Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation
The development of new reactions forming asymmetric carbon–carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either ge...
| Hlavní autoři: | , , , |
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| Médium: | Journal article |
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Nature Publishing Group
2015
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| _version_ | 1826306617032835072 |
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| author | You, H Rideau, E Sidera, M Fletcher, S |
| author_facet | You, H Rideau, E Sidera, M Fletcher, S |
| author_sort | You, H |
| collection | OXFORD |
| description | The development of new reactions forming asymmetric carbon–carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy—dynamic kinetic asymmetric transformation—involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield2. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods. |
| first_indexed | 2024-03-07T06:50:40Z |
| format | Journal article |
| id | oxford-uuid:fc74803e-bcfd-4cdb-a6ac-658f519a751d |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:50:40Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:fc74803e-bcfd-4cdb-a6ac-658f519a751d2022-03-27T13:20:47ZNon-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fc74803e-bcfd-4cdb-a6ac-658f519a751dORA DepositNature Publishing Group2015You, HRideau, ESidera, MFletcher, SThe development of new reactions forming asymmetric carbon–carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy—dynamic kinetic asymmetric transformation—involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield2. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods. |
| spellingShingle | You, H Rideau, E Sidera, M Fletcher, S Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation |
| title | Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation |
| title_full | Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation |
| title_fullStr | Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation |
| title_full_unstemmed | Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation |
| title_short | Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation |
| title_sort | non stabilized nucleophiles in cu catalysed dynamic kinetic asymmetric allylic alkylation |
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