Cyclopropane Motif Research Articles

Simmons-Smith Cyclopropanation: A Multifaceted Synthetic Protocol toward the Synthesis of Natural Products and Drugs: A Review.

Simmons-Smith cyclopropanation is a widely used reaction in organic synthesis for stereospecific conversion of alkenes into cyclopropane. The utility of this reaction can be realized by the fact that the cyclopropane motif is a privileged synthetic intermediate and a core structural unit of many biologically active natural compounds such as terpenoids, alkaloids, nucleosides, amino acids, fatty acids, polyketides and drugs. The modified form of Simmons-Smith cyclopropanation involves the employment of Et2Zn and CH2I2 (Furukawa reagent) toward the total synthesis of a variety of structurally complex natural products that possess broad range of biological activities including anticancer, antimicrobial and antiviral activities. This review aims to provide an intriguing glimpse of the Furukawa-modified Simmons-Smith cyclopropanation, within the year range of 2005 to 2022.

Cyclopropane as an Unsaturation "Effect Isostere": Lowering the Melting Points in Lipid-like Ionic Liquids.

The replacement of unsaturation with a cyclopropane motif as a (bio)isostere is a widespread strategy in bacteria to tune the fluidity of lipid bilayers and protect membranes when exposed to adverse environmental conditions, e.g., high temperature, low pH, etc. Inspired by this phenomenon, we herein address the relative effect of the cyclopropanation, both cis and trans configurations, on melting points, packing efficiency, and order of a series of lipid-like ionic liquids via a combination of thermophysical analysis, X-ray crystallography, and computational modeling. The data indicate there is considerable structural latitude possible when designing highly lipophilic ionic liquids that exhibit low melting points. While cyclopropanation of the lipid-like ionic liquids provides more resistance to aerobic degradation than their olefin analogs, the impact on the melting point decrease is not as pronounced. Our results demonstrate that incorporating one or more cyclopropyl moieties in long aliphatic chains of imidazolium-based ionic liquids is highly effective in lowering the melting points of such materials relative to their counterparts bearing linear, saturated, or thioether side chains. It is shown that the cyclopropane moiety effectively disrupts packing, favoring formation of gauche conformer in the side chains, resulting in enhancement of fluidity. This was irrespective of the configuration of the methylene bridge, although marked differences in the effect of cis- and trans-monocyclopropanated ILs on the melting points were observed.

Cobalt‐Catalyzed Diastereo‐ and Enantioselective Hydroarylation of Cyclopropenes with Arylboronic Acids

AbstractCatalytic diastereo‐ and enantioselective hydroarylation of 3,3‐disubstituted cyclopropenes with easily accessible arylboronic acids promoted by a chiral phosphine‐Co complex is presented. Such a process represents an unprecedented Co‐catalyzed approach for direct introduction of a variety of aryl groups onto the cyclopropane motif, affording multisubstituted cyclopropanes in up to 86% yield with greater than 95 : 5 dr and 99 : 1 er.

Rapid and Modular Access to Vinyl Cyclopropanes Enabled by Air‐stable Palladium(I) Dimer Catalysis

AbstractWhile vinyl cyclopropanes are valuable functional groups in drugs or natural products as well as established precursors to trigger a rich variety of synthetic transformations, their reactive nature can make their installation via direct catalytic approaches challenging. We herein present a modular access to (di)vinyl cyclopropanes under very mild conditions and full conservation of stereochemistry, allowing access to thecisortranscyclopropane‐ as well asEorZvinyl‐stereochemical relationships. Our protocol relies on air‐stable dinuclear PdIcatalysis, which enables rapid (<30 min) and selective access to a diverse range of vinyl cyclopropane motifs at room temperature, even on gram scale.

Rapid and Modular Access to Vinyl Cyclopropanes Enabled by Air-stable Palladium(I) Dimer Catalysis.

While vinyl cyclopropanes are valuable functional groups in drugs or natural products as well as established precursors to trigger a rich variety of synthetic transformations, their reactive nature can make their installation via direct catalytic approaches challenging. We herein present a modular access to (di)vinyl cyclopropanes under very mild conditions and full conservation of stereochemistry, allowing access to the cis or trans cyclopropane- as well as E or Z vinyl-stereochemical relationships. Our protocol relies on air-stable dinuclear PdI catalysis, which enables rapid (<30 min) and selective access to a diverse range of vinyl cyclopropane motifs at room temperature, even on gram scale.

Intramolecular H-Bonds in an Organocatalyst Enabled an Asymmetric Michael/Alkylation Cascade Reaction to Construct Spirooxindoles Incorporating a Densely Substituted Cyclopropane Motif.

A cascade Michael addition/alkylation reaction between 3-chlorooxindoles and α-cyano chalcones catalyzed using a multifunctional quinine-derived aminoindanol-thiourea substance was investigated. A series of spirooxindoles incorporating a densely substituted cyclopropane motif were efficiently obtained with moderate to excellent diastereo- and enantioselectivity and further transformed to products with versatile structural diversity. Density functional theory (DFT) calculations indicated that the tentative intramolecular hydrogen bonds in the chiral catalyst were crucial for the stereocontrol.

Zinc-Mediated Transformation of 1,3-Diols to Cyclopropanes for Late-Stage Modification of Natural Products and Medicinal Agents.

A method for incorporating cyclopropane motifs into complex molecules has been developed. Herein we report a zinc dust-mediated cross-electrophile coupling reaction of 1,3-dimesylates to synthesize cyclopropanes. 1,3-Dimesylates can be readily accessed from 1,3-diols, a functionality prevalent in many natural products and medicinal agents. The reaction conditions are mild, such that functional groups, including amides, esters, heterocycles, and alkenes, are tolerated. Notably, we have demonstrated late-stage cyclopropanation of statin medicinal agents.

Localization of Carbon-Carbon Double Bond and Cyclopropane Sites in Cardiolipins via Gas-Phase Charge Inversion Reactions.

Cardiolipins (CLs) are comprised of two phosphatic acid moieties bound to a central glycerol backbone and are substituted with four acyl chains. Consequently, a vast number of distinct CL structures are possible in different biological contexts, representing a significant analytical challenge. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) has become a widely used approach for the detection, characterization, and quantitation of complex lipids, including CLs. Central to this approach is fragmentation of the [CLs - H]- or [CL - 2H]2- anions by collision-induced dissociation (CID). Product ions in the resulting tandem mass spectra confirm the CL subclass assignment and reveal the numbers of carbons and degrees of unsaturation in each of the acyl chains. Conventional CID, however, affords limited structural elucidation of the fatty acyl chains, failing to discriminate isomers arising from different site(s) of unsaturation or cyclopropanation and potentially obscuring their metabolic origins. Here, we report the application of charge inversion ion/ion chemistry in the gas phase to enhance the structural elucidation of CLs. Briefly, CID of [CL - H]2- anions generated via negative ion ESI allowed for the assignment of individual fatty acyl substituents and phosphatidic acid moieties. Next, gas-phase derivatization of the resulting CL product ions, including fatty acyl carboxylate anions, was effected with gas-phase ion/ion charge inversion reactions with tris-phenanthroline magnesium reagent dications. Subsequent isolation and activation of the charge-inverted fatty acyl complex cations permitted the localization of both carbon-carbon double bond and cyclopropane motifs within each of the four acyl chains of CLs. This approach was applied to the de novo elucidation of unknown CLs in a biological extract revealing distinct isomeric populations and regiochemical relationships between double bonds and carbocyles.

Cobalt‐Catalyzed Diastereo‐ and Enantioselective Hydroalkylation of Cyclopropenes with Cobalt Homoenolates

AbstractCatalylic diastereo‐ and enantioselective hydroalkylation of 3,3‐disubstituted cyclopropenes with Co‐homoenolate generated in situ from ring‐opening of easily accessible cyclopropanols promoted by a chiral phosphine–cobalt complex is presented. Such a process represents the unprecedented and direct introduction of a wide range of functionalized alkyl groups without the need of pre‐formation of stoichiometric amounts of organometallic reagents onto the cyclopropane motif, affording multi‐substituted cyclopropanes in up to 99 % yield with &gt;95:5 dr and 98:2 er. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.

Cobalt-Catalyzed Diastereo- and Enantioselective Hydroalkylation of Cyclopropenes with Cobalt Homoenolates.

Catalylic diastereo- and enantioselective hydroalkylation of 3,3-disubstituted cyclopropenes with Co-homoenolate generated in situ from ring-opening of easily accessible cyclopropanols promoted by a chiral phosphine-cobalt complex is presented. Such a process represents the unprecedented and direct introduction of a wide range of functionalized alkyl groups without the need of pre-formation of stoichiometric amounts of organometallic reagents onto the cyclopropane motif, affording multi-substituted cyclopropanes in up to 99 % yield with >95:5 dr and 98:2 er. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.

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.

Cyclopropanes through C–H activation

Organic Chemistry Despite the strain inherent in triangular carbon rings, these cyclopropane motifs are surprisingly common in natural products and pharmaceuticals. Their synthesis often involves the addition of highly reactive carbenes to C=C double bonds. Clemenceau et al. now report an alternative route whereby a palladium catalyst and base pluck hydrogens off of alkyl groups straddling a benzylic center, which then join together to form the third edge of the triangle. The reaction is highly sensitive to the nature of the base, with pivalate yielding the desired product and carbonate leading to a competing cyclobutene motif. J. Am. Chem. Soc. 142 , 15355 (2020).

New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: Design, synthesis and biological evaluation.

Lysine-specific demethylase 1 (LSD1) is frequently elevated in acute myeloid leukemia (AML) and often leads to tumorigenesis. In recent years, numerous LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have reached clinical trials. Most TCP derivatives were modified at the amino site of cyclopropane motif. Herein, we for the first time introduced a sulfonamide group in TCP benzene ring of series a compounds and performed a systematical study on structure and activity relationships by varying sulfonamide groups. The introduction of sulfonamide significantly increased the targeting capacity of TCP against LSD1. Moreover, we discovered that the Boc attached LSD1 inhibitors (labelled as series b compounds) substantially improved their anti-proliferation capacity towards AML cells. The intracellular thermal shift and LC-MS/MS results implied that Boc enhanced the drug lipophilicity and might be removed under the cancerous acidic environment to release the real pharmacophore, evidenced by the fact that a structurally similar but acidic inert pivaloyl to replace Boc dramatically dropped the cellular anti-proliferation effect. Finally, a benzyl group installed at the amino site to appropriately increase lipophilicity led to trans-4-(2-(benzylamino)-cyclopropyl)-N,N-diethylbenzenesulfonamide a10 that showed better anti-proliferation activity in AML cells and enzymatic inhibition against LSD1. Taken together, our work offers a novel TCP-based structure and provides a prodrug strategy for the discovery of potent LSD1 inhibitors by having appropriate lipophilicity.

Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes.

This paper describes the synthesis of a series of organic liquid crystals (LCs) containing selectively fluorinated cyclopropanes at their termini. The syntheses used difluorocarbene additions to olefin precursors, an approach which proved straightforward such that these liquid crystal candidates could be efficiently prepared. Their physical and thermodynamic properties were evaluated and depending on individual structures, they either displayed positive or negative dielectric anisotropy. The study gives some guidance into effective structure–property relationships for the design of LCs containing selectively fluorinated cyclopropane motifs.

Total Synthesis of (−)‐Pepluanol B: Conformational Control of the Eight‐Membered‐Ring System

AbstractThe first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo‐epoxidation to control the eight‐membered‐ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight‐membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.

Assembly of the 6/3/5/6 tetracyclic core of rearranged-type C19-diterpenoid alkaloids

A synthetic study toward the structurally complex rearranged-type C19-diterpenoid alkaloids leading to construction of the strained 6/3/5/6 tetracyclic core is presented. The synthesis features an intramolecular Diels–Alder cycloaddition reaction to assemble the highly substituted central cyclopropane motif, which may serve as a key strategy for the total synthesis of relevant natural product molecules.

Cobalt‐Catalyzed Diastereo‐ and Enantioselective Hydroalkenylation of Cyclopropenes with Alkenylboronic Acids

AbstractCatalytic diastereo‐ and enantioselective hydroalkenylation of 3,3‐disubstituted cyclopropenes with readily accessible alkenylboronic acids, promoted by a chiral phosphine/Co complex, is presented. Such a process constitutes the unprecedented and direct introduction of a wide range of alkenyl groups onto the cyclopropane motif to afford multisubstituted cyclopropanes in up to 95 % yield with greater than 95:5 d.r. and 99:1 e.r. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.

Cobalt-Catalyzed Diastereo- and Enantioselective Hydroalkenylation of Cyclopropenes with Alkenylboronic Acids.

Catalytic diastereo- and enantioselective hydroalkenylation of 3,3-disubstituted cyclopropenes with readily accessible alkenylboronic acids, promoted by a chiral phosphine/Co complex, is presented. Such a process constitutes the unprecedented and direct introduction of a wide range of alkenyl groups onto the cyclopropane motif to afford multisubstituted cyclopropanes in up to 95 % yield with greater than 95:5 d.r. and 99:1 e.r. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.

Peyssonnosides A-B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow.

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A–B (1–2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.01,10.05,9] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.

Photoactivated Colibactin Probes Induce Cellular DNA Damage

AbstractColibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks+ bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative “warhead” and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks+ like phenotype in HeLa cells. Furthermore, results from DNA cross‐linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.