Cyclopropane Intermediates Research Articles

Alkynes to (Free) Carbenes to Polycyclic Cyclopropanes.

Carbenes and carbenoids are commonly employed for the synthesis of cyclopropane-containing compounds. Here we report the metal-free, intramolecular cyclopropanation of tethered alkenes by free carbenes derived from alkynes to construct structurally unique multicyclic cyclopropanes with perfect atom economy. The nature of the tether influences both the rate of carbene formation and subsequent competing reaction events. Some of the substrates lead to metastable cyclopropane intermediates that further fragment to furnish interesting isomeric products by mechanistically novel processes. A removable siloxane tether can be utilized to achieve formal intermolecular cyclopropanations and to access cyclopropanol derivatives.

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.

Selective C−H Bond Functionalization of Unprotected Indoles by Donor‐Acceptor Carbene Insertion

AbstractCopper catalysts containing alkoxydiaminophosphine (ADAP) ligand catalyze the selective C3−H functionalization of unprotected indoles upon carbene transfer from donor‐acceptor diazo compounds, the N−H bond remaining unaltered during the transformation. Mechanistic studies, including DFT calculations, allows proposing the existence of two competitive pathways, none of them occurring through the formation of cyclopropane intermediates, at variance with previously reported systems.

Theoretical study of the rearrangement reaction in bisorbicillinoid biosynthesis: insights into the molecular mechanisms involved.

Bisorbibutenolide and bisorbicillinolide are polyketide compounds with complex skeletons that are formed by the dimerization of sorbicillin. These compounds have long been of interest, with several reports of their biosynthesis, biological activity, and total synthesis. In this study, we theoretically investigated the detailed biosynthetic mechanism of the rearrangement reaction to form bisorbicillinolide. We showed that the presence of water molecules facilitates the intramolecular aldol reaction, determined the rate-limiting steps, and revealed that a cyclopropane intermediate is formed during the rearrangement process. Although computational chemistry has been widely applied to the carbocation chemistry present in terpene biosynthesis, it has seldom been used to investigate the carbonyl chemistry responsible for polyketide biosynthesis. This study shows that computational chemistry is a useful tool for studying anionic skeletal rearrangement reactions.

Stereoselective Synthesis of 1-Aminocyclopropanecarboxylic Acid Carnosadines via Inter-intramolecular Double Alkylation with Optically Active 2-Methylaziridine Derivatives.

The stereoselective and short-step synthesis of N-protected allo-carnosadine, ent-carnosadine, and carnosadine lactam was accomplished from a common cyclopropane intermediate. The inter-intramolecular double alkylation of diethyl malonate with an optically active 2-methylaziridine derivative gave the key cyclopropane in excellent yield and optical purity. The following monohydrolysis of the diester moiety using different reaction conditions provided both diastereomers of monoacids, which were converted to three carnosadine derivatives in 5-6 steps from the common diester.

Reaction of 3-Oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate with Dimethylsulfoxonium Methylide.

We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.

C-C Bond Cleavages of Cyclopropenes: Operating for Selective Ring-Opening Reactions.

This review highlights key reactivities relying on C-C bond cleavages of cyclopropenes. Metal-catalyzed and metal-free transformations are covered in reactions involving direct ring-opening processes or transformations through nonisolable cyclopropane intermediates generated from cyclopropenes. Special emphasis is on the synthetic utility and mechanistic aspects of methodologies discussed along the revision. Different types of reactivities are covered in separate sections including generation of vinyl carbenes and their reactions, metathesis processes, heterocycles syntheses, SEAr reactions, metalation-ring opening sequences, cycloadditions involving ring-cleavages or rearrangements. The focus is on results described from 2007 to the end of 2019, yet relevant pioneering transformations are eventually included.

Synthesis of Functionalized α-Vinyl Aldehydes from Enaminones.

An efficient RhII -catalyzed synthesis of functionalized α-vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes in situ to give the aminocyclopropane intermediates. Selective C-C bond cleavage of the cyclopropane intermediates leads to formation of α-vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.

Synthesis of Functionalized α‐Vinyl Aldehydes from Enaminones

AbstractAn efficient RhII‐catalyzed synthesis of functionalized α‐vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes in situ to give the aminocyclopropane intermediates. Selective C−C bond cleavage of the cyclopropane intermediates leads to formation of α‐vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.

Possible Intermediacy of Cyclopropane Complexes in the Isomerization of Aliphatic Amine Radical Cations.

The isomerization of aliphatic amine radical cations via intermediate [cyclopropane-NH3]+• and [cyclopropane-amine]+• ion-neutral complexes was studied experimentally with double-focusing mass spectrometers and computationally with composite ab initio methods. The results examine and extend Audier's suggestion that primary amine radical cations with alkyl substituents at the β- and/or γ-carbon atoms isomerize via transient complexes of NH3 and alkyl cyclopropanes; these are formed by ring closure of the easily accessible γ-distonic isomers. Ionized amines with substituents at the α-carbon may react analogously when trialkyl cyclopropane complexes can be formed. Isomerization via complex intermediates is a major reaction pathway when the internal energy of the amine radical cation is less than that required for simple CC-bond cleavage. Complexes of unsubstituted or monosubstituted ionized cyclopropanes rarely contribute to the isomerization reactions. Secondary and tertiary amine radical cations do not undergo isomerization via cyclopropane intermediates, whereas aliphatic ether radical cations do.

Characterization of Natural Colibactin-Nucleobase Adducts by Tandem Mass Spectrometry and Isotopic Labeling. Support for DNA Alkylation by Cyclopropane Ring Opening.

Colibactins are genotoxic secondary metabolites whose biosynthesis is encoded in the clb gene cluster harbored by certain strains of gut commensal Escherichia coli. Using synthetic colibactin analogues, we previously provided evidence that colibactins alkylate DNA by addition of a nucleotide to an electrophilic cyclopropane intermediate. However, natural colibactin-nucleobase adducts have not been identified, to the best of our knowledge. Here we present the first identification of such adducts, derived from treatment of pUC19 DNA with clb + E. coli. Previous biosynthetic studies established cysteine and methionine as building blocks in colibactin biosynthesis; accordingly, we used cysteine (Δ cysE) and methionine (Δ metA) auxotrophic strains cultured in media supplemented with l-[U-13C]Cys or l-[U-13C]Met to facilitate the identification of nucleobases bound to colibactins. Using MS2 and MS3 analysis, in conjunction with the known oxidative instability of colibactin cyclopropane-opened products, we were able to characterize adenine adducts derived from cyclopropane ring opening. This study provides the first reported detection of nucleobase adducts derived from clb + E. coli and lends support to our earlier model suggesting DNA alkylation by addition of a nucleotide to an electrophilic cyclopropane.

Gold‐Catalyzed Formal C−C Bond Insertion Reaction of 2‐Aryl‐2‐diazoesters with 1,3‐Diketones

The transition-metal-catalyzed formal C-C bond insertion reaction of diazo compounds with monocarbonyl compounds is well established, but the related reaction of 1,3-diketones instead gives C-H bond insertion products. Herein, we report a protocol for a gold-catalyzed formal C-C bond insertion reaction of 2-aryl-2-diazoesters with 1,3-diketones, which provides efficient access to polycarbonyl compounds with an all-carbon quaternary center. The aryl ester moiety plays a crucial role in the unusual chemoselectivity, and the addition of a Brønsted acid to the reaction mixture improves the yield of the C-C bond insertion product. A reaction mechanism involving cyclopropanation of a gold carbenoid with an enolate and ring-opening of the resulting donor-acceptor-type cyclopropane intermediate is proposed. This mechanism differs from that of the traditional Lewis-acid-catalyzed C-C bond insertion reaction of diazo compounds with monocarbonyl compounds, which involves a rearrangement of a zwitterion intermediate as a key step.

Intramolecular nucleophilic addition of carbanions generated from N-benzylamides to cyclopropenes.

An unusual reaction is described, involving a formal intramolecular nucleophilic substitution of bromocyclopropanes with nitrogen ylides generated in situ from N-benzyl carboxamides. It is shown that this reaction involves cyclopropene intermediates and allows for the facile and expeditious preparation of 3-azabicyclo[3.1.0]hexan-2-one scaffolds.

Cyclopropane Intermediates from Insertion Reactions of Platinum–Carbenes: A Route to Heterospiranes

Heteroaromatic-anchored enynals with a pendent alkene group were successfully cyclized through a Huisgen-type [3+2] cycloaddition to give a tetracyclic Pt–carbene complex that underwent insertion into the C–H bond in the β-position to give fused cyclopropanes that are otherwise inaccessible. On heating, the cyclopropanes smoothly rearranged to form the corresponding heterospiranes with excellent levels of stereoselectivity and high yields.

Isolation of a Reactive Cyclopropane Intermediate via a Unique Catalyst-Free Spontaneous Cyclopropanation Step at 0 °C.

A remarkably mild, catalyst-free cyclopropanation reaction is confirmed by low-temperature isolation of a fused bicyclic cyclopropane intermediate. This intermediate is one of two that were isolated and fully characterised in a three-step temperature-controllable reaction cascade.

What causes the nonclassical structure of 2-norbornyl ion?

A recent publication of a general carbocation rearrangement mechanism highlighted protonated cyclopropane (PCP+) intermediates, whose structures are meso between the nonclassical hypotheses of edge-PCP+ and corner-PCP+. Unlike the nonclassical structures, which possess 3-centre–2-electron bonds, the meso-PCP+ structures appear as closed classical structures. The 2-norbornyl ion, however, is known to have a nonclassical corner-PCP+ structure, and here we explore (using computational chemistry) the reasons why. The main reasons are due to the three 5-membered carbon rings, whose ring strain resist relaxation to a meso-PCP+ structure, but an additional reason is the trisubstitution on one side of the PCP+ face, which causes unfavourable C–C bond eclipsing.

ChemInform Abstract: Highly Regioselective Tandem Formal Substitution and Decarboxylation of 2‐Acyl‐1‐chlorocyclopropanecarboxylates with Sodium Sulfinates.

This article reported a highly regioselective tandem formal nucleophilic substitution and decarboxylation reaction of alkyl 2-acyl-1-chlorocyclopropanecarboxylates with sodium sulfinates under basic conditions. Actually, alkyl 2-acyl-1-chlorocyclopropanecarboxylates could be easily converted into cyclopropene intermediates by simple 1,2-elimination of hydrogen chloride, and this highly reactive cyclopropene quickly combines with sodium sulfinate via a regioselective 1,4-Michael addition. Subsequent esterolysis and decarboxylation of the 1,4-Michael adducts afforded 1-aroylsulfonyl-2-aroylcyclopropanes in high yields. This observation firstly demonstrates that direct Michael addition of sodium sulfinates with reactive cyclopropene is really workable.

Nucleophilic Addition of Cyclopropenes

This review encompasses addition reactions of cyclopropenes proceeding with retention of the small ring as well as cascade transformations involving ring-opening. Formal nucleophilic substitution of halocyclopropanes operating via a dehydrohalogenation-addition mechanism with the formation of cyclopropene intermediates is also discussed. Relevant literature published in the period of 2005-2015 is surveyed. Keywords: Cyclopropanes, cyclopropenes, nucleophilic addition, nucleophiles, strain release.

Highly regioselective tandem formal substitution and decarboxylation of 2-acyl-1-chlorocyclopropanecarboxylates with sodium sulfinates

This article reported a highly regioselective tandem formal nucleophilic substitution and decarboxylation reaction of alkyl 2-acyl-1-chlorocyclopropanecarboxylates with sodium sulfinates under basic conditions. Actually, alkyl 2-acyl-1-chlorocyclopropanecarboxylates could be easily converted into cyclopropene intermediates by simple 1,2-elimination of hydrogen chloride, and this highly reactive cyclopropene quickly combines with sodium sulfinate via a regioselective 1,4-Michael addition. Subsequent esterolysis and decarboxylation of the 1,4-Michael adducts afforded 1-aroylsulfonyl-2-aroylcyclopropanes in high yields. This observation firstly demonstrates that direct Michael addition of sodium sulfinates with reactive cyclopropene is really workable.

Enantioselective Carbene Cascade: An Effective Approach to Cyclopentadienes and Applications in Diels–Alder Reactions

AbstractAn asymmetric carbene cascade reaction, which proceeds through carbene/alkyne metathesis and formal (3+2) cycloaddition and converts alkynyl‐tethered enol diazoacetates to chiral bicyclic cyclopentadienes, is presented; and no catalytic asymmetric version of these carbene cascade transformations has been disclosed so far. The proton signals of the cyclopropene intermediates are observed in the mechanism study, which clearly demonstrate the reaction pathways. In addition, these products are intercepted via Diels–Alder reactions to provide bridged polycyclic structures in high yields and enantioselectivities.magnified image