Cyclopropane Derivatives Research Articles

Divergent Annulations of 5,6‐Dihydro‐4H‐1,2‐Oxazine N‐Oxides and Enol Diazoacetates for the Switchable Chemoselective Synthesis of Fused 1,2‐Oxazine Derivatives

AbstractReactions of 5,6‐dihydro‐4H‐1,2‐oxazine N‐oxides with enol diazoacetates were studied. A particular reaction path depends on the amount of catalyst and the order of the addition of the substrates. Use of Rh2(Oct)4 (2 mol.%) leads to chemoselective [3+3]‐annulation producing 1,2‐oxazine‐fused 1,2‐oxazine derivatives. With lower catalyst loadings (0.03 mol.%) enol diazoacetates are converted to cyclopropene derivatives, which in situ react with 1,2‐oxazine N‐oxides via tandem [3+2]‐cycloaddition‐rearrangement producing oxazine‐fused aziridines. Both transformations showed a wide substrate scope and produced target products with good yields and diastereoselectivity, thus allowing selective preparation of these rare heterocyclic systems. A mechanistic rationale for observed chemo‐ and stereo‐ selectivities was proposed.

Visible‐Light Photocatalytic Cyclopropanation of Alkenes with Dibromomethane

AbstractThe cyclopropane unit plays a crucial role in pharmaceutical compound design and organic transformation. In this study, we have developed a novel redox‐neutral photocatalytic cyclopropanation method involving dibromomethane and alkenes. This chemistry enables the synthesis of valuable functional group‐substituted cyclopropanes using readily available starting materials and practical reaction conditions. Additionally, we have demonstrated the versatility of the products as precursors for various cyclopropane derivatives with different substituents. Importantly, this protocol facilitates the synthesis of a key unit found in a specific type of T‐type calcium channel blocker. Furthermore, the proposed reaction mechanism is well‐supported by control experiments.

Theoretical insights into enantioselective [2 + 1] cyclopropanation reactions of diazo compounds with electron-deficient olefins.

The cyclopropane skeleton plays a significant role in bioactive molecules due to its distinctive structural properties. This has sparked keen interest and in-depth exploration in the field of stereoselective synthesis of cyclopropane derivatives. In the present study, the mechanism and the origin of stereoselectivity of diastereodivergent synthesis of cyclopropane derivatives via the catalyst-free [2 + 1]-cyclopropanation reactions of 3-diazo-N-methylindole (R1) with two types of electron-deficient olefins (R2 and R3) in both aqueous and toluene media have been studied using the DFT calculations. The findings indicate that these [2 + 1] cycloaddition reactions proceed in two stages, where the first step is not only the rate-determining step but also critically dictates the stereoselectivity of the product. The calculated diastereomeric ratios are in agreement with the experimental results. Furthermore, by utilizing non-covalent interaction (NCI) analysis and energy decomposition analysis based on molecular force fields (EDA-FF), we elucidated that the electrostatic interactions between reactant fragments in the transition state TS1s for the first step are the predominant factors determining the stereoselectivity, as opposed to the experimentally hypothesized steric hindrance and π-π stacking interactions. The geometrical structures of all minima and transition states on the potential energy surface (PES) in solvents water and toluene were fully optimized using the DFT method at the M06-2X(D3)/SMD/6-31 + G(d,p) level of theory. Single-point energy calculations were carried out based on the optimized geometries in the solution at the M06-2X(D3)/6-311 + G(d,p) level. All the DFT calculations were performed using the Gaussian 09 software. The optimized molecular structures were visualized using CYLview software. NCI analysis was performed using the Multiwfn and VMD softwares. The Multiwfn program was also used for CDFT and EDA-FF analyses.

Synthesis of Gem-Dimethyl Bicyclic [3.1.0] Proline as an Antiviral Drug Intermediate

Abstract: Gem-dimethyl bicyclic [3.1.0] proline, an azadicyclohexane derivative, constitutes a prevalent skeleton structure in drugs, which serves an important role in the synthesis of antiviral drugs, such as Nirmatrelvir, Boceprevir, Narlaprevir, etc. This study offers a comprehensive overview of the documented synthetic strategies for gem-dimethyl bicyclic [3.1.0] proline methyl ester and delves into the application characteristics of each synthetic strategy. These synthetic approaches can be divided into three major types: the first synthetic method uses proline derivatives as the starting material, the second one uses cyclopropane derivatives as the starting material, and the third one uses the bicyclic skeleton as the starting material. Of these strategies, the third method stands out as the most extensively adopted.

Breaking the Rules: On the Relative Stability of Some Methylencyclopropane and Methylcyclopropene Derivatives.

The structure of the spirocyclic product obtained by reacting catechol with 1,1-dichloro-2-(chloromethyl)cyclopropane is shown by NMR and X-ray analysis to be that of a 2-methylcyclopropene (MeCP), instead of the previously reported 2-methylenecyclopropane (MCP) one. The study of the equilibration between the two isomeric forms by experimental and computational means (including both Density Functional Theory - DFT - and Coupled Cluster with single, double, and perturbative triple excitations - CCSD(T) - calculations) revealed that, at variance with most of the alkylidenecyclopropane/alkylcyclopropene systems described to date, for the compounds of the present study the MeCP derivative is more stable by≈ 2.5-3.0 Kcal mol-1 than the MCP one. The extension of the DFT and CCSD(T) study to other spiro-MCP/MeCP pairs suggests that the origin of the unexpected shift of the equilibrium position can be tracked back to a combination of electronic and ring-strain effects. These findings lead to re-think a long-standing, and substantially undisputed belief in the area of unsaturated cyclopropane derivatives.

Photocatalytic O‐ to S‐Rearrangement of Tertiary Cyclopropanols

AbstractDespite the importance of heteroatom‐substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman‐Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O‐ to S‐rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols—that are difficult to access by other methods—can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

Photocatalytic O- to S-Rearrangement of Tertiary Cyclopropanols.

Despite the importance of heteroatom-substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman-Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O- to S-rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols-that are difficult to access by other methods-can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

Palladium-Catalyzed Addition of Trifluoroacetylsilanes to Alkenes and Allenes via the Cleavage of C-Si Bonds.

The palladium-catalyzed addition of trifluoroacetylsilanes to alkenes and allenes via the cleavage of the C-Si bonds is reported. When alkenes are used, cyclopropanation occurs to afford cyclopropane derivatives bearing CF3 and siloxy groups with a high degree of stereoselectivity. When allenes are used, silylacylation occurs to form alkenylsilane derivatives bearing a trifluoroacetyl group at the allylic position with complete regioselectivity. Both reactions allow for highly atom-economical access to densely functionalized fluorinated organosilane derivatives using simple building blocks.

Cyclization reactions of cyclopropane derivatives with conjugated carbo- and heterosystems

The strained structure of cyclopropanes serves as a kind of trigger for a variety of chemical transformations. Among others, processes involving conjugated unsaturated systems are of particular interest. The systems of unsaturated bonds are characterized by the possibility of flexibly varying their reactivity up to their full involvement in transformations. This review is the first to consider options for implementing the idea of combining the strain energy of cyclopropanes and the synthetic capacity of conjugated unsaturated systems within a single concept. A detailed analysis of processes involving activated cyclopropanes and numerous carbodiene and heterodiene systems is presented.<br> The bibliography includes 289 references.

Exploring Downhill Bifurcations in [3,3]-Sigmatropic Rearrangement by Finding Transitions from an Uphill Bifurcation to a Downhill Bifurcation.

Downhill bifurcation is a phenomenon in which an ensemble of trajectories passing through a transition state (TS), called an ambimodal TS, bifurcates into multiple products. Finding downhill bifurcations for unreported pairs of chemical transformations is essential, because they affect reaction selectivity. Marx et al. reported that perturbations such as applying mechanical stress or changing a substituent cause a transition from an uphill bifurcation to a downhill bifurcation in the ring-opening reaction of cyclopropane derivatives (ChemPhysChem, 2018, 19, 837-847). Investigating the occurrence of this phenomenon in other reactions, especially in pericyclic reactions, is interesting for understanding and controlling the reaction selectivity considering downhill bifurcations. In this study, we proposed a method for finding perturbation-induced downhill bifurcations and applied it to three pericyclic reactions. The transition from an uphill bifurcation to a downhill bifurcation occurred in two of the three pericyclic reactions, one of which was previously unreported. Interestingly, the occurrence of a downhill bifurcation by a perturbation depended on the directions of the intrinsic reaction coordinate paths of the two TSs when they emerged from the reactant minimum. Our method can be applied in mechanistic studies to avoid the risk of overlooking downhill bifurcations.

Direct access to furan and cyclopropane derivatives via palladium-catalyzed C-H activation/alkene insertion/annulation.

A practical and effective palladium-catalyzed C-H activation/alkene insertion/annulation has been reported for the synthesis of furans and cyclopropanes from cyclic 1,3-diketones or 1,3-indandione and diverse alkenes, resulting in moderate to good yields. This protocol demonstrates excellent selectivity and is well-compatible with a wide range of alkene substrates, exhibiting exceptional regioselectivities, high efficiency, and good functional group tolerance.

Rh-Catalysed Hydroacyloxylation of Cyclopropenes: Regio- and Diastereoselective Synthesis of Acyloxycyclopropanes

Cyclopropyl carboxylates are essential building blocks in biological and medicinal chemistry. However, their accessibility is severely limited by the need to pre-synthesise highly reactive cyclopropane derivatives. Herein, we report an...

Chemoenzymatic synthesis of optically active α-cyclopropyl-pyruvates and cyclobutenoates via enzyme-catalyzed carbene transfer with diazopyruvate.

Cyclopropanes are recurrent structural motifs in natural products and bioactive molecules. Recently, biocatalytic cyclopropanations have emerged as a powerful approach to access enantioenriched cyclopropanes, complementing chemocatalytic approaches developed over the last several decades. Here, we report the development of a first biocatalytic strategy for cyclopropanation using ethyl α-diazopyruvate as a novel enzyme-compatible carbene precursor. Using myoglobin variant Mb(H64V,V68G) as the biocatalyst, this method afforded the efficient synthesis of α-cyclopropylpyruvates in high diastereomeric ratios and enantiomeric excess (up to 99% ee). The ketoester moiety in the cyclopropane products can be used to synthesize diverse optically pure cyclopropane derivatives. Furthermore, the enzymatically obtained α-cyclopropylpyruvate products could be converted into enantiopure cyclobutenoates via a metal-free photochemical ring expansion without loss of optical activity.

Dirhodium-Catalyzed Enantioselective Synthesis of Difluoromethylated Cyclopropanes via Enyne Cycloisomerization.

(Difluoromethylated cyclopropane represents an important motif, which is widely found in bioactive and functional molecules. Despite significant progress in modern chemistry, the atom-economic and enantioselective synthesis of difluoromethylated cyclopropanes is still challenging. Herein, an Rh2 (II)-catalyzed asymmetric enyne cycloisomerization is described to construct chiral difluoromethylated cyclopropane derivatives with up to 99% yield and 99% ee in low catalyst loading (0.2 mol%), which can be easily transformed into highly functionalized difluoromethylated cyclopropanes with vicinal all-carbon quaternary stereocenters by ozonolysis. Mechanistic studies and the crystal structures of alkyne-dirhodium complexes reveal that the cooperative weak hydrogen bondings between the substrates and the dirhodium catalyst may play key roles in this reaction.).

Electro-generated base from amide derivative enables cyclopropanation of alkyl 2-chloroacetate without formation of trialkyl propane-1,2,3-carboxylate

Abstract Electro-generated base was found to be quite effective for the formation of cyclopropane derivatives from alkyl 2-chloroacetates in good yields, without the formation of trialkyl propane-1,2,3-carboxylates of the inseparable by-product. The reaction optimization for electro-generated bases as well as scope and limitations were conducted for the current report.

Front Cover: Photocatalyzed Energy Transfer for Atom Economical Synthesis of O‐Bridged Tricyclo‐Fused Cyclopropane Derivatives (Eur. J. Org. Chem. 45/2023)

Front Cover: Photocatalyzed Energy Transfer for Atom Economical Synthesis of O‐Bridged Tricyclo‐Fused Cyclopropane Derivatives (Eur. J. Org. Chem. 45/2023)

Photocatalyzed Energy Transfer for Atom Economical Synthesis of O‐Bridged Tricyclo‐Fused Cyclopropane Derivatives

AbstractHerein, we have disclosed a feasible approach to access oxygen bridged tricycle‐fused cyclopropane derivatives via visible light mediated photocatalyzed energy transfer process. This protocol describes one step multi‐fused ring formation under mild reaction conditions to furnish a wide range of the fused cyclopropane derivatives in moderate to high yields with excellent diastereoselectivities.

Stereoselective Synthesis of Cyclopropane Derivatives from Mixtures of (E)- and (Z)-Enol Acetates

Stereoselective Synthesis of Cyclopropane Derivatives from Mixtures of (E)- and (Z)-Enol Acetates

Taming of Furfurylidenes by Chiral Bismuth‐Rhodium Paddlewheel Catalysts. Preparation and Functionalization of Optically Active 1,1‐Disubstituted (Trifluoromethyl)cyclopropanes

AbstractAlthough 2‐furyl‐carbenes (furfurylidenes) are prone to instantaneous electrocyclic ring opening, chiral [BiRh]‐paddlewheel complexes empowered by London dispersion allow (trifluoromethyl)furfurylidene metal complexes to be generated from a bench‐stable triftosylhydrazone precursor. These reactive intermediates engage in asymmetric [2+1] cycloadditions and hence open entry into valuable trifluoromethylated cyclopropane or ‐cyclopropene derivatives in optically active form, which are important building blocks for medicinal chemistry but difficult to make otherwise.

Taming of Furfurylidenes by Chiral Bismuth-Rhodium Paddlewheel Catalysts. Preparation and Functionalization of Optically Active 1,1-Disubstituted (Trifluoromethyl)cyclopropanes.

Although 2-furyl-carbenes (furfurylidenes) are prone to instantaneous electrocyclic ring opening, chiral [BiRh]-paddlewheel complexes empowered by London dispersion allow (trifluoromethyl)furfurylidene metal complexes to be generated from a bench-stable triftosylhydrazone precursor. These reactive intermediates engage in asymmetric [2+1] cycloadditions and hence open entry into valuable trifluoromethylated cyclopropane or -cyclopropene derivatives in optically active form, which are important building blocks for medicinal chemistry but difficult to make otherwise.