Asymmetric Hydrogenation of Oximes Synergistically Assisted by Lewis and Brønsted Acids

Wang, Fangyuan; Chen, Yu; Yu, Peiyuan; Chen, Gen‐Qiang; Zhang, Xumu

doi:10.1021/jacs.2c07506

Cited by 16 publications

(7 citation statements)

References 49 publications

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“…Unfortunately, due to low substrate reactivity, no desired product was observed in THF under hydrogen gas (750 psi) at 50 °C for 40 h (Table , entry 1). We attempted to activate the substrate with various readily available Lewis or Brønsted acids. − Gratifyingly, the hydrogenation proceeded smoothly, with excellent conversion as well as enantioselectivity obtained using trichloroisocyanuric acid (TCCA) as the activator (entry 2). TCCA could in situ generate the strong Brønsted acid hydrogen chloride in the presence of iridium complex during the hydrogenation process, activating the substrate to improve the reactivity.…”

Section: Resultsmentioning

confidence: 99%

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor

Chen,

Li,

Wang

et al. 2024

J. Org. Chem.

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The chiral 4,5,6,pyrimidine is the key core skeleton of potent Bruton's tyrosine kinase (BTK) inhibitor Zanubrutinib, and the catalyst-controlled asymmetric hydrogenation of planar multinuclear pyrimidine heteroarenes with multiple N atoms could provide an efficient route toward its synthesis. Owing to the strong aromaticity and poisoning effect toward chiral transition metal catalyst, asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines with multiple nitrogen atoms is still a challenge for synthesizing the chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine. Herein, an efficient iridium-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines has been developed using substrate activation strategy, with up to 99% ee. The decagram scale synthesis further demonstrated the potential and promise of this procedure in the synthesis of Zanubrutinib. In addition, a mechanistic study indicated that the hydrogenation starts with 1,2-hydrogenation.

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Section: Resultsmentioning

confidence: 99%

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor

Chen,

Li,

Wang

et al. 2024

J. Org. Chem.

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“…The oxime intermediate 5a also served as a good hydroxylamine surrogate, enabling the development of a reliable protocol for the challenging enantioselective construction of protected or free hydroxylamines via a cascade formal hydrofunctionalization of 1,3-diene and reduction or hydrolysis of the oxime intermediate (Scheme ). Despite the high challenge for oxime reduction, , we envisioned that a sequential hydrofunctionalization of diene 1 with 5a and oxime reduction might provide a feasible access to enantioenriched allyl hydroxylamine motifs. A great deal of efforts demonstrated the feasibility of this strategy.…”

Section: Resultsmentioning

confidence: 99%

“…The oxime intermediate 5a also served as a good hydroxylamine surrogate, enabling the development of a reliable protocol for the challenging enantioselective construction of protected or free hydroxylamines via a cascade formal hydrofunctionalization of 1,3-diene and reduction or hydrolysis of the oxime intermediate (Scheme 4). Despite the high challenge for oxime reduction, 78,79 we envisioned that a sequential hydrofunctionalization of diene 1 with 5a and oxime reduction might Likewise, reasonable yields and high enantioselectivities were observed for the free hydroxylamine-tethered compounds (8a, 8e−8f, and 8k−8o) from a variety of diene substrates. For example, substrates containing ester, cyan, and Cl underwent this formal hydroaminoxylation reaction in 70−82% yield and 95:5−96:4 er (8k−8m).…”

Section: ■ Introductionmentioning

confidence: 99%

Catalytic Asymmetric Hydroalkoxylation and Formal Hydration and Hydroaminoxylation of Conjugated Dienes

et al. 2023

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The straightforward construction of stereogenic centers bearing unprotected functional groups, as in nature, has been a persistent pursuit in synthetic chemistry. Abundant applications of free enantioenriched allyl alcohol and allyl hydroxylamine motifs have made the asymmetric hydration and hydroaminoxylation of conjugated dienes from water and hydroxylamine, respectively, intriguing and efficient routes that have, however, been unachievable thus far. A fundamental challenge is the failure to realize transition-metal-catalyzed enantioselective C− O bond constructions via hydrofunctionalization of conjugated dienes. Here, we perform a comprehensive study toward the stereoselective formal hydration and hydroaminoxylation of conjugated dienes by synthesizing a set of new P,N-ligands and identifying an aryl-derived oxime as a surrogate for both water and hydroxylamine. Asymmetric hydroalkoxylation with new P,N-ligands is also elucidated. Furthermore, versatile derivatizations following hydration provide indirect but concise routes to formal hydrophenoxylation, hydrofluoroalkoxylation, and hydrocarboxylation of conjugated dienes that have been unreported thus far. Finally, a ligand-to-ligand hydrogen transfer process is proposed based on the results of preliminary mechanistic experiments.

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“…However, the related knowledge of chiral hydroxylamines is extremely lacking owing to the absence of efficient synthetic approaches. The isolated examples typically rely on catalytic asymmetric hydrogenation of preinstalled N–OH oxime substrates with higher oxidation states (Scheme B). , Despite good to excellent enantioselectivity, these protocols suffer from limited generality, are dominantly applicable to α,α-aryl-methyl hydroxylamines, and typically use noble metal catalysts. A general and practical, earth-abundant metal-catalyzed asymmetric approach to diversely functionalized chiral hydroxylamines is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Asymmetric Oxidation of Amines to Hydroxylamines

Wang,

Chen,

Jia

et al. 2023

J. Am. Chem. Soc.

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Chiral hydroxylamines are increasingly common structural elements in pharmaceuticals and agrochemicals, but their asymmetric synthesis remains challenging. Although enantioselective oxidation is the most straightforward method to prepare chiral oxides with a higher oxidation state, asymmetric and even nonasymmetric amine oxidation to hydroxylamines has been poorly addressed. We report a titanium-catalyzed asymmetric oxidation of racemic amines providing a broad range of structurally diverse chiral hydroxylamines with excellent chemo- and enantioselectivity. Notably, hydroxylamines bearing diverse substituent patterns on the stereocenters, including α,α-ester-alkyl, α,α-amide-alkyl, α,α-aryl-alkyl, α,α-alkynyl-alkyl, and α,α-dialkyl, are well tolerated with good functional group compatibility. Catalyst turnover numbers up to 5000 and selectivity factors up to 278 are observed. This finding offers a democratized platform to chiral hydroxylamines as design elements for drug discovery and provides insights into metal-catalyzed asymmetric oxidation of challenging substrates.

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Asymmetric Hydrogenation of Oximes Synergistically Assisted by Lewis and Brønsted Acids

Cited by 16 publications

References 49 publications

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor

Catalytic Asymmetric Hydroalkoxylation and Formal Hydration and Hydroaminoxylation of Conjugated Dienes

Catalytic Asymmetric Oxidation of Amines to Hydroxylamines

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