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Incoming links: Johnson-Claisen rearrangement
Propionic acid is a weak, relatively high-boiling acid: its normal boiling point is about , compared with about for acetic acid. It provides mild proton catalysis while remaining in the hot orthoester mixture more effectively. This is useful because ketene-acetal formation and the thermal Johnson-Claisen rearrangement require heating, whereas strong acid would threaten the pyran acetal.
This is a practical catalyst choice, not an absolute mechanistic prohibition on acetic acid; acetic-acid-catalysed orthoester rearrangements are also possible.
The first transformation is an Achmatowicz rearrangement, followed by protection and selective reduction; the last is a Johnson-Claisen rearrangement.
- Butyllithium removes the furan 2-proton, giving a 2-lithiofuran. Its carbon attacks the aldehyde carbonyl; protonation of the resulting alkoxide gives the furfuryl alcohol. Carbon-carbon bond formation occurs at the lithiated position.
- Electrophilic oxygen transfer from mCPBA to the electron-rich furan gives an oxidized, ring-opened intermediate. Opening the oxygenated furan gives a hydroxy enedicarbonyl: the original furfuryl hydroxyl then attacks the remote aldehyde intramolecularly. This expands the five-membered furan into a six-membered lactol containing an enone carbonyl. The original furfuryl oxygen becomes the pyran ring oxygen; oxidation of the furan supplies the new carbonyl and lactol functionality.
- AgO/MeI converts the lactol OH into its methyl acetal: oxygen attacks methyl iodide by SN2 reaction, with iodide removal and proton transfer. This protects the anomeric position.
- LiAlH delivers hydride to the remaining ketone carbonyl, followed by protonation. The methyl acetal survives these basic reducing conditions, leaving the depicted allylic alcohol.
- Under weak-acid catalysis, that allylic OH replaces an ethoxy group of triethyl orthoacetate. Loss of another ethanol molecule, with removal of a methyl proton, gives the mixed ketene acetal . A six-electron, chair-like Claisen rearrangement breaks the allyl-O bond, forms a bond between the terminal allyl carbon and the ketene-acetal CH, and moves the ring double bond one position. Carbonyl formation gives the substituent.
The acetal protects the other oxygenated position during hydride reduction. The orthoester transfers an acetate-derived two-carbon unit through a ketene acetal; it does not directly substitute the allylic OH with an intact acetate ion.
The first two operations invert the allylic hydroxyl group. Triphenylphosphine adds to the azodicarboxylate, generating the reagent pair that converts the alcohol into an alkoxyphosphonium leaving group. Benzoate displaces it with inversion at carbon, giving the inverted benzoate ester. Methoxide then cleaves that ester by nucleophilic acyl substitution, retaining the newly inverted carbon–oxygen stereochemistry because cleavage occurs at the acyl group, not by substitution at the stereogenic carbon.
The inverted allylic alcohol exchanges with the orthoacetate under acid catalysis. Ethanol loss produces an allyl ketene acetal, schematically . A six-membered suprafacial Johnson-Claisen rearrangement breaks the allylic C–O bond, shifts the ring alkene by one position and forms the new bond from the original alkene terminus to the ketene-acetal CH. The result is the substituent at the carbon that was the remote end of the original double bond. A chair-like transition state placing the larger substituents away from axial crowding explains the stereochemical transfer; the inverted alcohol configuration selects the corresponding face.
Finally, TiCl activates the anomeric methoxy group and methoxide departure creates an oxocarbenium ion. Hydride transfer from triethylsilane replaces that methoxy substituent by hydrogen. The ring oxygen and pendant OTBS group remain intact. The sequence is inversion, stereospecific allylic rearrangement, then reductive removal of the anomeric methoxy group, rather than direct reduction or hydrolysis of the ester introduced by the Claisen step.