Soft Enolization of 3-Substituted Cycloalkanones Exhibits Significantly Improved Regiocontrol vs Hard Enolization Conditions

Dwulet, Natalie C.; Ramella, Vincenzo; Vanderwal, Christopher D.

doi:10.1021/acs.orglett.1c03844

Cited by 2 publications

(3 citation statements)

References 29 publications

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“…We demonstrate here a small selection: oxidation to form acyloin 8 , installation of an α- tert -butyl group ( 9 ), conversion to the corresponding enol triflate 10 (itself another versatile intermediate), and Pd-catalyzed α-arylation ( 11 ) (Scheme ). In each example, the products were synthesized as a single regioisomer, which would not be possible using enolate nucleophiles generated through deprotonation of the corresponding ketone …”

Section: Resultsmentioning

confidence: 99%

“…In each example, the products were synthesized as a single regioisomer, which would not be possible using enolate nucleophiles generated through deprotonation of the corresponding ketone. 125 Finally, we developed a more general protocol for the isolation of TMS silyl enol ethers, which can be prone to hydrolysis in workup and during chromatography. This is needed because many silyl enol ether derivatization reactions require TMS groups 67,126−132 or demonstrate diminished reactivity when using bulkier, more easily isolated congeners.…”

Section: Exclusion Of Mechanisms Involving Uncatalyzed Ring-opening H...mentioning

confidence: 99%

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Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

et al. 2023

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Reactions that cleave C–C bonds and enable functionalization at both carbon sites are powerful strategic tools in synthetic chemistry. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of 3-carbon fragments, but general approaches to net C–C activation/difunctionalization are unknown. Herein, we demonstrate the cross-coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-opened products. A combination of experimental and theoretical studies rules out more established mechanisms and sheds light on how cooperation between the redox-active terpyridine (tpy) ligand and the nickel atom enables the C–C bond activation step. The reduced (tpy·–)NiI species activates the C–C bond via a concerted asynchronous ring-opening transition state. The resulting alkylnickel(II) intermediate can then be engaged by aryl, alkenyl, and alkylzinc reagents to furnish cross-coupled products. This allows quick access to products that are difficult to make by conjugate addition methods, such as β-allylated and β -benzylated enol ethers. The utility of this approach is demonstrated in the synthesis of a key (±)-taiwaniaquinol B intermediate and the total synthesis of prostaglandin D1.

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Section: Resultsmentioning

confidence: 99%

Section: Exclusion Of Mechanisms Involving Uncatalyzed Ring-opening H...mentioning

confidence: 99%

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

et al. 2023

View full text Add to dashboard Cite

show abstract

“…In each example, the products were synthesized as a single regioisomer, which would not be possible using enolate nucleophiles generated through deprotonation of the corresponding ketone. 125 Finally, we developed a more general protocol for the isolation of TMS silyl enol ethers, which can be prone to hydrolysis in workup and during chromatography. This is needed because many silyl enol ether derivatization reactions require TMS groups 67,[126][127][128][129][130][131][132] or demonstrate diminished reactivity when using bulkier, more easily isolated congeners.…”

Section: Exclusion Of Set Ring Opening (Schemementioning

confidence: 99%

Ligand-Metal Cooperation Enables Net C–C Activation Cross-Coupling Reactivity of Cyclopropyl Ketones

Gilbert

Trenerry

Longley

et al. 2023

Preprint

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Reactions that cleave C–C bonds and enable functionalization at both carbon sites are powerful strategic tools in synthetic chemistry. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of 3-carbon fragments, but general approaches to net C–C activation / difunctionalization are unknown. Herein we demonstrate the cross-coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-opened products. A combination of experimental and theoretical studies rule out more established mechanisms and shed light on how cooperation between the redox-active terpyridine (tpy) ligand and the nickel atom enables the C–C bond activation step. The reduced (tpy•–)NiI species activates the C–C bond via a concerted asynchronous ring-opening transition state. The resulting alkylnickel(II) intermediate can then be engaged by aryl-, alkenyl-, and alkylzinc reagents to furnish cross-coupled products. This allows quick access to products that are difficult to make by conjugate addition methods, such as β-allylated and β-benzylated enol ethers. The utility of this approach is demonstrated in the synthesis of a key (±)-taiwaniaquinol B intermediate and the total synthesis of prostaglandin D1.

show abstract

Soft Enolization of 3-Substituted Cycloalkanones Exhibits Significantly Improved Regiocontrol vs Hard Enolization Conditions

Cited by 2 publications

References 29 publications

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

Ligand-Metal Cooperation Enables Net C–C Activation Cross-Coupling Reactivity of Cyclopropyl Ketones

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