Kinugasa Reaction Research Articles

ChemInform Abstract: First Application of Fluorinated Nitrones for the Synthesis of Fluoroalkylated β‐Lactams via the Kinugasa Reaction.

The regioselective reactions of fluorinated nitrones with selected terminal alkynes (Kinugasa reaction) was studied in the presence of Cu(I) iodide and TEA as a base. After chromatographic purification the desired β-lactams were obtained in high yields (up to 93%) and high diastereoselectivities (up to 9:1). The reactions performed in the presence of chiral, enantiomerically pure ligands led to enantiomerically enriched products (ee values up to 26%) obtained as one of the possible diastereoisomers depending on the type of chiral ligand used.

ChemInform Abstract: Studies on the Enantioselective Kinugasa Reaction: Efficient Synthesis of β‐Lactams Catalyzed by N‐PINAP/CuX Complexes.

AbstractNoteworthy, the Cu salt is shown to have big influence on the enantioselectivity of the Kinugasa reaction in the presence of N‐PINAP ligands.

First application of fluorinated nitrones for the synthesis of fluoroalkylated β-lactams via the Kinugasa reaction

The regioselective reactions of fluorinated nitrones with selected terminal alkynes (Kinugasa reaction) was studied in the presence of Cu(I) iodide and TEA as a base. After chromatographic purification the desired β-lactams were obtained in high yields (up to 93%) and high diastereoselectivities (up to 9:1). The reactions performed in the presence of chiral, enantiomerically pure ligands led to enantiomerically enriched products (ee values up to 26%) obtained as one of the possible diastereoisomers depending on the type of chiral ligand used.

ChemInform Abstract: A New Direct Synthesis of α‐Methylene‐ and α‐Alkylidene‐β‐lactams.

AbstractThe application of the Kinugasa reaction to alkynes bearing a nucleofuge in propargylic position gives a very direct entry to α‐methylene‐ and α‐alkylidene‐β‐lactams.

Application of diethyl ethynephosphonate for the synthesis of 3-phosphonylated β-lactams via Kinugasa reaction

The easily available diethyl ethynylphosphonate reacts with diverse aldonitrones under Kinugasa reaction conditions at room temperature, providing 3-phosphonylated beta-lactams in good yields. In all cases, the reaction led to the trans-isomer exclusively. The trans-configuration was assigned based on 1H-NMR spectroscopic analysis.

ChemInform Abstract: Synthesis of Fluorine‐Containing Exoalkylidene β‐Lactams.

AbstractPropargylic gem‐difluorides are applied to the Kinugasa reaction affording novel exoalkylidene β‐lactams with a fluorine in the vinylic position.

Elucidation of Mechanisms and Selectivities of Metal-Catalyzed Reactions using Quantum Chemical Methodology.

Quantum chemical techniques today are indispensable for the detailed mechanistic understanding of catalytic reactions. The development of modern density functional theory approaches combined with the enormous growth in computer power have made it possible to treat quite large systems at a reasonable level of accuracy. Accordingly, quantum chemistry has been applied extensively to a wide variety of catalytic systems. A huge number of problems have been solved successfully, and vast amounts of chemical insights have been gained. In this Account, we summarize some of our recent work in this field. A number of examples concerned with transition metal-catalyzed reactions are selected, with emphasis on reactions with various kinds of selectivities. The discussed cases are (1) copper-catalyzed C-H bond amidation of indoles, (2) iridium-catalyzed C(sp(3))-H borylation of chlorosilanes, (3) vanadium-catalyzed Meyer-Schuster rearrangement and its combination with aldol- and Mannich-type additions, (4) palladium-catalyzed propargylic substitution with phosphorus nucleophiles, (5) rhodium-catalyzed 1:2 coupling of aldehydes and allenes, and finally (6) copper-catalyzed coupling of nitrones and alkynes to produce β-lactams (Kinugasa reaction). First, the methodology adopted in these studies is presented briefly. The electronic structure method in the great majority of these kinds of mechanistic investigations has for the last two decades been based on density functional theory. In the cases discussed here, mainly the B3LYP functional has been employed in conjunction with Grimme's empirical dispersion correction, which has been shown to improve the calculated energies significantly. The effect of the surrounding solvent is described by implicit solvation techniques, and the thermochemical corrections are included using the rigid-rotor harmonic oscillator approximation. The reviewed examples are chosen to illustrate the usefulness and versatility of the adopted methodology in solving complex problems and proposing new detailed reaction mechanisms that rationalize the experimental findings. For each of the considered reactions, a consistent mechanism is presented, the experimentally observed selectivities are reproduced, and their sources are identified. Reproducing selectivities requires high accuracy in computing relative transition state energies. As demonstrated by the results summarized in this Account, this accuracy is possible with the use of the presented methodology, benefiting of course from a large extent of cancellation of systematic errors. It is argued that as the employed models become larger, the number of rotamers and isomers that have to be considered for every stationary point increases and a careful assessment of their energies is therefore necessary in order to ensure that the lowest energy conformation is located. This issue constitutes a bottleneck of the investigation in some cases and is particularly important when analyzing selectivities, since small energy differences need to be reproduced.

Studies on the Enantioselective Kinugasa Reaction: Efficient Synthesis of β‐Lactams Catalyzed by N‐PINAP/CuX Complexes

AbstractCatalytic enantioselective Kinugasa reactions between acyclic and, for the first time, cyclic nitrones and terminal alkynes are described herein. A catalytic amount of the readily available PINAP/CuX complexes, generated in situ, efficiently catalyzed the Kinugasa reactions, leading to a series of β‐lactams with good enantioselectivities and moderate diastereoselectivities and yields. A broad range of nitrones and terminal alkynes, including the seldom reported alkyl‐substituted alkynes, were tolerated under the reaction conditions. Further investigations proved that the PINAP/CuX catalytic system enabled the synthesis of monobactams on the gram scale (without loss of stereoselectivity and yield) and also both enantiomers by the appropriate choice of readily available atropisomeric N‐PINAP ligands.

A new direct synthesis of α-methylene- and α-alkylidene-β-lactams

The Kinugasa reaction applied to alkynes bearing a nucleofuge in propargylic position affords directly, and in fair yields, α-methylene- or α-alkylidene-β-lactams.

Cu(i) mediated Kinugasa reactions of α,β-unsaturated nitrones: a facile, diastereoselective route to 3-(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones

A facile and highly diastereoselective synthesis ofcis-3-(hydroxyl/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-onesviacopper(i) mediated Kinugasa reactions of previously unexplored functionalized α,β-unsaturated nitrones.

Diastereoselective synthesis of β-lactams via Kinugasa reaction of acyclic chiral nitrones

An approach to β-lactams via a Kinugasa reaction between chiral copper acetylides and chiral acyclic nitrones bearing either 1,3-dioxane or 1,3-dioxolane moieties is reported. The stereochemical preferences observed in these reactions are discussed. The reaction provides access to a variety of interesting β-lactam structures. Electronic circular dichroism in combination with NMR spectroscopy was shown to be a useful and effective method for the reliable determination of the absolute configuration of all components of a complex mixtures of azetidinones. The effectiveness of the chiral analysis of complex mixtures was demonstrated for HPLC coupled on-line with electronic circular dichroism detection as well.

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction.

A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the β-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic β-lactam structures related to monobactams and nocardicins.

Synthesis of Fluorine‐Containing Exoalkylidene β‐Lactams

AbstractThe Kinugasa reaction, applied to propargylic gem‐difluorides, allows a very direct and efficient synthesis of new exoalkylidene β‐lactams with a fluorine in the vinylic position.

Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction.

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the β-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

ChemInform Abstract: A New Approach to the Synthesis of 4‐Phosphonylated β‐Lactams.

AbstractA Kinugasa reaction between phosphonylated nitrones and terminal alkynes leads to the title compounds as mixtures of only partially separable diastereomers.

Kinugasa reactions in water: from green chemistry to bioorthogonal labelling.

The Kinugasa reaction has become an efficient method for the direct synthesis of β-lactams from substituted nitrones and copper(I) acetylides. In recent years, the reaction scope has been expanded to include the use of water as the solvent, and with micelle-promoted [3+2] cycloadditions followed by rearrangement furnishing high yields of β-lactams. The high yields of stable products under aqueous conditions render the modified Kinugasa reaction amenable to metabolic labelling and bioorthogonal applications. Herein, the development of methods for use of the Kinugasa reaction in aqueous media is reviewed, with emphasis on its potential use as a bioorthogonal coupling strategy.

Theoretical study of mechanism and stereoselectivity of catalytic Kinugasa reaction.

The mechanism of the catalytic Kinugasa reaction is investigated by means of density functional theory calculations. Different possible mechanistic scenarios are presented using phenanthroline as a ligand, and it is shown that the most reasonable one in terms of energy barriers involves two copper ions. The reaction starts with the formation of a dicopper-acetylide that undergoes a stepwise cycloaddition with the nitrone, generating a five-membered ring intermediate. Protonation of the nitrogen of the metalated isoxazoline intermediate results in ring opening and the formation of a ketene intermediate. This then undergoes a copper-catalyzed cyclization by an intramolecular nucleophilic attack of the nitrogen on the ketene, affording a cyclic copper enolate. Catalyst release and tautomerization gives the final β-lactamic product. A comprehensive study of the enantioselective reaction was also performed with a chiral bis(azaferrocene) ligand. In this case, two different reaction mechanisms, involving either the scenario with the two copper ions or a direct cycloaddition of the parent alkyne using one copper ion, were found to have quite similar barriers. Both mechanisms reproduced the experimental enantioselectivity, and the current calculations can therefore not distinguish between the two possibilities.

A New Approach to the Synthesis of 4-Phosphonylated β-Lactams

The general and efficient method for the synthesis of 4-phosphonylated β-lactams from <i>N</i>-methyl-<i>C</i>-(diethoxyphosphonyl)nitrone and selected terminal alkynes via Kinugasa reaction was reported. Application of microwave irradiation significantly shortened the reaction time. Stereochemistry of diastereoisomeric products was established based on vicinal H3–H4 couplings in the β-lactam ring.

Side Arm Strategy for Catalyst Design: Modifying Bisoxazolines for Remote Control of Enantioselection and Related

In asymmetric catalysis, the remote control of enantioselection is usually difficult due to the long distance communication between the chiral center of the catalyst and the reactive site of the substrate. The development of efficient and highly enantioselective catalysts for such reactions is of great importance and highly desirable. The stereocontrol over an asymmetric reaction is a delicate process (ca. 3.0 kcal/mol difference in transition states can lead to >99/1 enantiomeric selectivity at room temperature), it therefore requires fine-tuning on the electronic nature of the central metal together with a precisely created cavity to accommodate the substrates and reagents. We envision that a solution is the design of new catalysts by finding an easy and efficient way to tune the electronic properties, the chiral space, and the shape of the catalytic site. Since an extra coordination group in the organometallic complex could not only alter the microenvironment around the metal center in a three-dimensional manner but also tune the electronic properties of the metal center, about 10 years ago, we introduced a side arm strategy for ligand/catalyst design. This Account describes our efforts toward this goal. Based on this side arm strategy, we have developed two series of ligands based on the bisoxazoline framework; namely, trisoxazoline (TOX) ligands and side armed bisoxazoline (SaBOX). The "side arms" are shown to play multiple roles in different cases, for example, as a ligating group, a steric group, or a directing group, which are dependent on the metal and the functionality at the side arm. Metal catalysts based on these ligands have proven to be highly efficient for a number of asymmetric transformations, including Friedel-Crafts reaction, Kinugasa reaction, Nazarov reaction, 1,2-Stevens rearrangement, Cannizzaro reaction, and cyclopropanation. In comparison with the parent BOX ligands, the metal catalysts based on these TOX and SaBOX ligands usually exhibit higher efficiency and diastereo- and enantioselectivity with better impurity tolerance and stability. Moreover, in several TOX-metal complex catalyzed reactions such as Friedel-Crafts reaction and [3 + 2] cycloaddition, stereoselectivity could be switched based on reaction conditions. These ligands were particularly prominent in the remote controls of enantioselection such as the conjugate additions to alkylidene malonates and ring-opening/cyclization cascades of cyclopropanes, for which high stereoselectivity is usually difficult to achieve due to the poor chiral communication. The works by us and other groups have demonstrated that the side arm strategy can be employed as a general principle for ligand and catalyst design and should not be limited to the BOX scaffolds and the reactions described in this Account. Wide application of the new strategy in organometallic homogeneous catalysis can be anticipated.

Synthesis of 18F‐Labelled β‐Lactams by Using the Kinugasa Reaction

Owing to their broad spectrum of biological activities and low toxicity, β-lactams are attractive lead structures for the design of novel molecular probes. However, the synthesis of positron emission tomography (PET)-isotope-labelled β-lactams has not yet been reported. Herein, we describe the simple preparation of radiofluorinated β-lactams by using the fast Kinugasa reaction between (18)F-labelled nitrone [(18)F]-1 and alkynes of different reactivity. Additionally, (18)F-labelled fused β-lactams were obtained through the reaction of a cyclic nitrone 7 with radiofluorinated alkynes [(18)F]-6 a,b. Radiochemical yields of the Kinugasa reaction products could be significantly increased by the use of different Cu(I) ligands, which additionally allowed a reduction in the amount of precursor and/or reaction time. Model radiofluorinated β-lactam-peptide and protein conjugates ([(18)F]-10 and (18)F-labelled BSA conjugate) were efficiently obtained in high yield under mild conditions (aq. MeCN, ambient temperature) within a short reaction time, demonstrating the suitability of the developed method for radiolabelling of sensitive molecules such as biopolymers.