GoKawiilPalladium catalysis enables stereocontrolled ketone homologation without diazo reagents
Researchers developed a palladium(II)/(IV)-catalyzed decarboxylative rearrangement that converts β-hydroxy carboxylic acids into homologated ketones and aldehydes through a concerted mechanism, rather than the radical or carbocation steps used in earlier electrochemical versions from 1960. The method proceeds via a six-membered Pd(IV) intermediate that fragments with carbon migration and loss of carbon dioxide, preserving stereochemical information at the migrating carbon while inverting the adjacent center. The team demonstrated its practical value by using this rearrangement as a key step in a short total synthesis of the natural product (+)-rupestine D.
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Ketone homologation—inserting a carbon into a carbonyl framework—has long relied on hazardous diazo compounds via the Tiffeneau–Demjanov or Büchner–Curtius–Schlotterbeck reactions, which also suffer from poor selectivity in unsymmetrical substrates. This palladium-based approach offers both safer reagents and superior control over which group migrates, potentially simplifying complex molecule synthesis. Its successful application to a natural product total synthesis shows it can serve as a practical tool for skeletal editing in drug and natural-product chemistry.
- A concerted Pd(II)/Pd(IV) mechanism allows stereochemically defined ketone homologation, avoiding classical radical/cationic side reactions.
- The method avoids hazardous diazo reagents while achieving higher migrating-group selectivity than traditional homologation reactions.
- The approach was validated in a concise total synthesis of (+)-rupestine D, showcasing its use for carbon-skeleton editing.
Source: nature.com — Gong, 2026-09-03
Published there as: “Ketone homologation via palladium-catalysed decarboxylative rearrangement”
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