Three-carbon Synthons Research Articles

Silylium-Ion-Promoted (3 + 2) Annulation of Allenylsilanes with Internal Alkynes Involving a Pentadienyl-to-Allyl Cation Electrocyclization.

A (3 + 2) annulation of allenyl- and, after rapid isomerization, propargylsilanes with internal 1-aryl-1-alkynes to form 4-methylenecyclopentenes is reported. The reaction is initiated by a silylium ion, and the catalytic cycle is subsequently maintained by the self-regeneration of the silylium-ion promoter. Unlike the well-established Danheiser annulation, where the allenylsilane serves as a three-carbon synthon, the present transformation engages the allenylsilane as a two-carbon synthon. Experimental observations and DFT calculations unveil a reaction cascade involving various β-silicon-stabilized carbocations, where a pentadienyl-to-allyl cation electrocyclization is the key step.

Lewis-Acid-Catalyzed (3+2) Annulation of 2-Indolylmethanols with Propargylic Alcohols to Access Cyclopenta[b]indoles.

Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

Base-Controlled Divergent Synthesis of Fluorine-Containing Benzo[4,5]imidazo[2,1-b][1,3]thiazines from 2-Mercaptobenzimidazoles and β-CF3-1,3-Enynes.

A base-controlled divergent cyclization between 2-mercaptobenzimidazoles and β-CF3-1,3-enynes providing either trifluoromethylated or fluorinated benzo[4,5]imidazo[2,1-b][1,3]thiazines has been developed. The β-CF3-1,3-enyne, as a three-carbon synthon, underwent a 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU)-catalyzed tandem hydroamination/intramolecular hydrothiolation to give CF3-substituted 3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine, whereas reaction with KOH afforded fluorinated 4H-benzo[4,5]imidazo[2,1-b][1,3]thiazine exclusively. In addition, the synthetic utility of this methodology was showcased through a variety of downstream derivatizations.

Merging Rh-Catalyzed C-H Functionalization and Cascade Cyclization to Enable Propargylic Alcohols as Three-Carbon Synthons.

Reported herein is a reactivity of propargyl alcohols as "Three-Carbon Synthons" in a Rh(III)-catalyzed C-H functionalization of acetanilides, leading to the synthesis of core structures of isocryptolepine, γ-carbolines, dihydrochromeno[2,3-b]indoles, and diindolylmethanes (DIM) derivatives. The transformation involves a rhodium(III)-catalyzed C-H functionalization and heteroannulation to yield indoles followed by a cascade cyclization with both external and internal nucleophiles to afford diverse products. The role of the hydroxy group, the key function of the silver additive, the origin of the reverse regioselectivity and the rate-determining step, are rationalized in conformity with the combination of experimental, noncovalent interaction analysis and DFT studies. This protocol is endowed with several salient features, including one-pot multistep cascade approach, exclusive regioselectivity, good functional group tolerance and synthesis of variety of molecular frameworks.

3+2] Cycloaddition of alkyl aldehydes and alkynes enabled by photoinduced hydrogen atom transfer

[3+2] Cycloaddition is a step- and atom-economic method for the synthesis of five-membered rings. Despite the great success of 1,3-dipolar cycloadditions, the radical [3+2] annulation of alkynes remains a formidable challenge. Herein, a photoinduced decatungstate-catalyzed [3+2] cycloaddition of various internal alkynes using abundant aliphatic aldehydes as a three-carbon synthon is developed, producing elaborate cyclopentanones in 100% atom economy with excellent site-, regio-, and diastereoselectivity under mild conditions. The catalytic cycle consists of hydrogen atom abstraction from aldehydes, radical addition, 1,5-hydrogen atom transfer, anti-Baldwin 5-endo-trig cyclization, and back hydrogen abstraction. The power of this method is showcased by the late-stage elaboration of medicinally relevant molecules and total or formal synthesis of (±)-β-cuparenone, (±)-laurokamurene B, and (±)-cuparene.

Selective Carbon-Carbon Bond Cleavage of Cyclopropanols.

The carbon-carbon (C-C) bond cleavage of cyclopropanols is a wide area of research with much current activity. This review highlights new developments in this area over the past two decades. A summary is made of the three main reactivity modes, namely, homoenolate chemistry, β-keto radical chemistry, and acid-catalyzed ring-opening, as well as all other methods for the C-C bond cleavage and functionalization of cyclopropanols, including base-mediated ring-opening, metal-catalyzed C-C insertions and eliminations, oxidative fragmentation using hypervalent iodine reagents, reactions of donor-acceptor cyclopropanols, and pericylic reactions. Emphasis is placed on the synthetic utility of cyclopropanols and related derivatives, which have emerged as unique three-carbon synthons.

Highly Chemoselective Esterification from O-Aminoallylation of Carboxylic Acids: Metal- and Reagent-Free Hydrocarboxylation of Allenamides.

Metal-free hydrocarboxylation of allenamides with various functionalized carboxylic acids were achieved with complete regio- and stereocontrol (>49:1). This environmentally compatible transformation affords γ-acyloxyenamides with exclusive E-selectivity. Electron rich, electron poor, aliphatic, aryl, and heterocyclic carboxylic acids all gave excellent yields (avg. 89 %, 47 examples). We demonstrate the synthetic potential of this transformation in the late-stage modification of complex natural carboxylic acids and simple modification of the products to three-carbon synthons with ample opportunity for further diversification. DFT studies revealed that the reaction occurs in a stepwise manner through the intermediacy of a conjugated iminum species, which is rapidly captured by the carboxylate ion, resulting in the observed linear selectivity.

Biomimetic 2-Imino-Nazarov Cyclizations via Eneallene Aziridination.

Amidoallyl cations are appealing three-carbon synthons for the preparation of complex amine-containing carbocycles; however, methods to generate and utilize these reactive species are limited and underexplored compared to those for oxallyl cations. Here we disclose a bioinspired strain-driven ring opening of bicyclic methyleneaziridines to 2-amidopentadienyl cation intermediates that readily engage in Nazarov cyclizations. Advantages of this strategy include ease of generation and improved reactivity compared to 3-pentadienyl cations, control over the ultimate position of the alkene, the potential for high dr between vicinal stereocenters, and the ability to further elaborate the products to fully substituted aminocyclopentanes. Experimental and computational studies support a dual role for the Rh2Ln complex as both a nitrene transfer catalyst and a Lewis acid promoter, insight that provides a framework for the future development of asymmetric 2-imino-Nazarov cyclizations.

GaCl3-Mediated "Inverted" Formal [3 + 2]-Cycloaddition of Donor-Acceptor Cyclopropanes to Allylic Systems.

A new process of "inverted" formal [3 + 2]-cycloaddition of donor-acceptor cyclopropanes (DACs) to allylic systems to give polyfunctionalized cyclopentanes has been developed. Unlike the classical version of formal [3 + 2]-cycloaddition, a DAC acts in this process as a two-carbon synthon (1,2-zwitterionic reactivity type), while an alkene acts as a three-carbon synthon. Tetramethylethylene, allylbenzenes, homoallylbenzene, terminal and internal aliphatic alkenes, and methylenecyclobutane were successfully used as alkenes. Furthermore, in order to suppress annulation at the aromatic ring in 2-arylcyclopropane-1,1-dicarboxylates and enhance the selectivity of the reaction with the allylic system of alkenes, we suggested a new approach for managing the reactivity of DACs involving substitution at both ortho positions of the aromatic ring. Multinuclear NMR spectroscopy was used to study the structure of the 1,2-zwitterionic gallium complexes generated and their properties and to examine the mechanisms of the occurring reactions.

ChemInform Abstract: Transition Metal‐Catalyzed Cycloadditions of Cyclopropanes for the Synthesis of Carbocycles: C‐C Activation in Cyclopropanes

AbstractReview: 140 refs.

Gold‐Catalyzed Cycloisomerization of Yne‐Vinylidenecyclopropanes: A Three‐Carbon Synthon for [3+2] Cycloadditions

A novel type of yne-vinylidenecyclopropanes (VDCPs) has been synthesized and applied in gold-catalyzed cycloisomerization reactions. It was found that these compounds can undergo an intramolecular cycloisomerization and perform as a three-carbon synthon for [3+2] cycloaddition under gold catalysis to give fused [4.3.0] and [5.3.0] bicyclic derivatives and VDCP rearranged products in moderated to good yields under mild conditions. The substrate scope of these novel transformations has been explored and plausible reaction mechanisms have been presented on the basis of deuterium labeling experiments and DFT calculations.

Transition metal-catalyzed cycloadditions of cyclopropanes for the synthesis of carbocycles: C-C activation in cyclopropanes.

Transition metal-catalyzed cycloadditions of cyclopropanes have been well developed over the past several decades, leading to numerous new types of cycloadditions which are complementary to the traditional cycloadditions for the synthesis of carbocycles. Cycloadditions of vinylcyclopropanes (VCPs) and methylenecyclopropanes (MCPs) constitute two main aspects of this field. VCPs can act either as five-carbon synthons or three-carbon synthons, depending on whether the vinyl substituent is acting as an additional two-carbon synthon or not. As five-carbon synthons, VCPs are involved in [5+1], [5+2], [5+2+1], and [5+1+2+1] cycloadditions. As three-carbon synthons, VCPs are mainly involved in [3+2] and [3+2+1] cycloadditions. MCPs mostly act as three-carbon synthons and can have [3+2] cycloadditions with different π systems. Other types of cycloadditions involving MCPs are also reviewed, such as [3+1], [3+2+2], and [4+3+2] cycloadditions. Cycloadditions of some other unusual cyclopropane derivatives are also introduced briefly. The cycloadditions of VCPs and MCPs have found applications in total synthesis and some representative molecules are tabulated as selected examples.

Synthesis of Tetrasubstituted Pyrazoles through Different Cyclization Strategies; Isosteres of Imidazole Fungicides

Formerly unknown 3-chloro-4,5-diaryl-1-methylpyrazoles have been prepared through two different synthesis pathways, one of which starts from 2,3-diarylacrylonitriles, the second from 3,3-dichloro-1,2-diarylpropenones. Both approaches rely on the cyclocondensation of diarylated three-carbon synthons with hydrazine derivatives and possess some unique features. One route uses a cyclization reaction, during which a chlorine atom is directly installed at the pyrazole ring that normally would be introduced in subsequent halogenation steps. The second pathway applies the Sandmeyer reaction to introduce this chloro substituent; an approach that is rarely described at the pyrazole nucleus. The obtained tetrasubstituted pyrazoles are isosteres of highly active imidazole fungicides and show good control of Uncinula necator (grape powdery mildew).

Construction of five- and six-membered heterocycles on both Cp rings of the ferrocene moiety of α-oxoketene-S,S-acetal and β-oxodithioester via heteroaromatic annulation

1,1′-Bis(1,1-dimethylsulfanyl-3-oxo-1-propene)ferrocene and 1,1′-Bis(methyl-3-hydroxy-prop-2-ene-dithioate)ferrocene have been shown to be useful three-carbon synthons for the efficient synthesis of hitherto unreported and synthetically demanding Fc-heterocycles. Five-membered (pyrazole, isoxazole, and thiophene) and six-membered (pyrimidine, coumarin, and quinoline) heterocycles have been constructed on both Cp rings of the ferrocene matrix via regioselective heteroaromatic annulation.

Rhodium(I)-Catalyzed Intramolecular [3+2] Cycloaddition of α-Ene-Vinylcyclopropanes

A novel rhodium-catalyzed intra­molecular [3+2] cycloaddition of α-ene-vinyl­cyclopropane (VCP) 1 was developed. The VCP moiety of the α-ene-VCP acts as a three-carbon synthon instead of the anticipated five-carbon synthon to provide both bicyclo[4.3.0]nonane and bicyclo[5.3.0]decane skeletons 2 in good yield and excellent diastereoselectivity.

Applications of Dithioacetals in Ester Synthesis

The α-oxoketene dithioacetals are simple synthetic intermediates widely utilized and implicated for the synthesis of a variety of heterocyclic compounds other than alicyclic and aromatic compounds. They act as 1,3-electrophilic three-carbon synthons. The α-oxoketene dithioacetal of pyrazolone derivatives can be efficiently converted through a base-catalyzed alcoholysis into the corresponding ester in a single one-step reaction with good yield of pure products. In this article, we summarize recent direct conversion of α-oxoketene dithioacetals to highly desirable esters. The overall process is an example of intramolecular rearrangement of bonds. Characterization and identification of all synthesized compounds were assigned through 1H NMR and mass spectroscopy.

Thieme Chemistry Journal Awardees - Where are They Now? Phosphine- and Water-Cocatalyzed [3+2] Cycloaddition Reactions of 2-Methyl-2,3-butadienoate with Fumarates: A Computational and Experimental Study

With the aid of computation and experiment, the phosphine- and water-cocatalyzed [3+2] cycloaddition reactions of 2-methyl-2,3-butadienoate with fumarates have been developed. In this reaction, 2-methyl-2,3-butadienoate is used as a three-carbon synthon generated through a water-catalyzed [1,4]-proton-shift process. The DFT calculations and isotopic labeling experiment have been done to explore how this [3+2] reaction occurs.

Rh(I)-Catalyzed Intramolecular [3 + 2] Cycloaddition of trans-Vinylcyclopropane-enes

Vinylcyclopropane (VCP) has been well applied as a five-carbon component, rather than a three-carbon component, in transition-metal catalyzed cycloadditions. Here we demonstrate a Rh(I)-catalyzed [3 + 2] reaction of trans-VCP-enes, where VCP acts as a three-carbon synthon to furnish five-membered carbocycles. This novel cycloaddition is efficient in generating bicyclic cyclopentanes in good yields from simple and easily prepared substrates. When cis-VCP-ene is used as the substrate, VCP acts as a five-carbon unit to give a [5 + 2] cycloadduct. Rationalization of the [3 + 2] and [5 + 2] cycloadditions of VCP-enes has been proposed.

Mechanism, Regioselectivity, and the Kinetics of Phosphine‐Catalyzed [3+2] Cycloaddition Reactions of Allenoates and Electron‐Deficient Alkenes

With the aid of computations and experiments, the detailed mechanism of the phosphine-catalyzed [3+2] cycloaddition reactions of allenoates and electron-deficient alkenes has been investigated. It was found that this reaction includes four consecutive processes: 1) In situ generation of a 1,3-dipole from allenoate and phosphine, 2) stepwise [3+2] cycloaddition, 3) a water-catalyzed [1,2]-hydrogen shift, and 4) elimination of the phosphine catalyst. In situ generation of the 1,3-dipole is key to all nucleophilic phosphine-catalyzed reactions. Through a kinetic study we have shown that the generation of the 1,3-dipole is the rate-determining step of the phosphine-catalyzed [3+2] cycloaddition reaction of allenoates and electron-deficient alkenes. DFT calculations and FMO analysis revealed that an electron-withdrawing group is required in the allene to ensure the generation of the 1,3-dipole kinetically and thermodynamically. Atoms-in-molecules (AIM) theory was used to analyze the stability of the 1,3-dipole. The regioselectivity of the [3+2] cycloaddition can be rationalized very well by FMO and AIM theories. Isotopic labeling experiments combined with DFT calculations showed that the commonly accepted intramolecular [1,2]-proton shift should be corrected to a water-catalyzed [1,2]-proton shift. Additional isotopic labeling experiments of the hetero-[3+2] cycloaddition of allenoates and electron-deficient imines further support this finding. This investigation has also been extended to the study of the phosphine-catalyzed [3+2] cycloaddition reaction of alkynoates as the three-carbon synthon, which showed that the generation of the 1,3-dipole in this reaction also occurs by a water-catalyzed process.

Synthesis of galactoglycerolipids found in the HT29 human colon carcinoma cell line

Synthesis of three galactoglycerolipids (3- O-(β- d-galactopyranosyl)-1- O-hexadecyl-2- O-palmitoyl- sn-glycerol, 3- O-(α- d-galactopyranosyl-(1→4)-β- d-galactopyranosyl)-1- O-hexadecyl-2- O-palmitoyl- sn-glycerol, 3- O-(α- d-galactopyranosyl-(1→4)-β- d-galactopyranosyl)-1- O-hexadecyl- sn-glycerol), and the corresponding glycerolipid (1- O-hexadecyl-2- O-palmitoyl- sn-glycerol) is described. The first two compounds were recently identified in the human colon carcinoma cell line HT29. The three-carbon synthon ( S)-glycidol was used for construction of the glycerol moiety. Glycosylation of ( S)-glycidol with protected galactosyl and digalactosyl donors produced galactosyl and digalactosyl glycidols. Lewis acid catalyzed opening of the epoxide produced protected galactosyl and digalactosyl glycerolipids. Deprotection, or palmitoylation followed by deprotection, yielded the target compounds. The corresponding glycerolipid was synthesized analogously and an oxidation–reduction procedure for tritiation was developed. The synthesized compounds will be used in studies of the role of galactosyl glycerolipids in differentiation and colon cancer development.