Sustainable biocatalytic approaches to pyridine and piperidine heterocycles
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
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Technical Summary
The aim of the proposed research is to combine recently developed methods for pyridinedicarboxylic acid generation from biomass, and pyridine reduction, to develop new biocatalytic routes from sustainable sources to substituted pyridines and piperidines, which are valuable intermediates for pharmaceutical synthesis.
WP1 will aim to convert the existing 2,4-PDCA and 2,5-PDCA products via chemical decarboxylation and biocatalytic reduction of the carboxylic sidechain to generate 3- and 4-substituted pyridines (sidechain -CO2H, -CHO, -CH2OH), for which no sustainable route exists at present, and which are valuable intermediates for pharmaceutical synthesis.
WP2 will aim to identify enzymes involved in the cyclisation of the pyridine ring in PDCA formation in Rhodococcus jostii RHA1. From preliminary work, we have identified two glutamate dehydrogenase isoenzymes which can catalyse cyclisation of a CHMS ring fission product in the presence of ammonia and NADPH. The specificity and scope of these enzymes will be studied, and the effect of their overexpression in R. jostii RHA1.
WP3 will utilise 4-substituted guaiacols, derived from reductive catalytic fractionation (chemocatalysis) of lignin, as feedstocks for biocatalytic conversion to 3-alkylsubstituted pyridines (sidechains n-propyl, 1-propenyl, 3-hydroxypropyl), which are valuable intermediates for pharmaceutical synthesis for which no sustainable route exists at present.
WP4 will investigate a combined chemocatalytic/biocatalytic route to bicyclic pyridines, using a bicyclic guaiacol obtained from chemocatalytical processing of lignin.
WP5 will aim to convert pyridine 3-carboxylic acid from WP1 via biocatalytic methylation and combined chemocatalytic/biocatalytic reduction to chiral piperidine 3-carboxylic acid, a valuable pharmaceutical intermediate for which there is currently no sustainable synthesis route. This route will then be applied to bioproducts from WPs1-4.
WP1 will aim to convert the existing 2,4-PDCA and 2,5-PDCA products via chemical decarboxylation and biocatalytic reduction of the carboxylic sidechain to generate 3- and 4-substituted pyridines (sidechain -CO2H, -CHO, -CH2OH), for which no sustainable route exists at present, and which are valuable intermediates for pharmaceutical synthesis.
WP2 will aim to identify enzymes involved in the cyclisation of the pyridine ring in PDCA formation in Rhodococcus jostii RHA1. From preliminary work, we have identified two glutamate dehydrogenase isoenzymes which can catalyse cyclisation of a CHMS ring fission product in the presence of ammonia and NADPH. The specificity and scope of these enzymes will be studied, and the effect of their overexpression in R. jostii RHA1.
WP3 will utilise 4-substituted guaiacols, derived from reductive catalytic fractionation (chemocatalysis) of lignin, as feedstocks for biocatalytic conversion to 3-alkylsubstituted pyridines (sidechains n-propyl, 1-propenyl, 3-hydroxypropyl), which are valuable intermediates for pharmaceutical synthesis for which no sustainable route exists at present.
WP4 will investigate a combined chemocatalytic/biocatalytic route to bicyclic pyridines, using a bicyclic guaiacol obtained from chemocatalytical processing of lignin.
WP5 will aim to convert pyridine 3-carboxylic acid from WP1 via biocatalytic methylation and combined chemocatalytic/biocatalytic reduction to chiral piperidine 3-carboxylic acid, a valuable pharmaceutical intermediate for which there is currently no sustainable synthesis route. This route will then be applied to bioproducts from WPs1-4.
