Enantioselective Conjugate Addition Reactions Research Articles

Tandem Isomerization/α,β-Site-Selective and Enantioselective Addition Reactions of N-(3-Butynoyl)-3,5-dimethylpyrazole Induced by Chiral π-Cu(II) Catalysts.

Allenes are important building blocks, and derivatization of products via cycloadditions of allenes could become a powerful strategy for constructing carbocyclic and heterocyclic rings. However, the development of catalytic site-selective and enantioselective cycloaddition reactions of allenes still presents significant challenges. Here, we report chiral π-Cu(II)-complex-catalyzed isomerization of N-(3-butynoyl)-3,5-dimethyl-1H-pyrazole to generate N-allenoylpyrazole in situ and subsequent α,β-site-selective and enantioselective [3 + 2], [4 + 2], or [2 + 2] cycloaddition or conjugate addition reactions. The asymmetric environment created by the intramolecular π-Cu(II) interactions provides the corresponding adducts in moderate to high yield with excellent enantioselectivity. To the best of our knowledge, this is the first successful method for chiral-Lewis-acid-catalyzed tandem isomerization/α,β-site-selective and enantioselective cycloaddition or conjugate addition reactions of latent non-γ-substituted allenoyl derivative.

Polymer-Supported Chiral Heterogeneous Copper Catalyst for Asymmetric Conjugate Addition of Ketones and Imines under Batch and Flow

Enantioselective conjugate addition reactions are powerful methods in synthesizing optically active molecules. Procedures that employ chiral homogeneous catalysts have been developed extensively, but ones that use chiral heterogeneous catalysts are less explored and remain a challenge. Here we report a polymer-supported chiral heterogeneous copper catalyst that demonstrated high reactivity and enantioselectivity in asymmetric conjugate addition reactions of both ketones and imines. It was found that reduced steric hindrance inside the micro catalytic environment and a 1:1 ligand to metal ratio was crucial for the high efficiency and reusability of the chiral heterogeneous catalyst. Various α,β-unsaturated carbonyl substrates, including pharmaceutical intermediates and natural products, could be transformed in high yields with high enantioselectivities. Successful application of this methodology in a continuous flow fashion further broadened its usage in dealing with sensitive organozinc reagents. In addition, production was successfully scaled up under the flow condition.

Advances in Synthesis of Enantioenriched Chiral Sulfones by Enantioselective Conjugate Addition Reactions

AbstractChiral sulfones, a class of organic compounds with broad application prospects in organic synthesis and pharmaceutical chemistry, are an important part of building bioactive molecules or functional materials. In this paper, the advances and the state of synthesizing chiral sulfones by addition reactions are reviewed. The methods described in the manuscript are classified according to the types of reaction. Moreover, each chapter is arranged in chronological order.

Copper(I) Complexes of P‐Stereogenic Josiphos and Related Ligands

AbstractStarting from (R)‐Ugi's amine, diastereoselective lithiation followed by Ar'PCl2 and then Ar’’MgBr led to the generation, as single diastereoisomers, of (R,Sp,Sphos) [Ar’=Ph, Ar’’=o‐Tol] and (R,Sp,Rphos) [Ar’=o‐Tol, Ar’’=Ph] PPFA ligand derivatives. Amine substitution of both with HPCy2 gave P‐stereogenic Josiphos ligands, and then addition of CuCl, the corresponding copper(I) complexes. The latter were also generated by using borane P and N protecting groups and in situ Cu(I) complexation, avoiding the isolation of air‐sensitive phosphine intermediates. This protection methodology was also applied to the synthesis of Josiphos/CuCl complexes derived from PCl3. In addition, related bulky cobalt‐sandwich complex‐based derivatives were also obtained. Preliminary investigation revealed isolated CuCl complexes as competent catalyst precursors for enantioselective conjugate addition reactions.

Enantioselective Conjugate Addition of Catalytically Generated Zinc Homoenolate

We report herein an enantioselective conjugate addition reaction of a zinc homoenolate, catalytically generated via ring opening of a cyclopropanol, to an α,β-unsaturated ketone. The reaction is promoted by a zinc aminoalkoxide catalyst generated from Et2Zn and a chiral β-amino alcohol to afford 1,6-diketones, which undergo, upon heating, intramolecular aldol condensation to furnish highly substituted cyclopentene derivatives with good to high enantioselectivities. The reaction has proved applicable to various 1-substituted cyclopropanols as well as chalcones and related enones. The chiral amino alcohol has proved to enable ligand-accelerated catalysis of the homoenolate generation and its conjugate addition. Positive nonlinear effects and lower reactivity of a racemic catalyst have been observed, which can be attributed to a stable and inactive heterochiral zinc aminoalkoxide dimer.

Organocatalytic enantioselective synthesis of β-amino sulfonic acid derivatives.

An unprecedented enantioselective conjugate addition reaction of sodium bisulfite to various nitrostyrenes occurred upon the influence of a bifunctional amino-thiourea organocatalyst; a strategy that opens a straightforward route to unprotected chiral taurine derivatives thanks to the reduction of the obtained β-nitroethanesulfonic acids into the corresponding amino derivatives.

Catalytic enantioselective synthesis of tetrasubstituted chromanones via palladium-catalyzed asymmetric conjugate arylation using chiral pyridine-dihydroisoquinoline ligands.

Highly enantioselective conjugate addition reactions of arylboronic acids to 2-substituted chromones catalyzed by palladium complexes with new chiral Pyridine-Dihydroisoquinoline (PyDHIQ) ligands have been developed. These reactions provide highly enantioselective access to chromanones containing tetrasubstituted stereocenters. Various arylboronic acids and 2-substituted chromones can be used in the catalytic reaction to afford the chiral tetrasubstituted chromanones in good yields and excellent enantioselectivities (25 examples, up to 98% yields, up to 99% ee).

Theoretical free energy profile and benchmarking of functionals for amino-thiourea organocatalyzed nitro-Michael addition reaction.

Amino-thiourea organocatalysis is an important catalytic process for enantioselective conjugate addition reactions. The interaction of the reactants with the catalyst has a substantial effect of dispersion forces and is a challenge for a reliable description when applying density functional theory. In this report, the classical addition of acetylacetone to β-nitro-styrene catalyzed by Takemoto's catalyst in toluene was studied using the PBE functional for geometry optimization and the DLPNO-CCSD(T) benchmark method for single point energy. The complete free energy profile calculated for the reaction was able to explain all experimental observations, including the fact that the carbon-carbon bond formation step is rate-determining. The overall barrier was calculated to be 22.8 kcal mol-1 (experimental value approximately 20 kcal mol-1), and the enantiomeric excess was calculated to be 88% (experimental value in the range of 84 to 92%). Some functionals were tested for single point energy. The hybrid B3LYP presented a high mean absolute deviation (MAD) from the DLPNO-CCSD(T) benchmark method by approximately 20 kcal mol-1. The inclusion of empirical dispersion correction in the B3LYP method decreased the MAD to 6 kcal mol-1. Even the double-hybrid mPW2-PLYP and B2GP-PLYP methods had MAD values of approximately 5 kcal mol-1. The inclusion of the dispersion correction decreased the MAD to 3.6 kcal mol-1. M06-2X and ωB97X-D3 were the most accurate among the tested functionals, with MADs of 2.5 kcal mol-1 and 1.8 kcal mol-1, respectively. Additivity approximation of the correlation energy was also tested and presented a MAD of only 0.6 kcal mol-1.

Catalytic Enantioselective Conjugate Addition of Stereodefined Di‐ and Trisubstituted Alkenylaluminum Compounds to Acyclic Enones

AbstractCatalytic enantioselective conjugate addition (ECA) reactions with readily accessible and stereochemically defined E‐, Z‐, di‐ and trisubstituted alkenyl aluminum compounds are disclosed. Transformations are promoted by various NHC‐copper catalysts (NHC=N‐heterocyclic carbene), which are derived from enantiomerically pure sulfonate imidazolinium salts. The desired products were obtained in up to 89% yield and >99:1 e.r.; the alkenyl moiety was transferred with complete retention of its stereochemical identity in all instances. The scope and limitations of the approach, key mechanistic attributes, and representative functionalization are presented as well.magnified image

An asymmetric tertiary carbon center with a tetrafluoroethylene (–CF2CF2–) fragment: Novel construction method and application in a chiral liquid crystalline molecule

An asymmetric carbon center with a tetrafluoroethylene fragment can be efficiently constructed via a highly enantioselective conjugate addition reaction of various arylboronic acids with β-(bromotetrafluoroethyl)-α,β-unsaturated ketones. This system can be successfully applied to an enantiomerically enriched tetrafluoroethylenated liquid crystalline molecule.

Copper-Catalyzed Enantioselective Boron Conjugate Addition: DFT and AFIR Study on Different Selectivities of Cu(I) and Cu(II) Catalysts

We present a mechanistic survey on the LCu-catalyzed (L = chiral 2,2′-bipyridine ligand) enantioselective boron conjugate addition reaction, carried out using density functional theory (DFT) and artificial force induced reaction (AFIR) methods. The computed catalytic cycle for Cu(I)- and Cu(II)-based catalysts consists of three steps: (a) boron–boron bond cleavage of B2(pin)2, (b) boron conjugate addition on the β carbon of chalcone, and (c) protonation. The enantioselectivity of the reaction with LCuI or LCuII catalysts is solely governed at the boron conjugate addition step. The multicomponent (MC)-AFIR search and the subsequent DFT calculations for the LCuI catalyst determined transition states (TSs), which lead to CuI-O-enolate and CuI-C-enolate, and both equally contribute to the C–B bond formation with no enantioselectivity. On the other hand, a MC-AFIR search and the subsequent DFT calculations for the analogous LCuII catalyst showed that only the transition state (TS) leading to CuII-O-enolate con...

Development of Chiral, Bifunctional Thiosquaramides: Enantioselective Michael Additions of Barbituric Acids to Nitroalkenes.

We report a general method for the synthesis of chiral thiosquaramides, a class of bifunctional catalysts not previously described in the literature. Thiosquaramides are found to be more acidic and significantly more soluble in nonpolar solvents than their oxosquaramide counterparts, and they are excellent catalysts for the unreported, enantioselective conjugate addition reaction of the barbituric acid pharmacaphore to nitroalkenes, delivering the chiral barbiturate derivatives in high yields and high enantioselectivities, even with catalyst loadings as low as 0.05 mol%.

An enantioselective conjugate addition reaction of 3-substituted benzothiophen-2-ones and 2-phthalimidoacrylates

A highly enantioselective conjugate addition reaction of 3-substituted benzothiophen-2-ones to 2-phthalimidoacrylates has been developed using a bifunctional tertiary-amine thiourea catalyst.

ChemInform Abstract: Organocatalytic Asymmetric Michael Addition of α‐Alkylidene Succinimides to Nitrostyrenes.

AbstractA squaramide‐catalyzed enantioselective conjugate addition reaction of alkylidenesuccinimides with β‐nitrostyrenes and a nitro diene gives the corresponding alkylidene(3‐nitropropyl)succinimides in good to excellent yields with high to excellent diastereoselectivities and enantioselectivities.

Organocatalytic Enantioselective Conjugate Addition of Malonic Acid Half Thioesters to Coumarin‐3‐carboxylic Acids Using N‐Heteroarenesulfonyl Cinchona Alkaloid Amides

AbstractWe disclose herein an efficient enantioselective conjugate addition reaction between coumarin‐3‐carboxylic acids and malonic acid half thioesters (MAHTs). The reaction was catalyzed by N‐heteroarenesulfonyl Cinchona alkaloid amides to afford double‐decarboxylative conjugate addition products in good yield with high enantioselectivity. The reaction of various coumarin‐3‐carboxylic acids with MAHTs gave products in high yield with high enantioselectivity.magnified image

ChemInform Abstract: Copper‐ and Silver‐Catalyzed Diastereo‐ and Enantioselective Conjugate Addition Reaction of 1‐Pyrroline Esters to Nitroalkenes: Diastereoselectivity Switch by Chiral Metal Complexes.

AbstractA stereodivergent asymmetric conjugate addition of pyrroline esters to nitroalkanes provides access to syn and anti adducts using copper and silver catalytic systems.

Asymmetric Synthesis of Multisubstituted Dihydrobenzofurans by Intramolecular Conjugate Addition of Short-Lived C-O Axially Chiral Enolates.

Enantioselective intramolecular conjugate addition reactions of short-lived C-O axially chiral enolates have been developed. The reactions proceeded with inversion of the configuration and provided dihydrobenzofurans with contiguous tetra- and trisubstituted carbon centers in up to 96% enantiomeric excess (ee).

Copper- and Silver-Catalyzed Diastereo- and Enantioselective Conjugate Addition Reaction of 1-Pyrroline Esters to Nitroalkenes: Diastereoselectivity Switch by Chiral Metal Complexes.

syn-Diastereoselective conjugate addition of 1-pyrroline esters to nitroalkenes in good yields with an excellent enantioselectivity by using CuOAc/Me-FcPHOX catalyst in the presence of pyridine. In contrast, AgOAc/tBu-ThioClickFerrophos catalyzed the anti diastereoselective conjugate addition with a high enantioselectivity without additional base. Thus, the preparation of chiral 1-pyrroline derivatives bearing diverse stereochemistry could be achieved. The diastereoselective reduction of the imine group in the conjugate adduct could afford the 2,5-cis-proline ester derivative.

ChemInform Abstract: Organocatalytic Enantioselective Conjugate Addition of 3‐Fluorooxindoles to Vinyl Sulfone.

AbstractHighly efficient catalytic enantioselective conjugate addition reactions of 3‐fluorooxindoles to activated vinyl sulfone (II) is achieved using a binaphthyl‐modified bifunctional urea catalyst bearing both central and axial chiral elements.

ChemInform Abstract: Diastereoselective and Enantioselective Conjugate Addition Reactions Utilizing α, β‐Unsaturated Amides and Lactams

AbstractReview: 284 refs.