Cyclopropane Opening Research Articles

Copper-Catalyzed 1,3-Aminocyclization of Cyclopropanes as a Rapid Entry to γ-Amino Heterocycles.

We herein report a copper-catalyzed 1,3-aminocyclization of cyclopropanes as a direct and versatile entry into important heterocycles. This reaction was initiated by a copper-catalyzed, NFSI-promoted ring opening of cyclopropanes, followed by nucleophilic cyclization. A variety of nucleophiles successfully participate in this transformation, including alcohols, carboxylic acids, sulfonamides, and amides, for the construction of diverse cyclic ethers, pyrrolidines, lactones, and iminolactones.

Photochemical Divergent Ring-Closing Metathesis of 1,7-Enynes: Efficient Synthesis of Spirocyclic Quinolin-2-ones.

A photocatalytic method for the ring-closing 1,7-enyne metathesis using the α-amino radical as an alkene deconstruction auxiliary is present. Preliminary mechanistic studies suggest that intramolecular 1,5-hydrogen atom transfer is the key to the generation and β-scission of the α-amino radical, while the dearomatization of arenes and ring opening of cyclopropanes are the key to construct spirocyclic quinolin-2-ones. This approach highlights the potential of ring-closing 1,7-enyne metathesis, providing a green, efficient, and step-economical way for the synthesis of spirocyclic quinolin-2-ones.

Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement Enabled by Pyridine-Assisted Boronyl Radical Catalysis.

An unprecedented VCP-CP (vinylcyclopropane-cyclopentene) rearrangement approach has been established herein by virtue of the pyridine-boronyl radical catalyzed intramolecular ring expansions. This metal-free radical pathway harnesses readily available catalysts and unactivated vinylcyclopropane starting materials, providing an array of cyclopentene derivatives chemoselectively under relatively mild conditions. Mechanistic studies support the idea that the boronyl radical engages in the generation of allylic/ketyl radical species, thus inducing the ring opening of cyclopropanes and the following intramolecular cyclization processes.

Conversion of Phorbol into Des-D-Ring Tricycle and Crotonianoid B via Peroxidation Reaction.

Phorbol (1) has a tetracyclic ABCD-ring and is readily isolable from a natural source. We previously synthesized 1 and 16 structurally related natural products using common ABC-ring intermediate 2. Here we report a new synthetic route to 2 using 1 as a starting material. Key features of the synthesis are chemoselective removal of the D-ring via cyclopropane opening, peroxidation, and retro-aldol reactions. The high utility of the peroxidation was further demonstrated in the first synthesis of crotonianoid B (9).

Visible light-mediated ring opening and cyclization of aryl cyclopropanes: efficient synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-ones with antineoplastic activity

This study describes an efficient and green approach for the synthesis of potentially bioactive pyrrolo[1,2-a]quinoxalin-4(5H)-ones with appreciable functional group tolerance and a wide substrate scope.

Cascade Ring-Opening/Cyclization Reaction of Spiro(nitrocyclopropane)oxindoles with Huisgen Zwitterions and Synthesis of Pyrazolo[3,4-b]indoles.

Herein, we report a ring-opening/cyclization cascade reaction of spiro(nitrocyclopropane)oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction provides an array of polyfunctionalized pyrazolo[3,4-b]indole derivatives in moderate-to-excellent yields and generally high stereoselectivities with a broad substrate scope. The annulation products obtained from di-tert-butyl azodicarboxylates can be readily transformed into aromatic-substituted pyrazolo[3,4-b]indoles in moderate yields upon treatment with trifluoroacetic acid, thus providing a new entry to this fused heterocycle skeleton. In terms of nitro-substituted donor-acceptor cyclopropane, this work significantly broadens the substrate scope for the annulation reaction of nitrocyclopropanes and HZs. The dual roles of the oxindole moiety in the ring opening of cyclopropane and a plausible mechanism for the cascade reaction are also discussed.

Visible-Light-Induced Decarboxylative Alkylation/Ring Opening and Esterification of Vinylcyclopropanes.

A visible-light-induced four-component reaction of vinylcyclopropanes, N-(acyloxy)phthalimide esters, N,N-dimethylformamide (DMF), and H2O through an oxidative ring opening of cyclopropane is presented. This procedure provides a new and effective way to construct formate esters. DMF is employed as both a solvent and the source of CHO. This difunctionalization of vinylcyclopropanes shows good functional group tolerance under room temperature. A radical pathway is involved, and carbonyl oxygen of ester originated from water in this transformation.

Visible-Light-Induced Photoannulation of α-Naphthyl Cyclopropane Carboxylic Esters to Functionalized Dihydrophenalenes.

A general synthetic entry to functionalized dihydrophenalenes has been found using naphthyl-cyclopropane esters as starting materials. The desired annulation was possible with visible light, Ir(Fppy)3 as photocatalyst, BnNMe2 or DABCO as electron donor, HAT-catalyst, and proton source. A broad scope of substituted naphthyl and azanaphthyl derivatives provided the photoannulation products in high yield. Deuteration studies support a photoredox mechanism involving the photoreductive cyclopropane opening to an enolate radical followed by an aryl radical trapping.

Enantioselective Total Synthesis and Structural Revision of Dysiherbol A.

A 12‐step total synthesis of the natural product dysiherbol A, a strongly anti‐inflammatory and anti‐tumor avarane meroterpene isolated from the marine sponge Dysidea sp., was elaborated. As key steps, the synthesis features an enantioselective Cu‐catalyzed 1,4‐addition/enolate‐trapping opening move, an Au‐catalyzed double cyclization to build up the tetracyclic core‐carbon skeleton, and a late installation of the C5‐bridgehead methyl group via proton‐induced cyclopropane opening associated with spontaneous cyclic ether formation. The obtained pentacyclic compound (corresponding to an anhydride of the originally suggested structure for dysiherbol A) showed identical spectroscopic data as the natural product, but an opposite molecular rotation. CD‐spectroscopic measurements finally confirmed that both the constitution and the absolute configuration of the originally proposed structure of (+)‐dysiherbol A need to be revised.

Ring Opening of Donor–Acceptor Cyclopropanes with Acyclic 1,3-Diketones for the Synthesis of 1,6-Dicarbonyl Compounds

1,6-Dicarbonyl compounds, representing the formal addition products of the α-position of acetophenone derivatives to donor-acceptor cyclopropanes, were synthesized in two steps via first ring opening of donor-acceptor cyclopropanes with acyclic 1,3-diketones followed by DBU catalyzed retro-Claisen-type C-C bond cleavage reactions. In the first step, acyclic 1,3-diketones selectively worked as C-nucleophiles to add to donor-acceptor cyclopropanes. In the second step, the alkyl ketone part of the ring-opening products resulting from unsymmetrical 1,3-diketones was selectively cleaved in the presence of DBU in methanol.

One-Pot Synthesis of γ-Azidobutyronitriles and Their Intramolecular Cycloadditions

Efficient gram-scale, one-pot approaches to azidocyanobutyrates and their amidated or decarboxylated derivatives have been developed, starting from commercially available aldehydes and cyanoacetates. These techniques combine (1) Knoevenagel condensation, (2) Corey–Chaykovsky cyclopropanation and (3) nucleophilic ring opening of donor-acceptor cyclopropanes with the azide ion, as well as (4) Krapcho decarboxylation or (4′) amidation. The synthetic utility of the resulting γ-azidonitriles was demonstrated by their transformation into tetrazoles via intramolecular (3+2)-cycloaddition. A condition-dependent activation effect of the α-substituent was revealed in that case. Thermally activated azide–nitrile interaction did not differentiate the presence of an α-electron-withdrawing substituent in γ-azidonitriles, whereas the Lewis acid mediated (SnCl4 or TiCl4) reaction proceeded much easier for azidocyanobutyrates. This allowed us to develop an efficient procedure for converting azidocyanobutyrates into the corresponding tetrazoles.

Catalytic Enantioselective Ring-Opening Reactions of Cyclopropanes.

This review describes the development of enantioselective methods for the ring opening of cyclopropanes. Both approaches based on the reaction of nonchiral cyclopropanes and (dynamic) kinetic resolutions and asymmetric transformations of chiral substrates are presented. The review is organized according to substrate classes, starting by the more mature field of donor-acceptor cyclopropanes. Emerging methods for enantioselective ring opening of acceptor- or donor-only cyclopropanes are then presented. The last part of the review describes the ring opening of more reactive three-membered rings substituted with unsaturations with a particular focus on vinylcyclopropanes, alkylidenecyclopropanes, and vinylidenecyclopropanes. In the last two decades, the field has grown from a proof of concept stage to a broad range of methods for accessing enantioenriched building blocks, and further extensive developments can be expected in the future.

Ring-opening reactions of donor-acceptor cyclopropanes with cyclic ketals and thiol ketals.

1,3-Cyclohexandione derived cyclic ketals and thiol ketals were used as O- and S-nucleophiles, respectively, for the ring opening of donor-acceptor cyclopropanes catalyzed by Cu(OTf)2 and a series of functionalized alkylene glycol diethers and dithiol diethers were obtained in good to high yields under mild conditions.

Ring Opening of Donor-Acceptor Cyclopropanes with Cyanide Ion and Its Surrogates.

A straightforward method for ring opening of donor-acceptor cyclopropanes with trimethylsilyl cyanide as a surrogate of cyanide ion in the presence of B(C6F5)3 or trifluoromethanesulfonic acid as a catalyst has been developed. The methodology provides a short route to γ-cyanoesters that can be useful synthetic intermediates for the synthesis of diverse bioactive molecules such as glutaric and δ-aminovaleric acid derivatives, 3-arylpiperidines, or other substituted phenethylamines. Oppositely, the attempts to synthesize these γ-cyanoesters by direct reaction of cyclopropanes with sodium cyanide under typical SN2 conditions led to the formation of 2-arylsuccinonitriles.

The Efficient Synthesis of Benzannulated Seven-Membered O-Heterocycles via the Intramolecular Ring-Opening Cyclization of Cyclopropanes.

An efficient and practical approach for the synthesis of substituted benzannulated seven-membered O-heterocycles from cyclopropane derivatives is described. The transformation proceeds via Lewis acid mediated ring opening of cyclopropanes followed by a concomitant 7-endo-tet cyclization to furnish the 4-benzoyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one derivatives in excellent yields (up to 92%). This potentially general method is featured by its high atom economy, broad substrate scope, and mild reaction conditions. Moreover, the representative products exhibited selective antifungal activity in vitro against the fungus Cryptococcus neoformans. Therefore, the present reaction will be useful for the development of novel antifungal therapeutic reagents.

Cu-Catalyzed Hydroboration of Benzylidenecyclopropanes: Reaction Optimization, (Hetero)Aryl Scope, and Origins of Pathway Selectivity.

The copper-catalyzed hydroboration of benzylidenecyclopropanes, conveniently accessed in one step from readily available benzaldehydes, is reported. Under otherwise identical reaction conditions, two distinct phosphine ligands grant access to different products by either suppressing or promoting cyclopropane opening via β-carbon elimination. Computational studies provide insight into how the rigidity and steric environment of these different bis-phosphine ligands influence the relative activation energies of β-carbon elimination versus protodecupration from the key benzylcopper intermediate. The method tolerates a wide variety of heterocycles prevalent in clinical and pre-clinical drug development, giving access to valuable synthetic intermediates. The versatility of the tertiary cyclopropylboronic ester products is demonstrated through several derivatization reactions.

Photoredox catalysed allylic trifluoromethylation via ring opening of vinyl cyclopropanes using Langlois reagent

Trifluoromethylation of vinylcyclopropanes (VCPs) has been developed under mild reaction conditions to synthesize allylic trifluoromethylated derivatives with high yield and E/Z selectivity using visible light photo-redox catalysis and Langlois reagent (CF3SO2Na) as a trifluoromethylation source. Further, we demonstrate a gram scale synthesis procedure for a trifluoromethylation of vinylcyclopropane.

Diastereoselective ring opening of fully-substituted cyclopropanes via intramolecular Friedel–Crafts alkylation

Diastereoselective ring opening of fully-substituted cyclopropanes via intramolecular Friedel–Crafts alkylation

Domino Synthesis of Thioflavones and Thioflavothiones by Regioselective Ring Opening of Donor-Acceptor Cyclopropane Using In-Situ-Generated Thiolate Anions.

A copper-catalyzed intramolecular ring opening of donor-acceptor cyclopropane is developed for the synthesis of 3-alkyl-carbonated thioflavones and further extended to 3-alkyl-carbonated thioflavothione, using xanthate as a sulfur surrogate. This reaction proceeds through thiolate formation/ring opening/Krapcho decarboxylation, followed by hydrogen abstraction, to give thioflavanone, which is further oxidized by in-situ-generated iodine from waste byproduct KI. Experimental studies prove that the charge-transfer complex is responsible for the conversion of thioketone to ketone.

Synthesis and biological evaluation of bromophenol derivatives with cyclopropyl moiety: Ring opening of cyclopropane with monoester

Trans-(1R*,2R*,3R*)-Ethyl 2-(3,4-dimethoxyphenyl)-3-methylcyclopropane-1-carboxylate (6) and its cis isomer 7 were obtained from the reaction of the methyl isoeugenol (5) with ethyl diazoacetate. The reduction and bromination reactions of the ester 6 and 7 together with the hydrolysis of all esters were carried out. Opening ring of cyclopropane was observed in the reaction of 7 with bromine. The opening of cyclopropane ring with COOR and synthesis of esters, alcohols and acids (6–26) are new. These obtained bromophenol derivatives (6–26) were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) and acetylcholinesterase (AChE) enzymes with Ki values in the range of 7.8 ± 0.9–58.3 ± 10.3 nM for hCA I, 43.1 ± 16.7–150.2 ± 24.1 nM for hCA II, and 159.6 ± 21.9–924.2 ± 104.8 nM for AChE, respectively. Acetylcholinesterase inhibitors are the most popular drugs applied in the treatment of diseases such as Alzheimer’s disease, Parkinson’s disease, senile dementia, and ataxia, among others.