Cyclopropane Ring Opening Research Articles

Mechanistic Insights on the Selectivity of the Tandem Heck-Ring-Opening of Cyclopropyldiol Derivatives.

The preparation of a new class of alkenyl cyclopropyl diols, easily available through a copper-catalyzed carbometalation reaction of cyclopropenes, has enabled the study of key mechanistic aspects of the tandem Heck–cyclopropane ring-opening reaction. Utilizing these substrates containing two distinct hydroxyl groups allowed us to examine parameters affecting the reaction outcome and selectivity. The combination of these experimental results with detailed DFT studies shed light on the mechanism governing the regio- and stereoselectivity of the cyclopropane ring-opening. A thorough investigation displayed the dual roles fulfilled by the hydroxyl group during the reaction, which is key to this remarkable transformation. In addition to its mechanistic implication, the reaction granted access to various lactones possessing up to four stereocenters as a single diastereomer, conveniently prepared in only two catalytic steps from easily accessible achiral cyclopropenes.

1,3-Oxyalkynylation of Aryl Cyclopropanes with Ethylnylbenziodoxolones Using Photoredox Catalysis.

Alkynes and cyclopropanes are vital motifs in chemistry. Herein, a photoredox catalyzed 1,3-oxyalkynylation of aryl cyclopropanes with ethylnylbenziodoxolones (EBXs) in an atom-economic fashion is described. This cascade comprises single-electron oxidation of the aryl cyclopropane and nucleophilic ring opening followed by radical alkynylation at the benzylic position. The EBX compounds act as bifunctional reagents providing the nucleophilic acid as well as the alkynyl entity. The introduced method features mild conditions and wide substrate scope.

Dearomative Cyclopropanation of Naphthols via Cyclopropene Ring-Opening.

The dearomatization of 2-naphthols represents a simple method for the construction of complex 3D structures from simple planar starting materials. We describe a cyclopropanation of 2-naphthols that proceeds via cyclopropene ring-opening using rhodium and acid catalysis under mild conditions. The vinyl cyclopropane molecules were formed with high chemoselectivity and scalability, which could be further functionalized at different sites. Both computational and experimental evidence were used to elucidate the reaction mechanism.

Concise Total Synthesis of Agarozizanol B via a Strained Photocascade Intermediate

AbstractThe 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.

Concise Total Synthesis of Agarozizanol B via a Strained Photocascade Intermediate.

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.

Synthesis of an allylic gem-difluoromethylene building block via radical-mediated difluorocyclopropane ring opening

We report an optimised and highly efficient synthetic route towards a valuable functionalised fluorinated building block. The key-steps include difluorocyclopropanation of a disubstituted alkene with a suitable difluorocarbene precursor, and a radical-induced cyclopropane ring-opening, operating via an iodide atom transfer reaction.

Donor-Acceptor Cyclopropane Ring Opening with 6-Amino-1,3-dimethyluracil and Its Use in Pyrimido[4,5-b]azepines Synthesis.

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.

An efficient synthetic approach for the transition metal-free preparation of 2-bromo-3-(bromomethyl)naphthalene from naphthalene

In this paper, a new efficient method for the synthesis of 2-bromo-3-(bromomethyl)naphthalene is reported. The synthesis is based on (1) preparation of 1,4-dihydronaphthalene via Birch reduction with mild conditions from the reaction of naphthalene, and (2) the reaction between 1,4-dihydronaphthalene and dichlorocarbene generated in situ from chloroform and t-BuOK, and (3) access to the key intermediate 1H-cyclopropa[b]naphthalene from the reaction of 1,1-dichloro-1a,2,7,7a-tetrahydro-1H-cyclopropa[b]naphthalene with t-BuOK, followed by ring-opening of the three-membered cyclopropane by bromination with molecular bromine (Br2). This synthetic sequence allows simple preparation of 2-bromo-3-(bromomethyl)naphthalene in higher yields compared to the two previously reported syntheses. The synthetic approach is modular, low cost, and rapid, and can be utilized to synthesize building blocks of naphthalene derivatives.

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Asymmetric Total Synthesis of Hetidine-Type C20-Diterpenoid Alkaloids: (+)-Talassimidine and (+)-Talassamine.

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.

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

Protic Ionic Liquid as Reagent, Catalyst, and Solvent: 1-Methylimidazolium Thiocyanate.

We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Brønsted 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.

Discovery and Surprises with Cyclizations, Cycloadditions, Fragmentations, and Rearrangements in Complex Settings.

We discuss a number of synthesis routes to complex natural products recently reported from our group. Although the structures are quite varied, we demonstrate the research endeavor as a setting to examine the implementation of cyclizations, cycloadditions, rearrangements, and fragmentations. We showcase how the various transformations enabled access to key core structures and thereby allowed the rapid introduction of complexity. Two different routes to (-)-mitrephorone A, the first case discussed, led to the use of Koser's reagent to effect oxetane formation from diosphenol derivatives. Even though the Diels-Alder cycloaddition reaction represents one of the workhorses of complex molecule synthesis, there are opportunities provided by the complexity of secondary metabolites for discovery, study, and development. In our first approach to (-)-mitrephorone A, Diels-Alder cycloaddition provided access to fused cyclopropanes, while the second synthesis underscored the power of diastereoselective nitrile oxide cycloadditions to access hydroxy ketones. The successful implementation of the second approach required the rigorous stereocontrolled synthesis of tetrasubstituted olefins; this was accomplished by a highly stereoselective Cr-mediated reduction of dienes. The diterpenoid (+)-sarcophytin provided a stage for examining the Diels-Alder cycloaddition of two electron-deficient partners. The study revealed that in the system this unusual combination works optimally with the E,Z-dienoate and proceeds through an exo transition state to provide the desired cycloadduct. Our reported pallambin synthesis showcased the use of fulvene as a versatile building block for the core structure. Fulvene decomposition could be outcompeted by employing it as a diene and using a highly reactive dienophile, which affords a bicyclic product that can in turn be subjected to chemo- and stereoselective manipulations. The synthesis route proceeds with a C-H insertion providing the core structure en route to pallambin A and B. The studies resulting in our synthesis of gelsemoxonine highlight the use of the acid-catalyzed rearrangement/chelotropic extrusion of oxazaspiro[2.4]heptanes to access complex β-lactams, which are otherwise not readily prepared by extant methods in common use. Mechanistic investigations of the intriguing ring contraction supported by computational studies indicate that the reaction involves a concerted cleavage of the N-O bond and cyclopropane ring opening under the extrusion of ethylene. The synthesis of guanacastepenes focused on the use of cyclohexyne in [2+2]-cycloadditions with enolates. The resulting cyclobutene can be enticed to undergo ring opening to give a fused six-seven ring system. The cycloinsertion reaction of cyclohexyne developed for the first time proves useful as a general approach to complex fused ring systems.

Azide Radical Initiated Ring Opening of Cyclopropenes Leading to Alkenyl Nitriles and Polycyclic Aromatic Compounds

AbstractWe report herein a radical‐mediated amination of cyclopropenes. The transformation proceeds through a cleavage of the three‐membered ring after the addition of an azide radical on the strained double bond and leads to tetrasubstituted alkenyl nitrile derivatives upon loss of N2. With 1,2‐diaryl substituted cyclopropenes, this methodology could be extended to a one‐pot synthesis of highly functionalized polycyclic aromatic compounds (PACs). This transformation allows the synthesis of nitrile‐substituted alkenes and aromatic compounds from rapidly accessed cyclopropenes using only commercially available reagents.

Azide Radical Initiated Ring Opening of Cyclopropenes Leading to Alkenyl Nitriles and Polycyclic Aromatic Compounds.

We report herein a radical-mediated amination of cyclopropenes. The transformation proceeds through a cleavage of the three-membered ring after the addition of an azide radical on the strained double bond and leads to tetrasubstituted alkenyl nitrile derivatives upon loss of N2 . With 1,2-diaryl substituted cyclopropenes, this methodology could be extended to a one-pot synthesis of highly functionalized polycyclic aromatic compounds (PACs). This transformation allows the synthesis of nitrile-substituted alkenes and aromatic compounds from rapidly accessed cyclopropenes using only commercially available reagents.

Recent advances in ring-opening of donor acceptor cyclopropanes using C-nucleophiles.

Ring-opening transformations of donor-acceptor cyclopropanes (DAC) with carbon-centered nucleophiles is a simple, straight-forward approach to 1,3-bifunctional compounds that has witnessed remarkable progress over the past several years. To date, different reactivity patterns of DACs have been successfully exploited in racemic/stereoselective syntheses of various acyclic compounds or carbocycles with an impressive structural diversity. The thriving strategies have been successfully utilized in multistep synthesis of complex target molecules. Herein, the recent advances (2015-present) in the ring-opening of DAC involving electron rich arenes and indoles, active methylene compounds, various dipolarophiles, organoborates/boronates, vinyl ethers etc. following Friedel-Crafts alkylation, annulation/formal cycloaddition reaction, organocatalytic reaction, Nazarov cyclisation etc. are presented.

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.

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

Abstract Metal homoenolates represent uniquely useful organometallic intermediates in synthetic chemistry, allowing umpolung synthesis of β-functionalized carbonyl compounds. While siloxycyclopropanes had been established as reliable precursors to homoenolates, often stoichiometric, for diverse carbon–carbon bond forming reactions, unprotected cyclopropanols have emerged as alternative and attractive precursors to homoenolates, often catalytically generated, in carbon–carbon and carbon–heteroatom bond-forming reactions. This review article provides an overview of the development of such homoenolate transformations, as classified with respect to the metals involved in the cyclopropane ring opening.

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.

Stereoselective Synthesis of Vinylcyclopropa[b]indolines via a Rh-Migration Strategy.

A mild rhodium catalytic system has been developed to synthesize vinylcyclopropa[b]indolines through cyclopropanation of indoles with vinyl carbenoids generated from ring opening of cyclopropenes in situ. By employing a Rh-migration strategy, the products can be obtained with good to excellent E:Z ratios (≤99:1) and complete diastereoselectivity (≤99:1). This method is easy, has a low catalyst loading, and works for a broad range of functionalities.