Synthesis of Enantiopure Piperidines via an Aziridinium Ring Expansion Reaction

Significance

Reported is an efficient and versatile synthesis of enantiopure 3-substituted piperidines 8 from the easily accessible chiral pyrrolinols 5 and 6, involving an irreversible regio-selective nucleophilic ring opening-ring expansion of an aziridinium salt 7 (see Review). This transformation was achieved via the irreversible formation of the aziridinium salt and subsequent ring expansion to form the piperidine under kinetic control, opening the aziridinium salt at the most hindered position. These aziridinium salts were formed by treating a hydroxymethylpyrroline with triflic anhydride in the presence of proton sponge at -15 ˚C. Then, a large variety of carbon, nitrogen, oxygen, sulfur and fluoride nucleophiles were introduced into the resulting tetrahydropyridine products. 5-Substituted pyrrolines are also compatible with this ring expansion. The diastereomeric purity and enantiomeric excess of the pyrroline is preserved. In all cases, only one isomer has been observed, except when organocuprates are used (-78 ˚C, anti-S_N2/syn-S_N2 = 18:1 when R^¹ = Me). A very interesting synthesis of substituted pyrrolinols 5 via a Petasis-Mannich and ring-closing-metathesis sequence (4 → 5) in >99% ee and de was also reported.