Catalytic Enantioselective Mannich-type Reaction Research Articles

First example of an organocatalytic asymmetric Mannich reaction between aldimines of glycinates and sulphonyl imines

The catalytic enantioselective Mannich-type reaction between glycinate Schiff base and imines has been one of the most efficient routes for accessing α,β-diamino acids. However, the glycinate Schiff bases used in the references were almost ketimines. Only several examples of aldimines were used in the presence of metal catalyst. We developed the first example of an asymmetric direct Mannich reaction using aldimines of glycinates instead of ketimines of glycinates. The reaction was well catalyzed by chiral guanidine with high yield (up to 92%) and moderate stereoselectivity (up to 65%).

ChemInform Abstract: Catalytic Enantioselective Synthesis of Chiral 3‐Amino‐2‐oxindoles by a Mannich Approach.

A catalytic enantioselective Mannich-type reaction of a cyclohexanone-derived alkenyl trichloroacetate with isatin imines was achieved using an (S)-BINOL-derived chiral tin dibromide possessing a 4-tert-butylphenyl group at 3- and 3′-positions as the chiral precatalyst in the presence of sodium methoxide, sodium iodide, and methanol. Optically active 3-alkylated 3-amino-2-oxindoles having up to 90% enantiomeric excess were diastereoselectively obtained in high yields under the influence of the in situ generated chiral tin iodide methoxide.

Direct catalytic enantioselective Mannich-type reaction of dichloroacetonitrile using bis(imidazoline)-Pd catalysts.

The catalytic enantioselective Mannich-type reaction of dichloroacetonitrile with imines has been developed. Good yields and enantioselectivity were observed for the reaction with various imines using chiral bis(imidazoline) catalysts. β-Aminonitriles or β-aminoamide were obtained from products without the loss of enantiopurity.

Catalytic Enantioselective Synthesis of Chiral 3-Amino-2-oxindoles by a Mannich Approach

A catalytic enantioselective Mannich-type reaction of a cyclohexanone-derived alkenyl trichloroacetate with isatin imines was achieved using an (S)-BINOL-derived chiral tin dibromide possessing a 4-tert-butylphenyl group at 3- and 3′-positions as the chiral precatalyst in the presence of sodium methoxide, sodium iodide, and methanol. Optically active 3-alkylated 3-amino-2-oxindoles having up to 90% enantiomeric excess were diastereoselectively obtained in high yields under the influence of the in situ generated chiral tin iodide methoxide.

Catalytic Enantioselective Mannich-Type Reaction via a Chiral Silver Enolate

A catalytic asymmetric Mannich-type reaction of alkenyl trichloroacetates with aldimines was achieved using SEGPHOS·AgOTf as the chiral precatalyst and N,N-diisopropylethylamine as the base precatalyst in the presence of 2,2,2-trifluoroethanol. Optically active β-amino ketones with up to >99% ee were syn-selectively obtained in moderate to high yields via the in situ generated chiral silver enolates.

ChemInform Abstract: Asymmetric Mannich‐Type Reactions of Fluorinated Ketoesters with Binaphthyl‐Modified Thiourea Catalysts.

E-mail: dyoung@sch.ac.krReceived December 31, 2010, Accepted February 4, 2011The catalytic enantioselective Mannich-type reaction promoted by chiral binaphthyl-modified bifunctionalorganocatalysts is described. The treatment of α-fluoro-β-ketoesters with N-Boc imines under mild reactionconditions afforded the corresponding β-aminated α-fluoro-β-ketoesters with excellent enantioselectivities (upto 98% ee).Key Words : Mannich reaction, Asymmetric catalysis, Bifunctional organocatalyst, α-Fluoro-β-ketoesters, N-Boc iminesIntroductionFluorinated molecules are of high importance in medicinaland organic chemistry.

Asymmetric Mannich-type Reactions of Fluorinated Ketoesters with Binaphthyl-Modified Thiourea Catalysts

The catalytic enantioselective Mannich-type reaction promoted by chiral binaphthyl-modified bifunctional organocatalysts is described. The treatment of <TEX>${\alpha}$</TEX>-fluoro-<TEX>${\beta}$</TEX>-ketoesters with N-Boc imines under mild reaction conditions afforded the corresponding <TEX>${\beta}$</TEX>-aminated <TEX>${\alpha}$</TEX>-fluoro-<TEX>${\beta}$</TEX>-ketoesters with excellent enantioselectivities (up to 98% ee).

ChemInform Abstract: Catalytic Enantioselective Mannich‐Type Reaction with β‐Phenyl Sulfonyl Acetonitrile.

AbstractTwo convenient methods to prepare enantioenriched α‐unsubstituted β‐amino nitriles are reported.

Catalytic Enantioselective Mannich-Type Reaction with β-Phenyl Sulfonyl Acetonitrile

The organocatalytic addition of beta-phenyl sulfonyl acetonitrile 1 to either N-Boc-protected alpha-amido sulfones or imines allowed the synthesis of enantioenriched alpha-unsubstituted beta-amino nitriles through a Mannich-type reaction.

Enantioselective Mannich‐Type Reaction of Sulfonylimines Having 2‐Pyridylsulfonyl Group as a Novel Stereocontroller.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Enantioselective Mannich-type reaction of sulfonylimines having 2-pyridylsulfonyl group as a novel stereocontroller

A catalytic enantioselective Mannich-type reaction of N-(2-pyridylsulfonyl)imines in the presence of chiral bis(oxazoline)s afforded the products with high enantioselectivity. Asymmetric induction was supposed to be efficiently controlled by a new chiral center on the sulfur dynamically induced through the discriminative coordination of a chiral Lewis acid to one of the sulfonyl oxygens.

Catalytic Enantioselective Mannich‐Type Reactions of Ketoimines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Catalytic Enantioselective Mannich-type Reactions of Ketoimines

The first example of catalytic enantioselective Mannich-type reactions of simple ketoimines is described. The optimized conditions for aromatic ketoimines include the use of CuOAc−DTBM−SEGPHOS as the catalyst (10 mol %) and (EtO)2Si(OAc)2 as the trapping reagent (1 equiv) of the intermediate copper amide (generated via the addition of a copper enolate to the imine). The trapping reagent significantly facilitated the catalyst turnover. Excellent enantioselectivity was produced from a range of aromatic ketoimines, including heteroaromatic and ethyl-substituted ketoimines. The optimized conditions for aliphatic ketoimines include the use of CuOAc−4-tBu−cyclohexyl−DuPHOS as the catalyst and (EtO)3SiF as the trapping reagent. When aliphatic substrates were used, the enantioselectivity was in the 77−81% ee range. The products were converted to β,β-disubstituted amino acids, which are a very important class of chiral building blocks for natural product synthesis, pharmaceuticals, and conformationally regulated artificial proteins.

Chiral Zirconium Catalysts Using Multidentate BINOL Derivatives for Catalytic Enantioselective Mannich-Type Reactions; Ligand Optimization and Approaches to Elucidation of the Catalyst Structure

Catalytic enantioselective Mannich-type reactions of silicon enolates with aldimines were investigated using chiral zirconium catalysts prepared from Zr(O(t)Bu)(4), N-methylimidazole, and newly designed multidentate BINOL derivatives. These new multidentate BINOL ligands were designed on the basis of an assumed transition state structure of a chiral zirconium catalyst derived from two molecules of (R)-6,6'-Br(2)-BINOL. Not only tetradentate BINOL 4 but also tridentate BINOL derivatives were found to be effective, and high enantioselectivities were attained. In a structural study of the most effective zirconium complex prepared from tridentate ligand 6e, several NMR experiments and DFT calculations were carried out. Consequently, the structure of an active catalyst and plausible mechanism of asymmetric induction were elucidated.

Stereoselective synthesis and structure-activity relationship of novel ceramide trafficking inhibitors. (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide and its analogues.

New ceramide trafficking inhibitors, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12) and a series of its analogues, were synthesized in diastereomerically and enantiomerically pure forms, and the structure-activity relationship was investigated. These analogues were stereoselectively synthesized via catalytic enantioselective Mannich-type reactions using a Cu(II)-chiral diamine 4 complex. Analysis of HPA-12 analogues having various lengths of the amide side chain showed that the optimal chain length for the inhibition of sphingomyelin biosynthesis is 13 with an IC(50) of approximately 50 nM. Masking of the hydroxy group at the 2'- or 3-position of HPA-12 was carried out by methylation, and it was revealed that these hydroxy groups were essential for the activity. Installation of another hydroxy group onto HPA-12 at the same position as that in the natural ceramide was also conducted, but no enhancement of the activity was observed.

A new enantioselective Mannich-type reaction catalyzed by bis-binaphthoxy iodo samarium

A new catalytic enantioselective Mannich type reaction involving a glyoxylic imine and a ketene silyl acetal is described. A chiral samarium catalyst coordinated to a binaphthol ligand is used in the presence of aniline as an additive. Under optimized conditions, at 30°C, enantiomeric excesses up to 90% are obtained.

Enantioselective Mannich-Type Reactions Using a Novel Chiral Zirconium Catalyst for the Synthesis of Optically Active β-Amino Acid Derivatives

Catalytic enantioselective Mannich-type reactions of silyl enol ethers with aldimines have been successfully performed using a novel chiral zirconium catalyst prepared from zirconium(IV) tert-butoxide (Zr(OtBu)4), 2 equiv of (R)-6,6‘-dibromo-1,1‘-bi-2-naphthol ((R)-6,6‘-Br2BINOL), and N-methylimidazole. The use of aldimines having N-substituted hydroxyphenyl moieties is essential for obtaining high selectivities, and the N-substituted groups were converted to free amines using oxidative cleavage. Aldimines derived from aromatic aldehydes as well as heterocyclic and aliphatic aldehydes reacted with silyl enol ethers smoothly to afford the corresponding β-amino acid derivatives in high yields and high enantioselectivities. Several NMR experiments have been conducted to clarify the structure of the chiral Zr catalyst and also the catalytic cycle of this asymmetric reaction. Finally, a new BINOL derivative, (R)-6,6‘-bis(trifluoromethyl)-1,1‘-bi-2-naphthol ((R)-6,6‘-(CF3)2BINOL), has been prepared. It was shown that the turnover of the catalyst using this novel ligand was improved, and high levels of yields and selectivities were obtained in the presence of a small amount of the zirconium catalyst.

ChemInform Abstract: Catalytic Activation of Imine Derivatives Using Novel Lewis Acids

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新しいルイス酸を用いるイミン類の触媒的活性化

The Lewis acid-mediated reactions of imine are one of the most powerful methods for preparation of nitrogen-containing compounds. However, there are few examples of the reactions using catalytic amounts of Lewis acids, because the strong coordination of the products (which are mostly secondly or tertiary amines), deactivates the acids. This article introduces several types of new achiral and chiral Lewis acids which can mediated the reactions of imines catalytically. The essence of the catalytic activation of imines by Lewis acids is the equilibrium between Lewis acids and bases (imines or products), and it has been revealed that rare earth triflates (lanthanide and scandium trifluoromethanesulfonate) are excellent catalysts for this purpose. Imino-aldol reactions, aza Diels-Alder reactions, allylation reactions, cyanation reactions, and three-component reactions of aldehydes, amines, and nucleophiles were successfully carried out in the presence of catalytic amounts of rare earth triflates. Polymer-supported reagents also worked well by using the triflates as catalysts. In addition, it was shown that group IV triflates (Zr and Hf triflates) were effective for catalytic activation of imines. The first truly catalytic asymmetric reactions of imines have been achieved using new chiral Lewis acids. In the presence of a catalytic amount of a chiral rare earth catalyst, imines derived from 2-aminophenol and aldehydes reacted with cyclopentadiene or vinyl ethers to afford 8-hydroxytetrahydroquinoline derivatives in high yields with high diastereo- and enantioselectivities. Moreover, the first catalytic enantioselective Mannich-type reactions of imines with silyl enolates using a novel chiral zirconium catalyst have been developed. High levels of enantioselectivities in the synthesis of chiral β-amino ester derivatives, β-amino alcohol derivatives, and tetrahydropyridine derivatives have been achieved using these reactions.