Pauson-Khand Research Articles

A Concise Total Synthesis of (+)-Waihoensene Guided by Quaternary Center Analysis.

The four contiguous all-carbon quaternary centers of waihoensene, coupled with the absence of any traditional reactive functional groups other than a single alkene, render it a particularly challenging synthetic target among angular triquinane natural products. Here, we show that its polycyclic frame can be assembled concisely by using a strategically chosen quaternary center to guide the formation of the other three through judiciously selected C-C bond formation reactions. Those events, which included a unique Conia-ene cyclization and a challenging Pauson-Khand reaction, afforded a 17-step synthesis of the molecule in enantioenriched form.

A Concise Total Synthesis of (+)‐Waihoensene Guided by Quaternary Center Analysis

AbstractThe four contiguous all‐carbon quaternary centers of waihoensene, coupled with the absence of any traditional reactive functional groups other than a single alkene, render it a particularly challenging synthetic target among angular triquinane natural products. Here, we show that its polycyclic frame can be assembled concisely by using a strategically chosen quaternary center to guide the formation of the other three through judiciously selected C−C bond formation reactions. Those events, which included a unique Conia‐ene cyclization and a challenging Pauson–Khand reaction, afforded a 17‐step synthesis of the molecule in enantioenriched form.

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).

Total Syntheses of Marrubiin and Related Labdane Diterpene Lactones.

Total syntheses of the labdane diterpene lactones marrubiin, marrulibacetal, desertine, marrulibacetal A, marrubasch F, cyllenine C, marrulanic acid, and marrulactone are described. The trans-decalin moiety of these molecules was constructed in a stereoselective manner by a Pauson-Khand reaction, and the resultant cyclopentenone was oxidatively cleaved for formation of the lactone ring. Elongation of the side chain at C9 was achieved by an epoxide-opening reaction with a variety of nucleophiles, and the functional group manipulations completed the syntheses of these natural products. Stereochemistries of desertine could be established by the transformations.

Versatile Catalytic Reactions of Norbornadiene Derivatives with Alkynes

AbstractNorbornadiene and its derivatives are important synthetic intermediates and useful building blocks in organic synthesis as they can serve as a general template to create highly substituted ring systems with high atom economy. Alkynes have always been one of the most important functional groups in organic chemistry because of their rigidity, electronic properties and numerous methods available for functionalization of the triple bond. The different kinds of reaction between these two classes of compounds, norbornadienes and alkynes, provide useful methods for the synthesis of various important compounds/frameworks, indicating the utility of these reactions in chemical synthesis. Indeed, norbornadienes undergo various reactions with alkynes – alkynylation, ring‐opening, cyclization, cycloaddition, Pauson–Khand and other tandem reactions. This review provides an overview of the achievements in the various reactions between norbornadiene and its derivatives with alkynes.magnified image

Asymmetric Total Synthesis of (+)-Waihoensene.

The asymmetric total synthesis of (+)-waihoensene, which has a cis-fused [6,5,5,5] tetracyclic core bearing an angular triquinane, a cis-fused six-membered ring, and four contiguous quaternary carbon atoms, was achieved through a sequence of chemical reactions in a stereochemically well-defined manner. The total synthesis features the following: (1) Cu-catalyzed asymmetric conjugated 1,4-addition; (2) diastereoselective Conia-ene type reaction; (3) diastereoselective intramolecular Pauson-Khand reaction; (4) Ni-catalyzed diastereoselective conjugated 1,4-addition; and (5) radical-initiated intramolecular hydrogen atom transfer (HAT). Control experiments and density functional theory calculations support the proposed HAT process.

SeO2-Mediated Oxidative Transposition of Pauson-Khand Products.

Oxidative transpositions of bicyclic cyclopentenones mediated by selenium dioxide (SeO2) are disclosed. Treatment of Pauson-Khand reaction (PKR) products with SeO2 in the presence or absence of water furnishes di- and trioxidized cyclopentenones, respectively. Mechanistic investigations reveal multiple competing oxidation pathways that depend on substrate identity and water concentration. Functionalization of the oxidized products via cross-coupling methods demonstrates their synthetic utility. These transformations allow rapid access to oxidatively transposed cyclopentenones from simple PKR products.

Combination of multicomponent KA2 and Pauson-Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones.

The Cu-catalyzed multicomponent ketone–amine–alkyne (KA2) reaction was combined with a Pauson–Khand cycloaddition to give access of unprecedented constrained spirocyclic pyrrolocyclopentenone derivatives following a DOS couple-pair approach. The polyfunctional molecular scaffolds were tested on the cyclopentenone reactivity to further expand the skeletal diversity, demonstrating the utility of this combined approach in generating novel spiro compounds as starting material for the generation of chemical libraries. The chemoinformatics characterization of the newly-synthesized molecules gave evidence about structural and physicochemical properties with respect to a set of blockbuster drugs, and showed that such scaffolds are drug-like but more spherical and three-dimensional in character than the drugs.

A Rh(iii)-catalyzed regioselective intermolecular oxa-Pauson–Khand reaction of alkynes, arylboronic acids and CO to form butenolides

A Rh(iii)-catalyzed regioselective intermolecular oxa-Pauson–Khand reaction of arylboronic acids, alkynes and CO for the synthesis of butenolides has been developed.

Catalytic Enantioselective Cyclopropenation of Internal Alkynes: Access to Difluoromethylated Three‐Membered Carbocycles

AbstractHerein we described an efficient RhII‐catalyzed enantioselective cyclopropenation reaction of internal alkynes with a masked difluorodiazoethane reagent (PhSO2CF2CHN2, Ps‐DFA). This asymmetric transformation offers efficient access to a broad range of enantioenriched difluoromethylated cyclopropenes (40 examples, up to 99 % yield, 97 % ee). The synthetic utility of obtained strained carbocycles is demonstrated by subsequent stereodefined processes, including cross‐couplings, hydrogenation, Diels–Alder reaction, and Pauson–Khand reaction.

Catalytic Enantioselective Cyclopropenation of Internal Alkynes: Access to Difluoromethylated Three-Membered Carbocycles.

Herein we described an efficient RhII -catalyzed enantioselective cyclopropenation reaction of internal alkynes with a masked difluorodiazoethane reagent (PhSO2 CF2 CHN2 , Ps-DFA). This asymmetric transformation offers efficient access to a broad range of enantioenriched difluoromethylated cyclopropenes (40 examples, up to 99 % yield, 97 % ee). The synthetic utility of obtained strained carbocycles is demonstrated by subsequent stereodefined processes, including cross-couplings, hydrogenation, Diels-Alder reaction, and Pauson-Khand reaction.

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.

The Fluoro-Pauson-Khand Reaction in the Synthesis of Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C-F Stereogenic Center.

A variety of enantioenriched fluorinated 6H-cyclopenta[c]pyridin-6-one bicycles, a scaffold present in several classes of monoterpenic alkaloids with varied biological activity, were synthesized in just five steps from simple aldehyde starting materials. The synthesis presented wide functional group tolerance and moderate to high yields and diastereoselectivities and could be carried out on a gram scale. These products were suitable for further transformations, such as hydrogenation and deprotection of the tert-butylsulfonyl protecting group.

Type-II Pauson-Khand reaction of 1,8-enyne in the attempt of building 7/5 ring of (-)-caribenol A and DFT understanding

An attempt to access the fused 7/5 ring of the highly biologically active terpenoid caribenol A by employing intramolecular Pauson-Khand reaction of 1,8-enyne gave bridged 8-5 ring, the type-II Pauson-Khand reaction product. DFT study has been carried out to elucidate this unexpected regioselectivity.

Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H.

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (-)-daphlongamine H has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson-Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (-)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B.

Dinickel catalyzed carbonylation reactions using metal carbonyl reagents as CO sources

Dinickel complexes promote stoichiometric Pauson–Khand reactions of enynes and CO (g). However, catalytic turnover is precluded by the strong binding of CO to the Ni2 active site. This article describes the use of M(CO)x reagents as stoichiometric CO precursors in Ni2-catalyzed carbonylation reactions. As part of these studies, well-defined heterotrinuclear Ni2Fe, Ni2Co, and Ni2Mn carbonyl clusters are synthesized using the [NDI]Ni2 platform as a template (NDI = naphthyridine–diimine).

Total Synthesis of (−)‐Indoxamycins A and B

AbstractThe concise total syntheses of (−)‐indoxamycins A and B is reported. The chemistry features a seven‐step preparation of a highly congested [5.5.6] tricyclic advanced common intermediate from a readily available R‐carvone derivative. Key steps involve a Pauson–Khand reaction for the rapid construction of a basic scaffold bearing a quaternary carbon, a copper‐catalyzed Michael addition for the introduction of another adjacent all‐carbon quaternary stereocenter, and a tandem retro‐oxa‐Michael addition/1,2‐addition/oxa‐Michael addition for the installation of a trisubstituted olefin side chain. This synthetic strategy allows for easy access to both enantiomers of this family of natural products and their analogues from cost‐effective starting material through straightforward chemical transformations.

Total Synthesis of (-)-Indoxamycins A and B.

The concise total syntheses of (-)-indoxamycins A and B is reported. The chemistry features a seven-step preparation of a highly congested [5.5.6] tricyclic advanced common intermediate from a readily available R-carvone derivative. Key steps involve a Pauson-Khand reaction for the rapid construction of a basic scaffold bearing a quaternary carbon, a copper-catalyzed Michael addition for the introduction of another adjacent all-carbon quaternary stereocenter, and a tandem retro-oxa-Michael addition/1,2-addition/oxa-Michael addition for the installation of a trisubstituted olefin side chain. This synthetic strategy allows for easy access to both enantiomers of this family of natural products and their analogues from cost-effective starting material through straightforward chemical transformations.

Vinyl Fluorides: Competent Olefinic Counterparts in the Intramolecular Pauson-Khand Reaction.

Despite the great advances achieved in the Pauson-Khand reaction and the ever-increasing demand for fluorinated compounds, the use of vinyl fluorides as olefinic counterparts in the above-mentioned transformation had been completely overlooked. Herein, we describe, for the first time, the intramolecular Pauson-Khand reaction of enynes containing a vinyl fluoride moiety.

Asymmetric Total Synthesis of Fawcettimine-Type Lycopodium Alkaloid, Lycopoclavamine-A.

An asymmetric total synthesis of lycopoclavamine-A (1), a structurally unique fawcettimine-type Lycopodium alkaloid, was achieved via a stereoselective Pauson-Khand reaction and a stereoselective conjugate addition to construct a quaternary carbon center at C-12.