Cyclopropane Formation Research Articles

"Cyclopropanation of Cyclopropanes": GaCl3-Mediated Ionic Cyclopropanation of Donor-Acceptor Cyclopropanes with Diazo Esters as a Route to Tetrasubstituted Activated Cyclopropanes.

A new ionic cyclopropanation process involving the addition of diazo esters to donor-acceptor cyclopropanes (DAC) activated by GaCl3 has been developed. The reactions occur via 1,2-zwitterionic gallium complexes with elimination of nitrogen in all cases to give 1,1,2,3-tetrasubstituted cyclopropanes as the main products. Also, a number of related processes with the formation of various polysubstituted cyclopropanes, alkenes, and cyclobutanes, including products of multiple diazo ester addition, have been developed. Obtained by the developed method tetrasubstituted cyclopropanes are activated cyclopropanes such as DAC and can be used for further synthesis in this capacity. Their new reaction with benzaldehyde promoted by TiCl4 and involving one of the additional functional groups has been demonstrated, which leads to five-membered lactones. The mechanisms of the occurring processes, as well as the structures and stereochemistry of a rich range of products formed, are discussed in detail.

Palladium Catalyzed Intramolecular Cyclization and C-H Activation Reaction Interesting Tool for the Synthesis of Some Exquisite Molecules

We have successfully investigated the palladium catalyzed cyclization in diene system to the formation of three unusual products. By varying the reaction conditions, we observed the formation of fused cyclopentane-cyclopropane rings, fused cyclopentane-cyclopentane rings or benzene ring formation from similar types of diene substrates. The most unexpected and unusual step, the formation of cyclopropane, was studied using density functional theory based calculations.

Stereoselective Gold(I)-Catalyzed Vinylcyclopropanation via Generation of a Sulfur-Substituted Vinyl Carbene Equivalent.

A stereoselective gold(I)-catalyzed vinylcyclopropanation of alkenes has been developed. A gold-coordinated cationic vinyl carbene species, readily generated via a rearrangement of the ethylenedithioacetal of propargyl aldehyde, reacts with a wide range of alkenes to afford thio-substituted vinylcyclopropanes. The gold-catalyzed vinyl cyclopropanation proceeds under mild conditions at room temperature and is generally selective for the formation of cis-substituted cyclopropanes. The reaction allows the formal introduction of a "naked" vinyl carbene, by subsequent chemoselective hydrodesulfurisation of the ethylenedithio-bridge. The synthetic utility of the new method is demonstrated by a short, racemic formal synthesis of the alkaloid cephalotaxin, hinging on a key vinyl cyclopropane-cyclopentene rearrangement.

Formation of Cyclopropanes via Activation of (γ-Methoxy)alkyl Gold(I) Complexes with Lewis Acids

Treatment of the gold 3-methoxy-3-phenylpropyl complex (P)AuCH2CH2CH(OMe)Ph [P = P(t-Bu)2o-biphenyl] with AlCl3 at −78 °C led to the immediate (≤5 min) formation of a 4:1 mixture of phenylcycloprop...

Corey-Chaykovsky Cyclopropanation of Nitronaphthalenes: Access to Benzonorcaradienes and Related Systems.

Nitronaphthalene derivatives react as Michael acceptors in the Corey-Chaykovsky reaction with alkyl phenyl selenones and alkyl diphenyl sulfonium salts. Mechanistic studies reveal that sterically demanding substituents at the carbanionic center favor formation of cyclopropanes and suppress competitive β-elimination to the alkylated products. The transformation, demonstrated also on heterocyclic nitroquinoline and nitroindazolines, is an example of transition metal-free dearomatization method.

Construction of All-cis-substituted Cyclopropane and Total Synthesis of Avenaol

The first total synthesis of avenaol was achieved using a new robust strategy involving all-cis-substituted cyclopropane formation via an alkylidene cyclopropane. The keys to success for the total synthesis were (i) Rh-catalyzed intramolecular cyclopropanation of an allene; (ii) Ir-catalyzed stereoselective double-bond isomerization to form an all-cis cyclopropane; and (iii) differentiation of two hydroxymethyl groups via regioselective cyclization and oxidation of tetrahydropyran based on the reactivity of cyclopropyl group. This strategy effectively avoids cyclopropane ring opening and undesired formation of a cage structure. Additionally, the proposed structure of avenaol, especially unique all-cis-substituted cyclopropane was confirmed correct by this total synthesis.

Chemical Changes On, and Through, The Bacterial Envelope in Escherichia coli Mutants Exhibiting Impaired Plasmid Transfer Identified Using Time-of-Flight Secondary Ion Mass Spectrometry.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) using a (CO2)6k+ gas cluster ion beam (GCIB) was used to analyze Escherichia coli mutants previously identified as having impaired plasmid transfer capability related to the spread of antibiotic resistance. The subset of mutants selected were expected to result in changes in the bacterial envelope composition through the deletion of genes encoding for FabF, DapF, and Lpp, where the surface sensitivity of ToF-SIMS can be most useful. Analysis of arrays of spotted bacteria allowed changes in the lipid composition of the bacteria to be elucidated using multivariate analysis and confirmed through imaging of individual ion signals. Significant changes in chemical composition were observed, including a surprising loss of cyclopropanated fatty acids in the fabF mutant where FabF is associated with the elongation of FA(16:1) to FA(18:1) and not cyclopropane formation. The ability of the GCIB to generate increased higher mass signals from biological samples allowed intact lipid A (m/z 1796) to be detected on the bacteria and, despite a 40 keV impact energy, depth profiled through the bacterial envelope along with other high mass ions including species at m/z 1820 and 2428, attributed to ECACYC, that were only observed below the surface of the bacteria and were notably absent in the depth profile of the lpp mutant. The analysis provides new insights into the action of the specific pathways targeted in this study and paves the way for whole new avenues for the characterization of intact molecules within the bacterial envelope.

Cu-catalyzed C-C bond formation of vinylidene cyclopropanes with carbon nucleophiles.

The development of Cu-catalyzed addition of carbon nucleophiles to vinylidene cyclopropanes was reported. The reactions with 1,1-bisborylmethane provided homopropargylic boronate products by forming a C-C bond at the terminal carbon atom of the allene moiety of vinylidene cyclopropanes. Alkynyl boronates are also suitable nucleophile precursors in reactions with vinylidene cyclopropanes, and skipped diynes were obtained in high yields. In addition, the Cu-enolate generated from the initial addition of nucleophilic copper species to vinylidene cyclopropanes can be intercepted by an external electrophile. As such, vinylidene cyclopropane serves as a linchpin to connect a nucleophile and an electrophile by forming two carbon-carbon bonds sequentially.

Ring‐Closing Strategy Utilizing Nitrile α‐Anions: Chiral Synthesis of (+)‐Norchrysanthemic Acid and Expeditious Asymmetric Total Synthesis of (+)‐Grandisol

Chiral syntheses of two distinct small cycloalkanes, (1R,3R)‐(1Z)‐norchrysanthemic acid and (+)‐grandisol, were performed by characteristic ring‐closing methodologies using carbanions at the α‐position of nitriles (nitrile α‐anions). (i) (1R,3R)‐(1Z)‐Norchrysanthemic acid, a highly potent ingredient of synthetic pyrethroid containing a cyclopropane structure, was synthesized from readily available (S)‐epoxide derived from 3‐methyl‐but‐2‐en‐1‐ol in 7 steps in 23 % overall yield and with > 98 % ee. This sequence involves a trans‐selective cyclopropane formation using the nitrile α‐anion of (S)‐3‐mesyloxynitrile as the key step. The present chiral synthesis was performed with effective stereocontrol of both the chirality in the 1,3‐positions on the cyclopropane and the Z‐geometry of the propenyl group. (ii) (+)‐Grandisol, an insect sex pheromone possessing a characteristic cyclobutane structure, was synthesized from commercially available cyclopropyl methyl ketone (route A) or from commercially available 3‐cyanopropylzinc bromide and 1‐bromo‐1‐methylpropene (route B) in 10 or 8 steps in 6 % or 8 % overall yield and with 80 % ee. This sequence involves a Shi asymmetric epoxidation of a trisubstituted olefin and a straightforward Stork‐type asymmetric cyclobutane formation with clean SN2 stereoinversion using the nitrile α‐anion of the chiral epoxynitrile. The present expedient method is the second asymmetric total synthesis starting from achiral compounds.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Radical-Triggered Tandem Cyclization of 1,6-Enynes with H2O: A Way to Access Strained 1 H-Cyclopropa[ b]naph thalene-2,7-diones.

A radical-triggered tandem cyclization of 1,6-enynes has been developed herein. Strained 1 H-cyclopropa[ b]naphthalene-2,7-diones are successfully obtained in moderate to good yields with excellent stereoselectivity. Mechanistic studies reveal a key role of water in generating a hydroxyl radical that initiates a sequential Michael addition/ring closure pathway. Importantly, the formed hydroxyl is proposed to be a good leaving group during the cyclopropane ring formation.

Silver-Catalyzed Regio- and Stereoselective Formal Carbene Insertion into Unstrained C−C σ-Bonds of 1,3-Dicarbonyls

SummaryA regio- and stereoselective silver-catalyzed formal carbene insertion into 1,3-dicarbonyls has been developed, using N-nosylhydrazones as diazo surrogates. Two new C−C bonds are constructed at the carbenic carbon center through the selective cleavage of the C−C(=O) σ-bond of acyclic 1,3-dicarbonyls, enabling the preparation of various synthetically useful polysubstituted γ-diketones, γ-ketoesters, and γ-ketoamides in high yields. The in situ formation of a donor-acceptor cyclopropane, via reaction of the enolate of the 1,3-dicarbonyl with an electrophilic silver carbenoid, is proposed as a key process in the catalytic cycle.

A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis

Cyclopropanation of unactivated olefinic bonds via addition of a reactive one-carbon species is well developed in synthetic chemistry, whereas natural cyclopropane biosynthesis employing this strategy is very limited. Here, we identify a two-component cyclopropanase system, composed of a HemN-like radical S-adenosyl-l-methionine (SAM) enzyme C10P and a methyltransferase C10Q, catalyzes chemically challenging cyclopropanation in the antitumor antibiotic CC-1065 biosynthesis. C10P uses its [4Fe-4S] cluster for reductive cleavage of the first SAM to yield a highly reactive 5′-deoxyadenosyl radical, which abstracts a hydrogen from the second SAM to produce a SAM methylene radical that adds to an sp2-hybridized carbon of substrate to form a SAM-substrate adduct. C10Q converts this adduct to CC-1065 via an intramolecular SN2 cyclization mechanism with elimination of S-adenosylhomocysteine. This cyclopropanation strategy not only expands the enzymatic reactions catalyzed by the radical SAM enzymes and methyltransferases, but also sheds light on previously unnoticed aspects of the versatile SAM-based biochemistry.

Pd-Catalyzed Asymmetric Cyclopropanation Reaction of Acyclic Amides with Allyl and Polyenyl Carbonates. Experimental and Computational Studies for the Origin of Cyclopropane Formation

Cyclopropanes with three chiral centers were afforded in good to high yields with dr ratio of 4–23:1 and ee of 83–99% in the reaction of acyclic amides with monosubstituted allyl carbonates as well as polyenyl carbonates under the Pd-catalysis in the presence of (Sphos,R)-SIOCPhox L1 as the ligand, while allylic alkylated products were provided only if (Rphos,R)-SIOCPhox L2 was the ligand. The amide group of product was easily reduced to hydroxymethyl group in high yield. The active reaction intermediate was determined and transition states for cyclopropanation and allylation were calculated. The origin of cyclopropane formation was investigated by experiments, NMR studies, X-ray analysis of allyl-Pd-ligand complexes, and DFT calculations.

SYNTHESIS OF HEXAHYDROPYRIDAZINE-3-ONES BY REACTIONS BETWEEN DONOR-ACCEPTOR CYCLOPROPANES AND PHENYLHYDRAZINE

The nickel perchlorate-initiated reaction between dimethyl esters of 2-aryl- and 2-styryl-substituted cyclopropane-1,1-dicarboxylic acids and phenylhydrazine proceeded with opening of the cyclopropane ring and formation of a mixture containing acyclic and cyclic products: [2-(1-phenylhydrazinyl)alkyl]malonates and 1-phenylhexahydropyridazin-3-ones. Reaction conditions were found for preparative synthesis of polyfunctional hexahydropyridazin-3-ones. Unlike the other starting materials, 2-(p-methoxystyryl)-substituted cyclopropane reacted with the terminal NH 2 group of phenylhydrazine, resulting in the formation of 1-(phenylamino)pyrrolidin-2-one.

Synthesis of hexahydropyridazin-3-ones by reactions between donor-acceptor cyclopropanes and phenylhydrazine

The nickel perchlorate-initiated reaction between dimethyl esters of 2-aryl- and 2-styryl-substituted cyclopropane-1,1-dicarboxylic acids and phenylhydrazine proceeded with opening of the cyclopropane ring and formation of a mixture containing acyclic and cyclic products: [2-(1-phenylhydrazinyl)alkyl]malonates and 1-phenylhexahydropyridazin-3-ones. Reaction conditions were found for preparative synthesis of polyfunctional hexahydropyridazin-3-ones. Unlike the other starting materials, 2-(p-methoxystyryl)-substituted cyclopropane reacted with the terminal NH2 group of phenylhydrazine, resulting in the formation of 1-(phenylamino)pyrrolidin-2-one.

Recent progress in insertion and cyclopropanation reactions of metal carbenoids from α-diazocarbonyl compounds

Metal–carbenoids from α-diazocarbonyl compounds are well-known reactive intermediates with a long history of useful applications in synthetic organic chemistry. The carbenoids, generated in situ from the catalytic decomposition of α-diazocarbonyls, react by different pathways such as insertions, cyclopropane formation, and cycloadditions of ylides, etc. in inter- and intramolecular versions of the reactions. These reactions have been employed in the architecture of several complex molecules of natural origin. The present review paper discusses the recent progress in catalytic insertion (X–H: X = C, N, O, S, Si, and B), and cyclopropane-forming reactions of α-diazocarbonyl compounds with a focus on regio-, diastereo-, and enantioselective reactions.

Asymmetric Copper‐Catalyzed Carbomagnesiation of Cyclopropenes

AbstractThe highly diastereo‐ and enantioselective formation of polysubstituted cyclopropanes was easily achieved through the asymmetric copper‐catalyzed carbomagnesiation reaction of nonfunctionalized cyclopropene derivatives. The carbometalated species generated in situ readily undergo C−C and C−X bond‐forming reactions with various electrophiles with complete retention of configuration.

Asymmetric Copper-Catalyzed Carbomagnesiation of Cyclopropenes.

The highly diastereo- and enantioselective formation of polysubstituted cyclopropanes was easily achieved through the asymmetric copper-catalyzed carbomagnesiation reaction of nonfunctionalized cyclopropene derivatives. The carbometalated species generated in situ readily undergo C-C and C-X bond-forming reactions with various electrophiles with complete retention of configuration.

Phospha-Claisen Type Reactions at Frustrated Lewis Pair Frameworks.

The C4-bridged unsaturated phosphane/borane frustrated Lewis pairs (P/B FLPs) 4 undergo borane induced phosphane addition to a variety of acetylenic esters or ketones to generate heterocyclic 10-membered intermediates that contain pairs of allyl phosphonium/allenic enolate functionalities. These subsequently undergo phospha-Claisen type rearrangement reactions to give the respective substituted phosphanyl pentadiene products. In two exceptional cases subsequent reactions leading to anomalous phospha-Claisen products were found. One example involved cyclopropane ring formation, and the other carbon-carbon bond activation. Potential mechanistic schemes leading to these products are discussed. Essential examples were characterized by X-ray diffraction.