Intermolecular Pauson-Khand Reaction Research Articles

The Intermolecular Pauson‐Khand Reaction: Applications, Challenges, and Opportunities

AbstractThe rapid assembly of complex organic molecules from simple and structurally diverse building blocks is a prevalent challenge in organic synthesis. The Pauson‐Khand reaction (PKR) is a method of choice for the construction of five membered rings that has historically been popularized as a late‐stage intramolecular cyclization method. The intermolecular version of the PKR, on the other hand, constitutes a powerful approach for the rapid assembly of densely functionalized cyclopentanic cores at early stages of a synthetic sequence. Despite its potential, the intermolecular PKR is much less prevalent in the organic synthesis literature due to several historical limitations, most importantly a reduced scope with respect to the alkene component of the reaction. The last decade has witnessed important developments in the area including a) experimental and theoretical studies that provide a good mechanistic understanding of the reaction and its selectivity, b) methodological developments that have broadened the scope of potential alkene partners, and c) the development of catalytic enantioselective versions that provide useful levels of enantioselectivity. In parallel, remarkable synthetic applications of the intermolecular PKR have emerged, including (enantioselective) total syntheses of complex natural products (polycyclic terpenes, alkaloids, prostanes) as well as examples of industrial relevance. A fundamental limitation of the PKR that needs to be addressed in the future is the current lack of a ligand‐accelerated version of the reaction, which would be a promising advance towards developing more efficient and general catalytic (enantioselective) reactions.

Advances in the cobalt-catalysed Pauson-Khand reaction: Development of a sulfide-promoted, microwave-assisted protocol

The development of a sulfide-promoted, microwave-assisted Pauson-Khand reaction has enabled the formation of fused cyclopentenones using sub-stoichiometric quantities of a cobalt mediator over rapid reaction times and with no requirement for an external source of toxic carbon monoxide gas. This protocol displays applicability to both intra- and intermolecular Pauson-Khand reaction examples.

Carbamate as an accelerating group in intermolecular Pauson-Khand reaction

The Pauson-Khand reaction (PKR) is a powerful means for the construction of cyclopentenones. However, its applications have been limited to the intramolecular version of this reaction because poor yield and regioselectivity are often the major problems in intermolecular PKR. Here we describe that a carbamate moiety in alkene substrate accelerates this intermolecular PKR. The reaction of N-4-dimethylaminophenyl O-allyl carbamate with alkyne-cobalt complex gave cyclopentenones in high yield (up to 90%) and regioselectivity (>9:1).

Access to Highly Functionalized Cyclopentenones via Diastereoselective Pauson-Khand Reaction of Siloxy-Tethered 1,7-Enynes.

A diastereoselective Co2(CO)8-mediated Pauson-Khand reaction (PKR) of siloxy-tethered 1,7-enynes for the synthesis of cyclopentaoxasilinones has been developed. This transformation can be performed on a multigram scale and is characterized by a broad substrate scope, functional group compatibility, and high chemo- and diastereoselectivity. Oxidation of the resulting cyclopentaoxasilinones delivers stereoenriched β-alkylated cyclopentenones, which are inaccessible by intermolecular PKRs. This research provides a practical solution to the challenges associated with the classical intermolecular PKR.

Total Synthesis of ( R)-Sarkomycin Methyl Ester via Regioselective Intermolecular Pauson-Khand Reaction and Iridium-Catalyzed Asymmetric Isomerization.

A new five-step enantioselective synthesis of ( R)-sarkomycin methyl ester is described. The cyclopentane scaffold was built by a regioselective intermolecular Pauson-Khand reaction. Enantioselectivity was introduced by a novel Ir-catalyzed isomerization reaction. The last steps involved a catalytic hydrogenation of the exocylic double bond, followed by the deprotection and elimination of the amino group. This route is the shortest enantioselective synthesis of this antibiotic reported to date.

Intermolecular Pauson–Khand reactions of N-substituted maleimides

Co2(CO)8-mediated intermolecular Pauson–Khand reactions of N-substituted maleimides with terminal alkynes are described, producing maleimide-fused cyclopentenones. The transformation differs from other intermolecular Pauson–Khand-type reactions of electron-deficient olefins, which react with Co2(CO)8 and alkynes to produce conjugated dienes, or generally require terminal, monosubstituted olefins to generate cyclopentenones. The reaction works well for N-benzyl, N-aryl, and N-alkyl substituted maleimides, and tolerates branching at the 3-position of the terminal alkyne. N–H maleimide, N–CO2Me maleimide, and maleic anhydride do not take part in the transformation.

Magic Additive for intermolecular Pauson–Khand Reactions

Magic Additive for intermolecular Pauson–Khand Reactions

Cycloaddition Reactions of Cobalt-Complexed Macrocyclic Alkynes: The Transannular Pauson-Khand Reaction.

The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2 + 2 + 1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Macrocyclic enyne and dienyne complexes were readily synthesized by palladium(II)-catalyzed oxidative macrocyclizations of bis(vinyl boronate esters) or ring-closing metathesis reactions followed by complexation with dicobalt octacarbonyl. Several reaction modalities of these macrocyclic complexes were uncovered. In addition to the first successful transannular Pauson-Khand reactions, other intermolecular and transannular cycloaddition reactions included intermolecular Pauson-Khand reactions, transannular [4 + 2] cycloaddition reactions, intermolecular [2 + 2 + 2] cycloaddition reactions, and intermolecular [2 + 2 + 1 + 1] cycloaddition reactions. The structural and reaction requirements for each process are presented.

Ethylene Glycol Assisted Intermolecular Pauson–Khand Reaction

The use of ethylene glycol as additive in the N-oxide-promoted intermolecular Pauson–Khand reaction (PKR) has been studied. The addition of 15% ethylene glycol to the reaction mixture consistently increased (from 20% up to 2–4-fold) the reaction yields.

Synthesis, Coordination Study, and Catalytic Pauson–Khand Reactions of QuinoxP*(CO)4-μ-Alkyne Dicobalt Complexes

The coordination of the P-stereogenic and sterically demanding bisphosphine QuinoxP* to μ-alkyne dicobalt hexacarbonyl complexes was studied experimentally and computationally. Whereas the coordination occurred exclusively in a chelating fashion, the diastereoselectivity was highly substrate dependent. However, it could be explained from the computed structure and energies of the different coordination modes. The fluxional behavior of these complexes was also studied computationally. Their performance as catalysts for the Pauson–Khand reaction was explored, and outstanding reactivity was observed. Although the asymmetric induction was low to moderate, the stereochemical outcome could be mechanistically rationalized. This report provides promising results in terms of reactivity and mechanistic understanding for further developments of highly active chiral catalysts for intermolecular Pauson–Khand reactions.

A catalytic scalable Pauson-Khand reaction in a plug flow reactor.

A catalytic, scalable intra- and intermolecular Pauson-Khand reaction protocol using generally 5 mol% of Co2(CO)8 as the catalyst in a plug flow reactor (PFR) is shown.

ChemInform Abstract: The Pauson—Khand Reaction Using Alkynylboronic Esters: Solving a Long‐Standing Regioselectivity Issue.

AbstractFor the first time, an intermolecular Pauson—Khand reaction between norbornadiene and internal alkynylboronic esters allows the installation of the boronic ester moiety at the β‐position of the resulting cyclopentenone with total regio‐ and stereoselectivity.

Intermolecular versus intramolecular Pauson-Khand reaction in gas phase: Limitation and feasibility

The intermolecular Pauson-Khand reaction has been reproduced in the gas phase by using electrospray ionization coupled to modified tandem mass spectrometry. It has been found, as in solution, that the use of a strained alkene is preferred because of its relatively high reactivity. To observe the final cyclopentenone product, the cobaltacycle produced after a first ion-molecule reaction must necessarily collide with CO. Furthermore, when competition between an inter versus an intra-molecular reaction is possible, the intermolecular reaction is favored.

The Pauson-Khand reaction using alkynylboronic esters: solving a long-standing regioselectivity issue.

The first intermolecular Pauson-Khand reaction, conducted using internal alkynylboronic esters, allows the installation of the boronic ester moiety at the β-position of the cyclopentenone with total regio- and stereoselectivity.

Chiral diphosphine derivatives of alkylidyne tricobalt carbonyl clusters – A comparative study of different cobalt carbonyl (pre)catalysts for (asymmetric) intermolecular Pauson–Khand reactions

Reaction of the tricobalt carbyne cluster [Co3(μ3-CH)(CO)9] with chiral diphosphines of the Josiphos and Walphos families affords the new clusters [Co3(μ3-CH)(CO)7(P–P∗)] in good yield (P–P∗=J004 (1), J005 (2), J007 (3), W001 (4), W003 (5)). The new alkylidyne tricobalt clusters, and the previously known [Co3(μ3-CH)(CO)7(μ-J003)], have been tested as catalysts/catalyst precursors for intermolecular Pauson–Khand cyclization, using norbornene and phenylacetylene as substrate. The diphosphine-substituted tricobalt carbonyl clusters proved to be viable catalysts/catalyst precursors that gave products in moderate to good yields, but the enantiomeric excesses were low. When the chiral diphosphine ligands were used as promoters/auxiliary ligands for the same Pauson–Khand reaction, using either [Co2(CO)8] or [Co4(CO)12] as catalyst precursors, both the overall yields and the selectivities with respect to cyclopentenone formation were significantly improved. The best results were obtained for ligands J007 and W001, with [Co4(CO)12] as pre-catalyst, where yields of 96%, and virtually 100% selectivity were obtained. However, the enantioselectivity of product formation was low or non-existent. The crystal structure of [Co3(μ3-CH)(CO)7(μ-J004)] is described. [J003=[(R)-1-{(S)-2-(dicyclohexylphosphino)-ferrocenyl} ethyldicyclohexylphosphine], J004=[(R)-1-{(S)-2-(dicyclohexylphosphino)-ferrocenyl} ethyldiphenylphosphine], J005=[(R)-1-{(S)-2-(diphenylphosphino)ferrocenyl}ethyl-di-3,5-xylylphosphine], J007=[(R)-1-{(S)-2-di-(4-methoxy-3,5-dimethylphenyl)phosphino)ferrocenyl} ethyldicyclohexylphosphine], W001=[(R)-1-{(R)-2-(2′-diphenyl phosphinophenyl)ferrocenyl} ethyldi(bis-3,5-trifluoromethylphenyl)phosphine], W003 [(R)-1-{(R)-2-(2′-diphenylphosphino-phenyl)ferrocenyl}ethyldi(3,5-xylyl)phosphine].

Regioselectivity of intermolecular Pauson-Khand reaction of aliphatic alkynes: experimental and theoretical study of the effect of alkyne polarization.

Generally judged poor electronic regioselectivity of alkyne insertion in intermolecular Pauson-Khand reaction (PKR) has severely restricted its synthetic applications. In our previous rational study concerning diarylalkynes (Fager-Jokela, E.; Muuronen, M.; Patzschke, M.; Helaja, J. J. Org. Chem. 2012, 77, 9134-9147), both experimental and theoretical results indicated that purely electronic factors, i.e., alkyne polarization via resonance effect, induced the observed modest regioselectivity. In the present work, we substantiate that the alkyne polarization via inductive effect can result notable, synthetically valuable regioselectivity. Computational study at DFT level was performed to disclose the electronic origin of the selectivity. Overall, the NBO charges of alkynes correlated qualitatively with regioisomer outcome. In a detailed computational PKR case study, the obtained Boltzmann distributions of the transition state (TS) populations correlate closely with experimental regioselectivity. Analysis of the TS-structures revealed that weak interactions, e.g., hydrogen bonding and steric repulsion, affect the regioselectivity and can easily override the electronic guidance.

ChemInform Abstract: A Concise Formal Synthesis of (‐)‐Hamigeran B (XIV).

AbstractThe sequence starts with the synthesis of cyclopentenone (IV) by intermolecular Pauson—Khand reaction of (I) with an excess of Me2S as promoter.

ChemInform Abstract: Asymmetric Intra‐ and Intermolecular Pauson—Khand Reactions: The Chiral Auxiliary Approach

AbstractReview: 104 refs.

Synthesis and Application of β‐Substituted Pauson–Khand Adducts: Trifluoromethyl as a Removable Steering Group

Against the rules: The synthesis of the previously unknown β-substituted regioisomers of the intermolecular Pauson–Khand reaction of terminal alkynes is reported. This regiochemistry was achieved by using the trifluoromethyl group as a removable directing group on the alkyne.

General Approach to Prostanes B1 by Intermolecular Pauson–Khand Reaction: Syntheses of Methyl Esters of Prostaglandin B1 and Phytoprostanes 16‐B1‐PhytoP and 9‐L1‐PhytoP

AbstractA synthetic approach to the methyl esters of Prostaglandin B1 and Phytoprostanes 16‐B1‐PhytoP (PPB1‐I) and 9‐L1‐PhytoP (PPB1‐II) based on the modified Julia olefination of a formylcyclopentenone and an appropriately protected hydroxy sulfone has been developed. The cyclopentenones were efficiently prepared by intermolecular Pauson–Khand reaction of a (silyloxymethyl)alkyne. The sulfone counterpart was prepared by regioselective ring‐opening of the appropriate chiral epoxides by 2‐mercaptobenzothiazole. The protecting group for the alcohol functionality on the sulfone proved to be crucial. Protection as a tert‐butyl ether was the best solution, giving better results than a tert‐butyldimethylsilyl ether.