Combined theoretical and experimental study on high diastereoselective chirality transfer based on [2.2]paracyclophane derivative chiral reagent

Biao Jiang, Lei Han, Yong Le Li, Xiao Long Zhao, Yang Lei, Dai Qian Xie, John Zhang

Research output: Contribution to journalArticle

Abstract

We report a paracyclophane N-Me thioamide chiral reagent for the asymmetric thio-Claisen rearrangement with high diasteroselectivity. Comparisons between candidate chiral reagent N-phenyl-N-([2.2]paracyclophan-4-yl)amide, N-methyl amide, N-phenyl thioamide, and N-methyl thioamide are made both by experiment and theoretical calculations to clarify the principle behind the high diasteroselectivity. Dynamic 1H NMR phenomenon tested by varying temperature (VT) experiments has proved that N-Ph amides have triple splitting peaks, while N-Ph thioamide would reduce the number to two, further substituting the Ph to Me made dynamic phenomenon disappear. So the side chain is thought to be the most rigid in N-Me thioamide, which accounts for a structure prerequisite favoring high efficient chirality transfer. This is confirmed by theoretical calculation: remarkable energy difference exists between the Re and Si faces of the chiral molecule. To further clarify the possible pathways for thio-Claisen rearrangement, theoretical prediction is adopted. The result implies that the cisoid pathways will dominate the process. Further experiment confirmed this: with N-Me thioamide, the asymmetrical reaction affords γ-unsaturated thioamides in good yields and high diastereoselectivities up to 98%. After removing the thioamide auxiliaries under hydrolysis conditions, product β,γ-substituted chiral alcohols reached high enantiopurity of 98% ee.

Original languageEnglish (US)
Pages (from-to)1701-1709
Number of pages9
JournalJournal of Organic Chemistry
Volume77
Issue number4
DOIs
StatePublished - Feb 17 2012

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Thioamides
Chirality
Derivatives
Amides
(2.2)paracyclophane
Experiments
Hydrolysis
Alcohols
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Combined theoretical and experimental study on high diastereoselective chirality transfer based on [2.2]paracyclophane derivative chiral reagent. / Jiang, Biao; Han, Lei; Li, Yong Le; Zhao, Xiao Long; Lei, Yang; Xie, Dai Qian; Zhang, John.

In: Journal of Organic Chemistry, Vol. 77, No. 4, 17.02.2012, p. 1701-1709.

Research output: Contribution to journalArticle

Jiang, Biao ; Han, Lei ; Li, Yong Le ; Zhao, Xiao Long ; Lei, Yang ; Xie, Dai Qian ; Zhang, John. / Combined theoretical and experimental study on high diastereoselective chirality transfer based on [2.2]paracyclophane derivative chiral reagent. In: Journal of Organic Chemistry. 2012 ; Vol. 77, No. 4. pp. 1701-1709.
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abstract = "We report a paracyclophane N-Me thioamide chiral reagent for the asymmetric thio-Claisen rearrangement with high diasteroselectivity. Comparisons between candidate chiral reagent N-phenyl-N-([2.2]paracyclophan-4-yl)amide, N-methyl amide, N-phenyl thioamide, and N-methyl thioamide are made both by experiment and theoretical calculations to clarify the principle behind the high diasteroselectivity. Dynamic 1H NMR phenomenon tested by varying temperature (VT) experiments has proved that N-Ph amides have triple splitting peaks, while N-Ph thioamide would reduce the number to two, further substituting the Ph to Me made dynamic phenomenon disappear. So the side chain is thought to be the most rigid in N-Me thioamide, which accounts for a structure prerequisite favoring high efficient chirality transfer. This is confirmed by theoretical calculation: remarkable energy difference exists between the Re and Si faces of the chiral molecule. To further clarify the possible pathways for thio-Claisen rearrangement, theoretical prediction is adopted. The result implies that the cisoid pathways will dominate the process. Further experiment confirmed this: with N-Me thioamide, the asymmetrical reaction affords γ-unsaturated thioamides in good yields and high diastereoselectivities up to 98{\%}. After removing the thioamide auxiliaries under hydrolysis conditions, product β,γ-substituted chiral alcohols reached high enantiopurity of 98{\%} ee.",
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AB - We report a paracyclophane N-Me thioamide chiral reagent for the asymmetric thio-Claisen rearrangement with high diasteroselectivity. Comparisons between candidate chiral reagent N-phenyl-N-([2.2]paracyclophan-4-yl)amide, N-methyl amide, N-phenyl thioamide, and N-methyl thioamide are made both by experiment and theoretical calculations to clarify the principle behind the high diasteroselectivity. Dynamic 1H NMR phenomenon tested by varying temperature (VT) experiments has proved that N-Ph amides have triple splitting peaks, while N-Ph thioamide would reduce the number to two, further substituting the Ph to Me made dynamic phenomenon disappear. So the side chain is thought to be the most rigid in N-Me thioamide, which accounts for a structure prerequisite favoring high efficient chirality transfer. This is confirmed by theoretical calculation: remarkable energy difference exists between the Re and Si faces of the chiral molecule. To further clarify the possible pathways for thio-Claisen rearrangement, theoretical prediction is adopted. The result implies that the cisoid pathways will dominate the process. Further experiment confirmed this: with N-Me thioamide, the asymmetrical reaction affords γ-unsaturated thioamides in good yields and high diastereoselectivities up to 98%. After removing the thioamide auxiliaries under hydrolysis conditions, product β,γ-substituted chiral alcohols reached high enantiopurity of 98% ee.

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