Oxyma and its derivatives
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1. Introduction to Oxyma

Chinese name: ethyl 2-oxime cyanoacetate
English name: Ethyl (hydroxyimino)cyanoacetate
CAS number: 3849-21-6



Oxyma structure


2. Application of Oxyma and its derivatives as coupling reagents

1. Oxyma Reagent

The amide bond is not only an important structural functional group of natural active compounds, such as various polypeptides and proteins, but also an important component of many organic compounds, especially pharmaceuticals. According to statistics, the proportion of drugs containing amide bonds is as high as 25%, so the synthesis of amide bonds is particularly important. There are related articles on the synthesis of amide bonds in the official account of Haofan Biology, and each detailed synthesis method will not be repeated here. There are many ways to synthesize amide bonds, but the most basic and direct method is to form amide bonds through dehydration of amino and carboxyl groups. Generally, the carboxyl group is first combined with the electron-withdrawing group to be activated, and then reacts with ammonia, primary or secondary amine to form an amide bond. This method activates the carboxyl group is the key to the reaction, and racemization is prone to occur, resulting in the loss of chirality. Therefore, when the carbodiimide condensing agent is used, a coupling additive is required to form a more stable active intermediate, reduce racemization and increase the yield. In 1973, Masumi Itoh and others designed Oxyma, which has strong acidity and nucleophilicity, and can inhibit racemization when combined with carbodiimide. The pKa=4.6 of the cyanoxime Oxyma with electron-withdrawing substituents, the acidity makes it have the potential of leaving groups, and it has good solubility in most solvents. Therefore, in the synthesis of amide bonds, the combination of Oxyma as a coupling additive and carbodiimide condensation agent has certain advantages.


The carboxylic acid first reacts with carbodiimide to form an active intermediate, and then undergoes acyl transfer with Oxyma, the carbodiimide leaves, and then the Oxyma active ester is aminolyzed to form an amide compound. In this process, the formation of highly stable by-products urea, phosphoramide or sulfonate is the main driving force of the reaction. The reaction mechanism is shown in the figure below:




In 2012, the Wang team reported the water-soluble 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate ethyl ester (Glyceroacetonide—Oxyma), using the inorganic base sodium bicarbonate in combination with EDCI in water, and Ammonia-protected amino acids condense in good yields with a low degree of racemization. In 2013, the Cherkupally team reacted Oxyma with potassium hydroxide to form potassium salt, which not only has good solubility in most organic solvents, but also dissolves in water and ethanol, and has good catalytic activity when used in combination with EDCI. The yield of Z-Phg-Pro-NH2 catalyzed by K-Oxyma combined with EDCI was 88%, and the DL/LL was 1.2%. In the same year, the Elfaham team reported that when using DIC in combination with Oxyma, the yield was 88% when catalyzing the coupling reaction of N-acetyllysine and 4-aminobenzoic acid, and NMR showed no impurities. When DIC is used in combination with HOBt, the yield is 82%, and NMR shows that there are impurities. It can be seen that Oxyma has higher yield and purity when catalyzing this reaction.


2. Cyclic Oxyma Reagent

Jad et al. designed a class of HONM containing a six-membered ring, which has very high activity. When it is combined with carbodiimide for the coupling reaction of amide bonds, there are many side reactions, and even the target product cannot be obtained. On this basis, Oxyma-B and Oxyma-T, barbiturate oxime derivatives, are designed. Because barbituric acid is relatively stable, its activity is moderate, and its structure does not contain ester bonds, so there are no by-products produced by esters. product. Their activation time is very short, generally about 3 minutes will have good results. When catalyzing Z-Phg-Pro-NH2, Oxyma-B is combined with DIC, and the yield reaches 90%, and the DL/LL is 1.0%; Oxyma-T Combined with DIC, the yield is 94.7%, and DL/LL is 0.7%. When the same condensing agent is DIC, combined with HOAt, the yield is almost the same at 91.5%, but DL/LL is 3.9%. It can be seen that the yield of Oxyma-B and Oxyma-T is not much different from that of HOAt, but it is obviously better than HOAt in inhibiting racemization.




3. Oxyma reagents protected by Boc, Fmoc, Alloc, etc.

Protecting groups such as Boc, Fmoc, and Alloc can inhibit the occurrence of racemization by forming mixed anhydrides, so Thalluri synthesized Boc-Oxyma, Fmoc-Oxyma, and Alloc-Oxyma. Taking Boc-Oxyma as an example, it can effectively activate carboxylic acids to form amides, peptides, esters, thioethers and hydroxamic acids, etc. The by-products are only easily removable carbon dioxide, 2-methyl-2-propanol and recyclable solids Oxyma. When catalyzing the synthesis of amides, the yield of both primary and secondary amines is above 85%. When catalyzing the synthesis of chiral compound Z-Gly-Phe-Val-OMe, no racemization occurs at all.




4. COMU Reagent

COMU is an Oxyma hexafluorophosphate containing morphineurea structure, which has good solubility and stability in common solvents. COMU contains a highly active CO bond, which makes it easily hydrolyzed into Oxyma and dimethylmorphine urea in a more polar solvent. However, it has good stability in acetonitrile and γ-valerolactone, and when TMP is used as a base to catalyze, the reaction process has obvious color changes, and the red color of the reaction solution disappears and becomes colorless at the end of the reaction. When COMU is used in combination with a condensing agent, it can suppress the occurrence of racemization to the greatest extent, and its by-products are water-soluble and easy to remove.




5. Oxyma phosphonium salt, uronium salt coupling condensation agent

With the continuous development of Oxyma reagent, its use is becoming more and more extensive. It can not only be used as an additive in combination with a condensing agent, but can also be used alone as a coupling condensing agent. Subirs et al introduced a class of phosphonium salt coupling condensing agents PyOxP and PyOxB, Jad et al. reported a group of uronium salt coupling condensing agents TOMBU and COMBU, the above mentioned several condensing agents do not need to be combined with carbodiimide Used in combination, it has a better catalytic effect.




3. Conclusion

Oxyma and its derivatives, as an important new coupling reagent, are becoming more and more popular in the field of organic synthesis and biomedicine. Wang Fengliang, Xu Ling, Department of Chemistry, University of Science and Technology of China, and others used Oxyma coupling agent to synthesize the polypeptide drug Liraglutide (Liraglutide) with the function of treating diabetes at one time on the resin, which has a high synthesis efficiency and the success of this scheme The implementation opened up the possibility of large-scale synthesis of liraglutide using chemical methods.

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