SYNTHESIS & APPLICATIONS OF LABELLED FORMYLATING REAGENTS

高效的甲酰化试剂在有机合成中具有广泛的用途 综合。除了简单和直接的反应性甲酰化 官能团，它们用于一个碳延伸反应， 以及脂肪族和芳香族化合物通过亚甲基环化 插入反应。几种甲酰化试剂，如 甲醛、甲酸、甲酰氟、甲酸酐或甲酸 醋酸酐已可用于非放射性合成 有机合成中的甲酰基，但只有氚甲醛 在1：99的水混合物中，比活度为25-100毫克/毫摩尔 可用于三硫甲酰化反应。几个 生物上重要的化合物，如叶酸，一种解药 作为叶酸拮抗剂的药物，叶绿素b，一种必不可少的 光合作用中的化合物，以及一组被称为 趋化性多肽(白细胞趋化剂，引导 细胞的迁移)携带其活动所必需的甲酰基。 在这最后一组中，兔和人的趋化反应 中性粒细胞对合成三肽的影响 N-甲酰-甲硫基-亮氨酰-苯丙氨酸被公认为 通过多肽与特定受体的相互作用来调节。在……里面 除了刺激趋化作用外，这种肽/受体的相互作用 在中性粒细胞中启动一系列事件，如溶酶体酶 钙的释放、超氧化物的形成和释放。N-甲酰基 基团似乎是自N-乙酰化以来良好活性所必需的， 除去a-氨基或由乙基取代得到 活动损失1000-10,000。开发一种高效的和 高比活性的氚甲酰化试剂将是 对阐明许多生物过程极其有用。 标题：标记甲酰化试剂的合成及应用 (续)我们建议合成三个选择性和高效的 三甲基甲酰化试剂如下：1.对硝基苯 三硫甲酸盐：该试剂可通过偶联反应合成。 对硝基苯酚与氚甲酸在四氢呋喃中的DCC分析。这 方法依赖于氚甲酸的合成。一个 该试剂的替代方法可以是三丁基三丁基锡 对硝基苯氯甲酸酯在催化剂存在下的还原反应 钯催化剂。在初步研究中，我们已经合成了 N-硝基苯基甲酸酯，化学产率高，该试剂是 成功地用于两种氨基酸的N-甲酰化反应， L-蛋氨酸和色氨酸甲酯。2. N-三硫甲酰氧基邻苯二甲酰亚胺是另一种可以被 偶联氚甲酸类似反应合成 N-羟基邻苯二甲酰亚胺。这种合成的另一种方法 可能涉及三硫甲酸锂的反应和 N-溴邻苯二甲酰亚胺在合适的溶剂(二甲基亚砜)中。3. 乙酸甲酸酐(AFA)是我们计划使用的第三种试剂 探索一下，因为它可以由甲酸的碱性盐类制成。 合成N-甲酰氧基邻苯二甲酰亚胺的实验正在进行中 和AFA。这是一个在杂环化学中应用广泛的领域。 以及一种标记各种杂环的氚的新方法。

Efficient reagents for formylation have a wide utility in organic synthesis. In addition to simple and direct formylation of reactive functional groups, they are used for one carbon extension reactions, and cyclization of aliphatic and aromatic compounds, through methine insertion reactions. Several formylating reagents such as formaldehyde, formic acid, formyl fluoride, formic anhydride or formic acetic anhydride have been available for non-radioactive synthesis of a formyl group in organic synthesis, but only tritiated formaldehyde at a specific activity of 25-100 mCi/mmole in 1:99 mixture with water is commercially available for tritioformylation reactions. Several biologically important compounds, such as folinic acid, an antidote to drugs that act as folic acid antagonists, Chlorophyll b, an essential compound in photosynthesis, and a group of bioactive peptides known as chemotactic peptides (leukocyte chemoattractants which direct the migration of cells) bear a formyl group necessary for their action. In this last group, the chemotactic response of the rabbit and human neutrophils to the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine is well established to be mediated via interaction of the peptide with a specific receptor. In addition to stimulating chemotaxis, this peptide/receptor interaction initiates a number of events in neutrophils such as lysosomal enzyme release, superoxide formation and release of calcium. The N-formyl group appears to be essential for good activity since N-acetylation, removal of the a-amino group, or replacement by an ethyl group results in 1000-10,000 loss in activity. The development of an efficient and high specific activity tritiated formylation reagent would be extremely useful for the elucidation of many biological processes. TITLE: Synthesis and Applications of Labelled Formylating Reagents (Continued) We propose the synthesis of three selective and efficient tritioformylating reagents as follows: 1. p-Nitrophenyl tritioformate: this reagent can be synthesized by coupling p-nitrophenol with tritiated formic acid using DCC in THF. This method relies on the synthesis of tritiated formic acid. An alternative method for this reagent can be the tributyltin tritide reduction of p-nitrophenyl chloroformate in the presence of a palladium catalyst. During preliminary studies we have synthesized N-nitrophenyl formate in high chemical yield, and this reagent was successfully used for the N-formylation of two amino acids, L-methionine and tryptophan methyl ester. 2. N-tritioformyloxyphthalimide is another reagent that can be synthesized by a similar reaction of coupling tritiated formic acid with N-hydroxyphthalimide. An alternative method for this synthesis might involve the reaction of lithium tritioformate and N-bromophthalimide in a suitable solvent (dimethylsulfoxide). 3. Acetic formic anhydride (AFA) is the third reagent we are planning to explore as it can be made from the alkaline salts of formic acid. Experiments are underway for the synthesis of N-formyloxyphthalimide and AFA. This is a field of wide application in heterocylic chemistry and a new approach to tritium labelling of a variety of heterocycles.