Dearomative | Amide | N-o Tethered Oxidopyrylium [ 5 + 2 ] Cycloaddition Reactions

Over the last decade, several developments and advancements have been made towards oxidopyrylium-based [5 + 2] cycloadditions which allow for the synthesis of natural products. Dearomative oxidopyrylium-based [5 + 2] cycloadditions allow the formation of complex polycyclic compounds from readily available aromatic rings in a single step. Dearomatization of electron rich aromatic systems directly adds functionality resulting in complex compounds with increased levels of stereogenic centers and chemical space. These structural features represent privileged complexes in drug discovery and development. Some major difficulties associated with these reactions are the disruption of the aromaticity of arenes, controlling the regioselectivity and stereoselectivity of the reaction, functional group compatibility and overcoming steric hindrance. These setbacks demand new reaction pathways and improvements to attain greater efficiency. In this regard, this study reports a dearomative [5 + 2] cycloaddition which involves thermal activation of amide-tethered intramolecular substrates that enables increased efficacy and scope. Effort towards this work entails synthesis of silyloxypyrone-amides which when subjected to dearomative conditions, affords the corresponding cycloadduct. In both cases of indole and furanbased dearomative studies, it became evident that less hindered silyloxypyrone amides yielded lower conversion rates to cycloadduct formation than bulky amides. Another aspect which emerged from our dearomative studies pertains to amide and N-O tethered tethered intramolecular [5 + 2] cycloadditions. Furthermore, our efforts of synthesizing of amide and N-O tethered silyloxypyrones cycloadduct have proven fruitful. A key factor contributing to this success is the ability to vary the substituent on the substrate, enabling the generation of diverse cycloadducts

Dual Catalysis in Enantioselective Oxidopyrylium-Based [5+2] Cycloadditions

A new method is reported for effecting catalytic enantioselective intramolecular [5+2] cycloadditions based on oxidopyrylium intermediates. The dual catalyst system consists of a chiral primary aminothiourea and a second achiral thiourea. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair which undergoes subsequent cycloaddition with high enantioselectivity.Chemistry and Chemical Biolog

Triethylamine Enables Catalytic Generation of Oxidopyrylium Ylides for [5+2] Cycloadditions with Alkenes: An Efficient Entry to 8-Oxabicyclo[3.2.1]octane Frameworks

An efficient method for the preparation of a range of 8-oxabicyclo[3.2.1]octane derivatives including synthetic intermediates of natural products is described, in which triethylamine effectively catalyzes [5+2] cycloaddition reactions between oxidopyrylium ylides and alkenes. This method can be applied not only to intermolecular cycloadditions with various alkenes but also to intramolecular cycloadditions. The key finding is that the combined use of organic bases having appropriate basicity and oxidopyrylium ylide precursors bearing a suitable leaving group facilitates the base-assisted generation of oxidopyrylium ylides in a catalytic manner.ArticleADVANCED SYNTHESIS & CATALYSIS.360(12):2377-2381(2018)journal articl

Photochemical formation of intricarene

Sunlight is the ultimate driver of biosynthesis but photochemical steps late in biosynthetic pathways are very rare. They appear to play a role in the formation of certain furanocembranoids isolated from Caribbean corals. One of these compounds, intricarene, has been suspected to arise from an intramolecular 1,3-dipolar cycloaddition involving an oxidopyrylium. Here we show, by a combination of experiments and theory, that the oxidopyrylium forms under photochemical conditions and that its cycloaddition occurs via a triplet state. The formation of a complex by-product can be rationalized by another photochemical step that involves a conical intersection. Our work raises the question whether intricarene is biosynthesized in the natural habitat of the corals or is an artefact formed during workup. It also demonstrates that the determination of exact irradiation spectra, in combination with quantum chemical calculations, enables the rationalization of complex reaction pathways that involve multiple excited states

Investigation of Intramolecular Oxidopyrylium-Based [ 5 +2 ] Cycloadditions

The cycloaddition reaction is an important transformation in the field of organic chemistry since it serves as an indispensable tool in organic synthesis. The oxidopyrylium-based [5+2] cycloaddition reaction has received enormous attention in chemical synthesis due to its usefulness in the formation of seven-membered heterocyclic ring systems present in bioactive natural products.1,2,3,4 In spite of the tremendous attention paid to this reaction, there still exist stereo and regioselectivity limitations. Further investigation is critical in light of these limitations. The intramolecular oxidopyrylium-based [5+2] cycloaddition is known to afford these ring systems with high stereo and regioselectivity since with the intramolecular type the olefin is always tethered to the pyrone. Previous work by the Mitchell research group revealed bulky transfer group, alkene substitution, and proximity of the tether to the transfer group to be of great importance for intramolecular oxidopyrylium-based [5+2] cycloadditions.5 Again, the Mitchell research group has demonstrated a room temperature intramolecular oxidopyrylium-based [5+2] cycloadditions for enamine-based reactions.6 To further extend the previous work in the Mitchell research group and establish an alternative approach for the intramolecular oxidopyrylium based [5+2] cycloadditions, N-heterocyclic carbine (NHC) catalyzed [5+2] cycloaddition was envisioned. Effort towards this work is the synthesis silyloxypyrone-ester which when subjected to enolate chemistry will afford the corresponding cycloadduct. We have established silyloxypyrone-aldehyde as a useful intermediate for the synthesis of many synthetic valuable pyrones. Again, we have established amides as useful functionality for intramolecular oxidopyrylium-based [5+2] cycloadditions with tert-butyl group enabling this reaction

Efficient generation of an oxidopyrylium ylide using a Pd catalyst and its [5+2] cycloadditions with several dipolarophiles

An efficient method for the generation of an oxidopyrylium ylide from 6-acetoxy-6-acetoxymethyl-2H-pyran-3(6H)-one using a Pd catalyst and [5+2] cycloadditions of the resulting ylide are described. Among substituted styrene derivatives as dipolarophiles, electron-rich styrenes showed higher yield (up to 80%). The [5+2] cycloaddition reactions can also be applied to exo-methylene cyclic compounds, and an improved method for the synthesis of polygalolide intermediate has been demonstrated.ArticleCHEMICAL COMMUNICATIONS.54(9):1109-1112(2018)journal articl

Routes to Advanced Intermediates in the Synthesis of Tetracarbocyclic Sesquiterpenoids Daphnenoid A and Artatrovirenols A and B

A short route from dihydrocarvone is described, which led to the tetracarbocyclic core common to artatrovirenol A and B and daphnenoid A. A variant of this route afforded guaia-4,6-dien-3-one (from Enterospermum madagascarensis) and its epimer. From 2-(2-oxoethyl)­furan, a 15-step sequence then delivered the complete carbon skeleton and all functionality necessary for daphnenoid A. Key steps in the route include diastereoselective intramolecular oxidopyrylium cycloaddition, oxa-bridge cleavage under “push–pull” conditions, and intramolecular Diels–Alder cycloaddition

Light-induced molecular processes in organic-based energy conversion and biomimetic synthesis of natural products

Processes initiated by sunlight are fundamental steps in photovoltaic devices as well as in biosyntheses. The present work investigates the photoinduced processes in organic-based energy conversion materials and biomimetic synthesis of natural products by quantum chemical calculations. The work is performed in close collaboration with experimental groups and enables a deeper understanding of the observations. The detailed knowledge allows to predict the optimal conditions to initiate the photochemical syntheses and the chemical substitution to achieve the desired properties. In the first and second part of the thesis, two classes of molecules commonly used in organic-based optoelectronic devices are considered and potential factors influencing the performance of the optical devices are revealed. In the third part, the photochemical and biomimetic syntheses of two natural products and the details of the complex reaction mechanisms are elucidated. In the first part of the present work the deactivation pathways from the first excited singlet state S1 of thiophene and of small oligothiophenes containing up to four rings are investigated by state-of-the-art quantum chemical methods. For thiophene a low-lying S1/S0 conical intersection seam is easily accessible and drives the fast internal conversion. In the oligothiophenes barriers in combination with fast intersystem crossing channels inhibit this passage. The calculated spin-orbit coupling strength together with the singlet-triplet energy gaps can explain the decreasing triplet and increasing fluorescence quantum yields for growing chain length. The present theoretical results allow a deeper understanding of the deactivation pathways of thiophene and small oligothiophenes and are of potential interest for the photophysics of longer oligothiophenes and polythiophenes used in optoelectronic devices. In the second part the photoinduced dynamics of perylene diimide dyads based on a donor-spacer-acceptor motif are considered. The dyads based on pyridine spacer undergo energy transfer from the donor to the acceptor with near-unity quantum efficiency. In contrast in the dyads with phenyl spacers the energy transfer decreases below 50%, suggesting the presence of a competing electron transfer from the spacer to the donor. However, the measurements indicate that the spacer itself mediates the energy transfer dynamics. Ab initio calculations reveal the existence of bright charge transfer states which enable the energy transfer. This new energy transfer represents a first example that show how electron transfer can be connected to energy transfer for the use in novel photovoltaic devices. Additional experiments and calculations of subsystems demonstrate that the solvation time and not the polarity of the solvent is surprisingly the crucial property of the solvent for the charge and energy transfer dynamics. In the last part the photochemical syntheses of the two natural products intricarene and aplydactone are studied. Intricarene was isolated from a Carribbean coral and according to its proposed biosynthesis it arises from an oxidopyrylium intermediate via an intramolecular 1,3-dipolar cycloaddition. By a combination of experiments and theory it is shown that oxidopyrylium indeed forms under biomimetic and photochemical conditions and that it represents the key intermediate in the complex reaction cascade leading to intricarene. Triplet states as well as conical intersections enable the formation of intricarene and of an intriguing by-product which may constitute a new natural product. In the second part of the last chapter a quantum chemical study of the [2+2] photocycloaddition of dactylone to aplydactone is performed. Both compounds were isolated from a Madagascan sea hare and especially aplydactone exhibits an unprecedented molecular structure. However, for both compounds no total syntheses have been reported yet. According to the proposed biosynthesis, aplydactone is formed by a photochemical [2+2] cycloaddition out of dactylone but attempts to synthesize aplydactone through irradiation of dactylone failed. In the present work quantum chemical calculations elucidate the optimal biomimetic conditions to initiate the photochemical reaction and the different reaction pathways on the excited state potential energy surface are revealed. Overall, the last chapter highlights the importance of weak absorption bands and long-lived triplet states for the photochemical synthesis of natural products

Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones

Chapter 1: This chapter gives a brief history of α-hydroxytropolones, how they were discovered and unique properties of these substrates. Included is a background on the bioactivity of these substrates in cellular targets such as bacteria, fungi, parasites, tumors and toxicity, as well as their ability to inhibit various metallo-based enzymes. Structure activity relationships studies are reviewed on important metalloenzymes HIV-Reverse Transcriptase (RT) and Inositol monophosphatase (IMPase). Finally the chapter finishes with a synthetic overview of α-hydroxytropolones including natural product targets such as puberulic acid, puberulonic acid, β-thujaplicinol, and β-hydroxytropolone. Chapter 2: A brief review on β-hydroxy-γ-pyrone based oxidopyrylium cycloadditions will be presented as well as important oxidopyrylium cycloaddition/ring opening procedures to yield natural tropolone products. Research from the Murelli laboratory will be highlighted. This chapter will discuss a new synthetic route toward functionalized α-hydroxytropolones. A β-hydroxy-γ-pyrone intermolecular oxidopyrylium cycloaddition with a range of alkynes that was optimized to an efficient and high yielding process will be discussed. Next two ring catalyzed ring openings will be discussed; one that utilizes boron trichloride that attains α-hydroxytropolones and 7-methoxytropolones, and a triflic acid mediated sequence that yields exclusive 7-methoyxtropolones and furans. Finally, a new reaction with the oxidopyrylium species will be highlighted that shows the exchange of alcohols in these reactive species. Chapter 3: Chapter three describes the background on three specific medicinal targets: ANT (2 )-Ia, HIV RT RNase H, and HBV RT RNaseH and preliminary structure activity relationship studies with β-hydroxytropolones synthesized in this research are outlined

Synthesis of Biologically Active Tropolones and Stereochemically Rich Compounds via Cross-Coupling Reactions

Over the past years the Murelli lab has established research based on the synthesis and biological evaluations of alpha-hydroxytropolones (alpha-HTs). These seven-membered aromatic rings have three contiguous oxygen atoms that chelates to metals, thus, biologically having the ability to bind dinuclear metalloenzymes and promoting inhibition. Synthetic routes to alpha-HT’s are scarce and therefore has been the main driving force in developing efficient and general synthetic methods to obtain variations in alpha-HTs, enabling SAR studies. The Murelli lab have therefore developed an oxidopyrylium cycloaddition/ring-opening strategy that is able to generate polysubstituted alpha-HTs starting from kojic acid, a cheap and readily available reagent. Adding to this, the Murelli lab have developed a scalable and reproducible procedure that obtains oxidopyrylium ylide in high purity without the need for column chromatography. This has enabled the synthesis and biological evaluations of libraries of alpha-HTs for many human diseases including herpes simplex virus, hepatitis B virus and other human pathogens. Atropisomerism is a form of chirality arising from conformational restriction of chiral axes and has an essential role in many compounds including, but not limited to, chiral ligands, and pharmaceutical drugs. Structural aspect of tropolones such as their large ring size, smaller bond angles, tropylium characteristics, potential ring-puckering, and configurational stability have enabled the synthesis of atropisomeric troponoid-benzenoid structures. Our ability to synthesize atropisomeric troponoid-benzenoid compounds, through cross-coupling reactions, paves the way for entry into a whole new ligand class and asymmetric catalysis in contrast to the abundant benzenoid based privileged ligands. The Biscoe lab studies asymmetric C–C bond formation utilizing cross-coupling reactions such as Suzuki and Stille reactions. The Stille reaction is a chemical reaction that involves the use of organotin compounds with a variety of electrophiles. Stereospecific transfer of chirality using configurationally stable enantioenriched carbastannatranes, as the organotin coupling partner, has been realized with control over retention or inversion of stereochemistry. This is accomplished using palladium catalysis in combination with an electron deficient Buchwald type ligand and copper (I) salts. Herein, we describe biological evaluations of synthetic alpha-HTs, identification of conditions for the atropselective cross-coupling of tropolones and benzenoid groups to generate axially chiral tropone-benzenoid biaryl systems. We also describe developments of cross-coupling methods that enables the stereospecific transfer of a stereogenic center utilizing the Stille reaction