Oxidopyrylium Ylides Research Articles

Silver-Catalyzed Tandem Cycloisomerization/[5 + 2] Cycloaddition of 3-Cyclopropylideneprop-2-en-1-ones with Oxidopyrylium Ylides to Form Bibridged Benzocycloheptanones.

Herein, we report a mild, one-pot method for silver-catalyzed tandem cycloisomerization/[5 + 2] cycloaddition reactions between readily accessible cyclopropyl-tethered allenyl ketones and benzopyranone-derived oxidopyrylium ylides. The reactions proceed via a cyclobutene-fused furan intermediate generated in situ by a cycloisomerization/1,2-carbene transfer/ring-expansion cascade. This method, which features an unprecedented formal [5 + 2] cycloaddition, delivers good to excellent yields of structurally complex bibridged benzocycloheptanones bearing a strained cyclobutane ring and an O-bridged ring.

Photoswitchable Oxidopyrylium Ylide for Photoclick Reaction with High Spatiotemporal Precision: A Dynamic Switching Strategy to Compensate for Molecular Diffusion

AbstractWe describe a novel type of photoclick reaction between 2,3‐diaryl indenone epoxide (DIO) and ring‐strained dipolarophiles, in which DIO serves as a P‐type photoswitch to produce mesoionic oxidopyrylium ylide (PY) to initiate an ultra‐fast [5+2] cycloaddition (k2hν=1.9×105 M−1 s−1). The photoisomerization between DIO and PY can be tightly controlled by either 365 or 520 nm photo‐stimulation, which allows reversion or regeneration of the reactive PY dipole on demand. Thus, this reversible photoactivation was exploited to increase the chemoselectivity of the [5+2] cycloaddition in complex environments via temporal dual‐λ stimulation sequences and to recycle the DIO reagent for batch‐wise protein conjugation. A dynamic photoswitching strategy is also proposed to compensate for molecular diffusion of PY in aqueous solution, enhancing the spatial resolution of lithographic surface decoration and bioorthogonal labeling on living cells via a spatiotemporal dual‐λ photo‐modulation.

Photoswitchable Oxidopyrylium Ylide for Photoclick Reaction with High Spatiotemporal Precision: A Dynamic Switching Strategy to Compensate for Molecular Diffusion.

We describe a novel type of photoclick reaction between 2,3-diaryl indenone epoxide (DIO) and ring-strained dipolarophiles, in which DIO serves as a P-type photoswitch to produce mesoionic oxidopyrylium ylide (PY) to initiate an ultra-fast [5+2] cycloaddition (k2hν =1.9×105 M-1 s-1 ). The photoisomerization between DIO and PY can be tightly controlled by either 365 or 520 nm photo-stimulation, which allows reversion or regeneration of the reactive PY dipole on demand. Thus, this reversible photoactivation was exploited to increase the chemoselectivity of the [5+2] cycloaddition in complex environments via temporal dual-λ stimulation sequences and to recycle the DIO reagent for batch-wise protein conjugation. A dynamic photoswitching strategy is also proposed to compensate for molecular diffusion of PY in aqueous solution, enhancing the spatial resolution of lithographic surface decoration and bioorthogonal labeling on living cells via a spatiotemporal dual-λ photo-modulation.

Enantioselective 1,3-Dipolar (5+3) Cycloadditions of Oxidopyrylium Ylides and Vinylcyclopropanes toward 9-Oxabicyclononanes.

We have developed an efficient and mild enantioselective palladium-catalyzed (5+3) cycloaddition of vinylcyclopropanes and oxidopyrylium ylides generated in situ from benzopyranones, in the presence of a chiral PHOX ligand. These reactions afford various highly functionalized bridged oxa-[3.3.1]carbocycles with three stereogenic centers that are challenging to synthesize, in moderate to good yields and enantioselectivities.

Total Synthesis of (±)-Jujuyane.

The first total synthesis of (±)-jujuyane, a cyclooctanoid natural product, was accomplished from a (5 + 3) dimerization product of oxidopyrylium ylide that forms the cyclooctanoid core structure along with inherited stereochemical bias. Selective functional group modifications of the highly oxygenated dimeric structure, followed by the tactical functional group manipulation around the eight-membered carbocyclic core, enabled the total synthesis of (±)-jujuyane, which will serve a guide for future applications of oxidopyrylium dimers to the natural product total synthesis.

Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems.

We have the investigated base mediated asymmetric intramolecular oxidopyrylium-alkene [5 + 2]-cycloaddition reaction which resulted in the synthesis of functionalized tricyclic ring systems containing an 8-oxabicyclo[3.2.1]octane core. Intramolecular cycloaddition constructed two new rings, three new stereogenic centers, and provided a tricyclic cycloadduct with high diastereoselectivity and isolated yield. We incorporated an α-chiral center and an alkoxy alkene tether on the substrates and examined the effect of the size of alkyl groups and alkene tether length on diastereoselectivity. The requisite substrates for the oxidopyrylium-alkene cycloaddition reaction were synthesized in a few steps involving alkylation of optically active α-hydroxy amide, furyllithium addition, reduction of resulting ketone, and Achmatowicz reaction followed by acylation of a lactol intermediate. We have proposed stereochemical models for the [5 + 2] cycloaddition reaction via the oxidopyrylium ylide. Interestingly, the alkoxy substituent on the stereocenter and the chain length are responsible for the degree of stereoselectivity of the cycloadduct.

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

Investigations into a Stoichiometrically Equivalent Intermolecular Oxidopyrylium [5 + 2] Cycloaddition Reaction Leveraging 3-Hydroxy-4-pyrone-Based Oxidopyrylium Dimers.

Oxidopyrylium [5 + 2] cycloaddition reactions are powerful strategies for constructing complex bicyclic architectures. However, intermolecular cycloadditions of oxidopyrylium ylides are limited due to competing dimerization processes; consequently, high equivalents of dipolarophiles are often used to help intercept the ylide prior to dimerization. Recent studies by our lab have revealed that oxidopyrylium dimers derived from 3-hydroxy-4-pyrones are capable of reverting back to ylides in situ and as a result can be used as clean oxidopyrylium ylide sources. The following manuscript investigates intermolecular cycloaddition reactions between 3-hydroxy-4-pyrone-derived oxidopyrylium dimers and stoichiometrically equivalent ratios of alkyne dipolarophiles under thermal conditions. With certain reactive alkynes, pure cycloadducts can be obtained following a simple evaporation of the solvent, which is a benefit of the completely atom-economical reaction conditions. However, when less reactive alkynes are used the yields suffer due to a competing dimer rearrangement. Finally, when reactive-yet-volatile alkynes are used, such as methyl propiolate, competing 2:1 ylide/alkyne cycloadducts are observed. Intriguingly, these complex cycloadducts, which can be obtained in good yields from the pure cycloadducts, form with high regio- and stereoselectivities; however, both the regio-and stereoselectivities differ remarkably based on the source of the oxidopyrylium ylide.

Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition.

Natural products containing bridged ring systems are widely identified and show significant biological activity. The development of efficient synthesis reactions and strategies to construct bridged ring systems is a long-standing but very significant challenge in organic chemistry. In 2014, our group developed a unique type II [5 + 2] cycloaddition reaction that provides a facile and direct methodology for constructing highly functionalized bridged bicyclo[4.3.1], bicyclo[4.4.1], bicyclo[5.4.1], bicyclo[6.4.1], and other bicyclo[m.n.1] systems containing a strained bridgehead double bond. In this Account, we summarize the methodology development and report the results of application of our unique strategy for the total synthesis of several natural products with bridged ring systems (i.e., cyclocitrinol, cerorubenic acid-III, and vinigrol) during the past 5 years in our laboratory. In the first part, we introduce the logic behind the design and discovery of type II [5 + 2] cycloadditions. The substrates can be easily synthesized by a modular approach, followed by base-promoted group elimination under heat to form an oxidopyrylium ylide, which can undergo cycloaddition under relatively mild conditions with a variety of double bonds to generate bridged bicyclo[m.n.1] frameworks in high yield. The diastereocontrol and unique endo selectivity of this methodology are favorable for further application to the synthesis of complex natural products. In the second part, we highlight our endeavors in the total synthesis of several different types of molecules bearing bridged ring systems using our methodology. The bridged bicyclo[4.4.1] system is the core structure of two different types of natural products, cyclocitrinol and cerorubenic acid-III, that can be efficiently constructed by type II [5 + 2] cycloadditions. The development of suitable strategies and methods for site-selective cleavage of the C-O bond of the oxa-[3.2.1] ring system in the products of type II [5 + 2] cycloadditions is also discussed and highlighted during the syntheses. Moreover, the bridged bicyclo[5.3.1] system is the core structure of vinigrol, which can be constructed through a novel ring contraction sequence of the bicyclo[5.4.1] system formed by a type II [5 + 2] cycloaddition. By combining with a ring contraction cascade, we believe that type II [5 + 2] cycloadditions have the potential to be used as a unified approach to constructing natural products containing bridged bicyclo[m.n.1] frameworks.

Maltol- and Allomaltol-Derived Oxidopyrylium Ylides: Methyl Substitution Pattern Kinetically Influences [5 + 3] Dimerization versus [5 + 2] Cycloaddition Reactions.

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.

Pathway Bifurcation in the (4 + 3)/(5 + 2)-Cycloaddition of Butadiene and Oxidopyrylium Ylides: The Significance of Molecular Orbital Isosymmetry.

By drawing analogies from the dimerization of cyclopentadiene, a novel reaction pathway bifurcation is uncovered in the cycloaddition of oxidopyrylium ylides and butadiene. Analysis of the potential energy surface (at the M06-2X/6-311+G(d,p) level of theory) in combination with Born-Oppenheimer molecular dynamics simulations (M06-2X/6-31+G(d)) demonstrate that both the (4 + 3)- and (5 + 2)-cycloaddition products are accessed from the same transition state. Key indicators of a pathway bifurcation (asynchronous bond formation, and a second transition state for the interconversion of the products) are also observed. The absence of a post-transition state bifurcation in the related oxidopyridinium systems of Krenske and Harmata is rationalized. Finally, the isosymmetry of the oxidopyrylium and cyclopentadiene molecular orbitals as well as the presence of "secondary orbital interactions" are emphasized as the common source of nonstatistical behavior. Application of these principles will allow for the rapid identification of new reaction pathway bifurcations.

Intermolecular Regio‐ and Stereoselective Hetero‐[5+2] Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines

AbstractWe have developed the first intermolecular hetero‐[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio‐ and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen‐containing seven‐membered rings—azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero‐[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition.

Intermolecular Regio- and Stereoselective Hetero-[5+2] Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines.

We have developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings-azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition.

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

AbstractAn 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.magnified image

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.

Catalytic Enantioselective Intermolecular [5 + 2] Dipolar Cycloadditions of a 3-Hydroxy-4-pyrone-Derived Oxidopyrylium Ylide.

The first catalytic enantioselective [5 + 2] dipolar cycloaddition of a 3-hydroxy-4-pyrone-derived oxidopyrylium ylide is described. These studies leveraged the recently recognized ability of oxidopyrylium dimers to serve as the source of ylide, which was found to be key to increasing yields and achieving enantiomeric excesses up to 99%. General reaction conditions were identified for an array of α,β-unsaturated aldehyde dipolarophiles. Reaction products possess four stereocenters, and subsequent reduction introduced a fifth contiguous stereocenter with total stereocontrol.

ChemInform Abstract: Aminocatalytic Enantioselective Cycloadditions

AbstractReview: [48 refs.

Aminocatalytic Enantioselective Cycloadditions

Aminocatalysis applied to cycloaddition chemistry has gained an outstanding level of efficiency and sophistication, with many examples in which the different organocatalytic activation manifolds have been applied to develop catalytic and enantioselective variants of synthetically relevant cycloaddition reactions. In this account, a selection of relevant contributions to this field carried out in our laboratories will be presented, showing that the catalytic generation of either electron-poor α,β-unsaturated iminium ions or, alternatively, electron-rich dienamines or trienamines can constitute a very useful approach for the activation of (poly)unsaturated aldehydes toward different types of reagents. Importantly, this account also shows that reactions can be designed from the beginning leading to the expected products and that proceed with excellent performance once an appropriate catalyst and conditions are selected. Alternatively, it is also shown that, in some cases, unexpected results are obtained which have led us to the discovery of interesting transformations that are unprecedented in the chemical literature. 1 Introduction 2 Formal [3+2] Cycloaddition with Azomethine Ylides 3 Attempted [3+2] Cycloaddition Using Hydrazones as Azomethine Imine Precursors 4 [5+2] Cycloaddition Between Oxidopyrylium Ylides and Enals under Dienamine Activation 5 [2+2] Cycloaddition Between Nitroalkenes and Enals under Dienamine Activation 6 Trienamine Activation. Unconjugated Dienals as Active Substrates in [4+2] Cycloaddition 7 Summary and Outlook

Mechanistic Insights into the Mode of Action of Bifunctional Pyrrolidine-Squaramide-Derived Organocatalysts.

The catalytic modes of action of three squaramide-derived bifunctional organocatalysts have been investigated using DFT methods. The [5+2] cycloaddition between oxidopyrylium ylides and enals was used as the model reaction. Two primary modes were possible for the different catalysts studied. The preference for one mode over the other was due to the possibility of additional favorable π-π interactions between the hydrogen-bond activated pyrylium ylide and an electron-deficient aromatic ring bonded to the squaramide NH group. The model can be extended to other reactions catalyzed by the same catalysts, such as formal [2+2] cycloadditions between nitroalkenes and α,β-unsaturated aldehydes. The computational results were in excellent concurrence with the available experimental reports on the observed total enantioselectivity and differences in diastereoselectivity depending on the substrate and the reaction.

ChemInform Abstract: Catalytic Enantioselective [5 + 2] Cycloaddition Between Oxidopyrylium Ylides and Enals under Dienamine Activation.

Benzopyrylium ylides generated in situ from 1-acetoxyisochroman-4-ones reacted with α,β-unsaturated aldehydes in the presence of a bifunctional secondary-amine/squaramide catalyst to furnish [5+2] cycloaddition products in good yield with high diastereo- and enantioselectivity. The reaction proceeds by dienamine activation and involves β,γ-functionalization of the enal. The dienamine intermediates showed exclusive β,γ-reactivity and provided direct access to compounds with the 8-oxabicyclo[3.2.1]octane framework. The ability of the bifunctional secondary-amine/squaramide catalyst to engage in hydrogen-bonding interactions with the ylide made it particularly effective in terms of both the yield and the stereoselectivity of the transformation.