Inverting the reactivity of troponoid systems in enantioselective higher-order cycloaddition

Frankowski, Sebastian; Skrzyńska, Anna; Albrecht, Łukasz

doi:10.1039/c9cc05638f

Cited by 29 publications

(15 citation statements)

References 69 publications

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“…An aminocatalytic [8 + 2]cycloaddition employing α,β-unsaturated aldehydes and the inherently unstable tropothione has recently been disclosed. 53 Isobenzofulvenes (IBFs), while less studied, also display a propensity to react as an 8π-component (this may also be considered a 4π-component if the fused benzo is not included in the electron count, but it does indeed experience bonding changes in the reaction). Hafner and Bauer reported the first synthesis of a dimethylamino-IBF derivative and its subsequent reaction with maleic anhydride in both [8 + 2]-and [10 + 2]fashions.…”

Section: [8 + 2]-and [10 + 4]-cycloadditionsmentioning

confidence: 99%

Expanding the Frontiers of Higher-Order Cycloadditions

et al. 2019

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The concept of pericyclic reactions and the explanation of their specificity through orbital symmetries introduced a new way of understanding reactions and looking for new ones. One of the 1965 Woodward−Hoffmann communications described "the (as yet unobserved) symmetry-allowed 6 + 4 combination", the prediction of a new field of "higher-order" cycloadditions, involving more than six electrons. Later these authors predicted exo-stereoselectivity for the [6 + 4]-cycloaddition. Chemists rushed to test this prediction (for the most part successfully). For more than half a century, chemists have hunted for additional higher-order cycloadditions. The application of catalysis within organic chemistry allows the accomplishment of previously unattainable reactions, including higherorder cycloadditions.The many examples of [8 + 2], [6 + 4], and cycloadditions of even higher electroncounts discovered since the Woodward−Hoffmann rules were introduced illustrate the difficulty in predicting which of these transformations will occur when two highly unsaturated molecules react. Periselectivity has been a challenge, and the development of enantioselective variants has been elusive. While progress was made, the rise of organocatalysis in asymmetric synthesis has led to a surge of interest in stereoselective versions of higher-order cycloadditions. Through organocatalytic activation of conjugated cyclic polyenes and heteroaromatic compounds, asymmetric [8 + 2]-, [6 + 4]-, and [10 + 4]-cycloadditions have been realized by our groups. In this century, [6 + 4]-cycloadditions have been found also to occur in enzyme-catalyzed reactions for the biosynthesis of spinosyn A, heronamide, and streptoseomycin natural products. A whole new class of enzymes, the pericyclases that catalyze pericyclic reactions, has been discovered. A remarkable aspect of these recent developments is the cross-disciplinary research involved: from organic synthesis to computational studies integrated with experimental studies of reaction mechanisms, intermediates, and dynamics, to understanding mechanisms of enzyme catalysis and engineering of enzymes. This Account describes how our groups have been involved in the expansion of the higher-order cycloaddition frontiers. We describe both the history and recent progress in higher-order cycloadditions, and how these advances have been made by our collaborative experimental and computational studies. Progress in asymmetric organocatalysis, incorporating enantioselective higher-order cycloadditions in organic synthesis, and the stereoselective synthesis of important scaffolds will be highlighted. Experimental progress and computational modeling with density functional theory (DFT) has identified ambimodal cycloaddition pathways and led to the realization that multiple products of pericyclic reactions are linked by common transition states. Molecular dynamic simulations have provided fundamental understanding of factors controlling periselectivity and have led to discoveries of a group of enzymes, the pericyclases, whic...

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Section: [8 + 2]-and [10 + 4]-cycloadditionsmentioning

confidence: 99%

Expanding the Frontiers of Higher-Order Cycloadditions

et al. 2019

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“…Very recently, tropothione 82 was employed as a hetero‐tetraene in the organocatalytic, enantioselective higher‐order cycloaddition for the first time (Scheme ) . Inspired by the work of Machiguchi, it was demonstrated that by introduction of the sulfur atom into the structure of tropone, its electronic properties are modified, making it reactive with its HOMO.…”

Section: Troponoid Systems In Organocatalytic Higher‐order Cycloadditmentioning

confidence: 99%

“…Very recently,t ropothione 82 was employeda sahetero-tetraene in the organocatalytic, enantioselective higher-order cycloaddition fort he first time (Scheme 23). [31] Inspired by the work of Machiguchi, [32] it was demonstrated that by introduction of the sulfur atom into the structure of tropone, its electronic properties are modified, making it reactivew ith its HOMO.A saconsequence, LUMO-lowering aminocatalytic activation strategy was employed for the first time in higher-order cycloadditions, thus inverting the commonr eactivity scheme. Iminium ions 84 derived from the a,b-unsaturateda ldehydes 54 and aminocatalyst 4g were identified as suitable tetraenophiles for this cycloaddition providing [8+ +2]-cycloadducts in ap eriselective fashion.…”

Section: Troponoid Systems In Organocatalytic Higher-order Cycloadditmentioning

confidence: 99%

The Game of Electrons: Organocatalytic Higher‐Order Cycloadditions Involving Fulvene‐ and Tropone‐Derived Systems

Frankowski

Romaniszyn

Skrzyńska

et al. 2019

Chemistry A European J

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The great progress that took place in the field of higher‐order cycloadditions involving fulvene‐ and tropone‐derived systems in the last few years is astonishing. By application of organocatalytic activation modes, new higher‐order reactivities have been identified and described in the literature. These approaches take advantage of the high reliability of organocatalysis, at the same time expanding its potential and paving new directions for its further evolution. In this Minireview, the progress in the field of organocatalytic higher‐order cycloadditions involving fulvene‐ and tropone‐derived systems is summarized and insights into mechanistic aspects of the developed reactivities are provided. Furthermore, the discussion on the nomenclatural issues related to cycloaddition reactions has been conducted and solutions to clarify the picture proposed.

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“…The construction of structurally complex molecular scaffolds traditionally relies on long synthetic sequences to ensure selective transformations. In recent years, organocatalytic higher-order cycloadditions have emerged as efficient tools for the controlled formation of complex cyclic systems in a single synthetic step. − Through catalytic generation, inherently unstable π-components of extended conjugation can be wielded under ambient conditions, and their utilization in cycloaddition chemistry can provide products which are unobtainable through traditional Diels–Alder processes. Specifically, strategies involving catalytic dearomatization to access reactive π-systems have recently been employed. − The development of such unorthodox cycloaddends expands the range of compounds accessible through cycloaddition chemistry.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

et al. 2021

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The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12πcomponents derived from 5H-benzo[a]pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo[a]cycl[3.2.2]azine (indolizino[3,4,5-ab]isoindole) with excellent enantio-and diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2πcomponents relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5H-benzo[a]pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.

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Inverting the reactivity of troponoid systems in enantioselective higher-order cycloaddition

Abstract: The first enantioselective higher-order cycloaddition involving a tropone derivative that acts as an electron-rich 8π-component is described.

Cited by 29 publications

References 69 publications

Expanding the Frontiers of Higher-Order Cycloadditions

Expanding the Frontiers of Higher-Order Cycloadditions

The Game of Electrons: Organocatalytic Higher‐Order Cycloadditions Involving Fulvene‐ and Tropone‐Derived Systems

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

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