Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes

Mechanism-Controlled trans Selectivity

Yulong Kuang, David Anthony, Joseph Katigbak, Flaminia Marrucci, Sunita Humagain, Tianning Diao

Research output: Contribution to journalArticle

Abstract

A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity. This cyclization reaction enables the efficient synthesis of trans-3,4-dimethyl gababutin, a pharmaceutical lead for treating neuropathic pain, and trans-3,4-dimethylpyrrolidine, a precursor to drug candidates and pesticides. The trans selectivity distinguishes this reaction from relevant precedents that proceed via hydrogen-atom transfer and lead to cis products. Mechanistic investigation, including kinetic, spectroscopic, and radical clock studies, attributes the trans diastereoselectivity to a classic, organometallic catalytic cycle mediated by Ni(I) and Ni(III) intermediates. The electron-rich Ni(I) intermediate, stabilized by a redox-active α-diimine ligand, is responsible for the chemoselectivity toward reductive cyclization as opposed to the redox-neutral cycloisomerization observed with previous Ni(II) catalysts.

Original languageEnglish (US)
Pages (from-to)268-280
Number of pages13
JournalChem
Volume3
Issue number2
DOIs
StatePublished - Aug 10 2017

Fingerprint

Cyclization
drug
Oxidation-Reduction
ligand
Cyclopentanes
pesticide
catalyst
Prodrugs
Neuralgia
Organometallics
hydrogen
Pesticides
electron
Pharmaceutical Preparations
kinetics
Drug products
Clocks
Hydrogen
Lead
Ligands

Keywords

  • mechanism
  • Ni(I) and Ni(III) intermediates
  • nickel catalysis
  • trans-diastereoselective

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Biochemistry
  • Environmental Chemistry
  • Materials Chemistry
  • Biochemistry, medical

Cite this

Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes : Mechanism-Controlled trans Selectivity. / Kuang, Yulong; Anthony, David; Katigbak, Joseph; Marrucci, Flaminia; Humagain, Sunita; Diao, Tianning.

In: Chem, Vol. 3, No. 2, 10.08.2017, p. 268-280.

Research output: Contribution to journalArticle

Kuang, Y, Anthony, D, Katigbak, J, Marrucci, F, Humagain, S & Diao, T 2017, 'Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-Controlled trans Selectivity', Chem, vol. 3, no. 2, pp. 268-280. https://doi.org/10.1016/j.chempr.2017.07.010
Kuang, Yulong ; Anthony, David ; Katigbak, Joseph ; Marrucci, Flaminia ; Humagain, Sunita ; Diao, Tianning. / Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes : Mechanism-Controlled trans Selectivity. In: Chem. 2017 ; Vol. 3, No. 2. pp. 268-280.
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abstract = "A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity. This cyclization reaction enables the efficient synthesis of trans-3,4-dimethyl gababutin, a pharmaceutical lead for treating neuropathic pain, and trans-3,4-dimethylpyrrolidine, a precursor to drug candidates and pesticides. The trans selectivity distinguishes this reaction from relevant precedents that proceed via hydrogen-atom transfer and lead to cis products. Mechanistic investigation, including kinetic, spectroscopic, and radical clock studies, attributes the trans diastereoselectivity to a classic, organometallic catalytic cycle mediated by Ni(I) and Ni(III) intermediates. The electron-rich Ni(I) intermediate, stabilized by a redox-active α-diimine ligand, is responsible for the chemoselectivity toward reductive cyclization as opposed to the redox-neutral cycloisomerization observed with previous Ni(II) catalysts.",
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N2 - A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity. This cyclization reaction enables the efficient synthesis of trans-3,4-dimethyl gababutin, a pharmaceutical lead for treating neuropathic pain, and trans-3,4-dimethylpyrrolidine, a precursor to drug candidates and pesticides. The trans selectivity distinguishes this reaction from relevant precedents that proceed via hydrogen-atom transfer and lead to cis products. Mechanistic investigation, including kinetic, spectroscopic, and radical clock studies, attributes the trans diastereoselectivity to a classic, organometallic catalytic cycle mediated by Ni(I) and Ni(III) intermediates. The electron-rich Ni(I) intermediate, stabilized by a redox-active α-diimine ligand, is responsible for the chemoselectivity toward reductive cyclization as opposed to the redox-neutral cycloisomerization observed with previous Ni(II) catalysts.

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