Chiral ligand-controlled asymmetric conjugate addition of lithium amides to enoates

The external chiral ligand-controlled asymmetric conjugate addition reaction of lithium amides with alpha,beta-unsaturated esters provided beta-amino esters in high yields and high enantioselectivities.     

Chiral ligand-controlled asymmetric conjugate addition of alpha-trimethylsilanylacetate to acyclic and cyclic enones

The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of alpha-trimethylsilanylacetate to acyclic and cyclic alpha,beta-unsaturated ketones was mediated by an external chiral ligand to give the corresponding 1,4-adducts in good enantioselectivity of 74% and good chemoselectivity.     

Asymmetric synthesis of intermediates for otamixaban and premafloxacin by the chiral ligand-controlled asymmetric conjugate addition of a lithium amide

A chiral ligand-controlled conjugate addition reaction of lithium benzyl(trimethylsilyl)amide with tert-butyl enoates gave the corresponding lithium enolates that were then treated with electrophiles, giving anti-alkylation products with high ee up to 98%. The benzyl group on the amino nitrogen was removed by the oxidation of secondary amines to imines and subsequent transoximation to give 3-aminoalkanoates in good yields. The products are the possible key intermediates of otamixaban and premafloxacin.     

Improved asymmetric synthesis of dopamine D1 full agonist, dihydrexidine, employing chiral ligand-controlled asymmetric conjugate addition of aryllithium to a nitroalkene

Asymmetric conjugate addition of 2-trityloxymethylpheyllithium to a nitroalkene was mediated by a chiral ligand to give the key intermediate for dopamine D1 full agonist dihydrexidine 1. The shortcut of both Curtius rearrangement and Pictet-Spengler type cyclization, which were the drawback of the previously reported synthesis involving asymmetric conjugate addition of phenyllithium to an enoate, was realized by the newly developed asymmetric reaction. Short and efficient synthetic way gave optically pure dihydrexidine in 45% overall yield via eight steps. Improved synthesis of the best chiral ligand 13 was realized under the Buchwald conditions.     

Simple camphor derivatives as chiral auxiliaries for asymmetric conjugate addition

The chiral enoates, $\text{4}$, readily available in two simple steps from (+)-camphor, Undergo asymmetric conjugate addition with the Gilman reagent LiBu₂Cu. Chemical yields are high (70–90%) and in the case of the naphthyl-substituted enoate $\text{4e}$ excellent diastereoselectivity (95% $\text{d.e.}$) is observed. 3-Methyl-heptan-l-ol of correspondingly high enantiomeric purity is obtained by reduction of the conjugate adduct with lithium aluminium hydride.     

Catalytic asymmetric conjugate addition of Grignard reagents to coumarins--synthesis of versatile chiral building blocks

A new protocol for the Cu-catalysed asymmetric conjugate addition of Grignard reagents to coumarins has been developed. The corresponding products are formed in high yields and enantioselectivities. Through a sequential protocol involving conjugate addition followed by nucleophilic ring opening of the chiral enolate, chiral esters and amides are readily accessible.     

A practical asymmetric conjugate addition to cyclic enones with chiral bifunctional Ru amido catalysts

A practical asymmetric C-C bond formation to synthetically useful β-chiral cyclic ketones (>99% ee) using bifunctional chiral amido Ru catalysts under an S/C = 1000, the highest ratio achieved so far in the literature for this class of reactions, is described. The catalytic reactivity decreases in the order of Ru(Msdpen)(hmb) > Ru(Pfbsdpen)(hmb) > Ru(Tsdpen)(hmb) > Ru(PMsdpen)(hmb), where Ru(Pfbsdpen)(hmb) is a newly developed chiral bifunctional catalyst. Complex Ru(Msdpen)(hmb) was identified as the best in terms of reactivity and enantioface selectivity, whereas Ru(PMsdpen)(hmb) gave unsatisfactory results. An importance of the NH proton in the bifunctional catalyst for determining the enantioselectivity has been experimentally demonstrated. Valuable information for the reaction mechanism was accumulated.     

Copper-catalyzed asymmetric conjugate addition of diethylzinc to substituted chalcones using a chiral phosphine ligand

A series of chiral phosphine PFAM and phosphine oxide POFAM ligands were studied for the copper-catalyzed asymmetric diethylzinc addition to enones. One of these ligands, PFAM2, was an efficient catalyst with a variety of enones to give conjugate addition products in up to 96% yield and 92% ee.     

Catalytic asymmetric conjugate addition of nitroalkanes to cycloalkenones

Nitroalkanes add to cyclic and acyclic enones in an enantioselective manner in the presence of catalytic quantities of L-proline and trans-2,5-dimethylpiperazine as excess additive.     

Copper-catalyzed asymmetric conjugate addition of trialkylaluminium reagents to trisubstituted enones: construction of chiral quaternary centers

Me3Al, Et3Al, and vinylalane species undergo enantioselective conjugate addition to a wide range of 2- or 3-substituted enones (cyclopent-2-enones, cyclohex-2-enones, 3-methyl cyclohept-2-enone) in the presence of catalytic amount of copper salt (copper thiophene carboxylate, [Cu(CH3CN)4]BF4 or [CuOTf]2C6H6) and tropos-phosphoramidite-based ligand. Thus, chiral quaternary centers can be built, with up to 98% ee after rigorous optimization of experimental conditions. It was shown that the main important parameter was the order of the introduction of the reagents. Then, the generated enantioenriched aluminium enolates and the chiral conjugate adducts were functionalized and used for subsequent reactions.     

A new class of chiral pyrrolidine-pyridine conjugate base catalysts for use in asymmetric Michael addition reactions

Direct catalytic asymmetric Michael addition reactions of ketones to nitroolefins using newly developed chiral pyrrolidine-pyridine conjugate bases as catalysts are described. The desired 1,4-adducts are obtained in excellent yields with high enantio- and diastereoselectivities.     

A chiral phosphepine–olefin rhodium complex as an efficient catalyst for the asymmetric conjugate addition

A monophosphine–olefin was synthesised from a 2,2′-bridged 1,1′-binaphthyl precursor, which served as a chiral bidentate ligand in the Rh catalysed 1,4-additions of arylboronic acids to cycloalkenones and 5,6-dihydro-2H-pyran-2-one. Fair yields (64–88%) and high asymmetric inductions (88–98% ee) have been obtained. The crystal structure of a corresponding cationic Rh(I) complex was determined.     

(S,S)-(+)-Pseudoephedrine as chiral auxiliary in asymmetric conjugate addition and tandem conjugate addition/alpha-alkylation reactions

Organolithium reagents undergo highly regio- and diastereoselective 1,4-addition to (S,S)-(+)-pseudoephedrine enamides furnishing the corresponding beta-alkyl-substituted adducts in excellent yields and diastereoselectivities. In addition, the intermediate lithium enolates generated after the conjugate addition step undergo a highly diastereoselective alkylation reaction, furnishing alpha,beta-dialkyl-substituted amides in high yields. The obtained adducts have been converted into chiral nonracemic beta-alkyl- and alpha,beta-dialkyl-substituted carboxylic acids and gamma-alkyl- and beta,gamma-dialkyl-substituted alcohols using very simple and high-yielding procedures.     

Copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted enones. Construction of all-carbon quaternary chiral centers

The copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted cyclic enones affords enantioenriched all-carbon quaternary centers with up to 96% ee. The chiral ligand is a diaminocarbene, directly generated in situ. The combination of Grignard reagent and diaminocarbene is unprecedented in conjugate addition, and the additon of the phenyl group, on such enones, cannot be done by other conjugate addition methods.     

Organocatalytic asymmetric conjugate addition to allenic esters and ketones

The first example of an organocatalytic enantioselective conjugate addition of cyclic beta-ketoesters and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding chiral beta,gamma-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The scope of the reaction for beta-ketoesters is outlined for allenes having a ketone or ester motif as electron-withdrawing group as well as different substituents in the 3-position, giving the optically active products in high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also proceeds for a number of cyclic beta-ketoesters having different ring sizes, ring systems, and substituents in high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus providing a rapid entry to optically active alpha-vinyl-substituted alpha-amino acid derivatives. It is shown that the enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination with the catalytic system used. The high synthetic value of the chiral products arising from these new catalytic processes is demonstrated by two straightforward transformations leading in one case to optically active hexahydrobenzopyranones and in the other to substituted pyroglutamates (gamma-lactames).     

Chiral ligand-controlled asymmetric conjugate amination of enoates with lithium mesitylmethyl(trimethylsilyl)amide

Lithium mesitylmethyl(trimethylsilyl)amide behaved as a nice amination agent in a chiral ligand-controlled conjugate addition reaction of tert-butyl cinnamate to give the conjugate amination product with 99% ee in 90% yield. Other acyclic and cyclic enoates were also aminated in reasonably high enantioselectivity, while the deprotonation of abstractable proton of enoates caused yield loss of the conjugate amination products, due to the bulkiness and enriched basicity of the lithium amide. Although such steric bulkiness made hard the hydrogenolytic cleavage of a mesitylmethyl-N bond of the adducts, a new protocol comprising N-chlorination-regioselective dehydrochlorination-transoximation was developed for N-dearylmethylation, giving 3-aminoalkanoates in reasonably good yields.     

Synthesis of chiral sulfinyl-substituted 1-indolyl enones and asymmetric conjugate addition by an arylcopper reagent

The asymmetric conjugate addition of arylcopper reagents to chiral 1-[2-(p-tolylsulfinyl)]indolyl and 1-[3-(p-tolylsulfinyl)]indolyl enones was examined. With the 2-sulfinyl-indolyl derivatives, the reaction of the arylcopper reagent gave high diastereoselectivities (81-88% de's) to afford the adducts in excellent yields, although the similar addition reaction of the 3-sulfinyl derivatives afforded poor diastereoselectivities.     

Novel imidazolidine-tetrazole organocatalyst for asymmetric conjugate addition of nitroalkanes

The Michael addition of nitroalkanes to alpha,beta-unsaturated enones catalyzed by a novel chiral imidazolidine-2-yltetrazole organocatalyst has been investigated. The new more soluble organocatalyst decreases reaction times and improves enantioselectivities compared to other catalysts. The Michael addition adducts were obtained with up to 92% ee. [reaction: see text]     

A versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones

5-Pyrrolidin-2-yltetrazole performs as an improved catalyst for the asymmetric addition of a range of nitroalkanes to cyclic and acyclic enones, with good to excellent enantioselectivity.     

Chiral amino alcohol-mediated asymmetric conjugate addition of arylalkynes to nitroolefins

[reaction: see text] The asymmetric reaction of nitroolefins with arylalkynes was mediated by dimethylzinc (or diethylzinc) and (1R,2R)-2-(dimethylamino)-1,2-diphenylethanol in toluene to provide the corresponding conjugate alkynylation products with high enantiomeric excess of up to 99% in good yields. The presence of 0.03 equiv of galvinoxyl improved the reaction yield.