Copper-Catalyzed Borylative Ring Closing C–C Coupling toward Spiro- and Dispiroheterocycles

Royes, Jordi; Ni, Shao‐Fei; Farré, Albert; Cascia, Enrico La; Carbó, Jorge J.; Cuenca, Ana B.; Maseras, Feliu; Fernández, Elena

doi:10.1021/acscatal.8b00257

Cited by 40 publications

(17 citation statements)

References 25 publications

(35 reference statements)

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“…Although Li + does not change the nature of the species, it induces some C−B lengthening (+0.04 Å) and pyramidalization of the carbanionic carbon (−30°), with respect to the free carbanion 1a pin . Note that introducing specific solvation molecules solvating Li + cation [41] would diminish its effect on the electronic structure of borata‐alkene. On the other extreme, the computed C−B bond order of palladium complex 1a pin ‐Pd is close to 1 and the corresponding distance (1.55 Å) is significantly larger than for 1a pin ‐Li .…”

Section: Resultsmentioning

confidence: 99%

Mapping the Electronic Structure and the Reactivity Trends for Stabilized α‐Boryl Carbanions

Maza

Fernández

Carbó

2021

Chemistry A European J

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The chemistry of stabilized α‐boryl carbanions shows remarkable diversity, and can enable many different synthetic routes towards efficient C−C bond formation. The electron‐deficient, trivalent boron center stabilizes the carbanion facilitating its generation and tuning its reactivity. Here, the electronic structure and the reactivity trends of a large dataset of α‐boryl carbanions are described. DFT‐derived parameters were used to capture their electronic and steric properties, computational reactivity towards model substrates, and crystallographic analysis within the Cambridge Structural Dataset. This study maps the reactivity space by systematically varying the nature of the boryl moiety, the substituents of the carbanionic center, the number of α‐boryl motifs, and the metal counterion. In general, the free carbanionic intermediates are described as borata‐alkene species with C−B π interactions polarized towards the carbon. Furthermore, it was possible to classify the α‐boryl alkylidene metal precursors into three classes directly related to their reactivity: 1) nucleophilic borata‐alkene salts with alkali and alkaline earth metals, 2) nucleophilic η2‐(C−B) borata‐alkene complexes with early transition metals, Cu and Ag, and 3) α‐boryl alkyl complexes with late transition metals. This trend map aids selection of the appropriate reactive synthon depending on the reactivity sought.

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Section: Resultsmentioning

confidence: 99%

Mapping the Electronic Structure and the Reactivity Trends for Stabilized α‐Boryl Carbanions

Maza

Fernández

Carbó

2021

Chemistry A European J

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“…However, the high-valent copper(III) species could be a transient species or a transition state of the concerted mechanism. 49,71 Finally, reductive elimination forms the new C−C bond to produce the alkylboration product 4xy with concomitant restoration of copper(I) alkoxide Int1.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Regio- and Stereoselective Synthesis of Multi-Alkylated Allylic Boronates through Three-Component Coupling Reactions between Allenes, Alkyl Halides, and a Diboron Reagent

2021

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Multisubstituted allylic boronates are attractive and valuable precursors for the rapid and stereoselective construction of densely substituted carbon skeletons. Herein, we report the first synthetic approach for differentially 2,3,3-trialkyl-substituted allylic boronates that contain a stereodefined tetrasubstituted alkene structure. Copper(I)-catalyzed regio- and stereoselective three-component coupling reactions between gem-dialkylallenes, alkyl halides, and a diboron reagent afforded sterically congested allylic boronates. The allylboration of aldehydes diastereoselectively furnished the corresponding homoallylic alcohols that bear a quaternary carbon. A computational study revealed that the selectivity-determining mechanism was correlated to the coordination of a boryl copper(I) species to the allene substrate as well as the borylcupration step.

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“…This intermediate was transformed to the iodo derivative 38 in a two-step sequence by reduction of the ester function with LiBH 4 to the alcohol followed by the Appel reaction to give the iodoalkene 38 . Finally, iodoalkenes 32 and 38 were transformed toward the desired spirocyclic intermediates 33 and 39 through a copper-catalyzed borylative ring-closing C–C coupling . The Csp 2 –Csp 3 Suzuki cross-coupling reaction between 33 and 39 and 4-bromo-2,6-dimethylpyridine yielded the spirocyclic amines 34 and 40 , which were deprotected in a final step under standard Boc and Bn deprotection reaction conditions (Scheme ).…”

Section: Results and Discussionmentioning

confidence: 99%

“…Subsequent reduction with LiAlH 4 to the alcohol followed by treatment with I 2 in the presence of PPh formed toward the desired spirocyclic intermediates 33 and 39 through a copper-catalyzed borylative ring-closing C−C coupling. 92 The Csp 2 −Csp 3 Suzuki cross-coupling reaction between 33 and 39 and 4-bromo-2,6-dimethylpyridine yielded the spirocyclic amines 34 and 40, which were deprotected in a final step under standard Boc and Bn deprotection reaction conditions (Scheme 3). Intermediates 43 and 45, where the northern heteroaromatic is linked to the spirobicyclic core by an oxygen atom, were prepared from the corresponding alcohols 22 and 26 through an O-alkylation reaction with 4-chloro-or 4-bromo-2,6dimethylpyridine using sodium hydride as the base followed by the cleavage of the Bn and Boc protecting groups, respectively (Scheme 4A,B).…”

Section: ■ Introductionmentioning

confidence: 99%

Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders

Martínez-Viturro¹,

Trabanco²,

Royes

et al. 2020

J. Med. Chem.

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O-GlcNAcylation is a post-translational modification of tau understood to lower the speed and yield of its aggregation, a pathological hallmark of Alzheimer’s disease (AD). O-GlcNAcase (OGA) is the only enzyme that removes O-linked N-acetyl-d-glucosamine (O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents a potential approach for the treatment of AD by preserving the O-GlcNAcylated tau protein. Herein, we report the multifactorial optimization of high-throughput screening hit 8 to a potent, metabolically stable, and orally bioavailable diazaspirononane OGA inhibitor (+)-56. The human OGA X-ray crystal structure has been recently solved, but bacterial hydrolases are still widely used as structural homologues. For the first time, we reveal how a nonsaccharide series of inhibitors binds bacterial OGA and discuss the suitability of two different bacterial orthologues as surrogates for human OGA. These breakthroughs enabled structure–activity relationships to be understood and provided context and boundaries for the optimization of druglike properties.

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Copper-Catalyzed Borylative Ring Closing C–C Coupling toward Spiro- and Dispiroheterocycles

Cited by 40 publications

References 25 publications

Mapping the Electronic Structure and the Reactivity Trends for Stabilized α‐Boryl Carbanions

Mapping the Electronic Structure and the Reactivity Trends for Stabilized α‐Boryl Carbanions

Regio- and Stereoselective Synthesis of Multi-Alkylated Allylic Boronates through Three-Component Coupling Reactions between Allenes, Alkyl Halides, and a Diboron Reagent

Diazaspirononane Nonsaccharide Inhibitors of O-GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders

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