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Polyamino acid’s application in asymmetric synthesis

Posted Date : 21/12/2011  Click : 281

Ye Runhui
(Wenzhou Industrial Design Institute, Wenzhou 325000)
Abstract 20th century 1980s found that poly (amino acid) (by 10-30 identical amino acid polymerization and) can be used as a catalyst for the asymmetric organic synthesis reaction, due to its potential value in theory research and in the synthesis of industrial applications, researchers is trying to reveal the catalytic mechanism and trying to large-scale application in the industrial synthesis. In this paper, the application of poly amino acid in asymmetric synthesis was discussed in this paper.
Keywords asymmetric synthesis of polymer with amino acid catalyst
Application of Polyamino Acids in Asymmetric Synthesis
Ye Runhui

(Wenzhou Industry Design Institute, Wenzhou 325003)
Abstract  It was found that amino acid polymers could be used as catalyst in asymmetric synthesis in the 1980’s. Considering its theory interesting and application potential in industry synthesis, much work is being done to study its mechanism of reaction and practical application. Mini-review about some of its applications achieved by our laboratory together with other laboratories has been made in this paper.

Key words   Amino acids, Catalysts, Asymmetric synthesis,Polymers
Enzyme is a macromolecular protein composed of 20 amino acids. As a kind of biological catalyst, enzyme can catalyze many reactions, such as hydrolysis of ester and amide, esterification of alcohols and reduction of ketones, which are widely existed in the organic synthesis. In these reactions, the enzyme has a high degree of substrate specificity and three dimensional chemical selectivity, which plays an important role in the process of industrial organic synthesis. Industry often requires a large number of tool enzymes, had to be artificially synthesized or recombinant expression. It is very difficult to synthesize active enzymes, and the cost is higher. Recombinant expression is a good choice for a large number of industrial enzymes. However, due to the complexity of protein structure, it is difficult to express the recombinant protein.
In 1980, Juli, with alanine synthesized a peptide, the peptide only by alanine polymerization and, it can check the catalytic epoxidation of chalcone (1), and the oxidation reaction with high enantioselectivity, this reaction is a synthetic polypeptide as the first example of asymmetric organic synthesis reaction catalyst [1]. Since then, more and more synthetic peptides have been used as catalysts for asymmetric organic synthesis. These amino acid polymers are known as enzyme synthetic or synthase (synzyme). With respect to the naturally occurring composed of different amino acid enzyme, poly (amino acid) for asymmetric organic synthesis catalyst has the following advantages: easy to get, cheap, easy from the reaction mixture separation purification, activity and stability, photochemical product purity is high, easy to effective recycling and reuse [J].
Preparation method of 1 poly amino acid
1.1 activation and polymerization of amino acids
Amino acids are needed to protect and activate the free amino groups and carboxyl groups before polymerization. Such as free amino acids into n-carboxyl anhydride (NCA), through the use of phosgene, or concentration of diphosgene, triphosgene to complete the reaction. In addition, can also be protected amino alkoxy carbonyl with thionyl chloride cyclization of N- carboxylic anhydride (NCA) [2]. NCA can be used in two ways, one is to use the wet box test method, the other is to use the appropriate amino initiator [3]. There are a lot of amino compounds that have been used as polymerization initiator, including fatty amines, polymer supported amino groups, and amino groups of resin bound amino groups. The amino acid polymer can be precipitated and separated by filtration through the amino group as initiator. The synthesis process of poly amino acid is expressed in the following formula.
Although the wetting box test method can be used to carry out the polymerization reaction. But by contrast, the polymerization product obtained by the amino initiated polymerization generally has a better quality. Moist chamber test method requires high quality crystalline NCA, and may lead to incomplete polymerization, there are more low molecular weight polymers, resulting in decreased catalytic activity.
Regeneration of 1.2 amino acid
When fixed in stromal reaction of poly amino acids are used repeatedly after, its catalytic activity will decrease and the reaction time will prolong gradually, stereoselective will gradually weaken, the need of polymers were purified and recycled. One kind of regeneration method is that the recovered poly amino acid is suspended in the toluene to carry out violent oscillation. With 4mol/L sodium hydroxide oscillation 16h can achieve the purpose of regeneration [2]. The method can make the catalytic activity and enantioselectivity of the polymer was largely restored; another regeneration method is similar with above method, different is, in addition to sodium hydroxide solution is added, still need to add a small amount of hydrogen peroxide solution. The basic principles of the two methods are the removal of small molecular polymers which have been degraded by the solvent.
2 poly amino acid catalyzed reaction
2.1 ring oxidation reaction
Up to now, the most widely used and studied is the ring oxidation reaction of poly amino acid catalysis.
2.1.1 reaction substrates are prepared by [4] many of the substrates used in the epoxidation of the poly amino acid catalyzed reactions can be directly obtained by the simple hydroxy aldehyde condensation reaction. If not be able to get epoxidation reactions of ketene substrate from the above method, the enone substrate is obtained by standard (Wittig) chemical synthesis pathway, R, R1 can be varied organic groups) such as phenyl, ring propyl, tert butyl and other groups), is shown as the following formula.
If more complex substrates are needed, a multi-step synthesis approach is needed.


2.1.2 reaction conditions and the initial oxidation of the product by the amino acid catalyzed by the amino acid polymer are all in the "three phase" reaction conditions. This "three phase" is a peroxide solution, an organic solvent and an amino acid polymer. Before joining the substrate, the amino acid polymer was swollen at least 6h in the mixture of oxidant and organic solvent. Check the chalcones under the reaction conditions can be very good to be oxidized, with aromatic ring substituents check chalcones under the condition can also be oxidized. In addition, under the condition of the reaction, oxidation reaction process can many improvements, the organic solvent can be varied, such as carbon tetrachloride, toluene and dichloromethane have successfully for the reaction system. The reaction system, the most commonly used oxidant hydrogen peroxide, but other oxidants such as tetrabutylammonium hydrogen peroxide and sodium perborate was also used, just different oxidants cause oxidation reaction time, table 1 is a three-phase reaction conditions epoxidation of some examples [5~8].
Reagents and conditions: a H2O2 solution, NaOH solution, toluene, poly (L) - alanine; B H2O2 solution, NaOH solution, CC14, poly (L - alanine; solution of cNaOH, n-hexane, EDTA, poly (L) - leucine; D H2O2 solution, NaOH solution, DCM, poly (d) - leucine; e H2O2 solution, NaOH solution, DCM, poly (L) - leucine; F H2O2 solution, NaOH solution, n-hexane, poly (L) - leucine; G H2O2 solution, NaOH solution, toluene, CLAMPS- poly (L) - leucine
Although the three-phase reaction system has a great advantage, but one obvious disadvantage is need too long reaction time, such as chalcone epoxidation of 1 to 24 hours to complete, also some important substrate reaction or response is slow, for example, diene 11 transform for 12 in three-phase reaction conditions and the rate of 78%, the photochemical purity >96% enantiomeric excess (EnantiomericExcess (EE), but need to reaction time was 72h, and is particularly suitable for the enolization of the substrate, for example, isopropyl 15 and methyl 17 ketone in H2O2 solution and NaOH solution. The presence of DCM and poly -L- leucine was very slow (168h) or almost no reaction.
Because of this, people began to search for more time and save the reaction conditions, resulting in the production of dual phase reaction system. Use urea hydrogen peroxide (UHP) complexes as the oxidant, the second aza bicyclic 11 carbon alkene (DBU) as a non pro nuclear organic alkali, with tetrahydrofuran (THF) as solvent [9]. A notable feature of this method is that the reaction time is greatly reduced. For example, the ring oxidation reaction of 30min can be completed, the conversion of 11 to 12, 3h can be completed, and the yield is 78%, >95%ee. Similarly, biphasic system, also can make a lot of substrate oxidation occurs, but unlike three-phase reaction system, two phase reaction system can also hydroxide ultra sensitive system reaction, make originally not reaction of some substrate to the epoxidation of, cases such as, methyl ketone 17 reaction 4h after transformation for 18 to 70% rate, 80%ee. Table 2 is a few examples of ring oxidation under two phase reaction conditions [10-14].
Table 1 epoxidation of some substrates under three phase reaction conditionsTab.1 Substrates epoxidised under triphasic reaction conditions

2.1.3 stereochemistry determination when using poly (L) - amino acid as a catalyst, check chalcone oxidation reaction of the main optical isomer products are left-handed; instead, when using poly (d) - polymers of amino acids as catalysts, the main optical isomer products is right-handed. Circular dichroism measurement was used to determine the absolute configuration of the product of the reaction [15].
2.2 other types of Michael reactions
The use of amino acid polymer as a catalyst in the Michael reaction of his type also has a successful example. Particularly noteworthy is the Thiophenol and chalcone coupling. Using poly (L) - leucine as a catalyst, beta phenyl sulfide, the photochemical purity can reach 45% enantiomeric excess (EE). The results show that if added slowly thiophenol to the reaction mixture can be obtained better reaction effect [5].
2.3 sulfide oxidation into the sub
Poly leucine can also be oxidized to become a sulfur ether, when poly leucine coated on the platinum electrode, it can catalyze the oxidation of sulfide to become a sub, its photochemical purity can reach 77%ee, the yield was 56%[16].


Table 2 epoxidation of some substrates under two phase reaction conditions
Tab.2 Substrates epoxidised under biphasic reaction conditions

Reagents and conditions: a.UHP, DBU, CLAMPS- poly (L) - leucine, B.; UHP DBU, THF, CLAMPS- poly (D) - leucine, THF; c.UHP, DBU, CLAMPS- poly (L) - leucine, EtOAc.
Effect of 3 amino acid chain length on catalytic reaction
The mechanism of the oxidation reaction catalyzed by poly amino acid is still a difficult problem to be answered. Julia et al. Originally synthesized a series of amino acid polymers, including poly (L) - alanine, poly 5- benzyl - (L) - glutamic acid as well as poly 5- butyl - (L) - glutamic acid. When these polymers were used for asymmetric catalytic reactions, only the poly alanine had a high catalytic activity and a strong selectivity to reflect the selectivity of [17]. Their study also found that the catalytic yield and selectivity of poly amino acids are very sensitive to the substitution of the aromatic ring, such as the ring oxidation reaction of the alkyl substituted. The epoxide yield is very low, and trans alpha and beta unsaturated ketones epoxidation no enantiomeric selectivity [18].
It is also found that the catalytic activity and selectivity of the epoxidation are also dependent on the molecular weight. By 10 to 30 amino acid polymerization of polymers, the catalytic efficiency and enantio selective activity with the increase of the molecular weight of the polymer increased [19], with poly (d) - alanine as a catalyst from the end product of epoxy check chalcone (epoxychalcone) and poly (L) - alanine as catalyst are final products have the same enantioselectivity, but with opposite configuration. But if with poly (D, L - alanine as catalyst and catalytic activity is very low and basically no enantio selective [20]. Thus, the composition of chiral amino acid polypeptide polymer not only to its catalytic activity are closely related, but also for enantioselectivity is crucial.
Conventional polymerization catalyzed by poly amino acid was carried out in the "three phase" system of polypeptide water toluene, when the epoxidation of the methyl ketone was carried out in methanol, the reaction selectivity was not seen. The carbon of the ear and the oxidant HOO can form hydrogen bond with the peptide, and the methanol can destroy the hydrogen bond. This indicates that the binding of hydrogen bonds is also crucial for the asymmetric epoxidation of peptides. These interactions may play an important role in the asymmetric oxidation reaction. In order to further prove these ideas, poly (L) - proline was synthesized, which could not form hydrogen bonds because of no amino hydrogen atom. It was found that there was no catalytic activity for the epoxidation reaction of [21].
The conformation of synthetic peptides also has an important influence on the selectivity of the epoxidation reaction. The study showed that, with the increase of alpha helical components in the polypeptide, their enantiomers were enhanced. The beta - fold composition of the synthetic polypeptide will result in a significant decrease in the activity of the enantiomers. Short peptides that do not form alpha helical structures have little to no activity on the [19]. It is also further explained why the 10 amino acids of the amino acids are necessary for their catalytic activity and selectivity, because 10 of the amino acid polymers are difficult to form alpha helical structures. Typically, N- and C- polypeptide end groups had little influence on the epoxidation reaction. How to realize the catalytic activity of poly amino acids, and how to realize the asymmetric synthesis of poly amino acids, is not clear.
4 outlook
In the organic synthesis industry, especially in the synthetic pharmaceutical industry, the application of poly amino acid catalyst is receiving more and more attention. In the pharmaceutical industry, the chemical purity of the drug is particularly concerned, because a heterogeneous body can be used to treat diseases, and its mirror isomer is likely to be detrimental to health. By poly amino acid catalytic synthesis of leukotriene anti agent SK&F104353 has been used for the treatment of bronchial asthma [22], Roberts, a professor at the University of Liverpool in the United Kingdom and the British chiral drug companies chiroscience have poly (leucine for drug synthesis industry. They are trying to synthesize Diltiazem (a potent antihypertensive drug) with the use of leucine as a catalyst [23]. In addition, polymers of amino acids catalyzed check ear ketones epoxidation was also used for the preparation of natural products, such as flavonoids, flavonoids) [24].
Although the oxidation mechanism of poly amino acid catalyzed oxidation is not clear at present, but with the further research, the catalytic mechanism will be more and more clear. Once you know the simple polypeptide molecules in the presence of organic solvent conditions is how to fold and how to form a can activate peroxide or / and ketene satisfactory completion of asymmetric oxidation reaction of chiral cavity or chiral surface, then in changing reaction conditions, by poly amino acid catalytic reaction will extend to other substrates, such as alpha, beta - unsaturated esters, nitro olefins, perhaps including the electron rich olefins.
Acknowledgements this thesis research has been funded by the Wenzhou Municipal People's government. The British Department of chemistry, University of Liverpool Roberts laboratory, thanks to the British Department of chemistry, University of Liverpool Roberts Professor, Dr. William, Paula, and corma Dr. in the writing process of great help!

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