Intramolecular Pauson-Khand Reaction Research Articles

Chirality Transfer Intramolecular Pauson-Khand Reaction with N-C Axially Chiral Sulfonamides Bearing an Ene-Yne Structure.

An intramolecular Pauson-Khand reaction with enantioenriched N-C axially chiral N-allyl-N-(2-alkynylphenyl)sulfonamide derivatives proceeded with complete chirality transfer from axial chirality (P configuration) to central chirality (R configuration), affording chiral nitrogen-containing tricyclic compounds (tetrahydrocyclopentaquinolin-2-one derivatives).

Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M-N, P.

The asymmetric total syntheses of cephalotaxus C19 diterpenoids, bearing a unique cycloheptene A ring with a chiral methyl group at C-12, were disclosed based on a universal strategy. Six members, including cephinoid P, cephafortoid A, 14-epi-cephafortoid A and fortalpinoids M-N, P, were accomplished for the first time. The concise approach relies on two crucial steps: (1) a Nicholas/Hosomi-Sakurai cascade reaction was developed to efficiently generate the cycloheptene ring bearing a chiral methyl group; (2) an intramolecular Pauson-Khand reaction was followed to facilitate the construction of the complete skeleton of target molecules. Our studies provide a new strategy for the synthetic analysis of cephalotaxus diterpenoids and structurally related polycyclic natural products.

Total Synthesis of (+)-Haperforin G.

(+)-Haperforin G was synthesized in 20 steps from commercially available starting materials. A Co-catalyzed intramolecular Pauson-Khand reaction was used for stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position. Light-initiated photocatalysis was used for convergent and asymmetric cross-coupling of the unstabilized C(sp3) radical with an enone. The developed chemistry paves the way to the synthesis of structurally diverse analogs of haperforin G (6).

Total Synthesis of (±)- and (-)-Daphnillonin B.

The first total synthesis of (±)- and (-)-daphnillonin B, a daphnicyclidin-type alkaloid with a new [7-6-5-7-5-5] A/B/C/D/E/F hexacyclic core, has been achieved. The [6-5-7] B/C/D ring system was efficiently and diastereoselectively constructed via a mild type I intramolecular [5+2] cycloaddition, followed by a Grubbs II catalyst-catalyzed radical cyclization. The [5-5] fused E/F ring system was synthesized via a diastereoselective intramolecular Pauson-Khand reaction. Notably, the synthetically challenging [7-6-5-7-5-5] hexacyclic core was reassembled by a unique Wagner-Meerwein-type rearrangement from the [6-6-5-7-5-5] hexacyclic framework found in calyciphylline A-type Daphniphyllum alkaloids.

A Density Functional Theory Study on the Cobalt-Mediated Intramolecular Pauson–Khand Reaction of Enynes Containing a Vinyl Fluoride Moiety

AbstractThe Co2(CO)8-mediated intramolecular Pauson–Khand reaction (PKR) is an effective method for constructing polycyclic structures. Recently, our group reported a series of this type of reaction involving fluorinated enynes that proceed with reasonable reaction rates and yields. However, mechanistic studies involving these fluorinated derivatives in intramolecular PKR are scarce. In this study, density functional theory calculations are used to clarify the mechanism and reactivity of enynes containing a vinyl fluoride moiety for this reaction. In agreement with previous studies, alkene insertion is considered to be the rate-determining step for the overall Pauson–Khand reaction of enynes containing a vinyl fluoride moiety. The effect of the substituent on the Co2(CO)8-mediated intramolecular Pauson–Khand reaction has also been investigated. When introducing heteroatoms as tethering units, the fluorinated enynes exhibited lower reactivity than the malonate homologues, whereas the use of a sulfur-based tether was unsuccessful. This computational study provides detailed information about the PKR mechanism and transition-state structures, and the results are validated with previous experimental results.

Total Synthesis of (-)-Principinol C.

We have achieved the first total synthesis of (-)-principinol C, which possesses an intriguing and complex 5/7/6/5 tetracyclic skeleton with eight contiguous stereocenters. The 5/7/6/5 tetracyclic skeleton of principinol C was assembled using an intramolecular Pauson-Khand reaction as the key step. This synthetic route represents the first application of the intramolecular Pauson-Khand reaction of enyne to construct the 7,5-bicyclic ring system in natural product synthesis.

Computational Study on the Co-Mediated Intramolecular Pauson-Khand Reaction of Fluorinated and Chiral N-Tethered 1,7-Enynes.

The Co2(CO)8-mediated intramolecular Pauson–Khand reaction is an elegant approach to obtain cyclopentenone derivatives containing asymmetric centers. In this work, we employed density functional theory calculations at the M11/6-311+G(d,p) level of theory to investigate the mechanism and reactivity for the Pauson–Khand reaction of fluorinated and asymmetric N-tethered 1,7-enynes. The rate-determining step was found to be the intramolecular alkene insertion into the carbon–cobalt bond. The stereoselectivity of the alkene insertion step was rationalized by the different transition states showing the coordination of the alkene through the Re- and Si-face. The effects of different fluorine groups and steric effects on both the alkenyl and alkynyl moieties were also theoretically investigated.

Asymmetric Total Syntheses of Hypoestin A, Albolic Acid, and Ceroplastol II.

The first asymmetric total synthesis of bioactive diterpenoid hypoestin A with an unprecedented [5-8-5-3] tetracyclic skeleton is accomplished in 15 steps from commercially available (R)-limonene. Furthermore, the second asymmetric total syntheses of sesterterpenoids albolic acid and ceroplastol II in 21 steps are also reported. The synthetically challenging and highly functionalized [X-8-5] (X = 5 or 7) tricarbocyclic ring systems found in hypoestin A, albolic acid, ceroplastol II, and schindilactone A, as well as other natural products, are efficiently and directly constructed via a unique intramolecular Pauson-Khand reaction of an allene-yne. This work represents the first reported use of the Pauson-Khand reaction to access synthetically challenging eight-membered-ring systems in natural product synthesis.

Oxygenated Cyclopentenones via the Pauson-Khand Reaction of Silyl Enol Ether Substrates.

We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson–Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.

Stereoselective Synthesis of (±)-Cephanolide B.

A concise and stereoselective total synthesis of (±)-cephanolide B was achieved in 15 steps. The key steps in the synthesis were as follows: (i) an intermolecular Diels-Alder reaction followed by lactonization to form the oxabicyclo[2.2.2]octane DE ring; (ii) a tandem reaction, featuring an intramolecular Pauson-Khand reaction, a 6π-electrocyclization, and an oxidative aromatization by O2, to construct the ABC-tricyclic rings (6-5-6); and (iii) a phthaloyl peroxide-mediated arene oxygenation to install the C-13 phenol group.

A Synthetic Route to The Core Structure of (-)-Retigeranic Acid A.

Retigeranic acid A is a uniquely structured pentacyclic sesterterpene bearing eight stereogenic centers. We report a concise route to the core structure of (-)-retigeranic acid A. The stereochemistry of its six chiral centers and three quaternary carbon centers was well-controlled. This route features two intramolecular Pauson-Khand reactions (IMPKRs): the first forged the D and E rings to deliver the triquinane subunit, and the second constructed the A and B rings and diastereoselectively installed the quaternary C6a center.

A new route to BCD tricyclic fragment of C19-diterpenoid alkaloids via intramolecular Pauson-Khand reaction followed by anionic 1,2-migration rearrangement

A robust synthetic approach for the rapid assembly of the bridged tricyclic BCD ring system of C19-diterpenoid alkaloids bearing a characteristic hydroxy group on ring C has been developed. The synthesis features an efficient intramolecular Pauson-Khand reaction and an exclusive anionic 1,2-migration rearrangement to generate the unique bicyclo[3.2.1]octane moiety of the CD-ring on the seven-membered B-ring.

Total Synthesis of the Diterpene Waihoensene

AbstractA racemic and scalable enantioselective total synthesis of (+)‐waihoensene was accomplished. (+)‐Waihoensene belongs to the diterpene natural product family, and it features an angular triquinane substructure motif. Its tetracyclic [6.5.5.5]backbone is all‐cis‐fused, containing six contiguous stereocenters, four of which are quaternary. These structural features were efficiently installed by means of a diastereoselective radical cyclization, followed by an intramolecular Pauson–Khand reaction, a diastereoselective α‐alkylation, and a diastereoselective 1,4‐addition reaction. Enantioselectivity was introduced at an early stage, by an asymmetric palladium catalyzed decarboxylative allylation reaction on gram scale.

Total Synthesis of the Diterpene Waihoensene.

A racemic and scalable enantioselective total synthesis of (+)‐waihoensene was accomplished. (+)‐Waihoensene belongs to the diterpene natural product family, and it features an angular triquinane substructure motif. Its tetracyclic [6.5.5.5]backbone is all‐cis‐fused, containing six contiguous stereocenters, four of which are quaternary. These structural features were efficiently installed by means of a diastereoselective radical cyclization, followed by an intramolecular Pauson–Khand reaction, a diastereoselective α‐alkylation, and a diastereoselective 1,4‐addition reaction. Enantioselectivity was introduced at an early stage, by an asymmetric palladium catalyzed decarboxylative allylation reaction on gram scale.

Total Synthesis of (+)-Haperforin G.

A concise chemical synthesis of (+)-haperforin G in 20 steps from commercially available starting materials is achieved with the integration of the Co-catalyzed intramolecular Pauson-Khand reaction for the stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position and the light-initiated photocatalysis for convergent and asymmetric cross-coupling of the unstabilized C(sp3)-radical with an enone. The developed chemistry paves the way to synthesizing structurally diverse analogs of haperforin G (6).

Synthesis of Cyclic Compounds Containing Aminobenzenesulfonamide

This review, based on my research work, introduces and summarizes the synthesis and characterization of novel cyclic compounds containing aminobenzenesulfonamide. The review discusses the (1) development of sequential Nicholas and Pauson-Khand reactions for the synthesis of unique polyheterocyclic compounds, (2) production of 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN) as a multifunctional click cycloalkyne agent, and (3) improvement of the intramolecular Pauson-Khand reaction of the nitroarene-enyne substrate for the synthesis of cyclopenta[c]piperidine alkaloids. This research work will facilitate the discovery of sulfonamide or sultam-based functional molecules and pharmaceuticals. Thus, I believe that aminobenzenesulfonamide derivatives are versatile and valuable chemical moieties not only in organic syntheses but also in the pharmaceutical industry. If you are interested in the details of this topic, please refer to the original papers.

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.

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.

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.

Theoretical prediction on the reactivity of the Co-mediated intramolecular Pauson-Khand reaction for constructing bicyclo-skeletons in natural products

The Co2(CO)8-mediated intramolecular Pauson-Khand reaction is an efficient approach for constructing polycyclic skeletons. Recently, some of us reported a series of this type reactions involving sterically-hindered enynes for synthesizing natural products with reasonable reaction rates and yields. However, the reason for the high reactivity of the reaction remains unclear. We employed density functional theory calculations to clarify the mechanism and reactivity for this reaction. In contrast with chain olefin reactants, CO insertion is considered to be the rate-determining step for the overall Pauson-Khand reaction of cyclooctene derivatives. The reduced activation free energy for the alkene insertion step is attributed to: i) the electron-withdrawing group in close proximity to the CC triple bond enhancing the reactivity of the alkyne moiety; ii) lower steric hindrance during alkene insertion when using the cyclooctene derivative. The effect of the substituent on the Co2(CO)8-mediated intramolecular Pauson-Khand reaction was then investigated. Internal alkenes exhibit lower reactivity than terminal alkenes because of the steric hindrance introduced by the substituted group. The cis internal alkene exhibits higher reactivity than the trans internal alkene. An ester group in close proximity to the CC triple bond significantly enhances the reactivity.