Pauson-Khand Research Articles

A Strategy for the Synthesis of Bicyclic Fused Cyclopentenones from MBH-Carbonates of Propiolaldehydes

AbstractAn effective synthetic approach has been demonstrated for the construction of diverse bicyclic fused cyclopentenones from Morita–Baylis–Hillman (MBH) carbonates of propiolaldehydes. The present transformation was initiated through the propargylation of an alkenylamine with an MBH carbonate followed by the Pauson–Khand reaction of the product methyl 3-(alkenylamino)-2-methylenealk-4-ynoate. This facile method provides diverse scaffolds of cyclopentenone fused with aza-cycles having additional functionality in good yields.

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.

Rh(I)-Catalyzed Allenic Pauson–Khand Reaction to Access the Thapsigargin Core: Influence of Furan and Allenyl Chloroacetate Groups on Enantioselectivity

Thapsigargin (Tg) is a potent SERCA pump inhibitor with the potential to treat cancer and COVID-19. We have extended the scope of the asymmetric allenic Pauson-Khand reaction to furan-tethered allene-ynes, a stereoconvergent transformation affording the 5,7,5-ring system of Tg in good yields and high enantioselectivity. Computational studies of the oxidative cyclization step show that the furan and chloroacetate groups contribute to this high selectivity.

Study of the Pauson-Khand reaction in flow over alkynylphenyl vinyl ethers: towards the synthesis of tricyclic multisubstituted benzofurans.

The use of flow methodology allows the use of alkynylphenyl vinyl ethers (benzo-fused 1,7 enynes) as substrates for the intramolecular Pauson–Khand reaction (PKr). Forced temperature and pressure conditions during a short reaction time minimize the substrate decomposition allowing the formation of the PK adduct. Substrates substituted at the internal position of the double bond and with internal triple bonds give better yields. The resulting products are cyclopentabenzofuranones present in diverse natural products and drugs that can be further functionalised.

Asymmetric synthesis of tricyclic 6,5,5-fused polycycles by the desymmetric Pauson–Khand reaction

A new rhodium(I)–BINAP-catalyzed enantioselective desymmetric Pauson–Khand (PK) reaction of prochiral 1,6-enynes with CO has been developed. Diverse tricyclic 6,5,5-fused bowl type polycycles were synthesized in one step with a single diastereomer.

Synthetic Approaches to Natural and Unnatural Tetraquinanes

AbstractIn this article we have highlighted various synthetic methodologies related to tetraquinane frameworks present in crinipellin derivatives. Additionally, we have also included other synthetic strategies to unnatural tetraquinanes. These include photocycloaddition, tandem radical cyclization, Pd‐catalyzed Pauson−Khand reactions (PKR), CH‐insertion, metathesis and photo‐thermal olefin metathesis etc. Emphasis has been put on overall strategies developed in the creation of core structure of tetraquinane, crinipellin. Synthetic strategies to various unnatural tetraquinanes which are useful precursors to complex molecules like dodecahedrane and peristylanes have also been presented.

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.

Rhodium-Catalyzed Enantioselective and Desymmetrizative Pauson-Khand Reaction: Access to Tricyclo[6.2.1.04,11]undecenes.

Rhodium-catalyzed asymmetric desymmetrization Pauson-Khand reaction of C4-alkynyl-tethered cyclohexadienones has been developed as a novel strategy for access to fused 6-5-5 tricycles bearing three consecutive stereogenic centers. An array of chiral tricyclo[6.2.1.04,11]undecenes have been synthesized in high yields and enantioselectivities in a single step under mild conditions. This strategy employs readily accessible internal-olefin-containing 1,6-enynes, providing a potentially powerful tool for constructing chiral polycyclic scaffolds of complex molecules containing cyclopentenones and cyclohexenones.

Studies on the Syntheses of Bioactive Natural Products Having a Fused Ring System Based on Novel Skeletal Construction Methods

Here, I describe a part of our efforts to develop synthetic strategies to construct bioactive natural products having a fused ring system. We have designed four chiral building blocks bearing contiguous quaternary stereocenters for the syntheses of bioactive C17-oxygenated steroids/triterpenoids and C9-oxygenated labdane diterpenoids. The compounds were stereoselectively synthesized from α-substituted glycolic acid (R)-3-methylcyclohex-2-enyl esters through Ireland-Claisen rearrangement to construct the stereocenters simultaneously. Synthetic utility of a β-type building block is highlighted by total syntheses of marrubiin (11 steps, 22%) and related seven labdane diterpene lactones, cyllenine C (12 steps, 29%), marrulactone (13 steps, 11%), marrulanic acid (14 steps, 10%), marrubasch F (12 steps, 14%), marrulibacetal (14 steps, 4%), marrulibacetal A (14 steps, 2%), and desertine (15 steps, 0.5%). These syntheses feature the construction of the [6.6.5]-tricyclic ring portion via a Pauson-Khand reaction, cleavage of the resultant cyclopentenone ring and an elongation of the C9 side chain by an epoxide opening reaction. The relative stereochemistry of desertine was determined to be 13R, 14S, 15S, 16R by some chemical conversions and NMR analysis. Further efforts toward total syntheses of oxygenated terpenoids using three other chiral building blocks and structure-activity relationship study of synthesized labdane diterpene lactones are currently underway in our laboratory and will be reported in due course.

Hang Shi.

"Chemistry is fun because you may get a surprise from your next reaction … My science 'heroes' are Robert Burns Woodward and Ernst Otto Fischer …" Find out more about Hang Shi in his Introducing … Profile.

Hang Shi

Angewandte ChemieVolume 133, Issue 40 p. 21790-21790 Introducing …Free Access Hang Shi First published: 07 August 2021 https://doi.org/10.1002/ange.202109583AboutSectionsPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract “Chemistry is fun because you may get a surprise from your next reaction … My science ‘heroes' are Robert Burns Woodward and Ernst Otto Fischer …” Find out more about Hang Shi in his Introducing … Profile. Hang Shi The author presented on this page has published his first article as a submitting corresponding author in Angewandte Chemie: “Catalytic SNAr Hydroxylation and Alkoxylation of Aryl Fluorides”: Q.-K. Kang, Y. Lin, Y. Li, L. Xu, K. Li, H. Shi, Angew. Chem. Int. Ed. 2021, 60, doi.org/10.1002/anie.202106440; Angew. Chem. 2021, 133, doi.org/10.1002/ange.202106440. Position: Assistant Professor, School of Science, Westlake University, Hangzhou (China) Homepage: hangshi.lab.westlake.edu.cn ORCID: orcid.org/0000-0002-3846-3698 Education: 2008 Bachelor degree, Hunan University (China) 2013 PhD supervised by Zhen Yang, Peking University (China) 2013–2015 Postdoc with Tobias Ritter, Harvard University (USA) 2015–2018 Postdoc with Jin-Quan Yu, Scripps Research Institute (USA) Research: Organic synthesis, catalysis Hobbies: Basketball, cartoon Chemistry is fun because you may get a surprise from your next reaction. My science “heroes” are Robert Burns Woodward and Ernst Otto Fischer. My first experiment was a Pauson–Khand reaction. I chose my current career path because I like to explore in unknown areas. A turning point in my current research project was when the reaction intermediate was successfully isolated and characterized. The most challenging part of my job is seeking a glimmer of hope from failed attempts and negative results. My favorite thing about my lab group is group trips and group meetings. I advise my students to always be patient and curious. I'm always in a good mood when I go into my lab. A good day at work starts with a cup of hot tea. If I had one year of paid leave I would travel around the world. When I was a kid I wanted to be a racing driver. My favorite molecule is bis(benzene)chromium, a sandwich compound. My favorite food is BBQ. My favorite music is pop. Behind the Science References 1Our research group aims to discover and understand new transition-metal catalyzed reactions. Given that an efficient conversion of aryl fluorides into phenols remains to be demonstrated, we started to investigate the feasibility by applying η6-coordination catalysis. In this Angewandte paper, we demonstrate a solution to prepare phenols from aryl fluorides by using a Rh catalyst. We have encountered two significant challenges: one is merging arene exchange and nucleophilic aromatic hydroxylation in one catalytic cycle; the other is tracing the elusive reaction intermediate. Google Scholar Volume133, Issue40September 27, 2021Pages 21790-21790 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. ReferencesRelatedInformation

Total Synthesis of (+)‐3‐Deoxyfortalpinoid F, (+)‐Fortalpinoid A, and (+)‐Cephinoid H

Abstract3‐Deoxyfortalpinoid F, fortalpinoid A, and cephinoid H are members of the Cephalotaxus diterpenoids class of natural products, which feature diverse chemical structures and valuable biological activities. We report herein the development of a diastereoselective Pauson–Khand reaction as an effective pathway to access the core tetracyclic skeleton, which is found widely in Cephalotaxus diterpenoids. Furthermore, we enabled the construction of the tropone moiety through a ring‐closing metathesis/elimination protocol. Based on the developed strategy, asymmetric synthesis of the title compounds has been achieved for the first time.

Total Synthesis of (+)-3-Deoxyfortalpinoid F, (+)-Fortalpinoid A, and (+)-Cephinoid H.

3-Deoxyfortalpinoid F, fortalpinoid A, and cephinoid H are members of the Cephalotaxus diterpenoids class of natural products, which feature diverse chemical structures and valuable biological activities. We report herein the development of a diastereoselective Pauson-Khand reaction as an effective pathway to access the core tetracyclic skeleton, which is found widely in Cephalotaxus diterpenoids. Furthermore, we enabled the construction of the tropone moiety through a ring-closing metathesis/elimination protocol. Based on the developed strategy, asymmetric synthesis of the title compounds has been achieved for the first time.

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.

Cover Picture: Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin (Angew. Chem. Int. Ed. 19/2021)

From thought to action. In the creative process of natural product synthesis, the mental movement of atoms to their desired positions encounters the boundaries of real reactivity. In their Communication on page 10521, Thomas B. Poulsen et al. report the highly efficient assembly of a series of alkaloid natural products in the streptazone and abikoviromycin family. Precise orchestration of (asymmetric) redox manipulations and rapid scaffold assembly via a selective Pauson–Khand reaction enabled the syntheses.

Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin**

AbstractStreptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B1, using a rhodium‐catalyzed distal selective allene‐ynamide Pauson–Khand reaction. A regio‐ and enantioselective epoxidation under chiral phase‐transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium‐catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N‐acetylcysteamine, was studied and revealed unanticipated transformations, including bis‐thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.

Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin*.

Streptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B1 , using a rhodium-catalyzed distal selective allene-ynamide Pauson-Khand reaction. A regio- and enantioselective epoxidation under chiral phase-transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium-catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N-acetylcysteamine, was studied and revealed unanticipated transformations, including bis-thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.

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 Natural Products Containing Enamine or Enol Ether Derivatives.

Enamine and enol ethers are nucleophilic functional groups that are well known to most chemists. When enamine or enol ethers are present in natural products, they are nearly exclusively found as derivatives having a direct connection to electron-withdrawing groups for stabilization, and the resulting larger entities, such as enamides or enol acylates, can be further extended or modified in the framework of natural products. The restricted conformational space that is associated with even simple enamine and enol ether derivatives can be a strong determinant of the overall molecular structure, and the more polarized derivatives can endow some natural products with electrophilic properties and thus facilitate covalent interactions with biological targets.In this Account, I describe our efforts (published since 2016) to prepare natural products from several different classes that all feature enamine or enol ether derivatives as key functionalities. Our choice of targets has been guided by a desire to illuminate unknown biological mechanisms associated with the compounds or, alternatively, to improve upon known biological activities that appear to be promising from a biomedical perspective. In the present text, however, the exclusive focus will be on the syntheses.First, I will discuss the basic properties of the functional groups and briefly present a small collection of illustrative and inspirational examples from the literature for their construction in different complex settings. Next, I will provide an overview of our work on the macrocyclic APD-CLD natural products, rakicidin A and BE-43547A1, involving the development of an efficient macrocyclization strategy and the development of methods to construct the hallmark APD group: a modified enamide. The synthesis of the meroterpenoid strongylophorine-26 is discussed next, where we developed an oxidative quinone methoxylation to build a vinylogous ester group in the final step of the synthesis and employed FeCl3-mediated cascade reactions for the rapid assembly of the overall scaffold to enable a short semisynthesis from isocupressic acid. An efficient core scaffold assembly was also in focus in our synthesis of the alkaloid streptazone A with the signature enaminone system being assembled through a rhodium-catalyzed Pauson-Khand reaction. Sequential, site-selective redox manipulations were developed to arrive at strepatzone A and additional members of the natural product family. Finally, I discuss our work to prepare analogs of complex polyether ionophores featuring functionalized tetronic acids as cation-binding groups. A method for the construction of a suitably protected chloromethylidene-modified tetronate is presented which enabled its installation in the full structure through a C-acylation reaction. This work exemplifies how components of abundant polyether ionophores can be recycled and used to access new structures which may possess enhanced biological activities.

Asymmetric Total Synthesis of (−)-Spirochensilide A, Part 2: The Final Phase and Completion

The final phase of the total synthesis of (-)-spirochensilide A is described. A tungsten-mediated cyclopropene-based Pauson-Khand reaction was developed to form the spiral CD ring system with desired stereochemistry at the C13 quaternary center. Other important steps enabling completion of this synthesis included an intermolecular aldol condensation to link the ABCD core with the EF fragment and a Cu-mediated 1,4-addition to stereoselectively install the C21 stereogenic center. The chemistry developed for this total synthesis of (-)-spirochensilide A (1) will aid the synthesis of polycyclic natural products bearing this unique spiral ring system.