Catalytic asymmetric synthesis of 1,4-enynes

1,4-Enyne units are ubiquitous skeletons in biologically active molecules and natural products. Especially, they represent versatile building blocks for abundant downstream derivatizations via controllable modifications of both alkene and alkyne units independently. Recently, great efforts have been made to establish efficient protocols to achieve optically active 1,4-enynes. Considering the enormous application potential of enantioenriched 1,4-enyne units but no related review on this topic has been described, here we aim to provide a comprehensive summary on the catalytic methods established for enantioselective constructions of these intriguing skeletons. According to the reaction types, this review is divided into five parts, including asymmetric allylic substitution, asymmetric propargylic substitution, asymmetric alkynylallylic substitution, asymmetric hydroalkynylation and asymmetric 1,2-addition of alkynes to conjugated imines or ketones.     

Copper-catalyzed synthesis of 1,3-enynes

[reaction: see text] We report a copper(I)-catalyzed procedure for the synthesis of 1,3-enynes. This method affords a variety of enynes in good to excellent yields. This method can tolerate a variety of functional groups, does not require the use of expensive additives, and is palladium-free.     

An enantioselective catalytic approach to syn deoxypropionate units combining asymmetric Cu-catalyzed 1,6- and 1,4-conjugate addition

A novel iterative approach to the synthesis of the naturally ubiquitous syn deoxypropionate motif is reported. The route comprises a new Horner–Wadsworth–Emmons reagent to prepare α,β,γ,δ-bisunsaturated thioesters. Next, two Me-substituents are introduced in high yield, regio- and enantioselectivity using sequential asymmetric Cu-catalyzed 1,6-conjugate addition, base-catalyzed olefin isomerization and Cu-catalyzed enantioselective 1,4-conjugate addition. After reduction to the aldehyde these transformations can be repeated to install three or more Me groups with a syn 1,3-relationship.     

Cu-catalyzed enantioselective conjugate addition of alkylzincs to cyclic nitroalkenes: catalytic asymmetric synthesis of cyclic alpha-substituted ketones

An efficient and highly enantioselective (>/=92% ee) catalytic method for conjugate addition of alkylzinc reagents to cyclic nitroalkenes is reported. Reactions are promoted in the presence of 0.5-5 mol % (CuOTf)2.C6H6 and 1-10 mol % of chiral amino acid-based phosphine ligands at 0 degrees C in toluene. The Cu-catalyzed reactions can be effectively carried out with small-, medium-, and large-ring nitroalkenes. Depending on the reaction conditions used, either the nitro or the corresponding alpha-substituted ketone product can be readily accessed by the present protocol.     

Synthesis of bromoallenyl pyrrolidines via 1,4-addition to 1,3-enynes

The discovery of the novel reactivity of conjugated enynes,mediated by readily available halogenation reagents,opens a broad range of mechanistically unique pathways for the synthesis of highly functionalized chiral allene derivatives.Bromoallenyl pyrrolidines can be synthesized via 1,4-addition of sulfonamide nitrogen nucleophiles and halogens to conjugated enynes.This process can lead to simultaneous formation of a highly functionalized axially chiral allene and a stereogenic center under economical and e...     

Catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides: diastereo- and enantioselective synthesis of imidazolidines

The first catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides have been established via SPINOL-derived chiral phosphoric acid-catalyzed pseudo four-component reactions of aldehydes and 2-aminomalonates, resulting in the stereoselective construction of chiral imidazolidine scaffolds with two stereogenic centers in generally high yields and with good stereoselectivities (up to 81% yield, all >20:1 dr, up to 93% ee). This protocol provides easy access to synthetically and pharmaceutically important chiral imidazolidines via the formation of one ring system, two stereogenic centers, and four new bonds in a single step.     

Cu-catalyzed one-pot multicomponent approach for the synthesis of symmetric and asymmetric 1,4-dihydropyridine (1,4-DHP) linked 1,2,3-triazole derivatives

Abstract

Synthesis of various symmetric and asymmetric 1,4-DHP linked 1,2,3-triazole derivatives from economical and readily available starting materials via a convenient methodology in a single-pot method using CuSO₄·5H₂O as an efficient catalyst has been reported. The reaction proceeded efficiently under the optimized reaction conditions with excellent functional group compatibility providing the desired products in good yields. The method appears to be an efficient combinatorial strategy for the synthesis of new 1,4-DHP linked triazole derivatives.     

Enantioselective reductive coupling of 1,3-enynes to glyoxalates mediated by hydrogen: asymmetric synthesis of beta,gamma-unsaturated alpha-hydroxy esters

Catalytic hydrogenation of 1,3-enynes 1a-8a in the presence of ethyl glyoxalate at ambient pressure and temperature using a rhodium catalyst modified by (R)-(3,5-tBu-4-MeOPh)-MeO-BIPHEP results in highly regio- and enantioselective reductive coupling to furnish the corresponding alpha-hydroxy esters 1b-8b. As demonstrated by the elaboration of alpha-hydroxy ester 1b, the terminal and internal olefin moieties embodied by the diene side chain are subject to selective manipulation, one over the other.     

Highly regioselective, catalytic asymmetric reductive coupling of 1,3-enynes and ketones

[reaction: see text] Highly regioselective, catalytic asymmetric reductive coupling reactions of 1,3-enynes and ketones have been achieved using catalytic amounts of Ni(cod)(2) and a P-chiral, monodentate ferrocenyl phosphine ligand. These couplings represent the first examples of catalytic, intermolecular reductive coupling of alkynes and ketones, enantioselective or otherwise, and afford synthetically useful 1,3-dienes possessing a quaternary carbinol stereogenic center in up to 70% ee.     

Metal-catalyzed enantioselective allylation in asymmetric synthesis

Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.     

Highly enantioselective and efficient synthesis of flavanones including pinostrobin through the rhodium-catalyzed asymmetric 1,4-addition

An efficient synthesis of bioactive chiral flavanones (1) was achieved through the Rh-catalyzed asymmetric 1,4-addition of arylboronic acid to chromone. The reaction in toluene proceeded smoothly at room temperature in the presence of 0.5% Rh catalyst with electron-poor chiral diphosphine MeO-F(12)-BIPHEP. In this reaction, the 1,2-addition to (S)-1 frequently occurred to yield (2S,4R)-2,4-diaryl-4-chromanol as a byproduct, which could be reduced by changing the reaction solvent to CH(2)Cl(2) to deactivate the Rh catalyst (3% required).     

Carbohydrates in asymmetric synthesis: enantioselective allylation of aldehydes

An enantioselective metal-mediated addition of allylic bromides to carbonyl compounds was achieved in the presence of the inexpensive and easily accessible carbohydrates saccharose and β-cyclodextrin. The desired products were obtained in moderate to excellent yields and with up to 93% enantiomeric excess.     

Enantioselective synthesis of beta-aryl-gamma-amino acid derivatives via Cu-catalyzed asymmetric 1,4-reductions of gamma-phthalimido-substituted alpha,beta-unsaturated carboxylic acid esters

A series of chiral beta-aryl-substituted gamma-amino butyric acid derivatives were synthesized in good enantioselectivities via the Cu-catalyzed asymmetric conjugate reduction of gamma-phthalimido-alpha,beta-unsaturated carboxylic acid esters using Cu(OAc)2 x H2O as a catalyst precursor, (S)-BINAP as a ligand, PMHS as a hydride source, and t-BuOH as an additive. The methodology has been applied successfully to the enantioselective synthesis of a chiral pharmaceutical, (R)-baclofen.     

Sugar-based phosphite and phosphoroamidite ligands for the Cu-catalyzed asymmetric 1,4-addition to enones

A modular sugar-based phosphoroamidite L1–L5a–g and phosphite L6–L9a–g ligand library was tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of β-substituted (cyclic and linear) and β,β′-disubstituted (cyclic) enones. The selectivity depended strongly on the configuration of carbon atom C-3, the size of the sugar backbone ring, the flexibility of the ligand backbone, the substituents and configurations in the biaryl phosphoroamidite moieties a–g, the type of functional group attached to the ligand backbone and the substrate structure. Therefore, by carefully selecting the ligand parameters, enantioselectivities of up to 60% for cyclic substrates and 72% for linear ones were achieved.     

Highly enantioselective Cu-catalysed asymmetric 1,4-addition of diphenylzinc to cyclohexenone

Highly enantioselective Cu-catalysed 1,4-addition of diphenylzinc to cyclohexenone has been achieved for the first time using a monodentate phosphoramidite ligand.     

Furanoside phosphite–phosphoroamidite and diphosphoroamidite ligands for Cu-catalyzed asymmetric 1,4-addition reactions

A sugar-based phosphite–phosphoroamidite and diphosphoroamidite ligand library L1–L5a–g was tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of β-substituted and β,β′-disubstituted enones. Our results indicated that the selectivity was strongly dependent on the ligand parameters and on the substrate structure. Moderate-to-good enantioselectivities (ees up to 84%) were obtained in the 1,4-addition of several types of β-substituted cyclic and linear substrates. Of particular note is the high enantioselectivity (ees up to 90%) obtained for the more challenging β,β′-disubstituted 3-methyl-cyclohexenone.