Application of the Mitsunobu reaction to ephedrines and some related amino alcohols. Aspects of intramolecular participation of the amino group

Article abstract of DOI:10.1002/recl.19941130704

Inversion of configuration at the benzylic hydroxyl group of (1S,2S)-pseudoephedrine (2) to afford (1R,2S)-ephedrine is known to be a difficult process.The Mitsunobu reactions of 1 and 2 might offer a route to achieve such inversions.In fact Mitsunobu reactions on 1 and 2 are known to proceed via aziridines formed on intramolecular S_N2 substitution by the amine functionality.The Mitsunobu reactions of N-methylated and N-benzylated ephedrines have been found to proceed via the corresponding aziridinium ions.These aziridinium ions can be opened (S_N2 substitution) by nucleophiles like phthalimide and thiols.Intramolecular participation in 2 can be avoided by use of the tert-butyloxycarbonyl-(BOC) or benzyloxycarbonyl- (CBZ) protected derivatives.Mitsunobu reactions on these derivatives lead to inversion of configuration at the benzylic hydroxyl center.In contrast the BOC and CBZ derivatives of 1 are deprotected under Mitsunobu conditions.The Mitsunobu reactions of threo (1S,2S)-2-amino-1,3-propanediol have also been examined.An attempt to achieve protection by reaction with dimethylformamide dimethyl acetal led to the more substituted 2-oxazoline as established by X-ray crystallography.The desired inversion of configuration of the benzylic hydroxylic group was eventually achieved by protection of the amino substituent as the phthalimide and protection of the primary hydroxyl group as the tosylate.