Asymmetric Hetero-Diels-Alder Reaction Of Diazenes Catalyzed By Chiral Metal Complexes

Optically active piperazines have been key structural elements prevalently presented in numerous natural products and pharmaceutically relevant molecules as exemplified by piperazimycin A, chloptosin, azafagomine, piperazic acid, etc. As a consequence, the development of efficient methods to access chiral piperazine structural motifs is highly desirable and will be of great synthetic importance in organic chemistry and pharmaceutical studies.We have developed a highly regio-and enantioselective azo-hetero-Diels-Alder (HDA) reaction of diazenes catalyzed by chiral gold(Ⅰ) complexes, leading to the construction of various optically active piperazine derivatives. The gold complexes were disclosed to be capable of coordinating with nitrogen of diazenes to lower the LUMO of N=N double bond and thereby facilitating the azo-HDA reaction. The chiral phosphoramidites which had been convinced to be excellent ligands in asymmetric gold catalysis provided satisfactory chiral environment for this transformation. Meanwhile, we established a cascade intramolecular enyne cycloisomerization/asymmetric azo-HDA reaction wherein the gold acted sequentially as a π-and a σ-Lewis acid catalyst. These findings provided a new rote to the synthesis of optically active piperazines and might stimulate further study on the gold catalysts in the form of σ-Lewis acids.To broaden the scope of substrates for diazene involved Diels-Alder cycyloaddition and better understood the interaction of metal and azo compounds, we developed chiral silver phosphate-catalyzed asymmetric hetero-diels-alder reaction of diazenes. Under the reaction conditions, structurally diverse substrates were well tolerated in this transformation, leading to the desired piperazines with high regio-and stereoselectivities. The noticed interaction hydroxyl group on substrates with silver were found able to switch the regioselection of products.Based on these works, we gradually established new catalyst system for the stereoselection of diazene involved cycloaddition. Structurally divers piperazines could be directly constructed under these reaction conditions. Bioactive compounds could be easily obtained with the derivatization of corresponding cycloadducts.