Lithium Hydroxide Assisted<i>Endo</i>‐Selective [4+4]‐Photocycloaddition of Pyran‐2‐ones

Li, Lei; Turnbull, William L.; McDonald, Robert; West, F. G.

doi:10.1002/ejoc.202100122

“…An alternative approach to obtain the cyclooctadiene core is the photochemical [4 + 4] cycloaddition . While the intramolecular version of this reaction has been successfully applied, − there is a lack of examples of intermolecular [4 + 4] photochemical cycloadditions as they generally require elevated reaction temperature often resulting in substrate degradation . Furthermore, the only enantioselective example is based on the use of a chiral auxiliary to harness the substrate bias toward the stereoselective formation of the hetero-[4 + 4] cycloadduct …”

Section: Introductionmentioning

confidence: 99%

Organocatalytic Enantioselective Thermal [4 + 4] Cycloadditions

Corti

¹

,

Barløse

²

,

Østergaard

³

et al. 2023

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Chiral eight-membered carbocycles are important motifs in organic chemistry, natural product chemistry, chemical biology, and medicinal chemistry. The lack of synthetic methods toward their construction is a challenge preventing their rational design and stereoselective synthesis. The catalytic enantioselective [4 + 4] cycloaddition is one of the most straightforward and atom-economical methods to obtain chiral cyclooctadiene derivatives. We report the first organocatalytic asymmetric [4 + 4] cycloaddition of 9H-fluorene-1-carbaldehydes with electron-deficient dienes affording cyclooctadiene derivatives in good yields and with excellent control of peri-, diastereo-, and enantioselectivities. The reaction concept is based on the aminocatalytic formation of a polarized butadiene component incorporated into a cyclic extended π-system, with restricted conformational freedom, allowing for a stereocontrolled [4 + 4] cycloaddition. FMO analysis unveiled that the HOMO and LUMO of the two reacting partners resemble those of butadiene. The methodology allows for the construction of cyclooctadiene derivatives decorated with various functionalities. The cyclooctadienes were synthetically elaborated, allowing for structural diversity demonstrating their synthetic utility for the formation of, for example, chiral cyclobutene- or cyclooctane scaffolds. DFT computational studies shed light on the reaction mechanism identifying the preference for an initial but reversible [4 + 2] cycloaddition delivering an off-cycle catalyst resting state, from which catalyst elimination is not possible. The off-cycle catalyst-bound intermediate undergoes a retro-[4 + 2] cycloaddition, followed by a [4 + 4] cycloaddition generating a cycloadduct from which catalyst elimination is possible. The reaction pathway accounts for the observed peri-, diastereo-, and enantioselectivity of the organocatalytic [4 + 4] cycloaddition.

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“…) [12] has proved to be a conceptually straightforward, practice friendly, and atom‐economical strategy for the synthesis of cyclooctanoids (Figure 2). This reaction has been further developed by Wender, [13] Chirik, [14] Dieck, [15] Cramer, [16] West [17] and very recently by Jorgensen [18] (Figure 2a). These reactions require 1,3‐dienes as substrates and fall into the category of [4π+4π] cycloaddition.…”

Section: Figurementioning

confidence: 91%

Type I [4σ+4π] versus [4σ+4π−1] Cycloaddition To Access Medium‐Sized Carbocycles and Discovery of a Liver X Receptor β‐Selective Ligand

Jiang,

Hu,

Shen

et al. 2024

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The transition‐metal‐catalyzed [4 + 4] cycloaddition leading to cyclooctanoids has been centralizing on dimerization between 1,3‐diene type substrates. Here, we extend a [4σ + 4π ‐ 1] and [4σ + 4π] cycloaddition strategy to access the 7/8‐membered fused carbocycles through Rh‐catalyzed coupling between the 4σ‐donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad scope (>40 examples) of 5‐6‐7 and 5‐6‐8 polyfused carbocycles was obtained with good yields (up to 90%). The density functional theory (DFT) calculations, kinetic monitoring and 13C‐labeling experiments were carried out, suggesting a plausible mechanism. Notably, the 5‐6‐7 tricycle 2v was found to be a very rare, potent, and selective ligand for the liver X receptor β (KD=0.64 μM), which is a potential therapeutic target for cholesterol‐metabolism‐related fatal diseases.

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“…) [12] has proved to be a conceptually straightforward, practice friendly, and atom‐economical strategy for the synthesis of cyclooctanoids (Figure 2). This reaction has been further developed by Wender, [13] Chirik, [14] Dieck, [15] Cramer, [16] West [17] and very recently by Jorgensen [18] (Figure 2a). These reactions require 1,3‐dienes as substrates and fall into the category of [4π+4π] cycloaddition.…”

Section: Figurementioning

confidence: 91%

Type I [4σ+4π] versus [4σ+4π−1] Cycloaddition To Access Medium‐Sized Carbocycles and Discovery of a Liver X Receptor β‐Selective Ligand

Jiang,

Hu,

Shen

et al. 2024

Angewandte Chemie

0

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The transition‐metal‐catalyzed [4 + 4] cycloaddition leading to cyclooctanoids has been centralizing on dimerization between 1,3‐diene type substrates. Here, we extend a [4σ + 4π ‐ 1] and [4σ + 4π] cycloaddition strategy to access the 7/8‐membered fused carbocycles through Rh‐catalyzed coupling between the 4σ‐donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad scope (>40 examples) of 5‐6‐7 and 5‐6‐8 polyfused carbocycles was obtained with good yields (up to 90%). The density functional theory (DFT) calculations, kinetic monitoring and 13C‐labeling experiments were carried out, suggesting a plausible mechanism. Notably, the 5‐6‐7 tricycle 2v was found to be a very rare, potent, and selective ligand for the liver X receptor β (KD=0.64 μM), which is a potential therapeutic target for cholesterol‐metabolism‐related fatal diseases.

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Lithium Hydroxide AssistedEndo‐Selective [4+4]‐Photocycloaddition of Pyran‐2‐ones

Cited by 4 publications

References 66 publications

Organocatalytic Enantioselective Thermal [4 + 4] Cycloadditions

Organocatalytic Enantioselective Thermal [4 + 4] Cycloadditions

Type I [4σ+4π] versus [4σ+4π−1] Cycloaddition To Access Medium‐Sized Carbocycles and Discovery of a Liver X Receptor β‐Selective Ligand

Type I [4σ+4π] versus [4σ+4π−1] Cycloaddition To Access Medium‐Sized Carbocycles and Discovery of a Liver X Receptor β‐Selective Ligand

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