Asymmetric Michael reaction involving chiral imines/secondary enamines: stereocontrolled synthesis of 2,2-disubstituted tetrahydrothiophen-3-ones

[reaction: see text] The asymmetric Michael reaction involving a chiral imine derived from 2-methyltetrahydrothiophenone-3-one and enantiopure (R)-1-phenylethylamine with a variety of electrophilic alkenes furnished 2,2-disubstituted tetrahydrothiophenone-3-ones with good yields and excellent stereoselectivity.     

Palladium-catalyzed, asymmetric Mizoroki-Heck reaction of benzylic electrophiles using phosphoramidites as chiral ligands

We report herein the first examples of asymmetric Mizoroki-Heck reactions using benzyl electrophiles. A new phosphoramidite was identified to be an effective chiral ligand in the palladium-catalyzed reaction. The reaction is compatible with polar functional groups and can be readily scaled up. Several cyclic olefins worked well as olefin components. Thirty-one examples are included.     

Michael reactions of unsubstituted aromatic chiral imines with substituted unsaturated acid esters

The Michael reaction of chiral imines 1–3, derived from aromatic ketones’ with substituted electrophilic olefins generated asymmetric tertiary carbon centers. Nevertheless, asymmetric inductions were weaker than those usually observed with cycloalkanone imines.     

The origin of the stereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions: a computational investigation

The diastereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions has been investigated with the help of AM1 calculations. The energetic differences between the two competing transition states involving enamino ketones 7d, 7g and methyl acrylate are in good agreement with the stereoselectivities observed with the corresponding chiral imines, derived from 1-phenylethylamine (de 95%) and from 1-cyclohexylethylamine (de 45%). The calculated transition structures indicate that steric factors govern the π-facial discrimination.     

The asymmetric Michael reaction using chiral imines under neutral conditions: Stereochemical evidences in support of a cyclic transition state

Stereochemical outcome observed in addition [6 + 7], [ent-6 + 15] and [18 + methyl acrylate] have been rationalized by evoking the participation of the corresponding compact approaches 14, 21 and 22.     

Catalytic asymmetric Michael reaction of beta-keto esters: effects of the linker heteroatom in linked-BINOL

We describe the development of a general catalytic asymmetric Michael reaction of acyclic beta-keto esters to cyclic enones, in which asymmetric induction occurs at the beta-position of the acceptors. Among the various asymmetric catalyst systems examined, the newly developed La-NR-linked-BINOL complexes (R = H or Me) afforded the best results in terms of reactivity and selectivity. In general, the NMe ligand 2 was suitable for the combination of small enones and small beta-keto esters, and the NH ligand 1 was suitable for bulkier substrates (steric tuning of the catalyst). Using the La-NMe-linked-BINOL complex, the Michael reaction of methyl acetoacetate (8a) to 2-cyclohexen-1-one (7b) gave the corresponding Michael adduct 9ba in 82% yield and 92% ee. The linker heteroatom in linked-BINOL is crucial for achieving high reactivity and selectivity in the Michael reaction of beta-keto esters. The amine moiety in the NR-linked-BINOL can also tune the Lewis acidity of the central metal (electronic tuning of the catalyst), which was supported by density functional studies and experimental results. Another advantage of the NR-linked-BINOL ligand as compared with O-linked-BINOL is the ease of modifying a substituent on the amine moiety, making it possible to synthesize a variety of NR-linked-BINOL ligands for further improvement or development of new asymmetric catalyses by introducing additional functionality on the linker with the amine moiety. The efficiency of the present asymmetric catalysis was demonstrated by the synthesis of the key intermediate of (-)-tubifolidine and (-)-19,20-dihydroakuammicine in only five steps compared to the nine steps required by the original process from the Michael product of malonate. This strategy is much more atom economical. On the basis of the results of mechanistic studies, we propose that a beta-keto ester serves as a ligand as well as a substrate and at least one beta-keto ester should be included in the active catalyst complex. Further improvement of the reaction by maintaining an appropriate ratio of the La-NMe-linked-BINOL complex and beta-keto esters is also described.     

Catalytic asymmetric carbalkoxyallylation of imines with the chiral bis-pi-allylpalladium complex

Carbethoxyallylstannane was employed along with the bis-pi-allylpalladium complex to achieve a useful conversion of prochiral imines to chiral 2-(2-aryl-2-aminoethyl)acrylates which are important building blocks for further asymmetric synthesis of a wide range of compounds.     

Enantioselective synthesis of (+)-α-vetivone through the Michael reaction of chiral imines

(+)-α-Vetivone has been synthesised in nine steps. The absolute stereochemistry of the two stereogenic centres is controlled in the same key step involving the stereoselective Michael addition of a chiral imine of 4-isopropylidene-2-methylcyclohexanone to phenyl crotonate.     

The first example of asymmetric Michael reaction catalyzed by chiral alkali metal alkoxides

Some chiral sodium alkoxides can be used as catalysts in the asymmetric Michael reaction as exemplified by the 1,4-addition of an achiral Ni^II complex of the Schiff base derived from glycine andN-(2-pyridylcarbonyl)-o-aminobenzophenone (1) to methyl methacrylate (2) or methyl acrylate (14). The products of the reaction of1 with2,viz., the corresponding diastereomeric complexes of 4-methylglutamic acid, are formed in dissimilar amounts (de 26–85%); theee value for the major diastereomer (2S,4R)-3a is 28%. After recrystallization, the enantiomeric purity of complex3a increases toee>85%. Acidcatalyzed hydrolysis of the enantiomerically enriched complex3a affords (2S,4R)-4-methylglutamic acid (ee>85%). The complex of glutamic acid15 resulting from the reaction of1 with14 is formed with anee of 45%. After recrystallization, the enantiomeric purities of complex15 and glutamic acid increase toee>90%.     

Catalytic, asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with activated olefins by quinidine-derived chiral amines

The chiral nitrogen Lewis base, tricyclic cinchona alkaloid derivative TQO, is an effective promoter in the catalytic, asymmetric aza‐Baylis–Hillman reaction of N‐sulfonated imines Ar? CH?NR′ 1 (R′ = Ts, Ms, Ns, SES) with various activated olefins such as methyl vinyl ketone (MVK), ethyl vinyl ketone (EVK), acrolein, methyl acrylate, phenyl acrylate, or α‐naphthyl acrylate to give the corresponding adducts in moderate to good yields with good to high ee (up to 99 %) at ?30 °C or 45 °C in various solvents, including DMF/MeCN (1:1, v/v). The first such reaction of 1 with the simplest Michael acceptor MVK and methyl acrylate has been achieved with excellent enantioselectivity. The adducts derived from MVK and EVK had the opposite absolute configuration to those from acrolein, methyl acrylate, phenyl acrylate, and α‐naphthyl acrylate. A plausible mechanism has been proposed on the basis of previous reports and the authors’ investigations. An effective bifunctional chiral nitrogen Lewis base–Brønsted acid system has been revealed in this type of aza‐Baylis–Hillman reaction.     

Catalytic asymmetric diethylzinc addition to diphenylphosphionyl imines using chiral tert-butanesulfinylphosphine ligands

A class of novel chiral tert-butanesulfinylphosphine ligands were designed and synthesized by a concise two-step route with high yields. High activities and enantioselectivities (up to 94% ee) were achieved when using them in catalytic asymmetric diethylzinc addition to diphenylphosphionyl imines.     

Highly convergent synthesis of chiral bicyclophosphinates by domino hydrophosphinylation/Michael/Michael reaction

Diastereoselective domino reactions of iminoalcohols and allenyl H-phosphinates produce chiral phosphorus bicycles in a regio- and stereoselective fashion. A predictive model for diastereoselection is used for these new chiral phosphinic esters.     

Axially chiral dicarboxylic acid-catalyzed asymmetric imino aza-enamine reaction/oxidation as a Strecker reaction surrogate

Axially chiral dicarboxylic acid-catalyzed highly enantioselective imino aza-enamine reaction was elaborated into a surrogate of the asymmetric Strecker reaction building on the fact that the N,N-dialkylhydrazone moiety can be easily converted to the cyanide moiety by treatment with peracid.     

Practical asymmetric synthesis of beta-trichloromethyl-beta-hydroxy ketones by the reaction of chloral or chloral hydrate with chiral imines

[reaction: see text] Chloral or its hydrate undergoes the carbon-carbon bond-formation reaction with various optically active imines in the absence of any additive, followed by hydrolysis, to produce the corresponding beta-trichloromethyl-beta-hydroxy ketones in good yields with high enantioselectivities. In addition, the products with higher ee values were obtained by a simple recrystallization process.     

Cyclic amino acid salts as catalysts for the asymmetric Michael reaction

Different chiral cyclic amino acid alkali metal and ammonium salts were used as catalysts for the asymmetric Michael addition of aldehydes to nitrostyrene. The reaction yield and stereoselectivity depend slightly on the salt cation. The highest yield of the reaction (up to 100%) was obtained with (S)-morpholine-3-carboxylic acid salts, which gave moderate to good enantioselectivities (up to 72% ee) and diastereoselectivities (dr up to 89:11) whereas the highest selectivity was obtained with proline sodium salt (ee 88%).     

Chlorotrimethylsilane promoted asymmetric Michael reaction of chiral enamines of α-alkyl β-keto esters

By the promotion of chlorotrimethylsilane, asymmetric Michael reaction of the chiral enamines (2) of α-alkyl β-keto esters (1) with methyl vinyl ketone and ethyl acrylate proceeded to afford, after hydrolysis, either enantiomer of the corresponding adducts (4) in a good enantioselectivity.     

Diastereoselective Baylis-Hillman reaction: first use of chiral 2,3-epoxy aldehydes as novel electrophiles

Chiral 2,3-epoxy aldehydes have been effectively utilized for the first time as novel electrophiles in Baylis-Hillman reactions with activated alkenes to result in densely functionalized adducts in good yields (61-80%) and in moderate to good diastereoselectivities (40-72% de).     

An asymmetric Ugi three-component reaction induced by chiral cyclic imines: synthesis of morpholin- or piperazine-keto-carboxamide derivatives

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.