Copper-catalyzed Asymmetric Henry Reaction Research Articles

1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid and Derivatives As Chiral Constrained Bridged Scaffolds for Foldamers and Chiral Catalysts

The improvement of molecular diversity is one of the major concerns of chemists since the continuous development of original synthetic molecules provides unique scaffolds usable in organic and bioorganic chemistry. The challenge is to develop versatile platforms with highly controlled chemical three-dimensional space thanks to controlled chirality and conformational restraints. In this respect, cyclic β-amino acids are of great interest with applications in various fields of chemistry. In addition to their intrinsic biological properties, they are important precursors for the synthesis of new generations of bioactive compounds such as antibiotics, enzyme inhibitors, and antitumor agents. They have also been involved in asymmetric synthesis as efficient organo-catalysts in their free form and as derivatives. Finally, constrained cyclic β-amino acids have been incorporated into oligomers to successfully stabilize original structures in foldamer science with recent successes in health, material science, and catalysis. Over the last ∼10 years, we focused on bicyclic β-amino acids possessing a bicyclo[2.2.2]octane structure. This latter is a structural key element in numerous families of biologically active natural and synthetic products and is an interesting template for asymmetric synthesis. Nonetheless, reported studies on bicyclic carbo-bridged compounds are rather limited compared to those on bicyclic-fused and heterobridged derivatives. In this Account, we particularly focused on the synthesis and applications of the 1-aminobicyclo[2.2.2]octane-2-carboxylic acid, named, ABOC, and its derivatives. This highly constrained bicyclic β-amino acid, with a sterically hindered bridgehead primary amine and an endocyclic chiral center, displays drastically reduced conformational freedom. In addition, its high bulkiness strongly impacts the spatial orientation of the appended functionalities and the conformation of adjacent building blocks. Thus, we have first expanded a fundamental synthetic work by a wide ranging study in the field of foldamers, in the design of various stable peptide/peptidomimetic helical structures incorporating the ABOC residue (11/9-, 18/16-, 12/14/14-, and 12/10-helices). In addition, such bicyclic residue was fully compatible with and stabilized the canonical oligourea helix, whereas very few cyclic β-amino acids have been incorporated into oligoureas. In addition, we have pursued with the synthesis of some ABOC derivatives, in particular the 1,2-diaminobicyclo[2.2.2]octane chiral diamine, named DABO, and its investigation in chiral catalytic systems. Covalent organo-catalysis of the aldol reaction using ABOC-containing tripeptide catalysts provided a range of aldol products with high enantioselectivity. Moreover, the double reductive condensation of DABO with various aldehydes allowed the building of new chiral ligands that proved their efficiency in the copper-catalyzed asymmetric Henry reaction.

Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed asymmetric Henry reaction

Levopimaric acid, a readily available starting material, was used in efficient syntheses of new enantiopure diamines and Schiff bases with good yields. The synthetic procedure is based on the fumaropimaric acid monomethyl ester conversion into the optically pure trans-1,2-diamine via a Curtius rearrangement. New diamines were studied as ligands in the copper-catalyzed asymmetric Henry reaction.

Recent progress in copper catalyzed asymmetric Henry reaction

Henry reaction is one of the most classical reactions to construct synthetically useful product nitro alcohol, which as a privileged skeleton is widely distributed in various pharmaceuticals. This review summarizes the recent progress of copper-catalyzed asymmetric Henry reaction from 2011 to 2016. The significant progress that has been made in this area will be highlighted and some of challenges that the author believes may be hindering further progress will be revealed.

L-Proline derived arylmethanamine ligands and their application in the copper-catalyzed asymmetric Henry reaction: a rare example of a Cu-complex with a dicopper tetraacetate core

A series of novel epimeric arylmethanamine ligands were synthesized from l-proline. Both epimers were subsequently examined in the copper(II)-catalyzed asymmetric Henry reaction. Product yield and stereoselectivity up to 92% ee indicated that the (S,S)-epimer was superior to the diamine with an (S,R)-configuration. An enhancement of enantioselectivity driven by the formation of a Cu(II) complex with a dicopper tetraacetate core was discovered. Two types of crystalline Cu(II) complexes were isolated, and their structures were established by X-ray analyses.

ChemInform Abstract: Merging Asymmetric Henry Reaction with Organocatalytic Cascade Reaction for the Construction of a Chiral Indolizidine Alkaloid Skeleton.

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition–hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1–copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral β-nitro alcohol and α,β-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Merging Asymmetric Henry Reaction with Organocatalytic Cascade Reaction for the Construction of a Chiral Indolizidine Alkaloid Skeleton

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition-hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1-copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral β-nitro alcohol and α,β-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Design of a Chiral Secondary Amine Ligand for Copper-Catalyzed anti-Selective Henry Reaction

A series of chiral binaphthyl-containing diphenylethylene­diamine (binaph-dpen) ligands was designed and synthesized for the copper-catalyzed asymmetric Henry reaction. The <i>N</i>-monobenzyl (<i>S</i>)-binaph-(<i>R</i>,<i>R</i>)-dpen ligand, with a secondary amine portion, promoted the Cu(OAc)₂-catalyzed Henry reaction with excellent enantioselectivity in an <i>anti</i>-selective manner.

Copper-Catalyzed Asymmetric Henry Reaction

Copper-Catalyzed Asymmetric Henry Reaction

Copper-Catalyzed Asymmetric Henry Reaction

Copper-Catalyzed Asymmetric Henry Reaction

Synthesis of new planar chiral [2.2]paracyclophane Schiff base ligands and their application in the asymmetric Henry reaction

A series of new planar and central chiral ligands based on [2.2]paracyclophane backbones were designed and prepared from enantiomerically pure 4-amino-13-bromo[2.2]paracyclophane and commercially available chiral amino alcohols. Their application in a copper-catalyzed asymmetric Henry reaction resulted in secondary alcohols with high yield and excellent selectivity for active aldehydes (up to 94% ee). This is a successful example of employing planar chiral [2.2]paracyclophane ligands in copper-catalyzed reaction.