Sodium Borohydride Reduction of Carbamoyl Azide Function: A Synthesis of N-Protected N-Formyl-gem-diaminoalkyl Derivatives

A simple, efficient two-step synthesis of N-protected N-formyl-gem-diaminoalkyl derivatives is reported. The procedure involves the unprecedented reduction of the carbamoyl azide of -N-Boc/Fmoc/Z-protected amino acids and dipeptides (Boc = tert-butoxycarbonyl, Fmoc = 9-fluorenylmethoxycarbonyl, Z = benzyloxycarbonyl) by treatment with NaBH4 at room temperature. The reaction proceeds rapidly (45 min) without detectable epimerization (by HPLC-ESI-MS analysis) and is not influenced by the nature of the starting carbamoyl azide. The H-1 and C-13 NMR analyses of the synthesized N-protected N-formamides were carried out in [D-6]DMSO. The spectra exhibited the presence of two rotameric forms in solution as a result of the restricted rotation around the N-CO formyl bond. The integration of the N-CH-N protons of the two isomers showed that the cis isomer (rotamer B) was the more abundant conformer by 60 to 78%. The reported synthesis represents the potential value of carbamoyl azides as versatile chiral starting materials for many synthetic purposes.