Uracil is an important pyrimidine derivative with a wide range of biological, medical and industrial applications. There have been a considerable number of research results on the synthesis of Uracil, including chemical synthesis, microbial synthesis and enzyme-catalyzed synthesis. This article will introduce the various synthetic methods of Uracil in detail.
1. Chemical synthesis:
Chemical synthesis is one of the earliest and most representative synthetic methods of Uracil. In chemical synthesis, Uracil is obtained through the condensation reaction of 5-chlorouracil and acetylacetone, with subsequent transformations through different reactions. Several classic chemical synthesis routes are listed below:
1.1 Take 5-chlorouracil as the synthetic route of starting material:
The classic synthetic route using 5-chlorouracil as the starting material started from the research of two scientists, Cory and Shepherdson. They synthesized Uracil by reacting 5-chlorouracil with pyridone or β-ketoester. Later, this synthetic route was improved and optimized by many researchers, the most famous of which include the research of Khorana and Dorfman et al.
In the 1950s, the Khorana team synthesized Uracil using 5-chlorouracil and acetylacetone as starting materials through a four-step reaction. Among them, the condensation reaction of 5-chlorouracil and acetylacetone is the core step to obtain the precursor 5-chloro-2-formyl-4-carboxypyrimidine (CMCP) of Uracil, followed by reduction, acid-catalyzed ring scission and dehydration Uracil was finally synthesized through multi-step conversion in the reaction.
Dorfman et al. improved the chemical synthesis of 5-chlorouracil, using sodium methyltrifluoromethanesulfonate (MeOTf) as a catalyst, and obtained CMCP in the condensation reaction, and through a combination of condensation, decarboxylation and other reactions Uracil was finally produced. Subsequently, some improvements of this route include the condensation reaction of pyridine with 2-oxourea, and the use of 1,3-dioxepane as an intermediate, etc.
1.2 Taking aminoketone as the synthetic route of starting material:
In addition to the synthetic route using 5-chlorouracil as the starting material, there is also a more concise method using aminoketone as the starting material. In this synthetic route, urease (Urease) is used as a driving agent to hydrolyze uric acid to diaminoacetic acid, and then obtain aminoketone under alkaline conditions. Subsequent oxidation of the aminoketone to the acyloxy group under the catalysis of hydrogen iodide gives Uracil. The method has high atom economy and environmental friendliness, and is a synthesis method in line with green chemistry.
2. Microbial synthesis:
Microbial synthesis refers to the synthesis of Uracil through microbial metabolic pathways. In nature, Uracil is a metabolite produced by eukaryotes and bacteria through the metabolism of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
In microbial synthesis, uric acid is usually used as the starting material, and Uracil is finally synthesized through multi-step metabolism. Examples are as follows:
In this route, uric acid is decomposed into urea and pyruvate through the catalysis of ureidase; subsequently, pyruvate is converted into uracil with the participation of various enzymes such as carboxylase and carboxylation-decarbonylase, and the subsequent The reaction of Uracil is obtained through the pantothenic acid amide pathway. The enzymatic mechanism of most microorganisms to synthesize Uracil is closely related to the metabolic pathway of pantothenic acid amide.
In addition, there have been reports on the construction of engineering bacteria to synthesize Uracil through genetic engineering, such as the use of hydroxybutyrate-3-carboxylate hydroxylase (HPCDH) that forms glycolic acid in Escherichia coli (E.coli) and dissociation to 9 With the participation of enzymes such as pyruvic acid decarboxylase (PDH-E2) of lipoyl coenzyme A, the biosynthesis of Uracil in engineering bacteria was realized for the first time using succinic acid and amino compounds as raw materials.
3. Enzyme-catalyzed synthesis:
Enzyme-catalyzed synthesis method utilizes enzyme-catalyzed reaction to synthesize Uracil, which has the advantages of environmental friendliness and mild reaction conditions. Several enzymes have been found to catalyze the synthesis of Uracil, mainly including: Uracil enzyme, urease and urease. Here are two examples:
3.1 Uracil enzyme-catalyzed synthesis:
Uracil enzyme can catalyze the reaction of uracil and other compounds through β-racemization isomerization to obtain Uracil. Among them, uracil is a compound that widely exists in biological systems and has the prospect of being widely used. Both Saccharomyces cerevisiae and Escherichia coli contain Uracil enzyme, which has a wide application space. By varying the reaction substrates, for example using different substrates such as lactate threonine and uracil, both the efficiency and product distribution can be varied.
3.2 Synthesis catalyzed by urease:
The enzyme-catalyzed synthesis method of Uracil also includes the catalyzed reaction of urease. Urease is an enzyme that can catalyze the conversion of urea into urea and ammonia, wherein urea can be further reacted to produce Uracil. By selecting different urea substrates, such as urea and phenylurea, and changing the catalytic conditions of the reaction, the laboratory-scale synthesis of Uracil can be realized.
In summary, Uracil can be synthesized in a variety of ways, including classic chemical synthesis, microbial synthesis, and enzyme-catalyzed synthesis. These synthetic methods have broad application prospects in different fields, and also provide multiple options for the large-scale production of Uracil.
Chemical properties:
1. Keto-alcohol tautomerism: In aqueous solution, uracil and its tautomer, hydrogen uracil, are transformed into each other through the influence of one proton difference.
2. N-glycosylation: Uracil can be methyl-glycosylated to produce 5-methyluracil.
3. Alkylation: Under alkaline conditions, uracil can be alkylated, usually using the methylating agent methyl methyl carbonate.
4. Carboxymethylation: The carboxyl group can be combined with uracil through carboxymethylation.
Reactive nature:
1. Alkaline hydrolysis reaction: Under alkaline conditions, uracil can be hydrolyzed to uracil acid, which is a way of DNA degradation.
2. Oxidation reaction: Uracil can be oxidized and converted to 5-hydroxyuracil, which is a common product formed during DNA damage.
3. Deamination reaction: Uracil can produce trihydrouracil through deamination reaction.
4. Amination reaction: Uracil can be converted into an intermediate for the synthesis of acetaminobenzenesulfonic acid (ATPS) by ammoniation.
Uracil is an important organic molecule involved in various reactions in cell metabolism. It has a variety of reactive properties, including ketol tautomerization, N-glycosylation, alkylation, carboxymethylation, etc. In addition, uracil is also involved in some important reactions, such as alkali hydrolysis, oxidation, deamination, ammoniation, etc. These reactions provide a wealth of research and application value. For example, chemical drugs can be synthesized through carboxymethylation, and the alkaline hydrolysis of uracil is a key pathway for DNA degradation. These studies provide us with an in-depth understanding of the role and significance of Uracil. important help.