SYNTHESIS & APPLICATIONS OF LABELLED FORMYLATING REAGENTS

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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.