Solvent- and Temperature-Dependent Functionalisation of Enantioenriched Aziridines

A highly stereo- and regioselective functionalisation of chiral non-racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio- and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N-alkyl trans-2,3-diphenylaziridines (S,S)-1a,b, two differently configured chiral aziridinyl-lithiums could be generated (trans-1a,b-Li in toluene and cis-1a,b-Li in THF), thus disclosing a solvent-dependent reactivity that is useful for the synthesis of chiral tri-substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)-1c showed a temperature-dependent reactivity to give chiral ortho-lithiated aziridine 1c-ortho-Li at -78 degrees C and alpha-lithiated aziridine 1c-alpha-Li at 0 degrees C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho- and alpha-functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X-ray and NMR spectroscopic analysis. The usefulness of chiral non-racemic functionalised aziridines has been demonstrated by reductive ring-opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2-, 1,3- and 1,5-aminoalcohols. It is remarkable that the solvent-dependent reactivity observed with (S,S)-1a,b permits the preparation of both the enantiomers of amines (11 and ent-11) and 1,2-aminoalcohols (13 and ent-13) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral alpha-lithiated aziridine (1c-alpha-Li) has been generated at 0 degrees C. In addition, ortho-hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.