Enantioselective Desymmetrization of Cyclobutanones: A Speedway to Molecular Complexity

Sietmann, Jan; Wiest, Johannes

doi:10.1002/anie.201910767

Cited by 52 publications

(18 citation statements)

References 136 publications

(66 reference statements)

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“…Thus, four-membered ring compounds have served as unique building blocks in organic synthesis. Earlier examples have been summarized in comprehensive reviews published in 1971, 1986, 2003, and 2011. − The present review focuses on examples that were unveiled during the period from 2011 to the end of 2019. For reactions of cyclobutenones and benzocyclobutenones, this review primarily features examples reported after 2016, since a relevant comprehensive review recently appeared which covered such reactions published prior to 2016 .…”

Section: Introductionmentioning

confidence: 99%

Cleavage of Carbon–Carbon σ-Bonds of Four-Membered Rings

2020

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This article reviews synthetic transformations involving cleavage of a carbon− carbon bond of a four-membered ring, with a particular focus on the examples reported during the period from 2011 to the end of 2019. Most significant is the progress of catalytic reactions involving oxidative addition of carbon−carbon bonds onto transition metals or β-carbon elimination of transition metal alkoxides. When they are looked at from synthetic perspectives, they offer unique and efficient methods to build complex natural products and structures that are difficult to construct by conventional methods. On the other hand, β-scission of radical intermediates has also attracted increasing attention as an alternative elementary step to cleave carbon−carbon bonds. Its site-selectivity is often complementary to that of transition metalcatalyzed reactions. In addition, Lewis acid-mediated and thermally induced ring-opening of cyclobutanone derivatives has garnered renewed attention. On the whole, these examples demonstrate unique synthetic potentials of structurally strained four-membered ring compounds for the construction of organic skeletons.

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Section: Introductionmentioning

confidence: 99%

Cleavage of Carbon–Carbon σ-Bonds of Four-Membered Rings

2020

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“…That is, it is commonplace for fragments to be produced as racemates, albeit often as pure diastereomers. Molecular complexity is lowered by circumventing enantiomers (in contrast to the case of desymmetrisation of cyclobutanes), [42] a significant feature relating back to the effect of higher complexity potentially resulting in lower hit rates of fragment screening [16] . The nucleophiles to be added can be diverse, yielding a strategy for the synthesis of achiral yet diastereomeric fragments with a cyclobutane core.…”

Section: Resultsmentioning

confidence: 99%

Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

et al. 2022

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Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.

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“…Remarkably, β-carbon elimination of metal–alcoholate species has become a more powerful and efficient approach for expedient access to carbonyl compounds . Among others, cyclobutanols, which have a propensity for releasing ring strain to undergo β-carbon elimination, routinely serve as versatile building blocks to construct a variety of γ-substituted ketones. , Mechanistically, a metal alkoxide, formed by the deprotonation of cyclobutanol, undergoes β-carbon elimination to generate a carbon–metal intermediate, which can be functionalized with various electrophiles (Figure a) . The direct elaboration of the C–C bond into a new C–C bond and a C–O bond renders coupling reactions of cyclobutanols more compelling and valuable.…”

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confidence: 99%

Palladium-Catalyzed Asymmetric Cross-Coupling Reactions of Cyclobutanols and Unactivated Olefins

Cao

Zhang

et al. 2021

Org. Lett.

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Transition-metal-catalyzed activations of carbon–carbons bonds of small strained rings have widespread applications in synthetic and medicinal chemistry. However, coupling reactions of cyclobutanols involving β-carbon elimination to construct C(sp3)–C(sp3) bonds have scarcely been developed. Here, we demonstrate a highly enantioselective Pd-catalyzed intermolecular C(sp3)–C(sp3) coupling reaction of a broad range of cyclobutanol derivatives and unactivated alkenes, allowing convenient access to a series of chiral benzene-fused cyclic compounds in a highly regio-, chemo-, and enantioselective manner.

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Enantioselective Desymmetrization of Cyclobutanones: A Speedway to Molecular Complexity

Cited by 52 publications

References 136 publications

Cleavage of Carbon–Carbon σ-Bonds of Four-Membered Rings

Cleavage of Carbon–Carbon σ-Bonds of Four-Membered Rings

Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

Palladium-Catalyzed Asymmetric Cross-Coupling Reactions of Cyclobutanols and Unactivated Olefins

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