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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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Potentials and applications in bridged-ring synthesisa, Construction of fused-bridged tricyclic structures. b, Potentials for developing an enantioselective transformation. c, Use of the carbonyl group in the product as a handle to access ring-contracted and expanded bridged rings.
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Figure 3: Potentials and applications in bridged-ring synthesisa, Construction of fused-bridged tricyclic structures. b, Potentials for developing an enantioselective transformation. c, Use of the carbonyl group in the product as a handle to access ring-contracted and expanded bridged rings.

Mentions: Substrate 1q with a spirocyclic center was also investigated for this transformation (Fig. 3a). Two diastereomers of the desired product were obtained due to the diastereotopic difference between the two α-C–C bonds. The products 2q-i and 2q-ii contain interesting tricyclic bridged and fused scaffolds, which have been found in a number of aconitum/delphinium alkaloids (Fig. 1a, vide supra). Structures of both products were unambiguously confirmed by X-ray crystallography of their 2,4-dinitrophenylhydrazone derivatives (see supplementary information). Furthermore, preliminary studies have revealed that chiral phosphoramidite ligands, such as 4, effect the desymmetrization of cyclobutanone 1b with promising levels of enantioselectivity (Fig. 3b, 37% ee).48–49 This result suggests that the “cofactor”-assisted C–C activation mode is amenable to asymmetric catalysis, and work on this topic is ongoing.


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

Ko HM, Dong G - Nat Chem (2014)

Potentials and applications in bridged-ring synthesisa, Construction of fused-bridged tricyclic structures. b, Potentials for developing an enantioselective transformation. c, Use of the carbonyl group in the product as a handle to access ring-contracted and expanded bridged rings.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Potentials and applications in bridged-ring synthesisa, Construction of fused-bridged tricyclic structures. b, Potentials for developing an enantioselective transformation. c, Use of the carbonyl group in the product as a handle to access ring-contracted and expanded bridged rings.
Mentions: Substrate 1q with a spirocyclic center was also investigated for this transformation (Fig. 3a). Two diastereomers of the desired product were obtained due to the diastereotopic difference between the two α-C–C bonds. The products 2q-i and 2q-ii contain interesting tricyclic bridged and fused scaffolds, which have been found in a number of aconitum/delphinium alkaloids (Fig. 1a, vide supra). Structures of both products were unambiguously confirmed by X-ray crystallography of their 2,4-dinitrophenylhydrazone derivatives (see supplementary information). Furthermore, preliminary studies have revealed that chiral phosphoramidite ligands, such as 4, effect the desymmetrization of cyclobutanone 1b with promising levels of enantioselectivity (Fig. 3b, 37% ee).48–49 This result suggests that the “cofactor”-assisted C–C activation mode is amenable to asymmetric catalysis, and work on this topic is ongoing.

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