Active Cyclopropane Research Articles

Asymmetric [3+n]‐Cycloaddition Reactions of Donor‐Acceptor Cyclopropanes

Abstract[3+n]‐Cycloaddition reactions that employ donor‐acceptor cyclopropanes using either chiral catalysts and racemic cyclopropanes or achiral catalysts and chiral, non‐racemic, cyclopropanes have become useful transformations for the construction of carbocyclic and heterocyclic compounds, with both processes offering mechanistic and structural advantages in ring formation. Although the vast majority of asymmetric cycloaddition reactions of donor‐acceptor cyclopropanes have been performed with racemic cyclopropane compounds catalyzed by Lewis acids with chiral ligands, optically active cyclopropane compounds can serve the same role using Lewis acids without chiral ligands. This review covers the use of chiral catalysts with racemic donor‐acceptor cyclopropanes and the use of chiral non‐racemic donor‐acceptor cyclopropanes with achiral Lewis acid catalysts.

Visible-Light-Induced Synthesis of 3-Alkyl Chromones under Catalyst- and Additive-Free Conditions.

Herein, we reported an efficient and facile visible-light-induced 3-alkyl chromone synthesis from easily accessible o-hydroxyaryl enaminones and α-diazo esters. In this protocol, excellent yields were obtained with a broad substrate scope at room temperature, tolerating various functional groups. Of note is that this eco-friendly methodology features catalyst- and additive-free, mild reaction conditions, simple operation procedure, and easy scale-up, which affords a convenient pathway for the preparation of 3-alkyl chromones. Experimental results and density functional theory (DFT) computation analyses confirm the participation of carbene species and active cyclopropane intermediate.

DNA-Conjugated Cyclopropane Derivatives Constructed from Sulfonium Ylides with α,β-Unsaturated Ketones.

Here, we report a DNA-compatible reaction for the generation of cyclopropane derivatives using thiolides with α,β-unsaturated ketones in the absence of transition metal and N2 protection, which is convenient for DNA encoded library (DEL) construction. This approach allows the rapid and efficient production of a series of DEL libraries of potentially biologically active cyclopropanes and spirocyclopropyl oxindole derivatives.

N‐Heterocyclic Carbene‐Catalyzed Activation of 3‐Membered Rings: Cyclopropanes, Epoxides, Azirines and Aziridines

AbstractThe activations of carbonyl compounds bearing cyclopropyl, epoxyl, azirine and aziridinyl groups by N‐heterocyclic carbene (NHC) organic catalysts are reviewed. The reactions are introduced and discussed from 3 aspects according to the activation modes involved in these transformations. A brief summary on the achievements and the remaining challenges in NHC‐catalyzed activation of cyclopropanes and their analogues is given at the end of this minireview. Our own perspectives on the future development within this highly active research field are also provided.

Engineered Myoglobin Catalysts for Asymmetric Intermolecular Cyclopropanation Reactions.

Biocatalysis has covered an increasingly important role in the synthesis and manufacturing of pharmaceuticals and other high value compounds. In the interest of expanding the range of synthetically useful reactions accessible via biocatalysts, our group has explored the potential and application of engineered myoglobins for 'abiological' carbene transfer catalysis. These transformations provide a direct route for the construction of new carbon-carbon and carbon-heteroatom bonds, including the synthesis of cyclopropane rings, which are key motifs and pharmacophores in many drugs and bioactive natural products. In this award article, we survey the progress made by our group toward the development of myoglobin-based catalysts for asymmetric intermolecular cyclopropanation reactions. The high stereoselectivity exhibited by these biocatalysts in these reactions, combined with their broad substrate scope, scalability, and robustness to high substrate loading and organic co-solvents, contribute to make these systems particularly useful for chemical synthesis and biocatalysis at the preparative scale. Extension of the scope of biocatalytic carbene transfer reactions to include different classes of carbene donor reagents has created new opportunities for the asymmetric synthesis of functionalized cyclopropanes. Furthermore, the integration of myoglobin-catalyzed stereoselective cyclopropanations with chemical diversification of the enzymatic products has furnished attractive chemoenzymatic strategies to access a diverse range of optically active cyclopropane scaffolds of high value for drug discovery, medicinal chemistry, and the synthesis of natural products.

C-C Bond Activation of Cyclopropanes Enabled by Phosphine-Catalyzed In Situ Formation of High-Strain Methylenecycopropane Intermediate.

An effective strategy for the ring-opening/elaboration of cyclopropanes by phosphine catalyst is documented, providing the 2,4-pentadiene sulfonamides and isoindolines in moderate to good yields. The key to the success of this reaction is phosphine-catalyzed introduction of a trigonal center into cyclopropanes, which results in the formation of higher ring strain cyclopropylidenemethyl phosphonium salt. Moreover, this methodology is employed as the key step for the synthesis of bioactive molecules.

An endo-Directing-Group Strategy Unlocks Enantioselective (3+1+2) Carbonylative Cycloadditions of Aminocyclopropanes.

An endo‐directing group strategy enables enantioselective (3+1+2) cycloadditions that are triggered by carbonylative C−C bond activation of cyclopropanes. These processes are rare examples of cycloadditions where C−C bond oxidative addition is enantiodetermining, and the first where this is achieved within the context of a multicomponent (higher order) reaction design.

An endo‐Directing‐Group Strategy Unlocks Enantioselective (3+1+2) Carbonylative Cycloadditions of Aminocyclopropanes

AbstractAn endo‐directing group strategy enables enantioselective (3+1+2) cycloadditions that are triggered by carbonylative C−C bond activation of cyclopropanes. These processes are rare examples of cycloadditions where C−C bond oxidative addition is enantiodetermining, and the first where this is achieved within the context of a multicomponent (higher order) reaction design.

Copper-Catalyzed Enantioselective Hydrosilylation of gem-Difluorocyclopropenes Leading to a Stereochemical Study of the Silylated gem-Difluorocyclopropanes.

Optically active cyclopropanes have been widely investigated especially from the views of pharmaceutical and agrochemical industries, and substituting one of the methylenes with the difluoromethylene unit should be promising for developing novel biologically relevant compounds and functional materials. In this paper, the copper‐catalyzed enantioselective hydrosilylation of gem‐difluorocyclopropenes to provide the corresponding chiral gem‐difluorocyclopropanes is presented. The use of copper(I) chloride, chiral ligands including bidentate BINAPs and monodentate phosphoramidites, and silylborane Me2PhSi‐Bpin accompanying sodium tert‐butoxide in methanol was appropriate for the enantioselective hydrosilylation of the strained C=C double bond, and the resultant chiral difluorinated three‐membered ring was unambiguously characterized. Subsequent activation of the silyl groups in enantio‐enriched gem‐difluorocyclopropanes showed substantial reduction of the enantiopurity, indicating cleavage of the distal C−C bond leading to the transient acyclic intermediates.

Cyclopropanes in organocatalytic transformations

Organocatalysis represents a powerful and reliable tool in modern organic chemistry. Cyclopropanes are a versatile compound class whose reactivity exceeds that of other cyclic hydrocarbons. The organocatalytic synthesis of cyclopropanes has become an established and well-studied transformation. However, the implementation of the cyclopropyl motif into the scaffolds of organocatalysts and the activation of cyclopropanes offers potential to further combine these two areas. Here, we discuss organocatalytic cyclopropanations together with organocatalytic reactions where the cyclopropane motif is implemented either in the catalyst or the substrate to demonstrate how organocatalysis can benefit from the unique reactivity of cyclopropanes. • Organocatalysis. • Aminocatalysis. • N -heterocyclic carbenes. • Phase-transfer catalysis.

Carbonylative C-C Bond Activation of Aminocyclopropanes Using a Temporary Directing Group Strategy.

Temporary directing groups (TDGs) underpin a range of C-C bond activation methodologies; however, the use of TDGs for the regiocontrolled activation of cyclopropane C-C bonds is underdeveloped. In this report, we show how an unusual ring contraction process can be harnessed for TDG-based carbonylative C-C bond activations of cyclopropanes. The method involves the transient installation of an isocyanate-derived TDG, rather than relying on carbonyl condensation events as used in previous TDG-enabled C-C bond activations.

Pyridine‐ and Quinoline‐Based Gold(III) Complexes: Synthesis, Characterization, and Application

Studies on gold(III) coordination of a series of prepared polydentate pyridine and quinoline based ligands are reported. Characterization (1H, 13C, 15N NMR, and XRD) of the novel gold(III) complexes, prepared in 31–98 % yield, revealed different coordination ability of the pyridine and quinoline nitrogen atoms. Testing of catalytic activity in cyclopropanation of propargyl ester and styrene demonstrated that all the new ligated gold(III) complexes were catalytically active and outperformed KAuCl4. The superior activity of the particular Au(III)‐pyridine‐oxazole complexes may indicate de‐coordination of the pyridine‐N ligand as a crucial step for efficient generation of catalytic activity.

Synthesis of Forms of a Chiral Ruthenium Complex Containing a Ru-Colefin(sp2) Bond and Their Application to Catalytic Asymmetric Cyclopropanation Reactions.

Organometallic complexes [Ru-Colefin(sp2)-Ru(II)-Pheox 2a-2d] containing a Ru-Colefin(sp2) bond have been prepared from unsaturated chiral oxazoline derivatives and evaluated for asymmetric cyclopropanation reactions. The corresponding optically active cyclopropanes were obtained with high yields and high stereoselectivities (≥99/<1 trans/cis, 99% trans ee). The enantioselectivities were found to be affected by the geminal substituent on the Ru-C(sp2) bond. In particular, Ru(II)-Prox catalyst 2c, in which there was no geminal substituent on the metal, was shown to have the highest enantioselectivities.

Lewis Base Catalysis Based on Homoconjugate Addition: Rearrangement of Electron-Deficient Cyclopropanes and Their Derivatives

Cyclopropane is one of the most reactive functionalities owing to its intrinsic ring strain. Transition-metal catalysis and Lewis acid catalysis have been extensively used in ring openings of cyclopropanes; however, Lewis base-catalyzed activation of cyclopropanes remains largely unexplored. Upon nucleophilic attack with Lewis bases, cyclopropanes undergo ring cleavage in a manner known as homoconjugate addition to form zwitterionic intermediates, which have significant potential for reaction development but have garnered little attention. Here, we present a brief overview of this area, with an emphasis on our recent efforts on Lewis base-catalyzed rearrangement reactions of electron-deficient cyclopropanes using the homoconjugate addition process.1 Introduction2 DABCO-Catalyzed Cloke–Wilson Rearrangement of Cyclopropyl Ketones3 Hydroxylamine-Mediated Tandem Cloke–Wilson/Boulton–­Katritzky Reaction of Cyclopropyl Ketones4 Phosphine-Catalyzed Rearrangement of Vinylcyclopropyl Ketones To Form Cycloheptenones5 Phosphine-Catalyzed Rearrangement of Alkylidenecyclopropyl Ketones To Form Polysubstituted Furans and Dienones6 Conclusion and Outlook

Stereospecific Copper(II)-Catalyzed Tandem Ring Opening/Oxidative Alkylation of Donor-Acceptor Cyclopropanes with Hydrazones: Synthesis of Tetrahydropyridazines.

Aerobic copper(II)-catalyzed tandem ring opening and oxidative C-H alkylation of donor-acceptor cyclopropanes with bisaryl hydrazones is accomplished to produce tetrahydropyridazines, in which copper(II) plays dual role as a Lewis acid as well as redox catalyst. The reaction is stereospecific, and optically active cyclopropanes can be reacted with high optical purities (89-98% enantiomeric excess). The substrate scope, functional group tolerance, dual role of the copper(II) catalyst, and the use of air as an oxidant are the important practical features. A product bearing a 3-bromoaryl group can be subjected to Pd-catalyzed Suzuki coupling with boronic acid in high yield.

Catalytic Asymmetric Intermolecular Cyclopropanation of a Ketone Carbene Precursor by a Ruthenium(II)‐Pheox Complex

AbstractThe diazo derivative of acetonyl acetate is a useful basic skeleton for the synthesis of cyclopropyl ketones. The intermolecular cyclopropanations of diazo acetoxy acetone with olefins are accomplished by using a novel p‐nitro‐Ru(II)‐diphenyl‐Pheox catalyst to give the corresponding optically active cyclopropane derivatives in good yields (up to 95%) with excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to 98% ee).magnified image

Origin of high stereocontrol in olefin cyclopropanation catalyzed by an engineered carbene transferase.

Recent advances in metalloprotein engineering have led to the development of a myoglobin-based catalyst, Mb(H64V,V68A), capable of promoting the cyclopropanation of vinylarenes with high efficiency and high diastereo- and enantioselectivity. Whereas many enzymes evolved in nature often exhibit catalytic proficiency and exquisite stereoselectivity, how these features are achieved for a non-natural reaction has remained unclear. In this work, the structural determinants responsible for chiral induction and high stereocontrol in Mb(H64V,V68A)-catalyzed cyclopropanation were investigated via a combination of crystallographic, computational (DFT), and structure-activity analyses. Our results show the importance of steric complementarity and non-covalent interactions involving first-sphere active site residues, heme-carbene, and the olefin substrate, in dictating the stereochemical outcome of the cyclopropanation reaction. High stereocontrol is achieved through two major mechanisms. First, by enforcing a specific conformation of the heme-bound carbene within the active site. Second, by controlling the geometry of attack of the olefin on the carbene via steric occlusion, attractive van der Waals forces and protein-mediated π-π interactions with the olefin substrate. These insights could be leveraged to expand the substrate scope of the myoglobin-based cyclopropanation catalyst toward non-activated olefins and to increase its cyclopropanation activity in the presence of a bulky α-diazo-ester. This work sheds first light into the origin of enzyme-catalyzed enantioselective cyclopropanation, furnishing a mechanistic framework for both understanding the reactivity of current systems and guiding the future development of biological catalysts for this class of synthetically important, abiotic transformations.

Synthesis of Nitrogen Heterocycles via Directed Carbonylative C-C Bond Activation of Cyclopropanes.

This review concentrates on recent developments from our laboratory concerning the Rh-catalyzed carbonylative C-C bond activation of cyclopropanes. Specifically, we have found that N-based directing groups are effective at controlling the regioselectivity of C-C bond activation during the formation of rhodacyclopentanone intermediates. These engage tethered π-unsaturated components (e.g. alkenes) or conventional nucleophiles in cycloaddition and heterocyclization processes, respectively. Using this approach, direct and modular access to a wide range of complex heterocyclic ring systems is achieved. The review summarizes the scope of our methodologies and outlines key mechanistic features.

Carbene capture in a myoglobin mutant

Metalloprotein activity can be tuned by altering first- and second-sphere interactions with the metal ion or ions. Here, a non-canonical haem axial ligand is introduced into a myoglobin variant, modulating both. The resulting enhancement of cyclopropanation activity illustrates the utility of expanding the suite of available amino acids for biocatalyst engineering.

Asymmetric cyclopropanation reactions catalyzed by carbohydrate-based crown ethers

Optically active cyclopropane derivatives were prepared by a novel, simple and green approach in high enantioselectivities using monosaccharide-based chiral crown ethers as phase transfer catalysts. The crown ethers having d-glucopyranoside, d-mannopyranoside and d-altropyranoside units proved to be efficient catalyst in a few asymmetric phase transfer cyclopropanation reactions. The Michael-initiated ring closure (MIRC) reactions of diethyl bromomalonate with chalcones took place with complete diastereoselectivity and up to 99% ee. Using benzylidenemalononitrile, 2-arylidenemalononitriles, 2-benzylidene-1,3-indandione, substituted 2-benzylidene-1,3-indandiones, 2-arylidene-1,3-indandiones and 2-benzylidene-1,3-diphenyl-1,3-propanediones enantioselectivities up to 92%, 99%, 54% 93%, 89% and 72%, respectively, were achieved, in the presence of chiral lariat ethers derived from different monosaccharides. The absolute configuration of a cyclopropane diester product was determined by a combined CD spectroscopic and theoretical study.