Executive Summary : | The N-heterocycles having chiral amine moiety are accounting for up to 40% of active pharmacological components. As a result, the pharmaceutical sector is highly interested in large-scale synthesis of secondary and tertiary amines as key structural motifs. Moreover, chiral amines are also key structural motifs widely found in many natural products as well as agrochemicals and fine chemicals. Among these seven-membered nitrogen and one more heteroatom (S, O, or N) containing heterocycles such as benzothiazepines, benzoxapines & benzodiazepines are of particular interest because because of their presence in several drug molecules which includes diltiazem, nitroxazepine, clobazam and clozapine. Therefore, tetrahydrobenzo-(thia, oxa & di)-azepines ring system containing compounds may be crucial for drug development. However, the chemical synthesis of these heterocycles uses chiral auxiliary, or transition metal catalysts and rely on the use of precious or heavy metals, high pressures and/or temperatures, organic solvents, stoichiometric hydride reductants, or potentially toxic alkyl halides. The recent advancement in the biocatalytic approach for the synthesis of chiral amines, have emerged as an attractive alternative for the synthesis of enantiopure 5- and 6-membered cyclic amines. As an advantage, the biocatalytic method offers sustainable processes under ambient aqueous conditions with high chemo-, regio-, and stereoselectivity with minimal hazardous waste. In the current proposal, we aim to develop, the first biocatalytic method for the preparation of 7-membered, variously substituted enantiopure tetrahydrobenzo-(thia, oxa & di)-azepines using various imine reductases (IRED). The successful implementation of the proposed project, will open the door for new, highly selective, and sustainable strategies for the synthesis of important, hard-to-make seven membered heterocycles of pharmaceutical relevance. In addition, the biological activities of new chiral substituted benzo-(thia, oxa & di)-azepines will help in the evaluation of seven membered heterocyclic molecule as potential drug candidates. |