Synthesis Of Planar Chiral [2.2]Paracyclophane Triazolium Salts And Their Applications In Copper Catalyzed Asymmetric Boration Reactions

Efficient methods to take chiral compounds from racemic starting materials arc in high demand, especially in the pharmaceutical and agricultural areas. The most important access to obtain the enantiopure compounds was enantiosclectively catalyzed pro-chiral starting materials. The Nobel Prize in chemistry2001was awarded jointly to William S. Knowlcs, Ryoji Noyori and K. Barry Sharpless for their pioneer works on chirally catalyzed hydrogenation reactions and oxidation reactions. Subsequently, chemists began to study asymmetric catalysis to obtain the optically pure compounds.Recently organoboron derivatives have become important synthetic intermediates because of their stable structures and easy modification of their functional groups. The most famous utilization was catalyzed cross coupling reactions which award the Nobel Prize in Chemistry2010. Preparation of chiral organoboron compounds remains an active area of research in chemical synthesis because the C-B bond can be converted into a wide variety of functional groups without loss of the enantiopurity. In the past few years, various methods have been devised for the synthesis of these compounds. The most common access to α-chiral organoboron compounds is asymmetric conjugate addition of diboron reagents to α,β-unsaturatcd compounds and a variety of catalytic systems have been developed, including chiral phosphors ligand and N-heterocyclic carbene (NHC) ligand.Cataiysis 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 Iigands, triazolium ligands always applied in organocatalyzed reactions while their applications in organomctallic catalyzed reactions are rare. In recent yeais, 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 participate in other N-heterocyclic carbene has not been studied.In conclusion, the chirai N-heterocyclic carbene is a focus for researchers. Based on the basis of our lab, we have designed and synthesized a novel class of planar chiral [2.2]paracyclophane triazolium salts and successfully applied in copper catalyzed asymmetric boration reactions.The main content of the thesis was 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 mainly applied in organocatalyzed reactions, including benzoin condensation, Stetter reaction, reactions of a,(3-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 common triazoliums synthesis method, we have found that the triazolium salts mainly derived from some stable hydrazine salts, and the yields are low, especially in some large functional groups. Then we explored a new method to synthesis the triazolium salts. We used the (Rp)-4-amino-13-bromo[2.2] paracyclophane and (Sp)-4-amino-13-bromo[2.2] paracyclophane as the starting materials. 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 Nl position, especially some unstable aromatic hydrazine compounds. Finally we confirmed the structure of the desired triazolium salt by single-crystal X-ray analysis.3. Asymmetric β-boration of α,β-unsaturated N-acyloxazolidinones by [2.2]paracyclophane-based triazolium salts and the reaction mechanism research.The chiral boron compounds can be transformed into a variety of chiral groups which have been attracted many research attentions. However, although progress on copper(I)-catalyzed asymmetric β-boration has been substantial, design and synthesis of new ligands to broaden the substrate scope and enhance the selectivity is s till a challenge. Firstly, we screened chiral triazolium salts derived from L-pyroglutamic acid and [2.2]paracyclophane, the results told that the triazolium salts showed high activities in asymmetric p-boration reactions. Then we screened the substrates which told us that the α,β-unsaturated N-acyloxazolidinone was the best substrate. Having identified the optimal set of reaction conditions, we then investigated the reactions with a variety of u,fl-unsaturatcd iV-acyloxazolidinones. The procedure tolerates a relatively wide range of substrates and shows excellent selectivity (up to99%ee) and high reactivity (up to96%yield). Finally we take the mechanism research, the catalyst-ligand combination provides the product with very high yield and enantioselectivity via a bifunctional mode of activation.4. Highly enantioselective β-boration of acyclic enones by [2.2]paracyclophane-based N-heterocyclic carbene copper(Ⅰ) catalystsAlthough our group identified a planar and central chiral bicyclic triazolium Iigand which induced exceptional enantioselectivities in the coppcr(Ⅰ)-mediated β-boration of α,β-unsaturated N-acyloxazolidinones. While the catalyst system induced the β-boration of α,β-unsaturated acyclic enones in only moderate enantioselectivity. In our quest to develop an efficient calalyst in asymmetric conjugate boration reaction, we therefore take a research in asymmetric copper(Ⅰ)-catalyzed β-boration of α,β-unsaturated acyclic enones. Firstly, we screened some known chiral triazolium salts derived from chiral amino acids. The experiment told us that phenylglycinol derived triazolium salt gave the best result. We were interested to see if introduction of a planar chiral [2.2]paracyclophane in triazolium salt could-enhance the enantioselectivity in asymmetric conjugate boration reaction. To our delight, the boration products obtained in good yield and enantioselectivity. Another improvement over the literature benchmark is that the reaction time was short, scaled up to a gram-quantity in only0.1mol%catalyst at room temperature could give the product in nearly quantitative yield and excellent enantioselectivity (95%ee) which is the most effective catalysis ever reported in an asymmetric boron conjugate addition reaction. Finally we take the mechanism research; the exceptional enantioselectivity is rationalized by avoiding the steric collision in the favored transition state.The main innovation of this thesis:1. Design and synthesis of a family of planar and central chiral bicyclic triazoliurn ligands derived from [2.2]paracyclophane. The procedure aiso 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 ligand successfully applied in copper(Ⅰ)-catalyzed asymmetric p-boration of α,β-unsaturated N-acyloxazolidinones and gave a variety of chiral secondary alkylboronates in excellent enantioselectivity. This is a new bifunctional catalyst in the asymmetric boration reaction. This is also the first time that a chiral triazolium salt ligand has been applied in a transition metal-catalyzed reaction.3. Developed a highly catalyzed system in p-boration of α,β-unsaturated acyclic enones. The designed triazolium salts behaved as powerfully as the triazolium salts used in organocatalytic processes. The catalyst was proved to be the most effective catalysis ever reported in an asymmetric boron conjugate addition reaction.