SYNTHESIS & APPLICATIONS OF LABELLED FORMYLATING REAGENTS

高效的甲酰基化试剂在有机合成中具有广泛的用途 合成. 除了简单直接的无功补偿外， 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的环化，通过次甲基 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 乙酸酐已可用于非放射性合成 有机合成中的甲酰基，但仅限于氚化甲醛 在与水的1：99混合物中，比活度为25-100 mCi/mmole 可商购用于三硫甲酰基化反应。 几 生物学上重要的化合物，如亚叶酸， 作为叶酸拮抗剂的药物，叶绿素B， 光合作用中的化合物，以及一组称为 趋化肽（白细胞趋化因子， 细胞迁移）带有它们的作用所必需的甲酰基。 在最后一组中，兔和人的趋化反应 中性粒细胞合成三肽 N-甲酰基-甲硫氨酰基-亮氨酰基-苯丙氨酸被公认为是 通过肽与特定受体的相互作用介导。 在 除了刺激趋化性，这种肽/受体相互作用 在中性粒细胞中引发许多事件，例如溶酶体酶 释放、超氧化物形成和钙的释放。 n-甲酰基 由于N-乙酰化， 除去α-氨基或用乙基取代， 在1000- 10，000活动损失。 建立一个高效、 高比活度氚标记的氚化试剂将 对许多生物过程的阐明极为有用。 标题：标记甲酰化试剂的合成与应用 （续）我们提出了三个选择性和有效的合成 三硫代甲酰化试剂如下：1. 对硝基苯基 三硫代甲酸酯：该试剂可通过偶联合成 在THF中使用DCC将对硝基苯酚与氚化甲酸反应。 这 方法依赖于氚化甲酸的合成。 一个 该试剂的替代方法可以是三丁基锡氚化物 氯甲酸对硝基苯酯的还原 钯催化剂 在初步研究中，我们合成了 N-硝基苯甲酸酯，化学产率高， 成功地用于两种氨基酸的N-取代， 甲硫氨酸和色氨酸甲酯。 2. N-三硫代甲酰氧基邻苯二甲酰亚胺是另一种可以与苯二甲酰亚胺反应的试剂。 通过偶联氚化甲酸的类似反应合成 N-羟基邻苯二甲酰亚胺。 这种合成的另一种方法是 可能涉及三硫代甲酸锂和 N-溴邻苯二甲酰亚胺在合适的溶剂（二甲基亚砜）中的溶液。 3. 乙酸甲酸酐（AFA）是我们计划使用的第三种试剂。 探索它可以由甲酸的碱性盐制成。 合成N-甲酰氧基邻苯二甲酰亚胺的实验正在进行中 和AFA。 这是杂环化学中一个应用广泛的领域 以及氚标记各种杂环化合物的新方法。

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.