Chiral Cyclic Amines Research Articles

Dendritic Organosilica Nanoparticle‐Based Metal‐Enzyme Hybrid Catalyst for Chemoenzymatic Deracemization of Cyclic Amines

AbstractThe synthesis of enantiopure chiral cyclic amines is of critical importance but highly challenging. In this study, a metal‐enzyme hybrid catalyst was fabricated by the co‐immobilization of palladium nanoparticles and monoamine oxidases on dendritic organosilica nanoparticles (DONs) for chemoenzymatic deracemization, furnishing a panel of chiral cyclic amines in high enantioselectivities (96–98 % ee). Catalyst optimization revealed that the ultra‐high specific surface area, mesoporous channels and hydrophobic microenvironment of the DONs are responsible for the improved catalyst stability, activity and catalytic efficiency.

Improvement of (S)-selective imine reductase GF3546 for the synthesis of chiral cyclic amines.

An engineered (S)-selective imine reductase from Streptomyces sp. GF3546 (SIR46) showed twice the activity of the wild type and high thermostability at 50 °C. Using a biocatalyst based on SIR46, we investigated the activity toward high-concentration 2-methyl-1-pyrroline up to 500 mM, conversion rates of other imines, and reductive amination activity.

Iridium‐Catalyzed Enantioselective Hydrogenation of 3‐Substituted Isoquinolinium Salts

AbstractChiral tetrahydroisoquinolines (THIQ) is a highly important molecular skeleton in natural alkaloids and biologically active compounds, and its derivatives are often used as key intermediates for the synthesis of drugs. Herein, we described an efficient enantioselective hydrogenation of 3‐substituted isoquinolinium salts catalyzed by a bromine‐bridged dimeric complex [{Ir(H)[(R,S,Sax)‐Ph‐ax‐Josiphos]}2(μ‐Br)3]+Br−. This efficient enantioselective transformation could provide a series of useful chiral cyclic amines, which were of great potential value in natural product modification and drug molecular preparation in high yields and moderate to excellent enantioselectivities (68–97% ee). Additionally, turnover number experiments and a gram‐scale synthesis of chiral 3‐phenyltetrahydroisoquinoline were conducted.

Zinc‐Catalyzed Asymmetric Hydrosilylation of Cyclic Imines: Synthesis of Chiral 2‐Aryl‐Substituted Pyrrolidines as Pharmaceutical Building Blocks

AbstractThe first successful enantioselective hydrosilylation of cyclic imines promoted by a chiral zinc complex is reported. In situ generated zinc‐ProPhenol complex with silane afforded pharmaceutically relevant enantioenriched 2‐aryl‐substituted pyrrolidines in high yields and with excellent enantioselectivities (up to 99% ee). The synthetic utility of presented methodology is demonstrated in an efficient synthesis of the corresponding chiral cyclic amines, being pharmaceutical drug precursors to the Aticaprant and Larotrectinib.magnified image

Enantioselective Direct Synthesis of Free Cyclic Amines via Intramolecular Reductive Amination.

Chiral cyclic amines can be prepared via intramolecular reductive amination of N-Boc-protected amino ketones in a one-pot process. With the complex of iridium and f-spiroPhos as the catalyst, a range of N-Boc-protected amino ketones are smoothly transformed into chiral cyclic free amines in high yields and excellent enantioselectivities (up to 97% ee). Moreover, this method can also be successfully applied to the synthesis of a κ-opioid receptor selective antagonist, (S)-1.

Enzyme Cascades in Whole Cells for the Synthesis of Chiral Cyclic Amines

The increasing diversity of reactions mediated by biocatalysts has led to development of multistep in vitro enzyme cascades, taking advantage of generally compatible reaction conditions. The construction of pathways within single whole cell systems is much less explored, yet has many advantages. Herein we report the generation of a successful whole cell de novo enzyme cascade for the diastereoselective and/or enantioselective conversion of simple, linear keto acids into valuable cyclic amine products. The pathway starts with carboxylic acid reduction that triggers a transamination, imine formation, and subsequent imine reduction. Construction and optimization of the system was achieved by standard genetic manipulation and the cascade required only starting material, amine donor, and whole cell catalyst with cofactors provided internally by glucose metabolism. A panel of synthetic keto acids provided access to piperidines in high conversions (up to 93%) and enantiomeric excess (up to 93%).

Synthesis of chiral cyclic amines via Ir-catalyzed enantioselective hydrogenation of cyclic imines.

A highly enantioselective hydrogenation of cyclic imines for synthesis of chiral cyclic amines has been realized. With the complex of iridium and (R,R)-f-spiroPhos as the catalyst, a range of cyclic 2-aryl imines were smoothly hydrogenated under mild conditions without any additive to provide the corresponding chiral cyclic amines with excellent enantioselectivities of up to 98% ee. Moreover, this method could be successfully applied to the synthesis of (+)-(6S,10bR)-McN-4612-Z.

A Hydrogenation/Oxidative Fragmentation Cascade for Synthesis of Chiral 4,5-Dihydro-1H-benzo[d]azepin-1-ones.

An iridium-catalyzed asymmetric hydrogenation/oxidative fragmentation of 6-substituted 5H-benzo[d] benzofuro[3,2-b]azepines has been developed, providing an efficient access to optically active 4-substituted 4,5-dihydro-1H-benzo[d]azepin-1-ones with up to 91% ee. A possible reaction pathway includes the asymmetric hydrogenation to furnish chiral cyclic amines and oxidative fragmentation under an air atmosphere.

Synthesis of chiral iridium complexes immobilized on amphiphilic polymers and their application to asymmetric catalysis

ABSTRACTThis article details the enantioselective catalytic performance of crosslinked, polymer immobilized, Ir‐based, chiral complexes for transfer hydrogenation of cyclic imines to chiral amines. Polymerization of the achiral vinyl monomer, divinylbenzene, and a polymerizable chiral 1,2‐diamine monosulfonamide ligand followed by complexation with [IrCl2Cp*]2 affords the crosslinked polymeric chiral complex, which can be successfully applied to asymmetric transfer hydrogenation of cyclic imines. Polymeric catalysts prepared from amphiphilic achiral monomers have high catalytic activity in the reaction and can be used both in organic solvents and water to give chiral cyclic amines with a high level of enantioselectivity (up to 98% ee). The asymmetric reaction allows for reuse of the heterogeneous catalyst without any loss in activity or enantioselectivity over several runs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 3037–3044

Iridium Catalyzed Asymmetric Hydrogenation of Cyclic Imines of Benzodiazepinones and Benzodiazepines

Highly enantioselective Ir-catalyzed hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodiazepines was achieved with up to 96% ee. This method provides a direct access to synthesize a range of chiral cyclic amines existing in numerous important natural products and clinical drugs.

Nucleophilic Addition of Nitrones to Ketones: Development of a New Catalytic Asymmetric Nitrone-Aldol Reaction

A new organic reaction has been discovered in which nitrones react with carbonyl compounds in an aldoltype reaction to give functionalized beta-hydroxynitrones. The alpha-carbon atom of the nitrone undergoes a nucleophilic addition reaction to electron-deficient ketones, such as alpha-ketoesters, alpha,beta-diketones, and trifluoromethyl ketones, to afford the products in moderate to good yields. The scope and potential of the reaction have been investigated and developed. The reaction can also be catalyzed by secondary amines. The use of chiral cyclic amines, such as L-proline leads to optically active beta-hydroxynitrones in moderate yield and with moderate to high enantiomeric excess. The reaction mechanism was studied by kinetic measurements, intermediate and product analysis, and determination of the absolute configuration of the product; based on these investigations a mechanism for the new reaction is proposed.

Applications of MTPA (Mosher) Amides of Secondary Amines: Assignment of Absolute Configuration in Chiral Cyclic Amines

Mosher's MTPA (methoxy(trifluoromethyl)phenylacetyl) technology is applied to the assignment of absolute configuration of several synthetic and natural chiral amines. The substrates are cyclic, secondary amines. The resulting amides usually contain significant populations of two rotamers, readily distinguished by 1H NMR spectroscopy. Thus, two complementary sets of Δδ values are obtained from a single analysis, thereby enhancing the power of the method. A strategy for the MTPA derivatization of (the N-methyl tertiary amine in) the tropane alkaloid, cocaine, is also described. The exceptionally large Δδ values observed for these MTPA amides make this a valuable and reliable method for assignment of amine configuration (even in some cases where only one diastereomeric MTPA amide is readily available).