Highly Efficient Enantioselective Construction of Bispirooxindoles Containing Three Stereocenters through an Organocatalytic Cascade Michael–Cyclization Reaction

Bispirooxindole derivatives containing three stereocenters, including two spiro quaternary centers, were synthesized in a high‐yielding, atypically rapid, and stereocontrolled cascade Michael–cyclization reaction between methyleneindolinones and isothiocyanato oxindoles catalyzed by a bi‐ or multifunctional organocatalyst. Mild conditions were used to construct bispirooxindoles with excellent enantio‐ and diastereomeric purities within less than 1 min. Catalyst reconfiguration offered access to the opposite enantiomer. This exceptionally highly efficient procedure will allow diversity‐oriented syntheses of this intriguing class of compounds with potential biological activities.     

In Situ Enamine Activation in Aqueous Salt Solutions: Highly Efficient Asymmetric Organocatalytic Diels–Alder Reaction of Cyclohexenones with Nitroolefins

Deep‐sea Diels–Alder : The asymmetric organocatalytic Diels–Alder reaction of cyclohexenones with aromatic nitroolefins can be carried out in seawater and brine. The reaction proceeds by an in situ enamine activation involving a one‐step concerted addition pathway (see scheme).

     

Organocatalytic Enantioselective Cross‐Vinylogous Rauhut–Currier Reaction of Methyl Coumalate with Enals

The organocatalytic enantioselective intermolecular cross‐vinylogous Rauhut–Currier (RC) reaction of methyl coumalate with α,β‐unsaturated aldehydes is reported, and the enals are activated by iminium catalysis to serve as the Michael acceptors and methyl coumalate is used as an activated diene to generate a latent enolate. The excellent selectivity is driven by the aromaticity of methyl coumalate, and the post transformation of this heterocyclic structure into other electron‐deficient arenes and heterocycles have addressed, in part, the challenging selectivity issues of the intermolecular cross‐RC reactions and the limited scope of iminium catalysis.     

Highly Stereoselective Synthesis of Natural‐Product‐Like Hybrids by an Organocatalytic/Multicomponent Reaction Sequence

In an endeavor to provide an efficient route to natural product hybrids, described herein is an efficient, highly stereoselective, one‐pot process comprising an organocatalytic conjugate addition of 1,3‐dicarbonyls to α,β‐unsaturated aldehydes followed by an intramolecular isocyanide‐based multicomponent reaction. This approach enables the rapid assembly of complex natural product hybrids including up to four different molecular fragments, such as hydroquinolinone, chromene, piperidine, peptide, lipid, and glycoside moieties. The strategy combines the stereocontrol of organocatalysis with the diversity‐generating character of multicomponent reactions, thus leading to structurally unique peptidomimetics integrating heterocyclic, lipidic, and sugar moieties.     

Asymmetric Total Synthesis of Indole Alkaloids Containing an Indoline Spiroaminal Framework

The total synthesis of the indole alkaloids, neoxaline, oxaline and meleagrin A, all containing a unique indoline spiroaminal framework, was accomplished through the stereoselective introduction of a reverse prenyl group to the congested benzylic carbon of furoindoline, a two‐pot transformation of indoline (containing three nitrogen atoms at appropriate positions) to the featured indoline spiroaminal framework, and elimination of carbonate assisted by the adjacent imidazole moiety to construct the (E)‐dehydrohistidine. The absolute stereochemistry of neoxaline was elucidated through our total synthesis. In addition, we evaluated the bioactivity, especially the anti‐infectious properties, of neoxaline and oxaline, and of some synthetic intermediates.     

Organocatalytic One‐Pot Synthesis of Highly Substituted Pyridazines from Morita–Baylis–Hillman Carbonates and Diazo Compounds

A biologically inspired organocatalytic one‐pot synthesis of highly functionalized pyridazines, which are ubiquitous structural units in a number of biologically active compounds, has been developed by starting from readily available diazo compounds and Morita–Baylis–Hillman (MBH) carbonates. Under mild reaction conditions, this synthetic route tolerated significant substrate variation to deliver a broad range of substituted products, including CF₃‐substituted pyridazines derivatives. Moreover, the introduction of trifluoromethyl groups into the ring of pyridazine could be completed conveniently from 2,2,2‐trifluorodiazoethane.     

Enantioselective Organocatalytic Diels–Alder Trapping of Photochemically Generated Hydroxy‐o‐Quinodimethanes

The photoenolization/Diels–Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light‐triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy‐o‐quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels–Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity‐defining event.     

Sultones and Sultines via a Julia–Kocienski Reaction of Epoxides

The development of the homologous Julia–Kocienski reaction has led to the discovery of two new reaction modes of epoxides with sulfones. These pathways allow rapid and direct access to a range of γ‐sultones and γ‐sultines.     

Organocatalytic Enantioselective Aza‐Friedel–Crafts Reaction of Cyclic Ketimines with Pyrroles using Imidazolinephosphoric Acid Catalysts

Organocatalytic enantioselective aza‐Friedel–Crafts reactions of cyclic ketimines with pyrroles or indoles were catalyzed by imidazoline/phosphoric acid catalysts. The reaction was applied to various 3H‐indol‐3‐ones to afford products in excellent yields and enantioselectivities. The chiral catalysts can be recovered by a single separation step using column chromatography and are reusable without further purification. Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

Enantioselective Organocatalytic One‐Pot Amination/aza‐Michael/Aldol Condensation Reaction Sequence: Synthesis of 3‐Pyrrolines with a Quaternary Stereocenter

Primary amine‐catalyzed direct conversion of α,α‐disubstituted aldehydes into 3‐pyrrolines with a quaternary stereocenter is reported. The one‐pot enantioselective sequence is based on a α‐amination, an aza‐Michael addition of hydrazine, an aldol condensation dehydratation and proceeds with good yields and excellent levels of enantioselectivity. Synthetically attractive applications including the formation of aziridinopyrrolidine or epoxypyrrolidine derivatives with good yields and selectivities are also described.     

FeCl3‐Mediated Three‐Component Cascade Reaction: An Effective Approach to the Construction of Highly Functionalized Pyrrolo[1,2‐c]quinazolinones

An unexpected FeCl₃‐mediated three‐component cascade reaction has been used to construct structurally diverse pyrrolo[1,2‐c]quinazolinone derivatives with potential biological activities. This method has advantages of mild conditions, simple work‐up, as well as wide substrate scope, which makes it a powerful approach to the synthesis of diverse pyrrolo[1,2‐c]quinazolinones. This cascade reaction involves 1,3‐dipolar cycloaddition between azomethine ylides and allenoates, followed by intramolecular nucleophilic addition in the presence of FeCl₃. The obtained products could be easily transformed into derivatives with the pyrrolo[2,3‐c]quinazoline alkaloid skeleton.