Zhenghu Xu

Asymmetric Inverse-Electron-Demand Hetero-Diels–Alder Reaction of Six-membered Cyclic Ketones: An Enamine/Metal Lewis Acid Bifunctional Approach†

The combination of organocatalysis with metal catalysis has emerged as a potentially powerful tool in organic synthesis. This new concept aims to achieve organic transformations that cannot be accessed by organocatalysis or metal catalysis alone. In our effort to combine organo-enamine catalysis with metal Lewis acid catalysis, we have developed a new class of bifunctional enamine/metal Lewis acid catalysts. These bifunctional catalysts displayed unusually high activity and high stereoselectivity in asymmetric direct aldol reactions. The challenge in the development of Lewis acid/Lewis base catalytic systems lies in the acid-base quenching reaction that leads to catalyst inactivation. A common and elegant approach to solving this problem is the use of a soft acid along with a hard base, or vice versa. Based on this approach, organo-enamine catalysis has been successfully combined with Cu, Ag, Pd, and Au. We use a different strategy to solve the acid-base problem. This new strategy complements the mixed soft/hard approach. In our system, the Lewis base (primary or secondary amine) is tethered to a chelating ligand, which serves as a “trap” for the incoming metal. In this way, the base and the metal Lewis acid are brought into close proximity in one molecule without interacting with each other (Figure 1). The bifunctional enamine/metal Lewis acid catalysts have two unique advantages. First, a large number of metals can be introduced. The Lewis acidity can be easily tuned by simply using a different metal, thereby offering great flexibility to this system. For example, stronger Lewis acids, such as La, can be used to activate the enamine acceptor more strongly. Second, the bifunctional catalysts can potentially convert an intermolecular reaction into a much more efficient intramolecular reaction. In addition, the intramolecular bifunctional nature of the catalysts would also enhance the stereoselectivity of the reaction. With these catalysts, we intend to develop new carbon–carbon or carbon–heteroatom bond-forming reactions involving difficult organic transformations. Herein, we report the first example of a highly chemoand enantioselective inverse-electron-demand hetero-Diels–Alder (HDA) reaction of cyclic ketones with b,g-unsaturated-a-ketoesters catalyzed by primary-amine-based enamine/metal Lewis acid bifunctional catalysts. Asymmetric inverse-electron-demand hetero-Diels– Alder (IED/HDA) reactions of electron-rich alkenes with an electron-deficient a,b-unsaturated ketone offers a valuable synthetic entry into dihydropyran derivatives, which are chemically and biologically of significant importance, allowing the construction of up to three stereogenic centers in one operation. In most of the inverse-electron-demand HDA reactions, enol ethers derived from aldehydes act as the electron-rich alkenes (dienophiles). Very recently, enaminebased organocatalytic asymmetric inverse-electron-demand HDA reactions, in which an in situ formed enamine from a chiral pyrolidine and an aldehyde serves as the dienophile, have been made possible. Ketones are much less reactive compared to aldehydes because of electronic and steric reasons. Asymmetric HDA reactions of ketones, in particular cyclic ketones, have remained a long-standing challenge. We are interested in developing a catalytic asymmetric enamine-based IED/HDA reaction of simple ketones with enones, as it would greatly generalize this method, and open it up to much wider exploitation. To achieve this we believe that the activation of enones should extend beyond hydrogen-bond methods, 8] for example, by using a strong metal Lewis acid. In contrast, the formation of a less congested enamine intermediate using a primary amine catalyst may also contribute to or facilitate this transformation. The primary-amine-based enamine/metal Lewis acid bifunctional catalysts developed in our laboratory appear to be ideal candidates to tackle this difficult problem. We envision that the primary amine/metal Lewis acid bifunctional catalyst would engage enone 3 and the cyclic ketone 2 intramolecularly (Scheme 1). The primary amine would form an enamine in situ with the ketone (A) and the Figure 1. Illustration of primary amine/metal Lewis acid bifunctional catalysts.

Copper(I)‐Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5‐Hetero‐Functionalized Triazoles

The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility.

Arylamine-catalyzed enamine formation: Cooperative catalysis with arylamines and acids

The explosive growth of organocatalysis has had a huge impact on asymmetric catalysis in the past decade. Transition-metal catalysis, on the other hand, has been established for a long time as one of the most powerful methods in organic synthesis. Aminocatalysis is a major field in organocatalysis. The combination of organocatalysis with the more traditional metal Lewis acid catalysis has emerged, aiming to achieve organic transformations that cannot be accomplished by organocatalysis or metal catalysis independently. Although it promises huge potential, this research area has grown only slowly. The major challenge lies in the incompatibility of the catalysts, in particular, the combination of enamine catalysis with harder metal Lewis acid is very difficult. The circumvention of this problem would represent an important breakthrough, given the huge number of substrates that can be activated by the large variety of metal Lewis acids. Herein, we present the solution to this longstanding problem by using arylamines as the catalysts in enamine catalysis. Very importantly, we demonstrate that arylamines can serve as efficient amine catalysts in direct asymmetric aldol reactions. Furthermore, we have developed a highly chemoand enantioselective three-component azaDiels–Alder reaction by combining arylamines with metal Lewis acids. The combination of enamine catalysis with metal Lewis acid catalysis was first reported by Ibrahem and Codava in 2006. Since then, considerable progress has been made in this area, leading to a series of exciting discoveries. However, these combinations were limited to soft metals, such as Cu, Ag, Au, Ir, and Pd or Pd, activating either p-allyl electrophiles or alkynes (Scheme 1,A and B). Combining enamine catalysis with harder metal Lewis acid (Scheme 1, C) turned out to be very challenging because of acid–base self-quenching reactions, which render the catalysts inactive. In asymmetric aminocatalysis involving either an enamine or an iminium intermediate, a chiral aliphatic secondary or primary amine serves as the catalyst. Aliphatic amines are hard bases, and thus likely to be compatible with softer metals based on the soft/hard approach, but less likely to be compatible with harder metals. We hoped to find an amine catalyst that is compatible with a large variety of metal Lewis acids to significantly extend the scope of enamine/ metal Lewis acid catalysis, and to facilitate the development of a new research area of iminium/metal Lewis acid catalysis. We considered to use arylamines, such as aniline, because they have a much lower pKa value (4–6) than aliphatic amines (9–11), and should be much softer because of the delocalization of the lone pair to the aromatic p system. It appeared to us that arylamines are ideal candidates for combination with harder metal Lewis acids. Despite their ubiquity in organic chemistry, arylamines have never been used in enamine catalysis. This may be mainly due to the general understanding that the nucleophilicity of arylamines is much lower compared to aliphatic amines. However, List and co-workers suggested the formation of enamine intermediates from arylamines as a step in organocatalytic cascade reactions. In a recent report, Gong and co-workers also suggested that an achiral arylamine played a crucial role in controlling the stereochemistry of a Friedl nder condensation by forming an enamine intermediate. We speculate that arylamines might be suitable to serve as an efficient amine catalyst in enamine catalysis in conjunction with a stronger metal Lewis acid. The lower nucleophilicity of enamines can be compensated by the following factors: 1) facilitated formation of enamine in the presence of a metal Lewis acid; 2) higher activation of the electrophiles by a metal Lewis acid. The asymmetric aza-Diels–Alder reaction (ADAR) is the most convenient and powerful method to form nitrogencontaining heterocycles, which are one of the most important structural motifs in natural products, pharmaceuticals, and biosystems. While the recent progress on normal-electrondemand ADARs based on dienamines and imine dienophiles Scheme 1. Combination of enamine catalysis with metal catalysis.

Synthesis of spiroaminals and spiroketals with bimetallic relay catalysis.

A novel tandem metal relay catalytic system was developed by combining gold-catalyzed cycloisomerization with an early transition-metal-catalyzed inverse-electron-demand hetero-Diels-Alder (IED-HDA) reaction. Various biologically important spiroaminals and spiroketals were obtained with very high efficiency under mild conditions.

Strain-Promoted Oxidative Annulation of Arynes and Cyclooctynes with Benzamides: Palladium-Catalyzed C–H/N–H Activation for the Synthesis of N-Heterocycles

Strained alkynes include arynes and cyclooctynes reacted with N-methoxyamides through palladium-catalyzed C-H/N-H activation for the first time. A variety of important N-heterocycles such as phenanthridinones and isoquinolones were constructed in one step with high efficiency.

Regioselective synthesis of multisubstituted 1,2,3-triazoles: moving beyond the copper-catalyzed azide–alkyne cycloaddition

Copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) is an essential click chemistry reaction that is widely used in chemical biology, medicinal chemistry and materials science. The CuAAC reaction of terminal alkynes provides a mild and efficient synthesis of 1,4-disubstituted 1,2,3-triazoles. However, the click reaction of internal alkynes with azides, giving trisubstituted triazoles, is very challenging. This feature article highlights the recent progress addressing this fundamental problem. Particular emphasis is on the current and emerging strategies to introduce functional groups to the C-5 position of triazoles in a regioselective manner.

Synthesis of fused bicyclic aminals through sequential gold/Lewis acid catalysis.

A novel sequential catalysis by combining gold catalysis with early transition metal catalysis was developed. Biologically important bicyclo[4.n.0] aminals were obtained under very mild conditions.

Cu/Pd-Catalyzed, Three-Component Click Reaction of Azide, Alkyne, and Aryl Halide: One-Pot Strategy toward Trisubstituted Triazoles

A Cu/Pd-catalyzed, three-component click reaction of azide, alkyne, and aryl halide has been developed. By using this Cu/Pd transmetalation relay catalysis, a variety of 1,4,5-trisubstituted 1,2,3-triazoles were quickly assembled in one step in high yields with complete regioselectivity, just like assembling Lego bricks. Notably, different from the well-established CuAAC click reactions only working on terminal alkynes, this reaction offers an alternative solution for the problem of the click reaction of internal alkynes.

Copper(I)-Catalyzed Three-Component Click/Alkynylation: One-Pot Synthesis of 5-Alkynyl-1,2,3-triazoles

A copper(I)-catalyzed tandem CuAAC/alkynylation reaction of various alkynes, organic azides, and bromoalkynes to provide rapid access to 5-alkynyl-1,2,3-triazoles has been developed. The reaction proceeded via a copper-catalyzed alkyne azide cycloaddition followed by interception of the in situ formed cuprate-triazole intermediate with bromoalkyne. This reaction offers a new method to afford fully substituted triazoles in high yields with complete regioselectivity under mild reaction conditions.

Primary amine-metal Lewis acid bifunctional catalysts: the application to asymmetric direct aldol reactions

The first example of metal Lewis acid-primary amine bifunctional cooperative catalyst derived from primary amino acids was developed, and it was found to catalyze aldol reactions of cyclic ketones highly efficiently with very good to excellent stereoselectivities.