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Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling.

Ko HM, Dong G - Nat Chem (2014)

Bottom Line: Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions.Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins.Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA.

ABSTRACT
Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp(2) carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

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The challenge of bridged-ring synthesisa, Selected alkaloid natural products with bridged-ring substructures. b, Comparison of the type II IMDA reaction - which is synthetically limited by the incipient strain in an unsaturated bridgehead carbon - and the approach described in this work. c, Previous work on metal-catalysed C−C activation of cyclobutanones towards coupling and potential challenges due to the decarbonylation of the ketones.
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Figure 1: The challenge of bridged-ring synthesisa, Selected alkaloid natural products with bridged-ring substructures. b, Comparison of the type II IMDA reaction - which is synthetically limited by the incipient strain in an unsaturated bridgehead carbon - and the approach described in this work. c, Previous work on metal-catalysed C−C activation of cyclobutanones towards coupling and potential challenges due to the decarbonylation of the ketones.

Mentions: The intramolecular Diels-Alder (IMDA) reaction, a [4π+2π] cycloaddition, is one of the most widely utilized reactions for preparing ring systems.1–10 According to how the diene motif is tethered to the dienophile, IMDA reactions are classified into two types: type I and type II.7 While vast success has been achieved for applying type I-IMDA (tethered at the 1-position of the diene) in fused-ring syntheses, in contrast, much limited scaffolds can be prepared by type II-IMDA (tethered at the 2-position of the diene) due to Bredt’s rule11 (unfavorable sp2 carbon at the bridge-head position). For example, while 6–6 and 5–6 bridged rings are commonly found in various bioactive molecules (Fig. 1a), formation of 6–6 bridged rings ([3.3.1]-bicycle) via type II-IMDA was mainly restricted in gas phase12–14 and to our knowledge, no 5–6 bridged rings ([3.2.1]-bicycle) has been observed to date using such an approach (Fig. 1b). Stimulated by the challenge of type II-IMDA, in this communication, we describe an alternative [4+2] coupling method that is capable of providing type II-IMDA-like products via a cooperative C–C bond activation of cyclobutanones. Using this methodology, a complementary scope of bridged skeletons, including a variety of 6–6 and 5–6 bridged rings, can be accessed; furthermore, the ketone group of the products can serve as a convenient handle to access other functional groups or ring systems.


Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling.

Ko HM, Dong G - Nat Chem (2014)

The challenge of bridged-ring synthesisa, Selected alkaloid natural products with bridged-ring substructures. b, Comparison of the type II IMDA reaction - which is synthetically limited by the incipient strain in an unsaturated bridgehead carbon - and the approach described in this work. c, Previous work on metal-catalysed C−C activation of cyclobutanones towards coupling and potential challenges due to the decarbonylation of the ketones.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150356&req=5

Figure 1: The challenge of bridged-ring synthesisa, Selected alkaloid natural products with bridged-ring substructures. b, Comparison of the type II IMDA reaction - which is synthetically limited by the incipient strain in an unsaturated bridgehead carbon - and the approach described in this work. c, Previous work on metal-catalysed C−C activation of cyclobutanones towards coupling and potential challenges due to the decarbonylation of the ketones.
Mentions: The intramolecular Diels-Alder (IMDA) reaction, a [4π+2π] cycloaddition, is one of the most widely utilized reactions for preparing ring systems.1–10 According to how the diene motif is tethered to the dienophile, IMDA reactions are classified into two types: type I and type II.7 While vast success has been achieved for applying type I-IMDA (tethered at the 1-position of the diene) in fused-ring syntheses, in contrast, much limited scaffolds can be prepared by type II-IMDA (tethered at the 2-position of the diene) due to Bredt’s rule11 (unfavorable sp2 carbon at the bridge-head position). For example, while 6–6 and 5–6 bridged rings are commonly found in various bioactive molecules (Fig. 1a), formation of 6–6 bridged rings ([3.3.1]-bicycle) via type II-IMDA was mainly restricted in gas phase12–14 and to our knowledge, no 5–6 bridged rings ([3.2.1]-bicycle) has been observed to date using such an approach (Fig. 1b). Stimulated by the challenge of type II-IMDA, in this communication, we describe an alternative [4+2] coupling method that is capable of providing type II-IMDA-like products via a cooperative C–C bond activation of cyclobutanones. Using this methodology, a complementary scope of bridged skeletons, including a variety of 6–6 and 5–6 bridged rings, can be accessed; furthermore, the ketone group of the products can serve as a convenient handle to access other functional groups or ring systems.

Bottom Line: Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions.Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins.Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA.

ABSTRACT
Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp(2) carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

Show MeSH
Related in: MedlinePlus