Synthesis of Novel Bile Acids

Abstract

<p>Bile acids are steroid structures with a carboxylic acid alkyl chain that are synthesised from cholesterol in the liver and function to regulate metabolism. They are mainly used as surfactants in the solubilization of lipids but they can also be used as cell signalling molecules targeting TGR5 and FXR receptors which have been implicated as important targets for the potential treatment of diseases such as inflammatory bowel disease, colorectal cancer and type 2 diabetes.1 Modifications to the structure of primary bile acids result in the selective activation of different receptors. 2 To further probe structure activity relationships, a library of new bile acid derivatives has been prepared.</p> <p><br></p> <p>The focus of this research is the exploration of cyclopropanation reactions of unsaturated C/D-ring alkenes resulting from a novel bile acid rearrangement. Stereoselective cyclopropanation has been achieved on a highly hindered, tetrasubstituted alkene using Furukawa’s method (EtZnCH2I)3, while Shi’s method (CF3CO2ZnCH2I)4 unexpectedly furnished a novel spiro-bile acid motif from the same alkene in an apparent skeletal rearrangement. </p> <p><br></p> <p>Intermolecular carbene additions to the double bond of tetrasubstituted alkenes were attempted using a range of transition metal-catalysed decompositions of ethyl diazoacetate (EDA), dichlorocarbene and difluorocarbene. The substrate proved to be too hindered for reaction with EDA; dichlorocarbene promoted CH insertion in allylic position to the double bond while reactions generating difluorocarbene effected double bond migration product. </p> <p><br></p> <p>Selective diazoacetylation of the bile acid alkene 7α-hydroxy substituent enabled the intermolecular decompositions to be probed using transition metal-catalysed and violet light (385 nm) mediated decompositions. A custom-built monochromatic LED reactor was designed and used for this purpose. Both light mediated reactions and a range of Cu(I), Cu(II) and Rh(II) and Re(VI) complexes effectively decomposed the diazo functionality but no intramolecular cyclopropanations were detected.</p> <p><br></p> <p>As an extension to attempting cyclopropanations, cheno- and urso-deoxycholic acids were selectively diazoacetylated at the 7α-hydroxy substituent using the successfully developed method above. Towards analogues of obeticholic acid a number of Doyle’s asymmetric Rh(II) catalysts were then probed in an attempt to effect C-H insertion by diazodecomposition.</p> <p><br></p> <p>Finally, a novel route for the synthesis of the A-ring 3-aza-bile acid starting from Chenodeoxycholic acid is presented. This route allowed us to synthesise the two isomeric intermediates tert-Butyl-2-hydroxy-7a-(benzyloxymethyl)oxy-4-amino-3-nor-3,4-seco-5b-cholan-24-oate and tert-Butyl-2-amino-4-hydroxy-7a-(benzyloxymethyl)oxy-3-nor-3,4-seco-5b-cholan-24-oate which could both be converted, by different methods, to the desired aza-bile acid. Interestingly, a novel tetrohydrofuran bile acid product and the 5α-H (allo) bile acid analogue was afforded from one of these isomers by these synthetic endeavours.</p>