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Showing papers on "Cyclopropane published in 2021"


Journal ArticleDOI
TL;DR: In this article, the authors describe their contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits.
Abstract: Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH3 bond with fluorine or a fluorinated group (such as CF3 or CF2H) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent. In the past decade, we have sought to develop new routes for the stereoselective synthesis of these building blocks using the most reliable cyclopropanation methods and convenient and readily available starting materials. The challenge that had to be undertaken was how we could use the unique properties of the fluorine atom to improve upon the efficiency of a given process rather than shutting it down. This could be overcome by defining new substrate/reagent reactivity guidelines and carefully selecting whether the fluorinated group was introduced on the electrophilic or nucleophilic partner for a given reaction. In this Account, we describe our contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits. Our initial investigation relied on the development of a Michael-initiated ring closure reaction using the Reformatsky enolate derived from readily available ethyl dibromofluoroacetate and α,β-unsaturated electrophiles. The reaction proceeded extremely well but with modest to good diastereoselectivities with ester acrylates. Further extension to various fluorinated nucleophiles such as oxazolidinone based and DABCO ylides led to similar selectivities.In order to access enantioenriched fluorocyclopropanes, we then investigated the chiral dioxaborolane mediated zinc carbenoid based approaches using the fluoroiodomethylzinc carbenoid/allylic alcohol combination or the iodomethylzinc carbenoid/fluoroallylic alcohol combination. Quite surprisingly, both approaches were equally successful at providing the corresponding fluorocyclopropanes with excellent diastereo- and enantioselectivities.To broaden the scope of fluorinated cyclopropane building blocks that could be prepared with good enantiocontrol, we then investigated the rhodium-catalyzed cyclopropanation of fluoro-, difluoromethyl-, and trifluoromethyl-substituted alkenes with acceptor-acceptor and donor-acceptor diazo reagents. Depending on the substrate/reagent combination, Hashimoto's Rh2((S)-TCPTTL)4 or Davies' Rh2((S)-BTPCP)4 catalyst proved be the most efficient catalysts providing the cyclopropane derivatives with the highest enantioselectivities.More recently, a collaboration with Fasan's group led to the use of engineered myoglobins to catalyze the reaction of ethyl diazoacetate and difluoromethyl-substituted alkenes. This biocatalyzed process led to high turnover number and high enantioselectivities.Although our work has significantly increased the number of tools in the organic chemist's toolbox, continuous efforts in this area would be beneficial to the development of diastereo- and enantioselective approaches to allow the preparation of any elusive isomers of these valuable chiral building blocks.

33 citations


Journal ArticleDOI
TL;DR: In this article, the authors proposed a triple role of protic ionic liquids with nucleophilic anions: a regenerable solvent, a Bronsted acid inducing diverse transformations via general acid catalysis and a source of a nucleophile.
Abstract: We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Bronsted acid inducing diverse transformations via general acid catalysis, and c) a source of a nucleophile. The efficiency of this strategy was demonstrated using thiocyanate-based protic ionic liquids for the ring-opening of donor-acceptor cyclopropanes. A wide variety of activated cyclopropanes were found to react with 1-methylimidazolium thiocyanate under mild metal-free conditions via unusual nitrogen attack of the ambident thiocyanate ion on the electrophilic center of the three-membered ring affording pyrrolidine-2-thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms, respectively, in a single time-efficient step. The ability of 1-methylimidazolium thiocyanate to serve as a triplex reagent was exemplarily illustrated by (4+2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopropane, epoxide ring-opening and other organic transformations.

32 citations


Journal ArticleDOI
TL;DR: A facile route to polysubstituted 2-pyrones from readily available 2-acylcyclopropane-1-aryl-1 carboxylates mediated by TfOH is reported in this article.
Abstract: A facile route to polysubstituted 2-pyrones from readily available 2-acylcyclopropane-1-aryl-1-carboxylates mediated by TfOH is reported. The strongly donating 1-aryl group is important for directing the C–C bond cleavage of the donor-acceptor cyclopropane ring, which then leads to the formation of the 2-pyrone ring through lactonization.

29 citations


Journal ArticleDOI
TL;DR: A palladium-catalyzed intermolecular cascade (4+3) cyclocondensation of salicylaldehydes and vinylcyclopropanes is reported in this paper.
Abstract: A palladium-catalyzed intermolecular cascade (4+3) cyclocondensation of salicylaldehydes and vinylcyclopropanes is reported. A key feature of the reaction is the use of a phosphonate group as an acceptor moiety on the cyclopropane, exploiting its propensity to undergo olefination with aldehydes. Subsequent O-allylation enabled the formation of a range of substituted benzoxepinsWith a novel chiral ligand, the products were obtained in generally good yield and with reasonable enantioselectivity.

25 citations


Journal ArticleDOI
TL;DR: In this paper, the authors investigated the origin of selectivity in the N-heterocyclic carbene (NHC)-catalyzed transformation of formylcyclopropane with an alkylidene oxindole.

23 citations


Journal ArticleDOI
TL;DR: In this article, an efficient copper(I)-catalyzed enyne oxidation/cyclopropanation for the modular synthesis of cyclopropane derivatives is described, which represents the first non-noble metal-catalystzed enynes oxidation and compropanization by the in situ generated α-oxo copper carbenes.

16 citations


Journal ArticleDOI
TL;DR: In this article, a charge inversion ion/ion chemistry in the gas phase was applied to the de novo elucidation of unknown cardiolipins in a biological extract revealing distinct isomeric populations and regiochemical relationships between double bonds and carbocyles.

16 citations


Journal ArticleDOI
TL;DR: The radical 1,5-chloropentafluorosulfanylation of vinyl cyclopropanes (VCPs) initiated by Et3B/O2 affords allylic pentafluoroulfanyl/homoallylic chloride products through the ring-strain release of the cyclopricane as mentioned in this paper.
Abstract: The radical 1,5-chloropentafluorosulfanylation of vinyl cyclopropanes (VCPs) initiated by Et3B/O2 affords allylic pentafluorosulfanyl/homoallylic chloride products through the ring-strain release of the cyclopropane. The VCP substitution pattern was investigated. The utility of this reaction was illustrated in post-transformation of the C═C bond by ozonolysis, giving access to valuable α-SF5 carbonyl compounds.

15 citations


Journal ArticleDOI
TL;DR: In this paper, it was shown that cyclopropanases can remove the 4-proS-H of 6-nitronorleucine during the cyclization, establishing the inversion and retention of the configuration at C4 during the BelL and HrmJ reactions.
Abstract: Belactosins and hormaomycins are peptide natural products containing 3-(2-aminocyclopropyl)alanine and 3-(2-nitrocyclopropyl)alanine residues, respectively, with opposite stereoconfigurations of the cyclopropane ring. Herein we demonstrate that the heme oxygenase-like enzymes BelK and HrmI catalyze the N-oxygenation of l-lysine to generate 6-nitronorleucine. The nonheme iron enzymes BelL and HrmJ then cyclize the nitroalkane moiety to the nitrocyclopropane ring with the desired stereochemistry found in the corresponding natural products. We also show that both cyclopropanases remove the 4-proS-H of 6-nitronorleucine during the cyclization, establishing the inversion and retention of the configuration at C4 during the BelL and HrmJ reactions, respectively. This study reveals the unique strategy for stereocontrolled cyclopropane synthesis in nature.

15 citations


Journal ArticleDOI
TL;DR: In this paper, a zinc-catalyzed β-allylation of cyclopropanols with MBH carbonates with retention of the cycloproane ring was reported.
Abstract: We report herein a zinc-catalyzed β-allylation of cyclopropanols with Morita-Baylis-Hillman (MBH) carbonates with retention of the cyclopropane ring. The reaction is promoted by a zinc aminoalkoxide catalyst, affording cyclopropyl-fused α-alkylidene-δ-valerolactone derivatives in moderate to good yields. Mechanistic experiments suggest that the present reaction does not proceed via direct β-C-H cleavage of the cyclopropanol, but involves zinc homoenolate and its enolization to generate a key bis-nucleophilic species. α-Allylation of this "enolized homoenolate" with MBH carbonate would be followed by regeneration of the cyclopropane ring and irreversible lactonization. The enolized homoenolate mechanism has also been proven to allow for β-functionalization with alkylidenemalononitrile as the reaction partner. A sequence of the present reaction and known cyclopropanol transformation provides an opportunity to transform a simple cyclopropanol into α,β- or β,β-difunctionalized ketones.

15 citations


Journal ArticleDOI
TL;DR: A trityl-cation-initiated annulation of benzyl-substituted vinylcyclopropanes (VCPs) with hydrosilanes is reported, which leads to an unprecedented silicon-containing 6/6/5-fused ring system.
Abstract: A trityl-cation-initiated annulation of benzyl-substituted vinylcyclopropanes (VCPs) with hydrosilanes is reported. Two Si–C(sp3) bonds and one C(sp2)–C(sp3) bond are formed in this process where an intramolecular 6-endo-tet Friedel–Crafts alkylation of a silylium-ion-activated cyclopropane ring is the rate-determining key step. The reaction mechanism is proposed based on computations and is in agreement with experimental observations. The new reaction leads to an unprecedented silicon-containing 6/6/5-fused ring system. A phenethyl-substituted VCP derivative yields another unknown tricycle having 6/6/6 ring fusion by reacting in a related but different way involving a 6-exo-tet ring closure.

Journal ArticleDOI
TL;DR: In this paper, the prezizane-type sesquiterpene agarozizanol B was synthesized employing a photochemical cascade reaction as the key step.
Abstract: The prezizane-type sesquiterpene agarozizanol B was synthesized employing a photochemical cascade reaction as the key step. Starting from a readily available 1-indanone with a tethered olefin, a strained tetracyclic skeleton was assembled which contained all carbon atoms of the sesquiterpene with the correct relative configuration. The conversion into the tricyclic prezizane skeleton was accomplished by a strategic cyclopropane bond cleavage. Prior to the cyclopropane ring opening an adaption of the oxidation state was required, which could be combined with a reductive resolution step. After removal of two functional groups, the natural product was obtained both in racemic form or, if resolved, as the (+)-enantiomer which was shown to be identical to the natural product.

Journal ArticleDOI
TL;DR: In this paper, a convenient route to 3-and 5-ylidenebutenolides from readily available cis-2-acylcyclopropane-1-carboxylates is described.

Journal ArticleDOI
TL;DR: In this article, a tertiary cyclopropyl carbagermatranes were obtained by the zinc-mediated decarboxylation of NHP esters, and they exhibited efficient reactivity in the palladium-catalyzed cross-coupling reaction and orthogonal reactivity with boron reagents.

Journal ArticleDOI
TL;DR: In this paper, a donor-acceptor cyclopropane with 6-amino-1,3-dimethyluracil was found to proceed as a three-membered ring opening via nucleophilic attack of the C(5) atom of an ambident nucleophile serving as an enamine equivalent.
Abstract: A scandium trifluoromethanesulfonate-catalyzed reaction of donor-acceptor cyclopropanes with 6-amino-1,3-dimethyluracil was found to proceed as three-membered ring opening via nucleophilic attack of the C(5) atom of an ambident nucleophile serving as an enamine equivalent. It was shown that, under basic conditions, the obtained products underwent cyclization to 6,7-dihydro-1H-pyrimido[4,5-b]azepine-2,4,8-triones, an interesting subclass of nucleobase analogues.

Journal ArticleDOI
TL;DR: Various substrates were converted into the corresponding multi-substituted cyclohexenones in good yields via decarboxylation, followed by 6-membered ring formation involving cyclopropane-ring-opening.

Journal ArticleDOI
TL;DR: In this article, it was shown that the [2+1] cycloaddition reaction of a metal carbene with an alkene can produce important cyclopropane products for synthetic intermediates, materials, and pharmaceutical applications.
Abstract: The [2+1] cycloaddition reaction of a metal carbene with an alkene can produce important cyclopropane products for synthetic intermediates, materials, and pharmaceutical applications. However, this reaction is often accompanied by side reactions, such as coupling and self-coupling, so that the yield of the cyclopropanation product of non-silver transition-metal carbenes and hindered alkenes is generally lower than 50 %. To solve this problem, the addition of a low concentration of diazo compound (decomposition of sulfonyl hydrazones) to alkenes catalyzed by either CuOAc or PdCl2 was studied, but side reactions could still not be avoided. Interestingly, however, the yield of cyclopropanation products for such hindered alkenes were as high as 99 % with AgOTf as a catalyst. To explain this unexpected phenomenon, reaction pathways have been computed for four different catalysts by using DFT. By combining the results of these calculations with those obtained experimentally, it can be concluded that the efficiency of the silver catalyst is due to the barrierless concerted cycloaddition step and the kinetic inhibition of side reactions by a high concentration of alkene.

Journal ArticleDOI
TL;DR: An alternative mechanism that begins with a Ni2-mediated oxidative coupling of (Me3Si)CHN2 and the diene generates the cyclopropane product is proposed that reproduces the experimentally observed regioselectivity and diastereoselectivities of the reaction.
Abstract: (NDI)Ni2 catalysts (NDI=naphthyridine-diimine) promote cyclopropanation reactions of 1,3-dienes using (Me3 Si)CHN2 . Mechanistic studies reveal that a metal carbene intermediate is not part of the catalytic cycle. The (NDI)Ni2 (CHSiMe3 ) complex was independently synthesized and found to be unreactive toward dienes. Based on DFT models, we propose an alternative mechanism that begins with a Ni2 -mediated coupling of (Me3 Si)CHN2 and the diene. N2 extrusion followed by radical C-C bond formation generates the cyclopropane product. This model reproduces the experimentally observed regioselectivity and diastereoselectivity of the reaction.

Journal ArticleDOI
TL;DR: The first total synthesis of shagenes was reported in this paper, where tricyclic terpenoids containing a cis-substituted cyclopropane were synthesized via ring-closing metathesis of an enamide and Ir-catalyzed double-bond isomerization of an alkylidenecyclopropANE.
Abstract: We report the first total synthesis of shagenes A and B, which are tricyclic terpenoids containing a cis-substituted cyclopropane, via ring-closing metathesis of an enamide and Ir-catalyzed double-bond isomerization of an alkylidenecyclopropane. Chemo- and diastereoselectivity in the distorted cis-substituted structures were controlled by the alkylidenecyclopropane reactivity and using the ketone functionality as a remote directing group for the Ir catalyst, respectively. The total synthesis suggested the absolute configuration of shagenes.

Journal ArticleDOI
TL;DR: In this paper, the rotational spectrum of cyclopropanone and triphenylphosphorane is presented for the first time, and the two lowest energy vibrationally excited states, ν17 and ν27, form a Coriolis-coupled dyad displaying small a-and b-type resonances.
Abstract: The gas-phase rotational spectrum of (cyanomethylene)cyclopropane, (CH2)2C═CHCN, generated by a Wittig reaction between the hemiketal of cyclopropanone and (cyanomethylene)triphenylphosphorane, is presented for the first time. This small, highly polar nitrile is a cyclopropyl-containing structural isomer of pyridine. The rotational spectra of the ground state and two vibrationally excited states were observed, analyzed, and least-squares fit from 130 to 360 GHz. Over 3900 R-, P-, and Q-branch, ground-state rotational transitions were fit to low-error, partial octic, A- and S-reduced Hamiltonians, providing precise determinations of the spectroscopic constants. The two lowest-energy vibrationally excited states, ν17 and ν27, form a Coriolis-coupled dyad displaying small a- and b-type resonances. Transitions for these two states were measured and least-squares fit to a two-state, partial octic, A-reduced Hamiltonian in the Ir representation with nine Coriolis-coupling terms (Ga, GaJ, GaK, GaJJ, Fbc, FbcJ, FbcK, Gb, and GbJ). The observation of many resonant transitions and nine nominal interstate transitions enabled a very accurate and precise energy difference between ν17 and ν27 to be determined: ΔE17,27 = 29.8975453 (33) cm-1. The spectroscopic constants presented herein provide the foundation for future astronomical searches for (cyanomethylene)cyclopropane.

Journal ArticleDOI
TL;DR: Peyssonnoside A is a marine-derived sulfated diterpenoid glucoside with a unique 5/6/3/6 tetracyclic skeleton with a highly substituted cyclopropane ring deeply embedded into the structure.
Abstract: Peyssonnoside A is a marine-derived sulfated diterpenoid glucoside with a unique 5/6/3/6 tetracyclic skeleton with a highly substituted cyclopropane ring deeply embedded into the structure. Herein,...

Journal ArticleDOI
TL;DR: A carbene-catalyzed formal umpolung of donor-acceptor cyclopropanes is described in this paper, where the cyclop-ropane moiety is connected to an acetyl aldehyde that can be activated by a carbene catalyst.
Abstract: A carbene-catalyzed formal umpolung of donor–acceptor (D–A) cyclopropanes is disclosed. The cyclopropane moiety is connected to an acetyl aldehyde that can be activated by a carbene catalyst. The initially electrophilic carbon attached to the donor group of the D–A cyclopropane aldehyde is inverted to form a nucleophilic reaction center. A subsequent reaction with isatins via a formal [3 + 2] process forms lactones bearing multiple functional groups with excellent enantio- and diastereoselectivities.

Journal ArticleDOI
TL;DR: In this paper, the authors describe the diastereoselective synthesis of α-epoxy-trans-disubstituted cyclopropane and α-hydroxy-trans disubstitizedcyclopropane using the Wadsworth-Emmons protocol.

Journal ArticleDOI
TL;DR: The first asymmetric total synthesis of (+)-talassimidine and (+-talassamine, two hetidine-type C20-diterpenoid alkaloids, was reported in this article.
Abstract: Here, we report the first asymmetric total synthesis of (+)-talassimidine and (+)-talassamine, two hetidine-type C20-diterpenoid alkaloids. A highly regio- and diastereoselective 1,3-dipolar cycloaddition of an azomethine ylide yielded a chiral tetracyclic intermediate in high enantiopurity, thus providing the structural basis for asymmetric assembly of the hexacyclic hetidine skeleton. In this key step, the introduction of a single chiral center induces four new continuous chiral centers. Another key transformation is the dearomative cyclopropanation of the benzene ring and subsequent SN2-like ring opening of the resultant cyclopropane ring with water as a nucleophile, which not only establishes the B ring but also precisely installs the difficult-to-achieve equatorial C7-OH group.

Journal ArticleDOI
28 Jan 2021-Synlett
TL;DR: In this article, the authors reported a new strategy for fluorinated cyclopropane synthesis using a nickel-catalyzed intramolecular cross-electrophile coupling reaction between a difluoromethyl moiety and a benzylic ether.
Abstract: Herein, we report a new strategy for fluorinated cyclopropane synthesis. Photocatalytic olefin difluoromethylation is coupled with a nickel-catalyzed intramolecular cross-electrophile coupling (XEC) reaction between a difluoromethyl moiety and a benzylic ether. To the best of our knowledge, this is the first example of a XEC reaction employing a difluoromethyl group as an electrophile. A plausible mechanism is highlighted, and DFT calculations are included to support the observed stereochemical outcome.


Journal ArticleDOI
TL;DR: In this article, the stereoselective and short-step synthesis of N-protected allo-carnosadine, ent-and carnosadines lactam was accomplished from a common cyclopropane intermediate.
Abstract: 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.


Journal ArticleDOI
TL;DR: In this paper, a direct stereodivergent route toward the synthesis of the four possible configurations of 4-spirocyclopropane furanoses, which have been transformed into the corresponding 4'-spirocyclic adenosine analogues, was reported.
Abstract: Cyclopropane fusion of the only rotatable carbon-carbon bond in furanosyl nucleosides (i.e., exocyclic 4'-5') is a powerful design strategy to arrive at conformationally constrained analogues. Herein, we report a direct stereodivergent route toward the synthesis of the four possible configurations of 4-spirocyclopropane furanoses, which have been transformed into the corresponding 4'-spirocyclic adenosine analogues. The latter showed differential inhibition of the protein methyltransferase PRMT5-MEP50 complex, with one analogue inhibiting more effectively than adenosine itself, demonstrating the utility of rationally probing 4'-5' side chain orientations.

Journal ArticleDOI
TL;DR: In this article, a mild photoredox-catalyzed intramolecular cyclopropanation of alkenes with α-bromo-β-keto esters in an aqueous medium was developed.
Abstract: A mild photoredox-catalyzed intramolecular cyclopropanation of alkenes with α-bromo-β-keto esters in an aqueous medium was developed. The sequential reaction process comprising the intramolecular radical addition of α-bromo-β-keto esters to olefins under photoredox catalysis, and subsequent cyclization to form cyclopropane proceeds in one-pot under exceptionally mild conditions at room temperature in the presence of 2,6-lutidine. A broad range of substrates consisting of various alkenes and both base- and acid-sensitive functionalized esters were feasible under the reaction conditions, resulting in a wide range of functionalized bicyclic cyclopropanes.