Zinc-Mediated Transformation of 1,3-Diols to Cyclopropanes for Late-Stage Modification of Natural Products and Medicinal Agents

McGinnis, Tristan M.; Thane, Taylor A.; Jarvo, Elizabeth R.

doi:10.1021/acs.orglett.2c02362

Cited by 4 publications

(5 citation statements)

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“…The catalytic cycle can be divided into two parts: (1) formation of the 1,3-diiodide intermediate and (2) Ni-catalyzed XEC reaction. Our previous study provided evidence that 1,3-diiodides are formed in situ from 1,3-dimesylates before entering the nickel catalytic cycle. , Therefore, the Ni-catalyzed XEC reaction begins with the active catalyst Ni 0 L n , A , and 1,3-diiodide. Halogen atom transfer (XAT) occurs to generate Ni(I) species B and secondary alkyl radical C .…”

Section: Resultsmentioning

confidence: 99%

“…The reaction with 1,3-dimesylate 1 was chosen as our computational model (eq ). Key questions included the identity of the nucleophilic iodide source and stereochemical outcome of iodide formation. …”

Section: Resultsmentioning

confidence: 99%

“…Building on these successes will require detailed analysis of the key mechanistic features that drive activation and selectivity in these transformations. In particular, we have developed intramolecular cross-electrophile coupling (XEC) reactions of 1,3-diols for formation of cyclopropanes . These transformations provide facile conversion of diols, functional groups that adorn natural products and synthetic intermediates, to cyclopropanes.…”

Section: Introductionmentioning

confidence: 99%

“…In particular, we have developed intramolecular cross-electrophile coupling (XEC) reactions of 1,3-diols for formation of cyclopropanes. 2 These transformations provide facile conversion of diols, functional groups that adorn natural products and synthetic intermediates, to cyclopropanes. As such, these deoxygenative reactions provide straightforward approaches toward structural remodeling of complex molecular architectures to incorporate the cyclopropropane structural element.…”

Section: Introductionmentioning

confidence: 99%

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A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

et al. 2023

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Understanding mechanistic details of the nickel-catalyzed coupling reactions of Csp3 alcohol derivatives is key to developing selective reactions of this widely prevalent functional group. In this manuscript, we utilize a combination of experimental data and DFT studies to define the key intermediates, stereochemical outcome, and competing pathways of a nickel-catalyzed cross-electrophile coupling reaction of 1,3-dimesylates. Stereospecific formation of a 1,3-diiodide intermediate is achieved in situ by the Grignard reagent. The overall stereoablative stereochemical outcome is due to a nickel-catalyzed halogen atom abstraction with a radical rebound that is slower than epimerization of the alkyl radical. Finally, lifetimes of this alkyl radical intermediate are compared to radical clocks to enhance the understanding of the lifetime of the secondary alkyl radical.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

et al. 2023

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“…24 After evaluation of a series of reaction conditions, we determined that zinc powder, in the absence of a nickel catalyst, was capable of transforming dimesylates to cyclopropanes (Scheme 14). 34 Critical to the reaction was addition of stoichiometric quantities of an iodide salt, NaI, consistent with formation of alkyl iodides in situ as key intermediates. With these reaction conditions, we can engage a range of substrates bearing sensitive functional groups including a series derived from statins.…”

Section: Part Ii: Stereoablative Reactions Of Alcohol Derivativesmentioning

confidence: 99%

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

Herbert,

Jarvo

2023

Acc. Chem. Res.

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Conspectus Nickel-catalyzed reactions of alkyl alcohol derivatives leverage the high prevalence of hydroxyl groups in natural products, medicinal agents, and synthetic intermediates to provide access to C(sp3)-rich frameworks. This Account describes our laboratory’s development of stereospecific and stereoconvergent C–C bond forming reactions employing C(sp3)–O and C(sp3)–N electrophiles. In the context of development of new transformations, we also define fundamental characteristics of the nickel catalysts. Part I details the nickel-catalyzed cross-coupling reactions developed by our group which hinges on stereospecific formation of stable π-benzyl intermediates. Acyclic and cyclic ethers, esters, carbamates, lactones, and sulfonamides undergo Kumada-, Suzuki-, and Negishi-type coupling reactions to produce enantioenriched products with high fidelity of stereochemical information. We describe extension to include ring-opening reactions of saturated heterocycles to afford acyclic 1,3-fragments in high diastereomeric ratios. We also describe our advances in stereospecific nickel-catalyzed cross-electrophile coupling reactions. Tethered C–O and C–X electrophiles proved fruitful for construction of a variety of carbocyclic frameworks. We report an intramolecular cross-electrophile coupling of benzylic pivalates with aryl bromides for the synthesis of indanes and tetralins. We found that 4-halotetrahydropyrans and 4-halopiperidines readily undergo stereospecific ring contraction to afford substituted cyclopropanes. Mechanistic investigations are consistent with closed-shell intermediates, a Ni(0)/Ni(II) cycle, and an intramolecular SN2-type reaction of a key organonickel intermediate to form the cyclopropane. Building toward more complex cascade reactions, we have demonstrated that 2-alkynyl piperidines incorporate MeMgI in a dicarbofunctionalization of the alkyne to afford highly substituted vinyl cyclopropanes. In Part II we present our development of stereoconvergent reactions of alkyl alcohol derivatives. In order to expand the utility of the intramolecular XEC reaction, we sought to employ unactivated alkyl electrophiles. Specifically, alkyl dimesylates engage in intramolecular XEC reactions to form alkyl cyclopropanes. In contrast to our previous work, these reactions proceed through open-shell intermediates and favor stereoconvergent formation of the trans-cyclopropane. Enantioselective aldol reactions can be employed in syntheses of 1,3-diols which furnish enantioenriched cyclopropanes in high ee. Experimental and computational evidence reveals that MeMgI mediates formation of alkyl iodides in situ. The coupling reaction initiates with halogen atom abstraction at the secondary alkyl iodide. The alkyl Ni(II) complex then proceeds through a stereospecific SN2-type ring closure to form cyclopropane. In an effort to increase functional group compatibility in the synthesis of cyclopropanes from alkyl dimesylates we developed a zinc-mediated reaction of 1,3-dimesylates prepared from medicinal analogues. In cha...

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Cobalt‐Catalyzed Facial‐Selective Hydroalkylation of Cyclopropenes

Zhang

et al. 2023

Angewandte Chemie

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Cyclopropene hydrofunctionalization has been a promising strategy for accessing multi-substituted cyclopropanes; however, cyclopropene hydroalkylation remains underdeveloped. Herein, we report a low-valent CoH-catalyzed facial-selective cyclopropene hydroalkylation to access multi-substituted cyclopropanes. This reaction exhibits a broad substrate scope of alkyl halides and cyclopropenes and tolerates many functional groups. Moderate-to-good facial-selectivity is obtained without any directing groups. Mechanism studies provide evidence that alkyl radicals are generated from alkyl halides and irreversible CoH insertion is responsible for the facial-selectivity. Our preliminary exploration demonstrates that asymmetric cyclopropene hydroalkylation can be realized without conspicuous auxiliary groups.

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Zinc-Mediated Transformation of 1,3-Diols to Cyclopropanes for Late-Stage Modification of Natural Products and Medicinal Agents

Cited by 4 publications

References 56 publications

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

Cobalt‐Catalyzed Facial‐Selective Hydroalkylation of Cyclopropenes

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