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)-p seudoephedrine (2) to afford (1R,2S)-ephedrine is known to be a diffic ult 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 k nown to proceed via aziridines formed on intramolecular S(N)2 substitu tion by the amine functionality. The Mitsunobu reactions of N-methylat ed and N-benzylated ephedrines have been found to proceed via the corr esponding aziridinium ions. These aziridinium ions can be opened (S(N) 2 substitution) by nucleophiles like phthalimide and thiols. Intramole cular participation in 2 can be avoided by use of the tert-butyloxycar bonyl- (BOC) or benzyloxycarbonyl- (CBZ) protected derivatives. Mitsun obu reactions on these derivatives lead to inversion of configuration at the benzylic hydroxyl center. In contrast the BOC and CBZ derivativ es of 1 are deprotected under Mitsunobu conditions. The Mitsunobu reac tions 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 t he 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.