Cyclopropanation Reactions Research Articles

Efficient Synthesis of Spirocyclic Nucleosides via Michael Addition-Initiated Intermolecular Cyclopropanation Reaction

Efficient Synthesis of Spirocyclic Nucleosides via Michael Addition-Initiated Intermolecular Cyclopropanation Reaction

A transition-metal-free & diazo-free styrene cyclopropanation.

An operationally simple and broadly applicable novel cyclopropanation of styrenes using gem-diiodomethyl carbonyl reagents has been developed. Visible-light triggered the photoinduced generation of iodomethyl carbonyl radicals, able to cyclopropanate a wide array of styrenes with excellent chemoselectivity and functional group tolerance. To highlight the utility of our photocyclopropanation, we demonstrated the late-stage functionalization of biomolecule derivatives.

Iron-catalyzed asymmetric intramolecular cyclopropanation reactions using chiral tetramethyl-1,1'-spirobiindane-based bisoxazoline (TMSI-BOX) ligands.

The versatile application of chiral bisoxazoline (BOX) ligands in diverse metal-catalyzed asymmetric reactions results in growing demand for novel BOX ligands containing different motifs. Herein, the successful development of a chiral spiro bisoxazoline ligand (TMSI-BOX) on the basis of the tetramethyl-1,1'-spirobiindane motif and bisoxazoline chelating units is described. The corresponding Fe complexes of TMSI-BOX proved to be excellent catalysts in the asymmetric intramolecular cyclopropanation reaction of diazo derivatives, providing synthetically versatile [3.1.0]bicycloalkane derivatives bearing two contiguous quaternary chiral centers with high enantiomeric purity.

Supramolecular Fullerene Sponges As Catalytic Masks for Regioselective Functionalization of C <sub>60</sub>

Isomer-pure poly-functionalizalized fullerenes are required to boost the development of fullerene chemistry in any field, and specifically in solar cell design. Easy-accessible mono-functionalized fullerenes are mainly used in organic- or perovskite-based solar cells, due to the hampered accessibility to pure-isomer poly-adduct derivatives. In a general basis, multi-adduct mixtures with uncontrolled regioselectivity are obtained, and chromatographic purification is prohibitively costly and time-consuming to be used in the production of solar cells. Moreover, single isomer poly-functionalized fullerenes are only accessible via stoichiometric, multistep paths entailing protecting-unprotecting sequences. Herein, a nanocapsule is used as a supramolecular mask to exert full control on the reactivity and the equatorial regioselectivity of Bingel-Hirsch cyclopropanation reactions of confined fullerene guests. Thus, equatorial bis-, tris- and tetrakis-C60 homo-adducts are exclusively obtained in a stepwise manner, completely avoiding over functionalization (always observed in bulk solution) and holding precise control on the number of additions. Regioselectivity is strictly dictated by the four cross-shaped open windows in the tetragonal prismatic supramolecular container. Furthermore, isomer-pure equatorial hetero-tetrakis-adducts or hetero-Th-hexakis-adducts are synthesized at will in one-pot synthesis for the first time. Remarkably, a synthetically useful biphasic protocol is designed to achieve selective and quantitative formation of exclusively tetrakis-adducts using catalytic amounts of nanocapsule. Therefore, the confinement control imposed by the capsule’s cavity conforms a unique practical strategy to infer regio-control to the synthesis of fullerene equatorial poly-adducts. This work provides a synthetically valuable path to produce a plethora of new pure-isomer poly-functionalized C60-based compounds, as candidates for testing in solar cell devices and for biomedical applications.

Network topology and cavity confinement-controlled diastereoselectivity in cyclopropanation reactions catalyzed by porphyrin-based MOFs

In this work, we show that the stereoselectivity of a reaction can be controlled by directing groups of substrates, by network topology and by local cavity confinement of metal–organic framework (MOF) catalysts.

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.

Blue-Light-Induced Carbene-Transfer Reactions of Diazoalkanes.

Carbenes are very important reactive intermediates to access a variety of complex molecules and are applied widely in organic synthesis and drug discovery. Typically, their chemistry is accessed by the use of transition metal catalysts. Herein, we describe the application of low-energy blue light for the photochemical generation of carbenes from donor-acceptor diazoalkanes. This catalyst-free and operationally simple approach enables highly efficient cyclopropenation reactions with alkynes and the rearrangement of sulfides under mild reaction conditions, which can be utilized for both batch and continuous-flow processes.

Computational chemical analysis of Ru(II)-Pheox-catalyzed highly enantioselective intramolecular cyclopropanation reactions.

Computational chemical analysis of Ru(II)-Pheox-catalyzed highly enantioselective intramolecular cyclopropanation reactions was performed using density functional theory (DFT). In this study, cyclopropane ring-fused γ-lactones, which are 5.8kcal/mol more stable than the corresponding minor enantiomer, are obtained as the major product. The results of the calculations suggest that the enantioselectivity of the Ru(II)-Pheox-catalyzed intramolecular cyclopropanation reaction is affected by the energy differences between the starting structures 5l and 5i. The reaction pathway was found to be a stepwise mechanism that proceeds through the formation of a metallacyclobutane intermediate. This is the first example of a computational chemical analysis of enantioselective control in an intramolecular carbene-transfer reaction using C1 -symmetric catalysts.

Copper-Catalyzed Asymmetric Aminocyanation of Arylcyclopropanes for Synthesis of γ-Amino Nitriles

A facile approach for the synthesis of enantiopure γ-amino nitriles by copper-catalyzed aminocyanation of arylcyclopropanes is disclosed, which undergoes the highly enantioselective ring-opening reaction of cyclopropanes. The strategy utilizes N-fluorobenzenesulfonimide as nucleophilic nitrogen source as well as oxidant and trimethylsilyl cyanide as the other nucleophile, and it probably operates via a key radical cation intermediate. This reaction provides an efficient platform for asymmetric 1,3-difunctionalization of cyclopropanes.

Reversible Metalation and Catalysis with a Scorpionate-like Metallo-ligand in a Metal-Organic Framework.

The installation of metallo-ligands in metal-organic frameworks (MOFs) is an effective means to create site-isolated metal centers toward single-site heterogeneous catalysis. Although trispyrazolyborate (Tp) and tripyrazolylmethane (Tpm) form one of the most iconic classes of homogeneous catalysts, neither has been used as a metallo-ligand for the generation of MOFs thus far. Here, we show that upon in situ metalation with CuI, a tricarboxylated Tpm ligand reacts with ZrOCl2 to generate a new MOF exhibiting neutral scorpionate-like chelating sites. These sites undergo for facile demetalation and remetalation with retention of crystallinity and porosity. When remetalated with CuI, the MOF exhibits spectroscopic features and catalytic activity for olefin cyclopropanation reactions that are similar to the molecular [Cu(CH3CN)Tpm*]PF6 complex (Tpm* = tris(3,5-dimethylpyrazolyl)methane). These results demonstrate the inclusion of Tp or Tpm metallo-ligands in a MOF for the first time and provide a blueprint for immobilizing Tpm* catalysts in a spatially isolated and well-defined environment.

Bottom‐Up Synthesis of Acrylic and Styrylic RhII Carboxylate Polymer Beads: Solid‐Supported Analogs of Rh2(OAc)4

We have developed a short and efficient bottom‐up synthesis of acrylic and styrylic polymer beads containing dirhodium(II) tetracarboxylates. The solid supported dirhodium(II) tetracarboxylate catalysts were synthesized in as little as two steps overall from dirhodium tetratrifluoroacetate and commercially available carboxylic acids, making the bottom‐up approach a viable alternative to the post‐modification approach commonly used. The dirhodium(II) tetracarboxylate polymer beads have a convenient size (ca. 100 µm), are easy to handle, and can be considered solid‐supported analogs of Rh2(OAc)4. Beads generated from dirhodium(II) tetracarboxylates with four polymerizable carboxylate ligands displayed the best catalytic performance and compared favorably to Rh2(OAc)4 in benchmarked cyclopropanation reactions. The results imply that the cumbersome synthesis of monomeric dirhodium(II) tetracarboxylates with mixed ligands systems can be avoided and that immobilized dirhodium(II)‐catalysts with a higher degree of crosslinking is a viable option to catalysts linked in an anchor‐like fashion. We demonstrate recovery and recycling, and a potential use of the beads as catalysts in a cyclopropanation reaction towards the insecticide chrysanthemic acid.

Highly Diastereo‐ and Enantioselective Synthesis of Nitrile‐Substituted Cyclopropanes by Myoglobin‐Mediated Carbene Transfer Catalysis

AbstractA chemobiocatalytic strategy for the highly stereoselective synthesis of nitrile‐substituted cyclopropanes is reported. The present approach relies on an asymmetric olefin cyclopropanation reaction catalyzed by an engineered myoglobin in the presence of ex situ generated diazoacetonitrile within a compartmentalized reaction system. This method enabled the efficient transformation of a broad range of olefin substrates at a preparative scale with up to 99.9 % de and ee and up to 5600 turnovers. The enzymatic product could be further elaborated to afford a variety of functionalized chiral cyclopropanes. This work expands the range of synthetically valuable, abiotic transformations accessible through biocatalysis and paves the way to the practical and safe exploitation of diazoacetonitrile in biocatalytic carbene transfer reactions.

Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis.

A chemobiocatalytic strategy for the highly stereoselective synthesis of nitrile-substituted cyclopropanes is reported. The present approach relies on an asymmetric olefin cyclopropanation reaction catalyzed by an engineered myoglobin in the presence of ex situ generated diazoacetonitrile within a compartmentalized reaction system. This method enabled the efficient transformation of a broad range of olefin substrates at a preparative scale with up to 99.9 % de and ee and up to 5600 turnovers. The enzymatic product could be further elaborated to afford a variety of functionalized chiral cyclopropanes. This work expands the range of synthetically valuable, abiotic transformations accessible through biocatalysis and paves the way to the practical and safe exploitation of diazoacetonitrile in biocatalytic carbene transfer reactions.

Computational Design of an Iron Catalyst for Olefin Metathesis

Olefin metathesis is a versatile reaction in synthetic chemistry. The use of iron compounds as olefin metathesis catalysts has attracted interest but has not succeeded because most Fe complexes catalyze cyclopropanation reactions preferentially to cycloreversion, which is a key step in the metathesis reaction cycle. In the present study, we performed density functional theory calculations to study the catalytic effect of ancillary pincer ligands in an Fe organometallic catalyst for olefin metathesis. We show here that the partial atomic charge on Fe in the metallocyclobutane intermediate is a descriptor for the tendency of the Fe complex to favor olefin metathesis over cyclopropanation. The results suggest that the pincer ligands can decrease the partial atomic charge on the Fe ion and that decreasing this charge can make the desired cycloreversion reaction more energetically favorable than the cyclopropanation side reaction. In this way, we found that the Fe carbene stabilized by N-heterocyclic dicarbene...

C‐Bridged Bispyrrolidines and Bispiperidines as New Ligands

The preparation of methylene‐bridged C2‐symmetric nitrogen‐heterocycles as a new class of ligands is described, including methylene‐bridged pyridines, quinolones, piperidines and pyrrolidines. These methylene‐bridged aromatic systems are obtained via a microwave assisted Ziegler‐type reaction. The separation of diastereomers and the application of the copper complexes of these ligands for cyclopropanation reactions proves the applicability of these new types of ligands.

Front Cover Picture: Visible-Light-Promoted Redox-Neutral Cyclopropanation Reactions of α-Substituted Vinylphosphonates and Other Michael Acceptors with Chloromethyl Silicate as Methylene Transfer Reagent (Adv. Synth. Catal. 23/2018)

Front Cover Picture: Visible-Light-Promoted Redox-Neutral Cyclopropanation Reactions of α-Substituted Vinylphosphonates and Other Michael Acceptors with Chloromethyl Silicate as Methylene Transfer Reagent (Adv. Synth. Catal. 23/2018)

Steroid–Fullerene Hybrids from Epiandrosterone: Synthesis, Characterization and Theoretical Study

New hybrid fullerene–steroid derivatives were prepared by using the Bingel–Hirsch protocol, by treatment of [60]fullerene with malonates bearing the appropriate steroid moieties obtained, in turn, from the functionalization of epiandrosterone, an important naturally occurring steroid hormone. Monocycloadduct C60‐steroid conjugates were obtained by functionalization of ring A or ring D of the steroid moiety. We have also described the multistep preparation of a [60]fullerene hybrid dumbbell endowed with two fullerene units connected through an epiandrosterone molecule by a cyclopropanation reaction. The new compounds have been spectroscopically characterized and their redox potentials, determined by cyclic voltammetry, reveal three reversible reduction waves for monocycloadducts (8, 9 and 11, 12), whereas dumbbell‐type derivative 10 exhibits the best electron‐accepting abilities of the Bingel‐type fullerene–steroid series. Theoretical calculations at semiempirical (AM1) and single point B3LYP‐D3/6‐31G+(d,p) levels have predicted the most stable conformations for the hybrid compounds and allow explaining the observed regioselectivity in the cyclopropanation reaction with dimalonate 7 during the synthesis of the dumbbell derivative.

Visible‐Light‐Promoted Redox‐Neutral Cyclopropanation Reactions of α‐Substituted Vinylphosphonates and Other Michael Acceptors with Chloromethyl Silicate as Methylene Transfer Reagent

AbstractThe alkene cyclopropanation with chloromethyl silicate as a methylene transfer reagent has been accomplished via visible‐light‐mediated redox‐neutral catalysis. This method features broad functional group tolerance and mild conditions. In addition to α‐substituted vinylphosphonates, a range of Michael acceptors including α,β‐unsaturated acrylate, ketone, amide and sulfone are suitable substrates for this photocatalytic cyclopropanation. An application of this protocol to the cyclopropanation of estrone derivative is also presented.magnified image

Organocatalytic Cyclopropanation of (E)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding

An undergraduate experiment combining synthesis, NMR analysis and mechanistic understanding is reported. The students perform an organocatalyzed cyclopropanation reaction of (E)-dec-2-enal and are then required to determine the diastereoselectivity and assign the relative configuration of each product using NMR spectroscopy.

Three-Component [1 + 1 + 1] Cyclopropanation with Ruthenium(II)

We report a one-step, Ru(II)-catalyzed cyclopropanation reaction that is conceptually different from the previously reported protocols that include Corey–Chaykovsky, Simmons–Smith, and metal-catalyzed carbene attack on olefins. Under the current protocol, various alcohols and esters are transformed into sulfone substituted cyclopropanes with excellent isolated yields and diastereoselectivities. This new reaction forms highly congested cyclopropane products with three new C–C bonds, three or two new chiral centers and one new quaternary carbon center. Twenty-two examples of isolated substrates are given. Previously reported synthetic routes for similar substrates are all multistep, linear routes that proceed with overall low yields and poor control of stereochemistry. Commercially available Ru(II) dehydrogenation catalysts, that were recently developed for the dehydrogenative synthesis of esters and amides from alcohol and amine substrates, were used in the reaction, with the best catalyst showing excellen...