Secondary Amine Organocatalysts Research Articles

Nonsilyl Bicyclic Secondary Amine Catalysts for the Asymmetric Transfer Hydrogenation of α,β-Unsaturated Aldehydes.

The first chiral synthesis of nonsilyl bicyclic secondary amine organocatalysts and their application to the asymmetric transfer hydrogenation of α,β-unsaturated aldehydes are disclosed. A lower catalytic loading (5 mol %) is demonstrated for the reduction of a wide range of α,β-unsaturated aldehydes (up to 97% yield and up to 99% ee). The application of this scalable methodology is showcased for the asymmetric synthesis of bioactive molecules such as phenoxanol, citronellol, ramelteon, and terikalant.

Development of Mefloquine-Based Bifunctional Secondary Amine Organocatalysts for Enantioselective Michael and Friedel-Crafts Reactions.

The chiral framework based on 11-aminomefloquine has been utilized for the first time to construct bifunctional organocatalysts. These catalysts demonstrate high enantioselectivity in both Michael additions and Friedel-Crafts reactions across a variety of substrates, achieving up to >99% ee. The distinctive feature is the incorporation of a secondary amine group, offering unique tight hydrogen-bonding capabilities in the protonated state, as supported by DFT computation. The diversity of these organocatalysts suggests their broad applicability across multiple reaction classes.

Enantio- and Diastereoselective Michael Addition of Cyclic Ketones/Aldehydes to Nitroolefins in Water as Catalyzed by Proline-Derived Bifunctional Organocatalysts.

New l-proline-derived bifunctional secondary amine organocatalysts were synthesized for enantioselective Michael reactions in water as a solvent. Application of these catalysts in Michael additions provided high yield (up to 97%) with high stereoselectivity (dr up to 99:1 and ee up to 99%). The effect of phenyl group at (R)-C6 in the catalyst was investigated and played a key role in successful catalysis by density functional theory computational calculations. The synthetic utility of this reaction was demonstrated by the formal synthesis of Sch 50971, which is a novel histamine H3 receptor agonist.

Catalyst Control over Twofold and Higher-Order Stereogenicity by Atroposelective Arene Formation.

Contradictory to the first intuitive impression that forging putatively flat aromatic rings evades stereoisomerism, a striking variety of atropisomeric compounds are conceivable by the formation of arenes, offering captivating avenues for catalyst-controlled stereoselective strategies. Since the assembled atropisomeric products that contain one or several rotationally restricted single bonds are characterized by especially well defined molecular architectures, they are distinctly suitable for numerous pertinent applications. In view of the fascinating arene-forming aldol condensation pathways taking place in polyketide biosynthesis (cyclases/aromatases (CYC/ARO)), the versatile small-molecule-catalyzed aldol reaction appeared as an exceptionally appealing synthetic means to prepare various unexplored atropisomeric compounds in our efforts presented herein. In our initial studies, the use of secondary amine organocatalysts provided excellent selectivities in stereoselective arene-forming aldol condensations for a broad range of atropisomeric products, such as biaryls and rotationally restricted aromatic amides. In further analogy to polyketide biosynthesis, it was also conceivable that several aromatic rings are formed in catalytic cascade reactions. The use of small-molecule catalysts thereby enabled us to transfer this concept to the conversion of unnatural and noncanonical polyketide substrates, thus giving access to atropisomers with particular value for synthetic applications. The versatility of the stereoselective aldol reactions with numerous catalytic activation modes further provided a strategy to individually control several stereogenic axes, similar to the various methodologies developed for controlling stereocenter configurations. By the use of iterative building block additions combined with catalyst-controlled aldol reactions to form the aromatic rings, stereodivergent pathways for catalyst-substrate-matched and -mismatched products were obtained. Besides secondary amines, cinchona-alkaloid-based quaternary ammonium salts also proved to be highly efficient in overcoming severe substrate bias. The obtained atropisomeric multiaxis systems, with all of the biaryl bonds suitably restricted in rotation even at high temperatures, are spatially distinctly defined. The helical secondary structure is therefore excellently suited for several captivating applications.While previous catalyst-controlled stereoselective methods distinguish two stereoisomers for each stereogenic unit, catalyst control beyond the realms of this dualistic stereoisomerism remained unexplored. By the selective preparation of O̅ki atropisomers characterized by their sixfold stereogenicity in Rh-catalyzed [2 + 2 + 2] cyclotrimerizations, one out of the six possible stereoisomers resulting from the restricted rotation of a single bond was shown to be catalytically addressable. Catalyst control over higher-order stereogenicity therefore further interconnects conformational analysis and stereoselective catalysis and offers captivating avenues to explore uncharted stereochemical space for creating a broad range of unprecedented molecular motifs.

Transfer hydrogenations catalyzed by streptavidin-hosted secondary amine organocatalysts.

Here, the streptavidin–biotin technology was applied to enable organocatalytic transfer hydrogenation. By introducing a biotin-tethered pyrrolidine (1) to the tetrameric streptavidin (T-Sav), the resulting hybrid catalyst was able to mediate hydride transfer from dihydro-benzylnicotinamide (BNAH) to α,β-unsaturated aldehydes. Hydrogenation of cinnamaldehyde and some of its aryl-substituted analogues was found to be nearly quantitative. Kinetic measurements revealed that the T-Sav:1 assembly possesses enzyme-like behavior, whereas isotope effect analysis, performed by QM/MM simulations, illustrated that the step of hydride transfer is at least partially rate-limiting. These results have proven the concept that T-Sav can be used to host secondary amine-catalyzed transfer hydrogenations.

Effect of the enamine pyramidalization direction on the reactivity of secondary amine organocatalysts

Chiral secondary amines are valuable catalysts for reactions that proceed through an enamine intermediate. Here, we explored the importance of the pyramidalization direction of the enamine-N on the reactivity of chiral enamines with a combination of computational, NMR spectroscopic, and kinetic experiments. Studies with peptidic catalysts that bear cyclic amines with different ring sizes revealed that endo-pyramidalized enamines are significantly more reactive compared to exo-pyramidalized analogs. The results show that the pyramidalization direction can have a greater effect than n→π* orbital overlap on the reactivity of chiral enamines. The data enabled the development of a catalyst with higher reactivity compared to the parent catalyst.

Enantioselective Construction of Octahydroquinolines via Trienamine-Mediated Diels-Alder Reactions.

A trienamine-mediated asymmetric Diels-Alder reaction using a 5-nitro-2,3-dihydro-4-pyridone derivative as a dienophile in the presence of a secondary amine organocatalyst derived from cis-hydroxyproline was discovered. The reaction provides optically active octahydroquinolines through an endo-selective [4 + 2] cyclization pathway. The following stereoselective denitration, isomerization, and/or hydrogenation generated divergent stereoisomers of decahydroquinolines, which are useful synthons for the total synthesis of Lycopodium alkaloids.

Carbapenems as water soluble organocatalysts

Background: Identification of organocatalysts functioning in aqueous environments will provide methods for more sustainable chemical transformations and allow tandem reactions with biocatalysts, like enzymes. Here we examine three water-soluble carbapenem antibiotics (meropenem, doripenem, and ertapenem) as secondary amine organocatalysts in aqueous environments. Methods: The Michael addition of nitromethane to cinnamaldehyde was used as the model reaction. The reactions were monitored by 1H NMR, and the enantioselectivity was determined by chiral HPLC. Results: The effects of buffer components, pH, organic co-solvents and anchoring into a protein scaffold were investigated. Moderate yields of the Michael addition were obtained in buffer alone. The use of methanol as a co-solvent in a ratio of 1:1 increases the yield by 50%. Anchoring of the catalysts into a protein backbone reverses the enatioselectivity of the reaction. Conclusions: Despite only moderate yields and enantioselectivities being obtained, this study lays the foundations for future development of efficient organocatalysis in aqueous environments.

Carbapenems as water soluble organocatalysts.

Background: Identification of organocatalysts functioning in aqueous environments will provide methods for more sustainable chemical transformations and allow tandem reactions with biocatalysts, like enzymes. Here we examine three water-soluble carbapenem antibiotics (meropenem, doripenem, and ertapenem) as secondary amine organocatalysts in aqueous environments. Methods: The Michael addition of nitromethane to cinnamaldehyde was used as the model reaction. The reactions were monitored by 1H NMR, and the enantioselectivity was determined by chiral HPLC. Results: The effects of buffer components, pH, organic co-solvents and anchoring into a protein scaffold were investigated. Moderate yields of the Michael addition were obtained in buffer alone. The use of methanol as a co-solvent in a ratio of 1:1 increases the yield by 50%. Anchoring of the catalysts into a protein backbone reverses the enatioselectivity of the reaction. Conclusions: Despite only moderate yields and enantioselectivities being obtained, this study lays the foundations for future development of efficient organocatalysis in aqueous environments.

Organocatalytic Asymmetric Synthesis of Trifluoromethylated Tetrahydrocarbazoles by a Vinylogous Michael/Aldol Formal [4+2] Annulation

A new protocol for the organocatalytic asymmetric synthesis of highly functionalized tetrahydrocarbazoles has been developed based on a vinylogous Michael/aldol reaction sequence between 3‐(trifluoroacetyl)‐2‐methyl‐indoles and enals. This formal [4+2] annulation occurs by cooperative catalysis between an achiral Brønsted base and a chiral secondary amine organocatalyst to afford tetrahydrocarbazole products bearing three vicinal stereocenters, including a trifluoromethylated tetrasubstituted stereocenter, in excellent yields, diastereo‐ and enantioselectivities.

Achieving Molecular Complexity via Stereoselective Multiple Domino Reactions Promoted by a Secondary Amine Organocatalyst.

In the last two decades, organocatalysis has emerged as an intensively investigated and rapidly growing area of research facilitating many known and many new transformations to provide efficient novel entries to complex molecules of high stereochemical purity. The organocatalysts have not only shown their efficiency for catalyzing the reactions in which one bond is formed, but they have also been effectively exploited in various versions of one-pot reactions. Domino reactions are one of the most important classes of one-pot reactions, where the target structure can be obtained in one pot without changing any reaction conditions while each reaction occurs as a consequence of the intermediates generated in previous steps. Owing to the synthetic importance and operational advantages associated with the use of organocatalysts and the development of domino reactions, various asymmetric transformations leading to a complex structure of choice have been explored. The early era of organocatalysis exhibits a limited growth in the development of asymmetric domino reactions with special emphasis on two reactions occurring one after the other. In 2006, our group made a step forward to develop more complex domino reactions catalyzed by a secondary amine organocatalyst, wherein three reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. This triggered our interest to develop new organocatalytic domino sequences, especially for multiple domino reactions. After our seminal contribution, domino reactions catalyzed by secondary amine organocatalysts not only became more popular, but they also could be catalyzed by other classes of organocatalysts, such as bifunctional hydrogen bonding catalysts, chiral Brønsted acids, and N-heterocyclic carbenes. The mode of activation in this triple domino reaction relied on the sequential generation of enamine and iminium intermediates using a proline-based chiral secondary amine organocatalyst. By employing this strategy, we have developed several triple domino reactions leading to the formation of carbo- and heterocyclic structures bearing multiple stereogenic centers with excellent levels of stereoselectivities. The applications of the secondary amine organocatalysts have been further extended to more complex quadruple domino sequences. Moreover, these multiple domino sequences have been combined successfully with other transformations in one pot to create densely functionalized polycyclic compounds. This Account gives an overview of our research in the area of organocatalytic asymmetric multiple domino reactions with special emphasis on the secondary amine catalyzed triple and quadruple domino reactions via a sequential generation of enamine and iminium intermediates. The multiple cascade reactions assisted by di- and tri-iminium and -enamine species as well as other types of organocatalysts have been excluded from the scope of this Account.

Asymmetric Visible-Light Photoredox Cross-Dehydrogenative Coupling of Aldehydes with Xanthenes

We report a methodology for the catalytic asymmetric cross-coupling of two C(sp3)–H bonds employing visible light as an economical and environmentally benign source of energy. Photoredox catalysis is used for the oxidation of a diarylmethane to the corresponding cation, which is then trapped by an enamine intermediate generated in situ from an aldehyde reactant and a secondary amine organocatalyst. Notably, this mild method is an ideal synthetic approach from the green chemistry point of view. It does not require preinstallation of functional groups, thereby constituting an atom economical, efficient transformation, and it allows the formation of a C–C bond with simultaneous installation of one or two new stereocenters in a highly enantio- and diastereoselective manner. Mechanistic studies by experimental and computational methods aid to clarify the origin of the observed enantioselectivity.

ChemInform Abstract: Alkaloid Synthesis Using Chiral Secondary Amine Organocatalysts

AbstractReview: [36 refs.

Alkaloid synthesis using chiral secondary amine organocatalysts

Over the last decade, several excellent enantioselective total syntheses of important alkaloids using asymmetric reactions mediated by chiral secondary amine organocatalysts as a key step have been accomplished. This perspective article examines the full strategies of these alkaloid syntheses, especially the application of the organocatalytic reaction to construct the alkaloid scaffolds.

Organocatalytic Diastereoselective Multicomponent Domino Knoevenagel/Diels-Alder Reaction: Synthesis of Densely Functionalized Spiro[5.5]undecane

The domino Knoevenagel/Diels-Alder condensation is a highly efficient strategy for the preparation of heterocyclic compounds. In order to study this reaction with an imine catalyst, a three-component reaction involving aromatic aldehydes, benzylideneacetone and meldrum acid catalyzed by a series of new organocyclic amino acid catalysts was developed. This simple experiment and environmentally friendly method is beneficial for us to get numerous pharmacological multi substituted spiro[5,5]undecane-1,5,9-triones in moderate to good yields (up to 81%) with excellent diastereolectivities (>99:1 dr). Moreover, we expanded the reaction substrates, such as barbituric acid, and the catalytic activity was compared with L-proline that is one of the most commonly secondary amine organocatalysts.

A highly enantioselective Mannich reaction of aldehydes with cyclic N-acyliminium ions by synergistic catalysis.

Matched combinations of Brønsted or Lewis acids with suitable pro-electrophiles and secondary amine organocatalysts enable the novel enantioselective syntheses of carbamoyl dihydroquinoline and tetrahydropyridine derivatives with concomitant formation of two stereocenters. A short formal asymmetric synthesis of (2R,2'R)-threo-methylphenidate (Ritalin) is also described.

Control of Regio‐ and Enantioselectivity in the Asymmetric Organocatalytic Addition of Acetone to 4‐(Trifluoromethyl)pyrimidin‐2(1H)‐ones

AbstractThe reactions of variously substituted 4‐(trifluoromethyl)pyrimidin‐2(1H)‐ones with acetone in the presence of L‐proline or chiral secondary amine organocatalysts were studied. As demonstrated, 4‐(trifluoromethyl)pyrimidin‐2(1H)‐ones unsubstituted at the 6‐position of the heterocyclic ring react with acetone at the endocyclic C=N or C=C bond depending on whether thermodynamic or kinetic control is operative in the addition reaction and also depending on the catalyst used. Racemic kinetically preferred regioisomers, 6‐(2‐oxopropyl)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐2(1H)‐ones, were found to undergo intermolecular organocatalytic rearrangement into enantioenriched thermodynamically stable products, 4‐(2‐oxopropyl)‐4‐(trifluoromethyl)‐3,4‐dihydropyrimidin‐2(1H)‐ones, with enantiomeric ratios up to 83:17.

ChemInform Abstract: Asymmetric Synthesis of Highly Functionalized γ‐Lactams Through an Organocatalytic aza‐Michael—Michael Reaction Cascade Using Fumaric Acid Amide Esters as Multi‐Reactive Substrates.

AbstractThe process employs primary and secondary amine organocatalysts allowing the synthesis of mono and bicyclic lactam frameworks.

Asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates

We developed a novel method for the asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of γ-lactams with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and diastereoselectivity.

Molecular recognition of ketomalonates by asymmetric aldol reaction of aldehydes with secondary-amine organocatalysts

A diastereo- and enantioselective aldol reaction between aldehydes and a synthetically useful ketomalonate 1c as a hydrated form was developed, and either anti- or syn-aldol adducts having a chiral tetrasubstituted carbon center were obtained in high enantioselectivities by use of a tetrazole analogue of L-proline (S)-2 or an axially chiral amino sulfonamide (S)-3 as catalyst.