The Design Of Enzyme Mimic System And Study Of Lysine Reaction Selectivity

With the industrial development of human society, humans have changed the environment sharply. After experiencing the early development of the environment-destructive, the goal of sustainable development has been more emphasis on the human and became a basic consensus. Chemical synthesis industry has changed from the past to provide synthetic methods become looking a simple, efficient, green, and environmentally friendly synthetic direction. A new method for the synthesis of determining whether the fine is no longer just confined to yield, but will go from more aspects to consider environmental impacts, operational requirements, etc.In the process of looking for new ways that nature organism gives the best example. Many in the laboratory and factory complex reactions require harsh conditions and steps to be able to get the product, can be efficiently synthesized in live organism at room temperature and atmospheric pressure. In this process, the living body enzymes play a decisive role. Almost all of the reactions involved in the living body enzyme are inseparable. In the presence of the enzyme, the reaction rate can be increased many times over. Same time as the enzyme itself has a complicated structure, which causes a high degree of enzymatic catalyzed reaction specificity. How to accurate simulation of chemical reactions in enzymes and study the role of the enzyme mechanism of action has always been a hot spot in chemical synthesis. Although nowadays many enzymes has been widely used in the production and life, due to the complex structure of the enzyme itself and the features a single catalytic reaction, large-scale application is from a large gap. How to to overcome these shortcomings have been a problem to be solved for chemists by means of chemical enzyme mimics.Since the Nobel Prize winner Professor Lehn proposed the concept of supramolecular chemistry in1985, supramolecular chemistry was experienced rapid development.One of the host-guest chemistry, self-assembly, molecular recognition is even more profound impact on the concept of multiple disciplines including biochemistry. As the force the living body enzyme and substrate can be largely used the concept of supramolecular chemistry to explain, so the use of supramolecular chemistry to simulate the characteristics of the enzyme provided a new way of thinking for chemists. In1970, Professor Breslow creatively deployed modified cyclodextrin complexes of transition metals, proposed the concept of artificial enzymes. Henceforth, the supramolecular host molecules endless variety of applications are increasingly being used, including crown ethers, cyclodextrins, calixarenes is one of the star molecules. Every year, the research group on its applications around the world reported. The biomimetic catalysis is one of the hot spots.Amino acids as well as the human body basic unit of matter consisting of peptides, have a significant purpose in many aspects of food, drug synthesis and functional materials. Meanwhile the chirality of amino acids are also important features distinguish it from other substances. Only the L-amino acid can be absorbed by the body. Only L-amino acids can be synthesized proteins in the body. The characteristics of these amino acids required a higher requirement of synthetic amino acid. In the essential amino acids of body, L-lysine, two amino groups with similar due to their reactivity under normal conditions caused great trouble for its practical application. In conventional chemical methods in order to get a single protected lysine, need to go through complicated steps, the introduction of third-party protecting groups and harsh reaction conditions. The whole process is not only the yield is low, and the introduction of a third protecting group cause of environmental pollution. However, in the living body, L-lysine amino group can be selective efficient reaction in the presence of the enzyme. How to simulate the process and mechanism of L-lysine analog future large-scale use and understanding of enzyme function have a huge significance. Taking into account the key body is in the process of peptide synthesis particular the chirality selective recognition of amino acids, from how to high enantioselectivity, the regioselectivity of the multiple selective identification of amino acid is also a very large enlightenment.In summary, it has been a research focus for enzymatic catalysis, due to the complex structure of the enzyme itself, and itself has high selectivity characteristics, make it as a common catalyst used in a class of reaction has always been a challenge.This requires us to have a more profound understanding between enzyme and substrate effects. The supramolecular chemistry concerns weaker reversible intermolecular interaction. These effects although not from the absolute magnitude of the energy, but the role is enormous. Through screening of supramolecular host, we developed a new method for efficiently selectively protected L-lysine. The mechanism has been reasonably predictable by means of two-dimensional NMR reaction. By changing the supramolecular host, the opposite selectivity has been artificially controlled. We apply this method to amino acids which structure similar to L-lysine and received satisfactory results. On this basis, we investigated selective conditions to generate an amide bond in the presence of various amino acids. Finally, in consideration of chiral, we reach region and enantioselectivity in the same reaction step simultaneously.The paper includes the following aspects:Chapter One Introduction to supramolecular chemistrySupramolecular chemistry studies reversible intermolecular forces, such as van der Waals forces, hydrogen bonding, covalent disciplines developed rapidly in recent years. Many of the concepts developed by the supramolecular chemistry, such as the host-guest chemistry, self-assembly, molecular recognition and so has been widely used in various studies in which modern science. Which includes both theoretical innovation, but also practical applications. There are many instances in the chemical synthesis,targeting and carrying drugs, natural product inclusion and enzymatic reactions.Chapter Two The design of enzymatic system and protection of L-lysineEnzymes are the most activity and selectivity catalyst in nature.Fine structure of the enzyme has a huge impact on the reaction.Theory of enzymatic focused on the binding of substrate to the enzyme, enzyme stabilization and activation of the transition state intermediate at this stage. The enzymatic reaction is always the hotspot in research.Since the L-lysine two amino groups having similar chemical activity under normal conditions, to obtain a single amino-protected L-lysine is essentially necessary step for further use. In conventional step to observe single-carbonxylic acid benzyl ester protected L-lysine, the introducing of copper ions under high temperature or benzaldehyde under low temperature is inevitable. These steps are not only cumbersome, due to the introduction of third-party groups, but also has a great influence on the reaction yield and the environment. We developed a new way to protect L-lysine. Under the conditions of room temperature and water as solvent, high selectivity (>99%) and high yield (>99%) benzyl ester protected s L-lysine are observed in short time (10min). This is a huge step forward for the traditional method. We studied the mechanism of this reaction, through the modifications of cyclodextrin structure we find important structural affect the reaction selectivity, selective can be inversion by rational design. We propose the reaction mechanism by NMR, IR. The theoretical calculate was also used in the mechanism study. We compare possible transition state in the reaction by the density functional theory. The calculated result was accord to our hypothesis.Chapter Three Selective amino acid amide bond formation in the presence of multiple amino acidsPeptide is the amino acid chain of monomer molecules through a peptide bond (the dehydration condensation of amino and carboxyl) connected. In recent years it has received many attentions in molecular biology and pharmaceutical chemistry. Peptides has a close relationship with many diseases in the human body like Acquired Immune Deficiency Syndrome, Alzheimer’s disease. In recent years, peptide drugs exhibit a number of excellent properties.Peptide antibody designed to allow molecular biologists to change the form of the protein for specific antibodies designed. The traditional method of peptide synthesis that solid-phase synthesis of amino acids in order to join and to protect all have strict requirements. This peptide synthesis a living body has a big difference. And that the key lies in the multi-system specific amino acids selection and activation. In the basis of the results we have achieved, we will expand the choice of amino acids to the multi-system and get good results.Chapter Four The new enzymatic sysntem and multiple selective of Iysine Selectivity and velocity of chemical reactions has been the most important aspects. In the selective area contains both regio, enantioselective, non enantioselective, a variety of factors. How to implement multiple selection in a reaction has been a hot research for chemists. For amino acids, chiral is one of the most important character. L-and D-amino acids in the body plays a very different role. For lysine, the amino group due to its chemical activity both under normal circumstances substantially the same effective area also involves the identification of its amino selectivity. Our achievements can make use of existing kinetic resolution of racemic lysine in a short time, within a short time (10min) to achieve a high regioselectivity (>99%) and enantioselectivity (>99%). This is the first report of multiple selective lysine. We also use other means of NMR and theoretical calculations confirmed the reasonableness of our assumptions mechanism.Chapter Five The mechanism study of Mukaiyama Aldol reation and the synthesis of Ixabepilone side chainAldol reaction is the classical way to form carbon-carbon bond, Mukaiyama make some process base on it. The chiral of product can be controlled by the chiral of substrate or catalyst. Ixabepilone is the new generation anticancer drug, the synthesis of its side chain is not reported in detail. Since the anaerobic reactions involving other harsh conditions over anhydrous, conventional monitoring method is difficult to accurately monitor the specific reaction conditions. We put the reaction the NMR tube to monitor the reaction online. By optimizing the reaction conditions (including reaction solvent, temperature and base filter), find the main factors affecting the reaction, to obtain the most suitable reaction conditions.Chapter Six Improved synthesis for lisinopril intermediatesLisinopril is a commonly used oral antihypertensive drugs, intermediates in the synthesis of conventional, involving the use of phosgene, a long reaction time, low yield, high cost, we chose a different protecting group reaction, development synthesized a variety of drug intermediates. Compared with the traditional method is easy to operate, low cost and high yield.The main innovation of this paper is as follows: 1. We developed a new supramolecular enzymatic way to protect single amino group of L-lsyine. In traditions ways, tedious steps and harsh conditions are necessary. The new way is easy to hand and environment friendly. This method is also applicable L-ornithine which structure is similar with L-lysine.2. We success apply our method in the amino acid selection in the present of multi amino acids. For DL-lysine high regioselectivity and enantioselectivity was achieved at the same time This is also the first case of lysine to achieve the dual selective in reactions.3. We used NMR to monitor the Mukaiyama Aldol reaction under anhydrous anaerobic conditions, a series of optimal reaction conditions was observed. Through the amplification reaction confirmed the feasibility of the conditions. And these conditions are applied in the synthesis of Ixabepilone branched chain.