The enantioselective organocatalytic 1,4-addition of electron-rich benzenes to alpha,beta-unsaturated aldehydes

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described.     

The first enantioselective organocatalytic Mukaiyama-Michael reaction: a direct method for the synthesis of enantioenriched gamma-butenolide architecture

The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.     

Organocatalytic asymmetric Friedel-Crafts alkylation of indoles with simple alpha,beta-unsaturated ketones

[structure: see text]. The first general and highly enantioselective organocatalytic Friedel-Crafts alkylation of indoles with simple alpha,beta-unsaturated ketones has been accomplished. Central to these studies has been the identification of a new catalyst amine salt, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis.     

Nickel-catalysed reactions with trialkylboranes and silacyclobutanes

Nickel catalysis enables us to develop new reactions with trialkylboranes and silacyclobutanes of modest reactivity. A combination of Ni(cod)(2) and tri-tert-butylphosphine catalyses alkylation reactions of aldehydes and alpha,beta-unsaturated esters with various trialkylboranes of modest reactivity, suppressing conceivable beta-hydride elimination from alkylnickel intermediates. A nickel catalyst is also useful for 1,4-addition of bis(pinacolato)diboron to alpha,beta-unsaturated esters and amides. Nickel-catalysed reaction of silacyclobutanes with aldehydes results in ring opening to afford the corresponding alkoxyallylsilanes. In contrast, the ring expansion reaction of benzosilacyclobutene with aldehydes yields benzoxasilacyclohexenes. A nickel catalyst prepared from Ni(cod)(2) and tricyclohexylphosphine realises direct silylation of terminal alkenes with silacyclobutane furnishing vinylsilanes.     

An efficient enantioselective method for asymmetric Michael addition of nitroalkanes to alpha,beta-unsaturated aldehydes

The addition of nitroalkanes to alpha,beta-unsaturated aldehydes under the catalysis of (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine and lithium acetate as additive afforded gamma-nitroaldehydes in good yield and up to 97% ee.     

Organocatalysed asymmetric beta-amination and multicomponent syn-selective diamination of alpha,beta-unsaturated aldehydes

An easy and affordable route for obtaining chiral beta-aminated- and alpha,beta-diaminated aldehydes, 1,3-aminoalcohols, and related compounds by using organocatalysis is presented. The chiral secondary amine (S)-2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine is used as the catalyst to activate alpha,beta-unsaturated aldehydes, which allows succinimide to add in a 1,4-regio- and stereoselective fashion thereby forming N-protected 1,3-aminoaldehydes in good yields and enantioselectivities. This is followed by two easy transformations giving rise to optically active 1,3-aminoalcohols, a common motif in many biologically active compounds, for example, fibrinogen receptor antagonists. Furthermore, optically active alpha,beta-syn-diaminated aldehydes were obtained by the addition of diethyl azodicarboxylate in a one-pot reaction.     

Tetrazolic acid functionalized dihydroindol: rational design of a highly selective cyclopropanation organocatalyst

Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of alpha,beta-unsaturated aldehydes with sulfur ylides. The new organocatalyst readily facilitates the enantioselective organocatalytic cyclopropanation, providing cyclized product in excellent diastereoselectivities ranging from 96% to 98% along with enantioselectivities exceeding 99% enantiomeric excess for all reacted alpha,beta-unsaturated aldehydes. The new catalyst provides the best results so far reported for intermolecular enantioselective organocatalyzed cyclopropanation.     

Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N-acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester surrogates

Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with various functional groups were synthesized by the Wittig reaction using ylide 2. A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst = 5000). The high turnover frequency and high volumetric productivity of the present reaction are also noteworthy. In addition, a sequential Wittig olefination-catalytic asymmetric epoxidation reaction was developed, providing efficient one-pot access to optically active epoxides from various aldehydes in high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This represents the first direct catalytic asymmetric Michael reaction of unmodified ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of the N-acylpyrrole unit for further transformations is demonstrated.     

Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation

The stereoselective alkylation of alpha,beta-unsaturated imines via C-H activation followed by imine hydrolysis produces tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. In the presence of a rhodium catalyst, alpha,beta-unsaturated N-benzyl imines derived from methacrolein, crotonaldehyde, and tiglic aldehyde undergo directed C-H activation at the beta-position and react with terminal alkenes and alkynes to form the tri- and tetrasubstituted alpha,beta-unsaturated imines with very high stereoselectivity. Hydrolysis to provide alpha,beta-unsaturated aldehydes can be performed under carefully controlled conditions that maintain the stereochemistry of the beta-alkylated imine products. Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer.     

Catalytic asymmetric nitroaldol (Henry) reaction with a zinc-Fam catalyst

Ferrocenyl-substituted aziridinylmethanol (Fam-1) was used as a catalyst with zinc for the asymmetric nitroaldol (Henry) reaction. This catalyst worked with a variety of aldehydes (aromatic, aliphatic, alpha,beta-unsaturated, and heteroaromatic) and alpha-ketoesters to give the nitroaldol product in up to 97% yield and 91% ee. The chiral ligand can be recovered and recycled without losing its activity.     

Enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indoles

An enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indolyl alpha,beta-unsaturated aldehydes has been developed. This powerful new strategy allows enantioselective access to THPIs and THBCs in a straightforward and atom-economical manner.     

Organocatalytic asymmetric epoxidation reactions in water-alcohol solutions

The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.     

Enantioselective Friedel-Crafts alkylations of alpha,beta-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes

An enantioselective Friedel-Crafts alkylation with alpha,beta-unsaturated 2-acyl imidazoles and electron-rich aromatic nucleophiles catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes has been accomplished. These alpha,beta-unsaturated 2-acyl imidazoles are effective electrophiles for the Friedel-Crafts reaction. The resulting adduct 2-acyl imidazole is easily converted to amides, esters, carboxylic acids, ketones, and aldehydes by methylation and subsequent displacement of the imidazole residue.     

Catalytic asymmetric epoxidation of alpha,beta-unsaturated esters using an yttrium-biphenyldiol complex

We succeeded in a catalytic asymmetric epoxidation reaction of alpha,beta-unsaturated esters via a conjugate addition of an oxidant using 2-10 mol % of the yttirium-chiral biphenyldiol catalyst. A variety of substrates with beta-aryl and beta-alkyl substituents were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy esters in up to 97% yield and 99% ee.     

Enantioselective organocatalytic Mukaiyama-Michael addition of silyl enol ethers to alpha,beta-unsaturated aldehydes

[reaction: see text] A highly enantioselective, organocatalytic Mukaiyama-Michael addition reaction of silyl ethers and alpha,beta-unsaturated aldehydes has been developed. The process, catalyzed by MacMillan's chiral imidazolidinone, affords delta-keto aldehydes in high yields (56-87%) and high enantioselectivities (85-97% ee). Moreover, the reaction is applicable to a wide range of silyl ethers and alpha,beta-unsaturated aldehydes and, as such, provides access to a range of important synthetic building blocks.     

One-pot synthesis of 2-substituted indoles from 2-aminobenzyl phosphonium salts. A formal total synthesis of arcyriacyanin A

The reaction of (2-aminobenzyl) triphenylphosphonium bromide with aromatic aldehydes or alpha,beta-unsaturated aldehydes under microwave-assisted conditions constitutes a new synthesis of 2-substituted indoles in high yields (81-97%) in a one-pot reaction. The adduct from indole-4-carboxaldehyde was an advanced intermediate in the synthesis of arcyriacyanin A.     

Enantioselective organocatalytic amine conjugate addition

The first enantioselective organocatalytic amine conjugate addition has been successfully developed. The application of LUMO-lowering iminium catalysis has enabled the highly chemo- and enantioselective 1,4-addition of a rationally designed N-silyloxycarbamate nucleophile (HOMO-raised) to alpha,beta-unsaturated aldehydes. Imidazolidinone 2*pTSA was found to catalyze the addition of various orthogonally N-protected silyloxycarbamate nucleophiles to a range of alpha,beta-unsaturated aldehydes, affording synthetically useful beta-amino aldehyde intermediates. The synthetic utility of the protocol was demonstrated in the rapid synthesis of enantioenriched beta-amino acids in one operation and 1,3-amino alcohol derivatives in three operations.     

Enantioselective organocatalytic hydride reduction

The first enantioselective organocatalytic hydride reduction has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated aldehydes to generate beta-stereogenic aldehydes. The use of imidazolidinone 2 as the asymmetric catalyst has been found to mediate the transfer of hydrogen to a large class of enal substrates from ethyl Hantzsch ester. The capacity of catalyst 2 to accelerate E-Z isomerization prior to selective E-olefin reduction allows the implementation of geometrically impure enals in this operationally simple protocol.     

Regiocontrolled, palladium-catalyzed bisfunctionalization of allenyl esters. Multicomponent coupling approaches to highly substituted alpha,beta-unsaturated delta-lactones

A palladium-catalyzed regioselective bisfunctionalization of allenyl esters with boronic acids (nucleophiles) and aldehydes (electrophiles) was demonstrated. The three-component coupling afforded alpha,beta-unsaturated delta-lactones under mild conditions and with excellent chemo-, regio-, and diastereoselectivity. Aromatic, heteroaromatic and vinylic boronic acids (R1B(OH)2) reacted with ethyl 2,3-butadienoate and benzaldehyde to afford the corresponding 4-R(1),6-Ph-disubstituted alpha,beta-unsaturated delta-lactones in 62-78% yields. Lactones derived from aromatic, heteroaromatic, and vinylic aldehydes were isolated in 51-58% yields, while aliphatic aldehydes were less reactive. The regiochemistry of bisfunctionalization of allenyl ester homologues remained controlled by the ester substituent, and the reactions afforded cis-4,5,6-trisubstituted alpha,beta-unsaturated delta-lactones and esters of (Z)-syn-3,4,5-trisubstituted-5-hydroxy-2-pentenoic acids in combined 47-65% yields. The superior performance of a pi-allylpalladium(II) dimer catalyst featuring an auxiliary allyl ligand derived from beta-pinene, among diverse palladium(II) catalysts, was demonstrated. A catalytic cycle involving an unsymmetrical bis-pi-allylpalladium complex as the key intermediate was proposed, and the communication highlights the synthetic potential of such intermediates. However, the efficiency of asymmetry transfer remained low (<20%).     

Synthesis of C3-symmetric tris(beta-hydroxy amide) ligands and their Ti(IV) complex-catalyzed enantioselective alkynylation of aldehydes

[reaction: see text]. A series of new chiral C3-symmetric tris(beta-hydroxy amide) ligands have been synthesized via the reaction of 1,3,5-benzenetricarboxylic chloride and optically pure amino alcohols (up to 96% yield). The asymmetric catalytic alkynylation of aldehydes with these new C3-symmetric chiral tris(beta-hydroxy amide) ligands and Ti (O(i)'Pr)4 was investigated. Ligand 4c synthesized from (1R,2S)-(-)-2-amino-1,2-diphenylethanol is effective for the enantioselective alkynylation of various aldehydes, and high enantioselectivity was obtained with aromatic aldehydes and alpha,beta-unsaturated aldehyde (up to 92% ee).