for asymmetric synthesis because these catalysts have several significant advantages over their phosphine counterparts, such as easy prepared and stable in air. The N-heterocyclic carbene precursors mainly include thiazolium, imidazolium, imidazolinium and triazolium. Compared to other ligands, triazolium ligands were always applied in organocatalytic reactions while their applications in organometallic catalysis are rare. In recent years, our lab focus on synthesis of planar chiral N-heterocyclic carbene precursors derived from [2.2]paracyclophane and their application in asymmetric catalysis, we have successfully synthesized planar chiral imidazolium ligand and imidazolinium ligand which have been applied in asymmetric rhodium-catalyzed1,2-addition of arylboronic acids to aldehydes. However, the [2.2]paracyclophane-based triazoliums used as N-heterocyclic carbene precursors for this asymmetric transformation have not been studied. In conclusion, the chiral N-heterocyclic carbene is the focus of the chemists’ attention. Based on the works of our lab, we have designed and synthesized a novel class of planar chiral [2.2]paracyclophane-based triazolium salts and successfully applied them in rhodium-catalyzed asymmetric addition of organoboron reagents to isatins.The main contents of the thesis were shown as follows:1. Review of the chiral triazolium ligand and [2.2]paracyclophane derivatives in asymmetric catalysis.The chiral triazolium salts derived from amino acids were mainly applied in organocatalytic reactions, including benzoin condensation, Stetter reaction, reactions of α,β-unsaturated aldehydes with a variety of electrophilic reagents, asymmetric hydroacylation, cooperative Lewis acid/N-heterocyclic carbene catalyzed reactions and asymmetric tandem reactions. In addition, the chiral ligands based on [2.2]paracyclophane have been applied in many asymmetric reactions, such as hydrogenation, organozinc addition reaction, allylic substitution reaction, Strecker reaction and hydrosilylation.2. Design and synthesis of1,2,4-triazolium salts based on [2.2]paracyclophane and their characterizations.First we have reviewed the synthetic methods of common triazoliums, we have found that the triazolium salts were mainly derived from some stable hydrazine salts, and the yields were low, especially in some large functional groups. Then we explored a new method to synthesize the triazolium salts. We used the (Rp)/(Sp)-4-amino-13-bromo[2.2] paracyclophane as the starting material. Then we obtained the formyl-protected hydrazine hydrochloride salts by debromination, diazotization, reduction and acidolysis. The triazolium salts were synthesized from formyl-protected hydrazine hydrochloride salts and lactams. Notably, this procedure also provides a new way to synthesize other kinds of triazolium salts with different aromatic groups in the N1position, especially some unstable aromatic hydrazine compounds. Finally we confirmed the structure of the desired triazolium salt by single-crystal X-ray analysis. 3. Asymmetric addition of organoboron reagents to isatins catalyzed by carbene-Rh derived from [2.2]paracyclophane-based triazolium salts.Oxindoles constitute a common structural motif in various natural products and biologically active compounds. Among them,3-aryl-3-hydroxy-2-oxindoles are a useful class of compounds found in several drug candidates. Owing to the signify-significance of this structural motif, the development of a catalytic asymmetric synthesis of these compounds is highly valuable, and the asymmetric arylation of isatins would be the most straightforward approach to this end. Herein, we report that the carbene-Rh derived from the triazolium salts catalyzed the asymmetric addition of organoboron reagents to isatins under mild conditions, achieving moderate enantioselectivity (44%).The main innovation of this thesis:1. Design and synthesis of a family of planar and central chiral bicyclic triazolium ligands derived from [2.2]paracyclophane. The procedure also provides a new way to synthesize other kinds of triazolium salts, especially some unstable aromatic hydrazine compounds.2. The planar and central chiral bicyclic triazolium ligands were first applied in rhodium-catalyzed asymmetric addition of organoboron reagents to isatins. The experimental detail data can guide us to optimize this methodology to other classes of substrates and to improve the enantioselectivity of the asymmetric addition.