APPLICATION OF THE MITSUNOBU REACTION TO EPHEDRINES AND SOME RELATED AMINO-ALCOHOLS - ASPECTS OF INTRAMOLECULAR PARTICIPATION OF THE AMINO GROUP

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(N)2 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(N)2 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 three (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.