Solvent- and Temperature-Dependent Functionalisation of Enantioenriched Aziridines

• Published in: Chemistry : a European journal 2011-01, Vol.17 (1), p.286-296
• Main Authors: de Ceglie, Maria Carolina, Musio, Biagia, Affortunato, Francesco, Moliterni, Anna, Altomare, Angela, Florio, Saverio, Luisi, Renzo
• Format: Article
• Language: English
• Subjects: Amines; Amines - chemical synthesis; Amines - chemistry; Amino Alcohols - chemical synthesis; Amino Alcohols - chemistry; asymmetric synthesis; Aziridines - chemistry; Derivatives; Lithium - chemistry; molecular dynamics; Molecular Structure; organolithiums; Oxidation-Reduction; Parents; regioselectivity; Solvents; Stereochemistry; Stereoisomerism; stereoselectivity; Toluene; Tuning
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201002172

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)‐1 a,b, two differently configured chiral aziridinyllithiums could be generated (trans‐1 a,b‐Li in toluene and cis‐1 a,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)‐1 c showed a temperature‐dependent reactivity to give chiral ortho‐lithiated aziridine 1 c‐ortho‐Li at −78 °C and α‐lithiated aziridine 1 c‐α‐Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho‐ and α‐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)‐1 a,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 α‐lithiated aziridine (1 c‐α‐Li) has been generated at 0 °C. In addition, ortho‐hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry. Choose the right conditions! When starting from enantioenriched parent aziridines, it is possible to address the regio‐ and stereoselectivity of the lithiation/electrophile trapping sequence by finely tuning the reaction conditions. Highly enantioenriched functionalised aziridines could be obtained (see graphic) and their usefulness has been demonstrated.