Enantioselective Reductive Amination Research Articles

Nickel-catalyzed enantioselective reductive amination of benzylic ketones in alcohols

Nickel-catalyzed enantioselective reductive amination of benzylic ketones in alcohols

Cobalt-Catalyzed Enantioselective Reductive Amination of Ketones with Hydrazides.

An efficient cobalt-catalyzed asymmetric reductive amination of ketones with hydrazides has been realized, directly producing valuable chiral hydrazines in high yields and enantioselectivities (up to 98% enantiomeric excess).

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

AbstractChiral primary amines widely exist in drugs and are exceptionally important subunits or synthons in the syntheses of chiral secondary and tertiary amines of medicinal interest. Metal-catalyzed enantioselective reductive amination (ERA) of ketones with ammonium salts or ammonia provides a direct method for their synthesis. Although very useful, progress in this field has been very slow and important advances have only been achieved in the last few years. Several major challenges exist in this reaction, including (1) the reversible formation of unstable NH-imine intermediates; (2) the strong coordination property of N-containing reagents toward metal species; and (3) the lack of efficient catalytic systems that enable high enantiocontrol. Generally, the efficiency and enantiocontrol of this reaction is dependent on the substrate type, for instance, the use of α-keto esters/amides or aryl alkyl ketones is well established and they have even been used in the industrial production of chiral amine drugs. However, highly enantioselective control in dialkyl ketones, cyclic ketones, and α-keto acids remains unsolved. Herein, the historical development of ERA reactions with ammonium salts or ammonia gas is summarized, and novel synthetic applications toward useful synthons or drugs are presented. In addition, the factors restricting the growth of this method are also discussed.1 Introduction2 Enantioselective Reductive Amination via Hydrogenation2.1 Enantioselective Reductive Amination of β-Keto Esters/Amides2.2 Enantioselective Reductive Amination of Simple Ketones2.3 Enantioselective Reductive Amination of α-Functionalized Ketones2.4 Enantioselective Reductive Amination/Cyclization Cascade Reactions2.5 Others3 Enantioselective Reductive Amination via Transfer Hydrogenation4 Synthetic Applications5 Conclusions and Outlook

Transition-Metal-Catalyzed Asymmetric Reductive Amination and Amidation Cascade Reaction for the Synthesis of Piperazinones.

An efficient enantioselective reductive amination and amidation cascade reaction has been developed. Catalyzed by iridium or rhodium complexes and with the help of sets of additives, the coupling of simple alkyl diamines and α-ketoesters occurs smoothly to afford the chiral cyclic piperazinone products. For disubstituted and monosubstituted alkyl diamine substrates, the corresponding reactions proceed through distinctive types of intermediates and thus require different transition metals to achieve high enantioselectivity, namely, iridium for the former and rhodium for the latter. In this transformation, the applied highly modular phosphoramidite-phosphine hybrid ligands displayed preeminent versatility and tunability.

Ruthenium-Catalyzed Enantioselective Reductive Amination

Ruthenium-Catalyzed Enantioselective Reductive Amination

Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

AbstractWe report here a short enantioselective synthesis of Ozanimod, a potent modulator of the enzyme Sphingosine‐1‐phosphate receptor (S1PR), recently approved by FDA and EMA for the treatment of relapsing‐remitting multiple sclerosis. Amongst different synthetic approaches explored, we achieved the best result introducing the stereogenic centre in the last step through imine asymmetric transfer hydrogenation (ATH) using Wills’ catalysts. Besides the reduced numbers of enantiomeric purity controls required, this process culminates in an exceptionally high enantioselective reductive amination obtained with commercially available tethered Ru catalysts. Starting from commercially available 4‐cyano‐indanone, enantiomerically pure Ozanimod was obtained in 5 steps in 62 % overall yield and 99 % ee.

Reductive Amination of Biobased Levulinic Acid to Unnatural Chiral γ-Amino Acid Using an Engineered Amine Dehydrogenase

Optically pure (S)-4-aminopentanoic acid is a pivotal precursor in the synthesis of therapeutic molecules and pyrrolidinone derivatives. Enantioselective reductive amination of levulinic acid catal...

Highly Enantioselective Ruthenium-Catalyzed Cascade Double Reduction Strategy: Construction of Structurally Diverse Julolidines and Their Analogues

A direct and facile construction of optically pure julolidine derivatives through ruthenium-catalyzed enantioselective cascade hydrogenation and reductive amination of 2-(quinolin-8-yl)ethyl ketones has been developed. By means of this protocol, various chiral julolidine compounds were obtained in high isolated yields (up to 94%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 99% ee) under mild conditions. Furthermore, the synthetic practicality of this protocol was illustrated by the preparation of hexahydrojulolidines and a chiral fluorescent molecular rotor.

Structure-guided engineering ofmeso-diaminopimelate dehydrogenase for enantioselective reductive amination of sterically bulky 2-keto acids

Structure-guided reshaping the substrate-binding pocket of ameso-diaminopimelate dehydrogenase (StDAPDH) led to a mutant W121L/H227I, which catalyzed the enantioselective reductive amination of some sterically bulky 2-keto acids.

Enzyme-Catalyzed Enantioselective Reductive Amination

Enzyme-Catalyzed Enantioselective Reductive Amination

Dynamic Kinetic Resolution in Enantioselective Reductive Amination ofα-Branched Aldehydes by Lewis Base Organocatalyzed Hydrosilylation

Dynamic Kinetic Resolution in Enantioselective Reductive Amination of<i>α</i>-Branched Aldehydes by Lewis Base Organocatalyzed Hydrosilylation

Chiral Phosphoric Acid-Catalyzed Enantioselective Reductive Amination of 2-Pyridyl Ketones: Construction of Structurally Chiral Pyridine-Based Ligands.

A chiral phosphoric acid-catalyzed one-pot enantioselective reductive amination of 2-pyridyl ketones was realized to provide chiral pyridine-based ligands in excellent yields with high enantioselectivities (up to 98% yield, 94% ee). Computational studies on the key intermediate imine and transition state of the hydride transfer process revealed that the nitrogen atom of the pyridyl ring might be an important factor to significantly promote both the reaction activity and enantioselectivity.

Enantioselective synthesis of planar-chiral 1,11-dioxa[11]paracyclophane-derived phosphoramidites and their use as chiral ligands

A library of bench-stable planar-chiral 1,11-dioxa[11]paracyclophane-derived phosphoramidites was synthesized by a three step procedure: enantioselective ortho-lithiation, reductive amination and coupling with phosphorochloridites. The efficacy of these phosphoramidite as chiral ligands was tested in the Pd-catalyzed allylic alkylation of dimethyl malonate and the Cu-catalyzed ethylation of chalcone under the reported conditions, with moderate enantioselectivity being obtained.

Nickel-Catalyzed Enantioselective Reductive Amination of Ketones with Both Arylamines and Benzhydrazide.

An asymmetric reductive amination of ketones using both arylamines and benzhydrazide in the presence of nickel catalysts was developed. A one-pot synthesis of tetrahydroquinoxalines was also developed starting directly from α-ketoaldehydes and 1,2-diaminobenzene. Formic acid was used as a safe and economic surrogate for high-pressure hydrogen gas. Strongly σ-donating bis(alkylphosphine)s are crucial ancillary ligands for both stereoselective hydride insertion and decarboxylation of the formate.

Nickel‐Catalyzed Enantioselective Reductive Amination of Ketones with Both Arylamines and Benzhydrazide

AbstractAn asymmetric reductive amination of ketones using both arylamines and benzhydrazide in the presence of nickel catalysts was developed. A one‐pot synthesis of tetrahydroquinoxalines was also developed starting directly from α‐ketoaldehydes and 1,2‐diaminobenzene. Formic acid was used as a safe and economic surrogate for high‐pressure hydrogen gas. Strongly σ‐donating bis(alkylphosphine)s are crucial ancillary ligands for both stereoselective hydride insertion and decarboxylation of the formate.

ChemInform Abstract: Enantioselective Synthesis of Fused Heterocycles with Contiguous Stereogenic Centers by Chiral Phosphoric Acid Catalyzed Symmetry Breaking.

Described herein is a highly enantioselective synthesis of fused piperidine and pyrrolidine derivatives with all-carbon stereogenic centers. The enantioselective reductive amination from Cs-symmetric 1,3-dione derivatives proceeded in a highly stereoselective manner by taking advantage of the desymmetrization approach to afford fused heterocycles with contiguous stereogenic centers in good to excellent enantioselectivities (up to 98% ee).

ChemInform Abstract: Enantioselective Synthesis of β‐Arylamines via Chiral Phosphoric Acid‐Catalyzed Asymmetric Reductive Amination.

AbstractA novel method for the synthesis of chiral β‐aryl amines (III) is achieved by Hantzsch ester promoted enantioselective reductive amination of benzyl methyl ketones with anisidine in the presence of a BINOL derived phosphonic acid catalyst.

Enantioselective Synthesis of β-Arylamines via Chiral Phosphoric Acid-Catalyzed Asymmetric Reductive Amination.

A new method for the synthesis of chiral β-aryl amines via chiral phosphoric acid-catalyzed enantioselective reductive amination of benzyl methyl ketone derivatives with Hantzsch ester was developed. Various chiral β-aryl amines were obtained in high yields and with good to high enantioselectivities. This transformation is applicable to gram-scale reactions, and the catalyst loading can be reduced to 1 mol % without sacrificing any catalytic efficacy. Furthermore, the resulting β-aryl amine was successfully converted into a tetrahydroisoquinoline compound without any loss of enantioselectivity.

Engineering of Amine Dehydrogenase for Asymmetric Reductive Amination of Ketone by Evolving Rhodococcus Phenylalanine Dehydrogenase

Triple mutant K66Q/S149G/N262C (TM_pheDH) of Rhodococcus phenylalanine dehydrogenase (pheDH) was engineered by directed evolution as the first enzyme for the highly enantioselective reductive amination of phenylacetone 1 and 4-phenyl-2-butanone 3, giving (R)-amphetamine 2 and (R)-1-methyl-3-phenylpropylamine 4 in >98% ee, respectively. The new amine dehydrogenase TM_pheDH with special substrate specificity is a valuable addition to the amine dehydrogenase family with very limited number, for asymmetric reductive amination of ketone, an important reaction in sustainable pharmaceutical manufacturing. Molecular docking provided insight into the role of key mutations of pheDH, being useful for engineering new amine dehydrogenases with higher activity and unique substrate scope.

Enantioselective synthesis of fused heterocycles with contiguous stereogenic centers by chiral phosphoric acid catalyzed symmetry breaking.

Described herein is a highly enantioselective synthesis of fused piperidine and pyrrolidine derivatives with all-carbon stereogenic centers. The enantioselective reductive amination from C(s)-symmetric 1,3-dione derivatives proceeded in a highly stereoselective manner by taking advantage of the desymmetrization approach to afford fused heterocycles with contiguous stereogenic centers in good to excellent enantioselectivities (up to 98% ee).