Amination Cascade Research Articles

1,2-Diamines as the Amine Sources in Amidation and Rhodium-Catalyzed Asymmetric Reductive Amination Cascade Reactions.

The sturdy chelation of 1,2-diamines and transition-metals would retard or even interrupt the routine catalytic cycles. In the amidation and asymmetric reductive amination (ARA) cascade reactions of diamines and ketoesters, we deployed sets of additives to ensure a smooth transformation catalyzed by the complexes of rhodium and versatile and highly modular phosphoramidite-phosphine ligands. The tunability of the ligands was fully exploited to accommodate various diamines and α-ketoesters for the efficient synthesis of chiral 3,4-dihydroquinoxalinones.

Biosensor and chemo-enzymatic one-pot cascade applications to detect and transform PET-derived terephthalic acid in living cells

SummaryPlastic waste imposes a serious problem to the environment and society. Hence, strategies for a circular plastic economy are demanded. One strategy is the engineering of polyester hydrolases toward higher activity for the biotechnological recycling of polyethylene terephthalate (PET). To provide tools for the rapid characterization of PET hydrolases and the detection of degradation products like terephthalic acid (TPA), we coupled a carboxylic acid reductase (CAR) and the luciferase LuxAB. CAR converted TPA into the corresponding aldehydes in Escherichia coli, which yielded bioluminescence that not only semiquantitatively reflected amounts of TPA in hydrolysis samples but is suitable as a high-throughput screening assay to assess PET hydrolase activity. Furthermore, the CAR-catalyzed synthesis of terephthalaldehyde was combined with a reductive amination cascade in a one-pot setup yielding the corresponding diamine, suggesting a new strategy for the transformation of TPA as a product obtained from PET biodegradation.

Catalytic Hydration/Enantioselective Reductive Amination Cascade Reaction of Propargyl Ethers

Catalytic Hydration/Enantioselective Reductive Amination Cascade Reaction of Propargyl Ethers

Electrochemical enaminone C–H thiolation/C–N amination cascade for thiazole synthesis and its diastereoselective dearomatization

The electrochemical annulation of enaminones/analogous enamines and thioureas providing 2-aminothiazoles has been realized. Modulating the electrolyte enables the diastereoselective synthesis of 4,5-dialkoxyl thiazolines by dearomatization.

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades*.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof‐of‐principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed‐bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross‐reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O‐methylnorbelladine.

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross-reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine.

PQQ-dependent Dehydrogenase Enables One-pot Bi-enzymatic Enantio-convergent Biocatalytic Amination of Racemic sec-Allylic Alcohols.

The asymmetric amination of secondary racemic allylic alcohols bears several challenges like the reactivity of the bi‐functional substrate/product as well as of the α,β‐unsaturated ketone intermediate in an oxidation‐reductive amination sequence. Heading for a biocatalytic amination cascade with a minimal number of enzymes, an oxidation step was implemented relying on a single PQQ‐dependent dehydrogenase with low enantioselectivity. This enzyme allowed the oxidation of both enantiomers at the expense of iron(III) as oxidant. The stereoselective amination of the α,β‐unsaturated ketone intermediate was achieved with transaminases using 1‐phenylethylamine as formal reducing agent as well as nitrogen source. Choosing an appropriate transaminase, either the (R)‐ or (S)‐enantiomer was obtained in optically pure form (>98 % ee). The enantio‐convergent amination of the racemic allylic alcohols to one single allylic amine enantiomer was achieved in one pot in a sequential cascade.

Asymmetric Hydrogenation–Reductive Amination Cascade for the Synthesis of Julolidines

Asymmetric Hydrogenation–Reductive Amination Cascade for the Synthesis of Julolidines

Palladium/Norbornene Chemistry in the Synthesis of Polycyclic Indolines with Simple Nitrogen Sources

An efficient procedure has been developed to synthesize ­indoline derivatives through a palladium-catalyzed Heck reaction/C–H activation/dual amination cascade in one pot. This constitutes the first intermolecular catalytic approach to directly access N-alkylindolines with a broad substrate scope in the absence of any ligands. This method highlights the use of readily available amines and ureas as the required nitrogen sources in building up the indoline core.

Synthesis of 3,4-Fused Tricyclic Indoles Using 3-Alkylidene Indolines as Versatile Precursors.

In this personal account, our recent studies of novel synthetic methods of 3,4-fused tricyclic indole derivatives using 3-alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4-fused tricyclic 3-alkylidene indolines were developed based on a palladium-catalyzed intramolecular Heck insertion to an allene-allylic amination cascade and a platinum-catalyzed intramolecular Friedel-Crafts type C-H coupling-allylic amination cascade. Furthermore, three types of 3,4-fused tricyclic indoles were accessible from a single 3-alkylidene indoline precursor via acid-promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4-fused tricyclic indole skeleton, (-)-aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.

Enantioselective formal synthesis of (−)-aurantioclavine using Pd-catalyzed cascade cyclization and organocatalytic asymmetric aziridination

The enantioselective formal synthesis of (−)-aurantioclavine is described. The core tricyclic skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The stereocenter was constructed by a highly enantioselective organocatalytic asymmetric aziridination reaction.

Synthetic Study of Dragmacidin E: Construction of the Core Structure Using Pd-Catalyzed Cascade Cyclization and Rh-Catalyzed Aminoacetoxylation.

We developed a novel synthetic method of the core structure of dragmacidin E bearing a 7-membered ring-fused bis(indolyl)pyrazinone skeleton. Formation of the 7-membered ring-fused tricyclic indole skeleton was accomplished using a palladium-catalyzed Heck insertion-allylic amination cascade. Vicinal difunctionalization of the 7-membered ring was realized via a rhodium-catalyzed aminoacetoxylation.

Copper-Promoted Double Oxidative C-H Amination Cascade for the Synthesis of Imidazo[1,5-a]quinolines.

A copper-promoted cascade reaction of 2-methylazaarenes and benzylamines has been developed via sequential double oxidative C(sp(3))-H aminations. This protocol provides straightforward access to imidazo[1,5-a]quinoline derivatives without employing prefunctionalized substrates.

Highly Regio- and Enantioselective Alkoxycarbonylative Amination of Terminal Allenes Catalyzed by a Spiroketal-Based Diphosphine/Pd(II) Complex.

An enantioselective alkoxycarbonylation-amination cascade process of terminal allenes with CO, methanol, and arylamines has been developed. It proceeds under mild conditions (room temperature, ambient pressure CO) via oxidative Pd(II) catalysis using an aromatic spiroketal-based diphosphine (SKP) as a chiral ligand and a Cu(II) salt as an oxidant and affords a wide range of α-methylene-β-arylamino acid esters (36 examples) in good yields with excellent enantioselectivity (up to 96% ee) and high regioselectivity (branched/linear > 92:8). Preliminary mechanistic studies suggested that the reaction is likely to proceed through alkoxycarbonylpalladation of the allene followed by an amination process. The synthetic utility of the protocol is showcased in the asymmetric construction of a cycloheptene-fused chiral β-lactam.

Palladium/norbornene chemistry: an unexpected route to methanocarbazole derivatives via three Csp3-Csp2/Csp3-N/Csp2-N bond formations in a single synthetic sequence.

A Catellani reaction terminated by palladacycle amination leading to methanocarbazoles is reported. The outcome is the formation of three different Csp(3)-Csp(2)/Csp(3)-N/Csp(2)-N bonds through a Heck reaction/C-H activation/double amination cascade in one process.

Asymmetric synthesis of heteroaryl atropisomers via a gold-catalyzed cycloisomerization–amination cascade reaction

The chiral gold(i) complex enables enantioselective cycloisomerization-amination of 2-(alkynyl)phenyl boronic acids and diazenes in high yields. A wide scope of substrates bearing various functional groups was tolerated to generate structurally different hydrazide derivatives as a new type of atropisomer.

Bifunctional solid catalysts for chemoselective hydrogenation–cyclisation–amination cascade reactions of relevance for the synthesis of pharmaceuticals

The benzodiazepines olanzapine and clozapine are nowadays manufactured by a three-step process with a final yield below 50%. An approach to environmentally-friendly intensive processes consists in the development of multifunctional solid catalyst able to catalyze multistep reactions. Here, a bifunctional metal-acid solid catalyst has been prepared and is able to carry out hydrogenation–cyclisation–amination reactions in a cascade process. The catalytic system is illustrated for the synthesis of these important antipsychotics, being an alternative for the current industrial process that requires three steps batch reactions, using mineral acids and bases, and stoichiometric amounts of SnCl2.

Efficient Synthetic Approaches to the Common Scaffold of Indole Alkaloids

Birch reductive alkylation of 2-aminobiphenyls affords access to highly functionalized polyenes that react through a Pd(II)-catalyzed oxidative amination cascade or through a double 1,4-addition process to provide the tetracyclic skeleton of indole alkaloids with up to four stereogenic centers created in a single-pot operation.

Stereoselective synthesis of 2-dienyl-substituted piperidines using an η4-dienetricarbonyliron complex as the stereocontrolling element in a double reductive amination cascade

In the presence of NaBH(OAc)(3), a 1,5-keto-aldehyde, contained within a side-chain of an eta(4)-dienetricarbonyliron complex, undergoes a double reductive amination sequence with a series of primary amines, to provide the corresponding piperidine products in good to excellent yield. The dienetricarbonyliron complex functions as a powerful chiral auxiliary in this cascade process, exerting complete control over the stereoselectivity of the reaction, with the formation of a single diastereoisomeric product. The sense of stereoinduction has been confirmed by X-ray crystallography. Removal of the tricarbonyliron moiety can be effected with CuCl(2) to afford the corresponding 2-dienyl-substituted piperidine in excellent yield. Attempted extension of this cyclisation strategy to the corresponding azepane ring system using a 1,6-keto-aldehyde as the cyclisation precursor was unsuccessful; in this case, the reaction stopped after a single reductive amination on the aldehyde to provide an acyclic keto-amine product.

Novel Synthesis of Castanospermine and 1-Epicastanospermine

[reaction: see text] Polyhydroxylated indolizidines have potential for treatment of HIV, hepatitis C and HSV infection, multiple sclerosis, angiogenesis, cancer, and diabetes. A new synthetic approach to the title compounds from a 5-C-methoxypyranosyl azide has been developed. The route incorporates the aldol reaction and a novel catalytic reductive amination cascade to generate the indolizidine ring.