Asymmetric Construction of Benzindoloquinolizidine: Application of An Organocatalytic Enantioselective Conjugate Addition-Cyclization Cascade Reaction

Abstract

The synthesis of complex natural products and biologically active compounds has attracted the attention of organic chemists for a long time.1 Many new types of chemical reactions have been developed to facilitate easier synthesis of complex compounds. Among the strategies, domino reactions, which have been utilized for the efficient and stereoselective construction of complex molecules from simple precursors in a single process, are widely used due to their high synthetic efficiency by reducing both the number of synthetic operation required and the quantities of chemicals and solvents used.2 In recent years, organocatalysis has emerged as a powerful tool in asymmetric one-pot and domino reactions that provides efficient and environmentally benign access to enantiomerically pure complex molecules. 3,4 In addition, the organocatalysts used in this process are generally non-toxic, readily available, and air-stable, which result in better reproducibility and greater operational simplicity than traditional metal catalysts. Herein we report an asymmetric synthetic strategy for the preparation of enantioenriched benzindoloquinolizidines, which involves an organocatalyst-mediated cascade reaction.As part of a research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 5 we recently developed a novel catalytic asymmetric conjugate additioncyclization domino reaction of o-N-protected aminocinnamaldehydes using an organocatalyst, which afforded chiral tetrahydroquinoline derivatives with high enantioselectivities (Scheme 1); Moreover, the most satisfactory results were obtained when Ts or Cbz group was used as a the protecting group for the oaminocinnamaldehydes. 6 To further investigate these findings, we considered the use of another useful protecting group for o-aminocinnamaldehydes that could participate in the subsequent reaction, and so we examined the feasibility of using a 3-indoleacetyl moiety instead of Cbz or Ts as the protecting group. It was believed that the organocatalytic asymmetric conjugate additioncyclization cascade reaction of 3-indoleacetyl protected o-aminocinnamaldehydes with dialkyl malonate could enable the direct synthesis of enantioenriched benzindoloquinolizidine derivatives asymmetric conjugate additioncyclization cascade reaction of 3-indoleacetyl protected oaminocinnamaldehydes with dialkyl malonate could enable the direct synthesis of enantioenriched benzindoloquinolizidine derivatives. The quinolizidine structural unit is common to many naturally occurring compounds that have a wide spectrum of biological activities.7 Therefore, natural alkaloids, together with non-natural derivatives containing quinolizidine scaffold, have long attracted extensive biological, chemical, and synthetic interest. 8 The conceptual proposal of our synthetic strategy is shown in Scheme 2. In this process, the conjugate addition of 3-indoleacetyl protected o-aminocinnamaldehyde 1 with a nucleophile in the presence of chiral organocatalyst...