Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

Zheng, Yongxiang; Huang, Weichen; Dhungana, Roshan K.; Granados, Albert; Keeß, Sebastian; Makvandi, Mehran; Molander, Gary A.

doi:10.1021/jacs.2c11501

Cited by 125 publications

(47 citation statements)

References 53 publications

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“…Recent developments in the synthesis of more highly functionalised BCBs should also enable more detailed investigations of these scaffolds and the effect that alternative substitution has on BCB reactivity. This is a rapidly developing field and during the review process of this manuscript further investigations towards bridged bicyclic 97,98 , spirocyclic 99 , and other structural motifs 100,101 have been reported. As the preparation of structurally complex architectures becomes more important to our ability to design the next generation of pharmaceuticals, the chemistry of the smallest fused hydrocarbon will certainly have its part to play.…”

Section: Discussionmentioning

confidence: 92%

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

2023

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Bicyclobutanes are among the most highly strained isolable organic compounds and their associated low activation barriers to reactivity make them intriguing building-blocks in organic chemistry. In recent years, numerous creative synthetic strategies exploiting their heightened reactivity have been presented and these discoveries have often gone hand-in-hand with the development of more practical routes for their synthesis. Their proclivity as strain-release reagents through their weak central C–C bond has been harnessed in a variety of addition, rearrangement and insertion reactions, providing rapid access to a rich tapestry of complex molecular scaffolds. This review will provide an overview of the different options available for bicyclobutane synthesis, the main classes of compounds that can be prepared from bicyclobutanes, and the associated modes of reactivity used.

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Section: Discussionmentioning

confidence: 92%

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

2023

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“…Recently, we discovered that simple diboron(4) compounds, via formation of Lewis base-stabilized boron-centered radicals, could serve as efficient catalysts in radical [2π + 2σ] cycloaddition of alkenes and cyclopropanes. , On the other hand, the groups of Glorius, Brown, Procter, and us have independently reported photosensitizer, SmI 2 or diboron(4)-catalyzed [2π + 2σ] cycloaddition of alkenes with BCBs. Herein, we wish to disclose a diboron(4)-catalyzed intermolecular [2σ + 2σ] cycloaddition of cyclopropyl ketones with BCBs as a modular and selective method for preparation of highly substituted BCHs that are not readily accessible by known methods …”

Section: Introductionmentioning

confidence: 99%

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

et al. 2023

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In contrast to the traditional and widely-used cycloaddition reactions involving at least a π bond component, a [2σ + 2σ] radical cycloaddition between bicyclo[1.1.0]butanes (BCBs) and cyclopropyl ketones has been developed to provide a modular, concise, and atom-economical synthetic route to substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes and core skeleton of a number of terpene natural products. The reaction was catalyzed by a combination of simple tetraalkoxydiboron(4) compound B 2 pin 2 and 3-pentyl isonicotinate. The broad substrate scope has been demonstrated by synthesizing a series of new highly functionalized BCHs with up to six substituents on the core with up to 99% isolated yield. Computational mechanistic investigations supported a pyridine-assisted boronyl radical catalytic cycle.

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“…We tried to understand the mechanism of this [2 + 2] reaction and the factors affecting its regiochemistry, which is our primary goal in this study. We were also interested in using the mechanistic insights to realize experimentally the cross [2 + 2] reaction of ene-keteniminium ions so that we can provide a new way to synthesize molecules with a challenging bicyclo[3.1.1]heptane skeleton, which is important in the synthesis and is also a highly pursued bioisostere in medicinal chemistry …”

Section: Introductionmentioning

confidence: 99%

Kinetic, Thermodynamic, and Dynamic Control in Normal vs. Cross [2 + 2] Cycloadditions of Ene-Keteniminium Ions: Computational Understanding, Prediction, and Experimental Verification

Zhang

2023

J. Am. Chem. Soc.

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Almost all reported intramolecular [2 + 2] reactions of ene-keteniminium ions gave normal [2 + 2] products with a fused bicycle framework, but not cross [2 + 2] products with a bicyclo[3.1.1]heptane skeleton, a highly pursued bioisostere in pharmaceutical chemistry. How to rationalize this and design new cross [2 + 2] reactions? Theoretical studies using density functional theory, high-level ab initio single-point energy calculations, and molecular dynamics showed that this [2 + 2] reaction has all three patterns of regiochemical control: the reaction is controlled either kinetically, thermodynamically, or dynamically. A carbocation model of forming endo and exo carbocations has been proposed to rationalize the reaction outcomes, revealing that the tethers (between alkenes and keteniminium ions), substituents (on the alkenes), and alkene configurations in ene-keteniminium ions play critical roles. These understandings were further used to predict that introducing a substituent in the terminal position of alkene with a trans configuration in eneketeniminium ions can realize the cross [2 + 2] reaction, which is dynamically controlled for alkyl substituents or kinetically controlled for aryl substituents. These and more other predictions were realized experimentally, and many cross [2 + 2] products with a bicyclo[3.1.1]heptane skeleton can be achieved. Both molecular dynamics and new experiments have also been applied to correct a key but misassigned [2 + 2] product reported in the literature, further supporting the insightful mechanisms reported here.

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Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

Cited by 125 publications

References 53 publications

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

Kinetic, Thermodynamic, and Dynamic Control in Normal vs. Cross [2 + 2] Cycloadditions of Ene-Keteniminium Ions: Computational Understanding, Prediction, and Experimental Verification

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