Highly Stereoselective One-Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

摘要

Intramolecular nitrone/alkene cycloadditions have received a great deal of attention as a useful methodology for the formation of the intriguing frameworks found in natural products and biologically interesting compounds. The key feature of this approach is the suitable elaboration of the primary cycloadducts, which has proven to be a practical strategy for making different heterocyclic systems. Owing to the labile nature of the N-O bond under mild reducing conditions, the isoxazolidines provide easy access to a variety of 1,3-difunctional amino alcohols. Particularly, if the intramolecular cycloaddition of nitrone is linked to olefin moiety by a tether of appropriate length, the regio- and diastereo-selectivities can be dramatically improved. Most importantly, the introduction of a stereogenic center at the a position of the nitrone can result in asymmetric induction, leading to the generation of new stereocenters having defined configurations.'41 However, multistep synthetic routes were required to synthesize molecules bearing stereocenters at the a position of the nitrone and the olefin moiety from optical sources, such as amino acids and sugars. Although several organocatalytic asymmetric nitrone [3+2] cycloadditions have been documented, the enantioselective intramolecular version remains a challenge. Herein, we disclose an organocatalytic one-pot asymmetric synthesis of bicyclic isoxazolidines through a domino process involving a Michael addition/ in situ condensation/intramolecular nitrone [3+2] cycloaddition sequence.