Enantioselective Amination Research Articles

ChemInform Abstract: Construction of the N1—C3 Linkage Stereogenic Centers by Catalytic Asymmetric Amination Reaction of 3‐Bromooxindoles with Indolines.

AbstractThe enantioselective amination of 3‐bromooxindoles with indolines under mild conditions is presented.

Cooperative Catalysis by Palladium and a Chiral Phosphoric Acid: Enantioselective Amination of Racemic Allylic Alcohols

AbstractCooperative catalysis by [Pd(dba)2] and the chiral phosphoric acid BA1 in combination with the phosphoramidite ligand L8 enabled the efficient enantioselective amination of racemic allylic alcohols with a variety of functionalized amines. This catalytic protocol is highly regio‐ and stereoselective (up to e.r. 96:4) and furnishes valuable chiral amines in almost quantitative yield.

Cooperative catalysis by palladium and a chiral phosphoric acid: enantioselective amination of racemic allylic alcohols.

Cooperative catalysis by [Pd(dba)2] and the chiral phosphoric acid BA1 in combination with the phosphoramidite ligand L8 enabled the efficient enantioselective amination of racemic allylic alcohols with a variety of functionalized amines. This catalytic protocol is highly regio- and stereoselective (up to e.r. 96:4) and furnishes valuable chiral amines in almost quantitative yield.

Cooperative Catalysis with Iron and a Chiral Brønsted Acid for Asymmetric Reductive Amination of Ketones

AbstractThe direct asymmetric reductive amination (DARA) of ketones with anilines is described by combining a chiral Brønsted acid (TRIP) and the non‐chiral Knölker iron complex as the catalyst system. In situ‐formed imines are reduced with molecular hydrogen to give chiral amines in high yields (90%) and enantioselectivities of up to 99% ee.magnified image

ChemInform Abstract: Catalytic Enantioselective Amination of Alcohols by the Use of Borrowing Hydrogen Methodology: Cooperative Catalysis by Iridium and a Chiral Phosphoric Acid.

AbstractThe first enantioselective amination of secondary alcohols with aromatic amines using a binary catalyst comprising a chiral Ir complex and a BINOL‐derived phosphoric acid is presented.

Highly enantioselective synthesis of chiral cyclic allylic amines via Rh-catalyzed asymmetric hydrogenation.

Highly regioselective and enantioselective asymmetric hydrogenation of cyclic dienamides catalyzed by an Rh-DuanPhos complex has been developed, which provides a readily accessible method for the synthesis of chiral cyclic allylic amines in excellent enantioselectivities (up to 99% ee). The products are valuable chiral building blocks and could be easily transformed to multisubstituted cyclohexane derivatives.

Catalytic Enantioselective Amination of Alcohols

Key words alcohols - amination - hydrogenation - chiral phosphoric acids - iridium

ChemInform Abstract: Development of a Chiral Bis(guanidino)iminophosphorane as an Uncharged Organosuperbase for the Enantioselective Amination of Ketones.

AbstractNewly developed bis(guanidino)iminophosphoranes possess the highest basicity among chiral organocatalysts reported to date.

Synthesis of Bulky Aryl Group-substituted Chiral Bis(guanidino)iminophosphoranes as Uncharged Chiral Organosuperbase Catalysts

Uncharged chiral bis(guanidino)iminophosphorane organosuperbase catalysts substituted by bulky aryl groups were synthesized. The synthetic procedure for the 7,7-membered spiro-cyclization step was modified to enhance the chemical yield of bis(guanidino)iminophosphorane derived from (1S,2S)-1,2-diphenyl-1,2-ethanediamine. In accordance with the amended procedure, bis(guanidino)iminophosphoranes with bulky aryl substituents were newly synthesized and evaluated as chiral organosuperbase catalysts in the enantioselective amination of 2-methyltetralone.

Catalytic Enantioselective Amination of Alcohols by the Use of Borrowing Hydrogen Methodology: Cooperative Catalysis by Iridium and a Chiral Phosphoric Acid

AbstractThe catalytic asymmetric reduction of ketimines has been explored extensively for the synthesis of chiral amines, with reductants ranging from Hantzsch esters, silanes, and formic acid to H2 gas. Alternatively, the amination of alcohols by the use of borrowing hydrogen methodology has proven a highly atom economical and green method for the production of amines without an external reductant, as the alcohol substrate serves as the H2 donor. A catalytic enantioselective variant of this process for the synthesis of chiral amines, however, was not known. We have examined various transition‐metal complexes supported by chiral ligands known for asymmetric hydrogenation reactions, in combination with chiral Brønsted acids, which proved essential for the formation of the imine intermediate and the transfer‐hydrogenation step. Our studies led to an asymmetric amination of alcohols to provide access to a wide range of chiral amines with good to excellent enantioselectivity.

Catalytic Enantioselective Amination of Alcohols by the Use of Borrowing Hydrogen Methodology: Cooperative Catalysis by Iridium and a Chiral Phosphoric Acid

The catalytic asymmetric reduction of ketimines has been explored extensively for the synthesis of chiral amines, with reductants ranging from Hantzsch esters, silanes, and formic acid to H2 gas. Alternatively, the amination of alcohols by the use of borrowing hydrogen methodology has proven a highly atom economical and green method for the production of amines without an external reductant, as the alcohol substrate serves as the H2 donor. A catalytic enantioselective variant of this process for the synthesis of chiral amines, however, was not known. We have examined various transition-metal complexes supported by chiral ligands known for asymmetric hydrogenation reactions, in combination with chiral Brønsted acids, which proved essential for the formation of the imine intermediate and the transfer-hydrogenation step. Our studies led to an asymmetric amination of alcohols to provide access to a wide range of chiral amines with good to excellent enantioselectivity.

Development of a Chiral Bis(guanidino)iminophosphorane as an Uncharged Organosuperbase for the Enantioselective Amination of Ketones

Chiral bis(guanidino)iminophosphoranes were designed and synthesized as chiral uncharged organosuperbase catalysts that facilitate activation of less-acidic pro-nucleophiles. The newly developed bis(guanidino)iminophosphoranes, which possess the highest basicity among chiral organocatalysts reported to date, were proven to be a superb class of chiral organosuperbases by reaction of azodicarboxylates with 2-alkyltetralones and their analogues as the less acidic pro-nucleophiles.

Engineering an Enantioselective Amine Oxidase for the Synthesis of Pharmaceutical Building Blocks and Alkaloid Natural Products

The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.

Efficient synthesis of d-branched-chain amino acids and their labeled compounds with stable isotopes using d-amino acid dehydrogenase

D-Branched-chain amino acids (D-BCAAs) such as D-leucine, D-isoleucine, and D-valine are known to be peptide antibiotic intermediates and to exhibit a variety of bioactivities. Consequently, much effort is going into achieving simple stereospecific synthesis of D-BCAAs, especially analogs labeled with stable isotopes. Up to now, however, no effective method has been reported. Here, we report the establishment of an efficient system for enantioselective synthesis of D-BCAAs and production of D-BCAAs labeled with stable isotopes. This system is based on two thermostable enzymes: D-amino acid dehydrogenase, catalyzing NADPH-dependent enantioselective amination of 2-oxo acids to produce the corresponding D-amino acids, and glucose dehydrogenase, catalyzing NADPH regeneration from NADP(+) and D-glucose. After incubation with the enzymes for 2h at 65°C and pH10.5, 2-oxo-4-methylvaleric acid was converted to D-leucine with an excellent yield (>99%) and optical purity (>99%). Using this system, we produced five different D-BCAAs labeled with stable isotopes: D-[1-(13)C,(15)N]leucine, D-[1-(13)C]leucine, D-[(15)N]leucine, D-[(15)N]isoleucine, and D-[(15)N]valine. The structure of each labeled D-amino acid was confirmed using time-of-flight mass spectrometry and nuclear magnetic resonance analysis. These analyses confirmed that the developed system was highly useful for production of D-BCAAs labeled with stable isotopes, making this the first reported enzymatic production of D-BCAAs labeled with stable isotopes. Our findings facilitate tracer studies investigating D-BCAAs and their derivatives.

ChemInform Abstract: Rhodium‐Catalyzed Regio‐ and Enantioselective Amination of Racemic Secondary Allylic Trichloroacetimidates with N‐Methyl Anilines

Abstractleading to allylic N‐methyl arylamines (III) as major products

Enantioselective Organocatalytic Amination of Pyrazolones

Easy as py: The organocatalytic enantioselective amination of pyrazolones is reported. The reaction between pyrazolones and diazodicarboxylates is simple and is catalyzed by quinine to afford the final aminopyarazolone derivatives in excellent yields and good enantioselectivity.

Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Tertiary Allylic Trichloroacetimidates with Anilines

The rhodium-catalyzed regio- and enantioselective amination of racemic tertiary allylic trichloroacetimidates with a variety of aniline nucleophiles is a direct and efficient route to chiral α,α-disubstituted allylic N-arylamines. We describe the first dynamic kinetic asymmetric transformations of racemic tertiary allylic electrophiles with anilines utilizing a chiral diene-ligated rhodium catalyst. The method allows for the formation of α,α-disubstituted allylic N-arylamines in moderate to good yields with good to excellent levels of regio- and enantioselectivity.

ChemInform Abstract: Organocatalytic Enantioselective Amination of Morita—Baylis—Hillman Carbonates with Masked Ammonia: A Facile Method for the Synthesis of Unprotected α‐Methylene‐β‐amino Esters.

ChemInform Abstract: Organocatalytic Enantioselective Amination of Morita—Baylis—Hillman Carbonates with Masked Ammonia: A Facile Method for the Synthesis of Unprotected α‐Methylene‐β‐amino Esters.

Development of an Amine Dehydrogenase for Synthesis of Chiral Amines

A leucine dehydrogenase has been successfully altered through several rounds of protein engineering to an enantioselective amine dehydrogenase. Instead of the wild-type α-keto acid, the new amine dehydrogenase now accepts the analogous ketone, methyl isobutyl ketone (MIBK), which corresponds to exchange of the carboxy group by a methyl group to produce chiral (R)-1,3-dimethylbutylamine.

Rhodium-catalyzed regio- and enantioselective amination of racemic secondary allylic trichloroacetimidates with N-methyl anilines

We report the chiral diene ligated rhodium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic secondary allylic trichloroacetimidates with a variety of N-methyl anilines, providing allylic N-methyl arylamines in high yields, regioselectivity, and enantiomeric excess. The rhodium-catalyzed DYKAT method addresses limitations previously associated with this particular class of aromatic nitrogen nucleophiles.