Ketone homologation via palladium

Abstract The decarboxylative semi-pinacol rearrangement of β-hydroxy carboxylic acids under electrochemical oxidation conditions was first reported in 19601. However, its further development has remained limited owing to stepwise radical and carbocationic pathways that induce side reactions and result in the loss of stereochemical information at the α-carbon. Herein, we demonstrate that this transformation can instead be realized through a concerted mechanism under Pd(II)/Pd(IV) catalysis. The reaction proceeds via the formation of a six-membered Pd(IV) chelate, which undergoes fragmentation accompanied by β-to-α carbon migration and carbon dioxide extrusion, with Pd(IV) serving as the redox center. This closed-shell pathway enables precise stereochemical control: the migrating carbon retains its absolute configuration, while the α-stereocenter undergoes inversion. For unsymmetrical ketones, the reaction displays markedly higher migrating-group selectivity than the classical Tiffeneau–Demjanov2 and Büchner–Curtius–Schlotterbeck reactions3. Broadly applicable to cyclic and acyclic ketones and aldehydes, this method avoids hazardous diazo reagents. Its utility is illustrated by a concise total synthesis of (+)-rupestine D, where the rearrangement serves as a key carbon-skeleton-editing step. This is a preview of subscription content, access via your institution Access options Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $32.99 / 30 days cancel any time Subscribe to this journal Receive 52 print issues and online access $199.00 per year only $3.83 per issue Rent or buy this article Prices vary by article type from$1.95 to$39.95 Prices may be subject to local taxes which are calculated during checkout Author information Authors and Affiliations Corresponding author Supplementary information Supplementary Information (download PDF ) Materials and Methods, containing the following sections: 1. General information; 2. Preparation of substrates; 3. Optimization of reaction conditions for palladium catalyzed decarboxylative ring-expansion process; 4. Representative procedures of the palladium catalyzed decarboxylative 1,2-rearrangement process; 5. Preparation and key reactions of 1bc, (2R*, 3R*)-1bc and (2S*, 3R*)-1bc; 6. Hammett plots for a series of para-substituted aryl β-carboxylic acids; 7. Migratory selectivity study and one carbon ring expansion of natural ketone derivatives; 8. Iterative homologation of cyclobutanone; 9. Total synthesis of natural product; 10. Crystallographic data; 11. Copies of NMR Spectra; and 12. References. Rights and permissions About this article Cite this article Gong, J., Wang, Q. & Zhu, J. Ketone homologation via palladium-catalysed decarboxylative rearrangement. Nature (2026). https://doi.org/10.1038/s41586-026-11091-5 Received: Accepted: Published: DOI: https://doi.org/10.1038/s41586-026-11091-5