Epoxide-Initiated Electrophilic Cyclization of Azides

Org. Lett., 5 (4), 583 -585, 2003.

Cation-induced cyclization is one of the most powerful techniques used in the synthesis of polycyclic frameworks.¹ With the advent of more efficient cation terminators, the importance of the epoxide-initiated electrophilic cyclization in the stereoselective synthesis of natural products is expanding rapidly.² In recent years, azide has gained remarkable attention as a cation terminator, since the subsequent skeletal rearrangement (Schmidt reaction) after cyclization offers a novel approach to azabicyclic ring systems.^3,4 Acid-mediated inter- and intramolecular Schmidt reaction of azidoalkenes³ and azidoketones⁴ has been extensively studied; however, the synthetic potential of the corresponding epoxide-initiated Schmidt reaction is yet to be explored.

The azabicyclic ring skeleton is an important structural subunit present in numerous biologically active natural products.⁵ In this family, indolizidine alkaloids are the most important class of compounds, known for their wide range of pharmaceutical applications (Scheme 1).⁶ Herein, for the first time, we report a general and highly diastereoselective approach for the construction of 5-hydroxymethyl azabicyclic compounds and its application in the synthesis of indolizidine alkaloids based on epoxide-initiated electrophilic cyclization of azides.