{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:19:54Z","timestamp":1790309994700,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T00:00:00Z","timestamp":1649203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"New Zealand Ministry of Business, Innovation and Employment","award":["RTVU1202"],"award-info":[{"award-number":["RTVU1202"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure\u2013activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C\/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective \u03b1-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro\u2013furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.<\/jats:p>","DOI":"10.3390\/molecules27072364","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T21:08:22Z","timestamp":1649365702000},"page":"2364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis of Novel C\/D Ring Modified Bile Acids"],"prefix":"10.3390","volume":"27","author":[{"given":"Roselis A.","family":"Landaeta Aponte","sequence":"first","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7574-8027","authenticated-orcid":false,"given":"Andreas","family":"Luxenburger","sequence":"additional","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-8622","authenticated-orcid":false,"given":"Scott A.","family":"Cameron","sequence":"additional","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Weymouth-Wilson","sequence":"additional","affiliation":[{"name":"ICE Group, New Zealand Pharmaceuticals Ltd., 68 Weld Street, RD2, Palmerston North 4472, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H.","family":"Furneaux","sequence":"additional","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4214-1018","authenticated-orcid":false,"given":"Lawrence D.","family":"Harris","sequence":"additional","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5245-9767","authenticated-orcid":false,"given":"Benjamin J.","family":"Compton","sequence":"additional","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fiorucci, S., and Distrutti, E. (2019). Handbook of Experimental Pharmacology 256: Bile Acids and Their Receptors, Springer International Publishing.","DOI":"10.1007\/978-3-030-22005-1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1126\/science.284.5418.1362","article-title":"Identification of a nuclear receptor for bile acids","volume":"284","author":"Makishima","year":"1999","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1126\/science.284.5418.1365","article-title":"Bile acids: Natural ligands for an orphan nuclear receptor","volume":"284","author":"Parks","year":"1999","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/S0006-291X(02)02550-0","article-title":"Identification of membrane-type receptor for bile acids (M-BAR)","volume":"298","author":"Maruyama","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9435","DOI":"10.1074\/jbc.M209706200","article-title":"A G protein-coupled receptor responsive to bile acids","volume":"278","author":"Kawamata","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1172\/JCI21025","article-title":"Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c","volume":"113","author":"Watanabe","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1073\/pnas.0506982103","article-title":"Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice","volume":"103","author":"Zhang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1172\/JCI25604","article-title":"Farnesoid X receptor is essential for normal glucose homeostasis","volume":"116","author":"Ma","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11039","DOI":"10.1074\/jbc.M510258200","article-title":"The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice","volume":"281","author":"Cariou","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.22519","article-title":"Farnesoid X Receptor Antagonizes Nuclear Factor kappa B in Hepatic Inflammatory Response","volume":"48","author":"Wang","year":"2008","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1124\/jpet.105.085597","article-title":"Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis","volume":"315","author":"Fiorucci","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.cmet.2009.08.001","article-title":"TGR5-mediated bile acid sensing controls glucose homeostasis","volume":"10","author":"Thomas","year":"2009","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1053\/j.gastro.2014.08.042","article-title":"The Bile Acid Receptor TGR5 Activates the TRPA1 Channel to Induce Itch in Mice","volume":"147","author":"Lieu","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1113\/jphysiol.2010.192146","article-title":"Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of K-ATP channels","volume":"588","author":"Lavoie","year":"2010","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1007\/s10620-016-4143-0","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations","volume":"61","author":"Sherif","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25019","DOI":"10.1021\/acsomega.1c04199","article-title":"Synthesis of 12beta-Methyl-18-nor-bile Acids","volume":"6","author":"Luxenburger","year":"2021","journal-title":"ACS Omega"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ure, E.M., Harris, L.D., Cameron, S.A., Weymouth-Wilson, A., Furneaux, R.H., Pitman, J.L., Hinkley, S.F., and Luxenburger, A. (2022). Synthesis of 12\u03b2-Methyl-18-nor-Avicholic Acid Analogues as Potential TGR5 Agonists. Org. Biomol. Chem., Advance Article.","DOI":"10.1039\/D1OB02401A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12501","DOI":"10.1002\/chem.201502148","article-title":"A Geomimetic Approach to the Formation and Identification of Fossil Sterane Biomarkers in Crude Oil: 18-nor-D-homo-Androstane and 5 alpha,14 beta-Androstane","volume":"21","author":"Bender","year":"2015","journal-title":"Chem. Eur. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S0040-4039(00)70491-6","article-title":"The Preparation of 14-Beta, 18-Cyclo-Progesterone from Conessine Via N-Desmethyl-4,N(20)-Conadiene-3-One","volume":"3","author":"Dauben","year":"1962","journal-title":"Tetrahedron Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1135\/cccc19622771","article-title":"On Steroids.70. Cyclopropane Ring Formation on Deamination of 18-Amino Steroids","volume":"27","author":"Hora","year":"1962","journal-title":"Collect. Czechoslov. Chem. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1021\/jm00372a007","article-title":"Bile-Acids with a Cyclopropyl-Containing Side-Chain.1. Preparation and Properties of 3-Alpha,7-Beta Dihydroxy-22,23-Methylene-5beta-Cholan-24-Oic Acid","volume":"27","author":"Pellicciari","year":"1984","journal-title":"J. Med. Chem."},{"key":"ref_22","unstructured":"He, H., Li, P., Xiao, H., Chen, Z., Zhang, Y., Chen, S., Hu, G., and Li, J. (2016). Chenodeoxycholic Acid. (Publication Number WO\/2016\/173524), Derivative. Patent."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1021\/cr010007e","article-title":"Stereoselective cyclopropanation reactions","volume":"103","author":"Lebel","year":"2003","journal-title":"Chem. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1055\/s-0033-1340838","article-title":"Asymmetric Cyclopropanation Reactions","volume":"46","author":"Bartoli","year":"2014","journal-title":"Synthesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8712","DOI":"10.1021\/acs.jmedchem.6b00472","article-title":"The \u201cCyclopropyl Fragment\u201d is a Versatile Player that Frequently Appears in Preclinical\/Clinical Drug Molecules","volume":"59","author":"Talele","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7315","DOI":"10.1039\/C8OB01187G","article-title":"Recent advances in the synthesis of cyclopropanes","volume":"16","author":"Wu","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"ref_27","first-page":"1555","article-title":"Effect of the zinc-copper couple on methylene iodide","volume":"188","author":"Emschwiller","year":"1929","journal-title":"C. R. Hebd. Acad. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5323","DOI":"10.1021\/ja01552a080","article-title":"A New Synthesis of Cyclopropanes from Olefins","volume":"80","author":"Simmons","year":"1958","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4256","DOI":"10.1021\/ja01525a036","article-title":"A New Synthesis of Cyclopropanes","volume":"81","author":"Simmons","year":"1959","journal-title":"J. Am. Chem. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Charette, A.B., and Beauchemin, A. (2004). Simmons-Smith Cyclopropanation Reaction, Organic Reactions; Wiley.","DOI":"10.1002\/chin.200319242"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1021\/om301220a","article-title":"The Renaissance of Zinc Carbenoid in Stereoselective Synthesis in Acyclic Systems","volume":"32","author":"Pasco","year":"2013","journal-title":"Organometallics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1016\/S0040-4039(01)82791-X","article-title":"A Novel Route to Cyclopropanes from Olefins","volume":"7","author":"Furukawa","year":"1966","journal-title":"Tetrahedron Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0040-4020(68)89007-6","article-title":"Synthesis of Cyclopropanes by Reaction of Olefins with Dialkylzinc and Methylene Iodide","volume":"24","author":"Furukawa","year":"1968","journal-title":"Tetrahedron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6974","DOI":"10.1021\/jo00025a007","article-title":"A Comparison of (Chloromethyl)Zinc and (Iodomethyl)Zinc Cyclopropanation Reagents","volume":"56","author":"Denmark","year":"1991","journal-title":"J. Org. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8621","DOI":"10.1016\/S0040-4039(98)01954-6","article-title":"Exploring new reactive species for cyclopropanation","volume":"39","author":"Yang","year":"1998","journal-title":"Tetrahedron Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1021\/jo030312v","article-title":"A novel class of tunable zinc reagents (RXZnCH2Y) for efficient cyclopropanation of olefins","volume":"69","author":"Lorenz","year":"2004","journal-title":"J. Org. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12440","DOI":"10.1021\/ja0529687","article-title":"Iodomethylzinc phosphates: Powerful reagents for the cyclopropanation of alkenes","volume":"127","author":"Lacasse","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/19490976.2015.1127483","article-title":"Consequences of bile salt biotransformations by intestinal bacteria","volume":"7","author":"Ridlon","year":"2016","journal-title":"Gut Microbes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8856","DOI":"10.1074\/jbc.M306422200","article-title":"The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion","volume":"279","author":"Lew","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3986","DOI":"10.1016\/j.bmc.2016.06.039","article-title":"Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease","volume":"24","author":"Yu","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_41","first-page":"588","article-title":"A Facile Route to Ursodeoxycholic Acid Based on Stereocontrolled Conversion and Aggregation Behavior Research","volume":"48","author":"Dou","year":"2016","journal-title":"Synthesis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1021\/jo00412a017","article-title":"Cyclopropanation of Some Simple Olefinic Compounds\u2014By-Product Formation in Excess Simmons-Smith Reagent","volume":"43","author":"Takakis","year":"1978","journal-title":"J. Org. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1021\/ja00291a034","article-title":"Stereoelectronic effects in the cationic rearrangements of [4.3.2]propellanes","volume":"107","author":"Smith","year":"1985","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5530","DOI":"10.1021\/ja01168a046","article-title":"Oxidation of Steroids. III. Selective Oxidations and Acylations in the Bile Acid Series","volume":"72","author":"Fieser","year":"1950","journal-title":"J. Am. Chem. Soc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4137","DOI":"10.1016\/j.tetlet.2011.05.140","article-title":"A stereoselective synthesis of the allo-bile acids from the 5 beta-isomers","volume":"52","author":"Li","year":"2011","journal-title":"Tetrahedron Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/lipd.12013","article-title":"Chemical Synthesis of Rare Natural Bile Acids: 11alpha-Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids","volume":"53","author":"Namegawa","year":"2018","journal-title":"Lipids"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/7\/2364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:49:18Z","timestamp":1760136558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/7\/2364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,6]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["molecules27072364"],"URL":"https:\/\/doi.org\/10.3390\/molecules27072364","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,6]]}}}