Sustainable Biocatalytic Approaches to Pyridine and Piperidine Heterocycles

At present the chemicals and solvents used to make plastics, pharmaceuticals and agrochemicals are derived primarily from crude oil. As we seek to create a more sustainable world in the 21st century, our society needs to dramatically reduce its dependence upon crude oil, which means finding new, sustainable routes to make feedstock chemicals. Pyridines and piperidines are 6-membered heterocyclic rings that are commonly found in pharmaceutical drugs, and at present there is no sustainable route to substituted pyridines and piperidines. Prof Bugg's research group has discovered a biotransformation to pyridine-dicarboxylic acids from polymeric lignin found in plant biomass, using engineered Rhodococcus jostii RHA1. This proposal aims to expand this route to make a range of substituted pyridines that could be valuable feedstock chemicals. A further biotransformation is able to reduce substituted pyridines to make the corresponding saturated piperidines. We will therefore aim to use this biotransformation to generate substituted piperidines from the same route. We will also investigate the enzymes that are responsible for making the pyridine ring in Rhodococcus jostii RHA1. This research will be of considerable interest to process development scientists in the pharmaceutical industry, and we will collaborate with Astra Zeneca Pharmaceuticals to further develop this technology.

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.