Catalytic Enantioselective Desymmetrization Research Articles

Catalytic Enantioselective Synthesis of Axially Chiral Imidazoles by Cation-Directed Desymmetrization.

Axially chiral five-membered heterobiaryls synthesized by enantioselective catalysis typically feature large ortho-substituents or a heteroatom in the chiral axis to maintain a stable configuration. Herein we report a cation-directed catalytic enantioselective desymmetrization method that enables rapid access to axially chiral imidazoles with the basic nitrogen at the ortho position and efficiently integrates π-stacking moieties to ensure a stable axial configuration for further applications. The process is operationally simple, is highly enantioselective, and can be performed on the gram scale. The majority of the products are obtained in >90% ee, but interestingly even those with only moderate ee can readily be enriched to near optical purity by selective racemate crystallization. Together with a mild phosphine oxide reduction method, axially chiral imidazoles such as StackPhos and its derivatives are readily prepared in high yield and excellent enantioselectivity on the gram scale. The method also enables the preparation of new chiral non-phosphine-bearing imidazoles.

Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters

Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles.

Catalytic Enantioselective Desymmetrization of meso-Cyclopropane-Fused Cyclohexene-1,4-diones by a Formal C(sp2)–H Alkylation

AbstractA bicyclo[4.1.0]heptane framework consisting of cis-fused cyclopropane and cyclohexane rings is found in several bioactive compounds. Given the symmetry of this core, catalytic desymmetrization can be considered as the most straightforward strategy for its enantioselective synthesis. Known desymmetrization reactions of meso-bicyclo[4.1.0]heptane derivatives proceed with opening of the cyclopropane ring. We now report the first ring-retentive desymmetrization of bicyclo[4.1.0]heptane derivatives, namely meso-cyclopropane-fused cyclohexene-1,4-diones, through a formal C(sp2)-H alkylation using a nitroalkane as the alkylating agent. This reaction is catalyzed by a dihydroquinine-derived bifunctional tertiary aminosquaramide and generates the products with up to 97:3 er. An application of this reaction is demonstrated by the first catalytic enantioselective synthesis of the natural product (–)-car-3-ene-2,5-dione.

Chiral Crown Ethers Accessed from Catalytic Enantioselective Desymmetrization Reactions.

A diversity of unprecedented chiral aza-crown ethers were synthesized straightforwardly from readily available and inexpensive aza-crown ethers. Catalyzed by a chiral phosphoric acid, desymmetrization of an array of symmetric N-arylated aza-crown ethers through tert-amino reaction proceeded efficiently under mild conditions to produce novel tetrahydroquinoline-fused aza-crown ethers in good to excellent yields with up to 96% ee. Our strategy opens a new route to functionalized chiral crown ethers.

Catalytic Enantioselective Desymmetrization of Prochiral Triacylamines via Pseudopeptidic Guanidine-Guanidinium Catalysis.

Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Catalytic Enantioselective Desymmetrization of Cyclobutane-1,3-diones by Carbonyl-Amine Condensation.

A chiral phosphoric acid-catalyzed enantioselective condensation of 2,2-disubstituted cyclobutane-1,3-diones with a primary amine is described. This reaction offered a mild and efficient protocol for constructing quaternary carbon-containing cyclobutanes in good to high yields and enantioselectivities. This reaction is the first catalytic desymmetrizing carbonyl-amine condensation reaction and also represents the first catalytic desymmetrizing reaction of prochiral cyclobutane-1,3-dione.

Recent Progress in Catalytic Enantioselective Desymmetrization of Prochiral Organosilanes for the Synthesis of Silicon-Stereogenic Compounds

It is highly important to develop efficient synthetic methods for various enantioenriched chiral compounds due to their high significance in our life. In this regard, asymmetric catalysis is one of the most attractive ways of synthesizing such compounds from achiral precursors. Although various methods have been developed for the enantio­selective preparation of carbon-stereogenic compounds, the corresponding methods for silicon-stereogenic compounds are much less established. In particular, little progress has been made on catalytic enantioselective synthesis using prochiral organosilanes until recently. This account focuses on the recent progress in the catalytic enantio­selective preparation of silicon-stereogenic organosilanes through ­desymmetrization of prochiral organosilanes.1 Introduction2 Desymmetrization of Diorganodihydrosilanes3 Desymmetrization of Tetraorganosilanes3.1 Desymmetrization through Cleavage of Silicon–Carbon Bonds3.2 Desymmetrization without Cleavage of Silicon–Carbon Bonds4 Conclusion

Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents

Meso compounds represent a particular family of achiral molecules bearing elements of chirality. Their desymmetrization through enantioselective catalytic methods usually leads to elaborate chiral building blocks containing several stereogenic elements, which can be a very useful and elegant approach in the context of total synthesis. In the present review, the power of this strategy is illustrated through the different possibilities of catalytic enantioselective desymmetrization. From the combination of the hidden symmetry detection and the catalytic enantioselective transformations a new type of economy emerges: the economy of chiral reagents. 1 Introduction 1.1 What Is a Meso Compound? 1.2 Why Is the Catalytic Enantioselective Desymmetrization of Meso Compounds a Powerful Strategy in Total Synthesis? 1.3 Toward an Economy of Chiral Reagents 2 Enzymatic Desymmetrization 2.1 (–)-Sceptrin (Baran, 2006) 2.2 cis-Solamin (Stark, 2006) 2.3 Crocacin C (2010, Bressy/Pons) 3 Metallocatalyzed Desymmetrization 3.1 Quadrigemine C (2002, Overman) 3.2 (+)-Homochelidonine (2007, Lautens) 3.3 (–)-Cyanthiwigin F (2008, Stoltz) 3.4 [5]-Ladderanoic Acid (2016, Gonzalez-Martinez/Boxer/Burns) 4 Organocatalyzed Desymmetrization 4.1 (+)-Hirsutene (2008, List) 4.2 Alstoscholarines (2011, Neuville/Zhu) 4.3 (–)-Diospongin A (2015, Chuzel/Bressy) 5 Conclusion

Catalytic Enantioselective Desymmetrization of meso-Aziridines with Fluoromalonates

Catalytic Enantioselective Desymmetrization of meso-Aziridines with Fluoromalonates

Desymmetrization of aziridine with malononitrile using cinchona alkaloid amide/zinc(ii) catalysts.

The catalytic enantioselective desymmetrization of aziridines with malononitrile has been developed. Good yield and enantioselectivity were obtained by using cinchona alkaloid amide/Zn(ii) catalysts. The obtained product can be converted to β-aminoester, β-aminoamide and triamide compounds.

ChemInform Abstract: Catalytic Enantioselective Desymmetrization Reactions to All‐Carbon Quaternary Stereocenters

AbstractReview: 237 refs.

Organocatalytic Enantioselective Desymmetrization of meso-Aziridines and Prochiral Azetidines

Catalytic enantioselective desymmetrization of meso-aziridines and azetidines is a powerful strategy for rapid synthesis of chiral building blocks. This review summarizes the progress in the development of these reactions by organocatalysis. Keywords: Organocatalysis, desymmetrization, aziridine, azetidine, strained ring.

Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenters.

This Review summarizes the advances in the construction of all-carbon quaternary stereocenters via catalytic enantioselective desymmetrization of prochiral and meso-compounds, highlights the power and potential of this strategy in the total synthesis of natural products and biologically active compounds, and outlines the synthetic opportunities still available.

ChemInform Abstract: Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1‐Diborylalkanes via Suzuki—Miyaura Cross‐Coupling.

AbstractAn enantioselective desymmetrization of 1,1‐diboryl alkanes is optimized.

Catalytic enantioselective intermolecular desymmetrization of azetidines.

The first catalytic asymmetric desymmetrization of azetidines is disclosed. Despite the low propensity of azetidine ring opening and challenging stereocontrol, smooth intermolecular reactions were realized with excellent efficiency and enantioselectivity. These were enabled by the suitable combination of catalyst, nucleophile, protective group, and reaction conditions. The highly enantioenriched densely functionalized products are versatile precursors to other useful chiral molecules. Mechanistic studies, including DFT calculations, revealed that only one catalyst molecule is involved in the key transition state, though both reactants can be activated. Also, the Curtin-Hammett principle dictates the reaction proceeds via amide nitrogen activation.

Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1-Diborylalkanes via Suzuki-Miyaura Cross-Coupling.

A method for enantioselective desymmetrization of 1,1-diborylalkanes through a stereoselective Pd-catalyzed Suzuki-Miyaura cross-coupling has been thoroughly optimized. The most effective ligand was found to be a α,α,α,α-tetra-aryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-derived phosphoramidite. Results show that in order to achieve high selectivity, a suitable balance between the sterics of the aryl groups and the amino group on the ligand must be achieved. While the base has been known to facilitate transmetallation in cross-coupling reactions, mechanistic studies on this desymmetrization process reveal that the base, in the presence of KHF2, likely plays an additional role in the hydrolysis of the pinacol boronates to the corresponding boronic acids. Through an in depth optimization of the chiral ligand and mechanistic studies, it was possible to obtain ee values over 90% for several aryl bromides and to develop a reliably scalable process (up to one gram of 1,1-diborylalkane substrate).

Brønsted Acid Catalyzed Asymmetric Silylation of Alcohols

We report a catalytic enantioselective desymmetrization of meso-1,2-diols by monosilylation using a chiral enantiopure Brønsted acid as catalyst and hexamethyldisilazane (HMDS) as silyl source.

Catalytic enantioselective desymmetrization of 1,3-diazido-2-propanol via intramolecular interception of alkyl azides with diazo(aryl)acetates.

The first catalytic enantioselective desymmetrization of 1,3-diazido-2-propanol via an intramolecular interception of alkyl azides by Cu-carbenoids has been realized. A wide range of 1,3-diazidoisopropyl diazo(aryl)acetates were converted to cyclic α-imino esters in the presence of bisoxazoline ligand (S,S)-Ph-Box with good to excellent yields, and the enantiomeric excess was up to 97%.

Catalytic Enantioselective Desymmetrization of Meso Cyclic Anhydrides via Iridium-Catalyzed Hydrogenation

Catalytic Enantioselective Desymmetrization of <i>Meso</i> Cyclic Anhydrides via Iridium-Catalyzed Hydrogenation