Asymmetric Pauson-Khand Reaction Research Articles

Mechanism and Origins of Enantioselectivity in the Rh(I)-Catalyzed Pauson–Khand Reaction: Comparison of Bidentate and Monodentate Chiral Ligands

The narrow substrate scope of the asymmetric Pauson–Khand reaction (PKR) presently limits its synthetic utility. We recently reported an example of an enantioselective PKR with a precursor not comp...

Computationally Guided Catalyst Design in the Type I Dynamic Kinetic Asymmetric Pauson–Khand Reaction of Allenyl Acetates

The Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR could provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives, such as thapsigargin, a cytotoxic natural product with potent antitumor activity. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a dynamic kinetic asymmetric transformation (DyKAT). A combined experimental and computational approach was taken to develop an effective catalytic system to achieve the asymmetric transformation. The optimization of the denticity, and steric and electronic properties of the ancillary ligand (initially (S)-MonoPhos, 58:42 er), afforded a hemilabile bidentate (S)-MonoPhos-alkene-Rh(I) catalyst that provided α-acyloxy cyclopentenone product in up to 14:86 er. Enantioselectivity of the Rh(I)-(S)-MonoPhos-alkene catalyst was rationalized using ligand-substrate steric interactions and distortion energies in the computed transition states. This asymmetric APKR of allenyl acetates is a rare example of a Type I DyKAT reaction of an allene, the first example of DyKAT in a cyclocarbonylation reaction, and the first catalyst-controlled enantioselective APKR.

ChemInform Abstract: Bimetallic Chiral Nanoparticles as Catalysts for Asymmetric Synthesis

AbstractReview: [44 refs.

ChemInform Abstract: Total Synthesis of (‐)‐Nakadomarin A.

A highly efficient 12-step synthesis of the marine alkaloid (-)-nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson-Khand reaction, an Overman rearrangement reaction, a ring-closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (-)-nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.

Total Synthesis of (−)‐Nakadomarin A

AbstractA highly efficient 12‐step synthesis of the marine alkaloid (−)‐nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson–Khand reaction, an Overman rearrangement reaction, a ring‐closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (−)‐nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.

Total Synthesis of (-)-Nakadomarin A.

A highly efficient 12-step synthesis of the marine alkaloid (-)-nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson-Khand reaction, an Overman rearrangement reaction, a ring-closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (-)-nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.

Rhodium-Catalyzed Pauson–Khand Reaction Using a Small-Bite-Angle P-Stereogenic C1-Diphosphine Ligand

The asymmetric Pauson–Khand reaction catalyzed by [Rh(COD)(MaxPHOS)]BF4 is described. Several 1,6-enynes have been chosen as model substrates affording moderate yields and selectivities of up to 86% ee. Besides binap-type ligands, we have demonstrated that the P-stereogenic C1-symmetry small-bite-angle ligand MaxPHOS is a viable ligand in this process. The formation of [2+2+2] cycloaddition compounds has shown to be a competitive process. A mechanism is proposed to account for the observed results. The intermediate rhodium dicarbonyl complex 6 was synthesized, and its solid-state structure was elucidated by X-ray crystallography.

Catalytic Asymmetric Pauson–Khand Reaction Using Cobalt

Catalytic Asymmetric Pauson–Khand Reaction Using Cobalt

MESP: An efficient method to validate an ONIOM partition for the modelization of phosphine ligands commonly used in the Pauson–Khand reaction

In this study we discuss the modelization of phosphine ligands commonly used in inorganic and organometallic chemistry as for example the asymmetric Pauson–Khand reaction by means of ONIOM method. A fundamental question that arises after the decision of using QM/MM methods for a certain study is how to partition the system. Which atoms are going to be included in the QM region and which atoms are going to be included in the MM region? Chemical knowledge is most of the time the guiding line for this choice, but tests should be run in case of uncertainty. For the setting of the QM/MM border, two criteria have been employed: results from geometry optimizations of the ligand complexed to tungsten penta(tetra)carbonyl and calculations of the molecular electrostatic potential (MESP) for the ligand alone. We have shown that these two methods give similar conclusions and thus MESP can be used to validate the ONIOM partition of these systems. This later approach has the advantage of being fast and computationally inexpensive.

ChemInform Abstract: Asymmetric Catalytic Pauson-Khand Reactions with Chiral Phosphine Ligands: Dramatic Effects of Substituents in 1,6-Enyne Systems.

Abstract A cobalt-catalyzed reaction of 1,6-enyne systems under a carbon monoxide atmosphere using chiral phosphine ligands provides a facile entry to optically active 2-cyclopentenone derivatives. (S)-BINAP was demonstrated to be the most effective in the cobalt-catalyzed cyclization of 1,6-enynes among various chiral bidentate phosphine ligands employed, affording chiral 2-cyclopentenone derivatives with high enantioselectivity. The dramatic effects of the substituents in the 1,6-enynes were observed in this asymmetric synthesis. A plausible mechanism for the asymmetric induction is proposed on the basis of the stereochemical outcome obtained.

ChemInform Abstract: Catalytic Use of Chiral Phosphine Ligands in Asymmetric Pauson-Khand Reactions.

Abstract Catalytic asymmetric Pauson–Khand reactions with chiral bidentate phosphines as ligands have been successfully accomplished. The catalytic use of ( S )-BINAP as a ligand was demonstrated to be the most effective in the cobalt-catalyzed reactions of 1,6-enynes, providing a facile entry to optically active 2-cyclopentenone derivatives with high enantioselectivity. A plausible mechanism for the asymmetric induction is proposed on the basis of the stereochemical outcome obtained.

ChemInform Abstract: The Brucine N-Oxide Promoted Asymmetric Pauson-Khand Reaction.

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Origin of enantioselectivity in asymmetric Pauson–Khand reactions catalyzed by [(BINAP)Co 2(CO) 6

The quantum mechanics/molecular mechanics (QM/MM) ONIOM(B3LYP:UFF) approach is applied to the study of the asymmetric carbonylative intramolecular cycloaddition of a HCC–CH 2–N(Ts)–CH 2–CH CH 2 enyne (Ts = tosyl) catalyzed by [(BINAP)Co 2(CO) 6] (BINAP = (1,1′-binaphtalene)-2,2′,diylbis(diphenylphosphine)). The experimental results, showing formation of the R product when the S-BINAP ligand is used, are reproduced. Comparison of the structures of the computed transition states leading to the R and S products provides a qualitative explanation for the origin of selectivity based on steric repulsions between specific substituents.

The conjugate addition–Peterson olefination reaction for the preparation of cross-conjugated cyclopentenone, PPAR-γ ligands

5-Alkylidenecyclopent-2-enones 15a-q may be prepared via a conjugate addition-Peterson olefination sequence, best achieved in one-pot, using exo-2-trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-methanoinden-1-one 12, followed by a retro-Diels-Alder reaction. The geometry of the exocyclic alkene may be controlled according to the use of organometallic species in the conjugate addition step; organocuprate reagents are found to selectively lead to the formation of E-exocyclic alkene adducts, whereas Grignard reagents favour the formation of Z-alkenyl isomers. The use of enantiomerically enriched 12, accessed from an asymmetric Pauson-Khand reaction, affords the corresponding enantioenriched 5-alkylidenecyclopent-2-enones and this approach is exemplified by the short, stereoselective total syntheses of two cyclopentenone phytoprostanes 51 and 13,14-dehydrophytoprostane J1 65. The ability of this family of synthetic compounds to activate the peroxisome proliferator activated receptor-gamma is reported.

Electronic and Steric Effects of Atropisomeric Ligands SYNPHOS® and DIFLUORPHOS®vs. BINAPs in Rh(I)‐Catalyzed Asymmetric Pauson–Khand Reaction

AbstractThe electronic and steric effects of chiral biaryl diphosphine ligands on the Rh(I)‐catalyzed asymmetric Pauson–Khand type reaction were examined. We demonstrated that enantioselectivity and reaction yield were influenced by the electronic density on phosphorus, the dihedral angle of ligands and the electronic density of the alkyne substrate. Ligands bearing a narrower dihedral angle than Binap, such as Synphos (L4) and Difluorphos (L5), were found to increase substantially the enantioselectivity of the reaction, compared to Binap‐type ligands. Ligands having a deshielded phosphine, such as p‐CF3‐Binap (L3) and Difluorphos (L5) provided better enantioselectivity than Binap, with reduced formation of side products, especially with electron‐poor alkyne substrates.

A Study of [Co2(alkyne)(binap)(CO)4] Complexes (BINAP=(1,1′‐Binaphthalene)‐2,2′‐diylbis(diphenylphosphine))

Understanding the interaction of chiral ligands, alkynes, and alkenes with cobaltcarbonyl sources is critical to learning more about the mechanism of the catalytic, asymmetric Pauson-Khand reaction. We have successfully characterized complexes of the type [Co2(alkyne)(binap)(CO)4] (BINAP=(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine)) and shown that diastereomer interconversion occurs under Pauson-Khand reaction conditions when alkyne=HC[triple bond]CCO2Me. Attempts to isolate [Co2(alkyne)(binap)(CO)x] complexes with coordinated alkenes led to the formation of cobaltacyclopentadiene species.

Cluster-based catalysts for asymmetric synthesis

In this work, the synthesis and characterisation of new low-valence transition metal carbonyl clusters, and an investigation into their viability to act as catalysts/catalyst precursors in asymmetric synthesis, are described. Carbonyl clusters based on ruthenium and osmium have been tested as (pre)catalysts for asymmetric hydrogenation of alpha-unsaturated carboxylic acids, and cobalt carbonyl clusters have been used as (pre)catalysts in (asymmetric) Pauson-Khand synthesis. The clusters [Os3(µ-H)2(CO)8(µ-1,2-P-P)] (x=1,2; P-P=chiral diphosphine) did not show any tendency to catalyse hydrogenation of the prochiral substrate tiglic acid. The new triosmium clusters were found to be generally inert and did not react with carbon monoxide or acetylene, or undergo hydride exchange with styrene-d8, all of which are reactions characteristic for the parent cluster [Os3(µ-H)2(CO)10]. Clusters of the type [H4Ru4(CO)12-2x(P-P)x] (x=1,2; P-P=chiral diphosphine) are viable as catalysts for (asymmetric) hydrogenation. Their reactivity strongly depends on the phosphine ligand coordinated. The reactivity of the ruthenium clusters derivatised with ferrocene-based chiral diphosphines showed a significant increase in reactivity compared to other clusters investigated. In the case of clusters coordinated with Walphos ligands, enantiomeric excess of >90 % was obtained in hydrogenation of tiglic acid. The Pauson-Khand reaction was catalysed by cobalt carbonyl clusters of the general formulae [Co3(µ3-CH)(CO)9-x(PR3)x] (x=1-3; PR3=achiral/chiral monophosphines) and Co3(µ3-CH)(CO)7(P-P) (P-P=chiral diphosphine). The clusters were tested both in the intermolecular and the asymmetric intramolecular versions of the Pauson-Khand reaction. In the asymmetric Pauson-Khand reaction, it was found that the clusters that gave the highest product yields also gave racemic mixtures. In contrast, the cluster that gave the lowest cyclopentenone yield (6%), [Co3(µ3-CH)(CO)7(CHIRAPHOS)] was able to generate the highest enantiomeric excess of 13 %. The absence of the original cobalt cluster after the catalytic tests indicates that the cobalt clusters act as catalyst precursors. Regardless of the nature of the active catalyst, the results obtained with these cluster-based catalytic systems are too poor to make these cobalt clusters of practical use in cyclopentenone synthesis.

Asymmetric Pauson–Khand reaction with chiral, electron-deficient mono- and bis-phosphine ligands

The intermolecular Pauson–Khand reaction between norbornene and dicobalt carbonyl complexes of phenylacetylene substituted with chiral phosphorus ligands has been investigated. High yields (⩾98%) and enantiomeric excesses of up to 56% have been observed.

Cobalt—Phosphite‐Catalyzed Asymmetric Pauson—Khand Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cobalt-phosphite-catalyzed asymmetric Pauson-Khand reaction.

A complex formed from dicobalt octacarbonyl and a chiral aryl bisphosphite served as a catalyst for the intramolecular asymmetric Pauson-Khand reaction. Bicyclic cyclopentenones were obtained in up to 75% enantiomeric excess. For a terminal 1,6-enyne, the incremental enantiomeric excess was found to increase from 4 to 26% over the course of the reaction. The scope of this process was examined for a variety of 1,6- and 1,7-enynes, and a moderate degree of enantioselectivity was maintained only in the case of aryl-substituted 1,6-enynes.