Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines
A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxa...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2019.00614/full |
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| author | Pantaleo Musci Marco Colella Flavio Fanelli Flavio Fanelli Angela Altomare Luisa Pisano Claudia Carlucci Renzo Luisi Leonardo Degennaro |
| author_facet | Pantaleo Musci Marco Colella Flavio Fanelli Flavio Fanelli Angela Altomare Luisa Pisano Claudia Carlucci Renzo Luisi Leonardo Degennaro |
| author_sort | Pantaleo Musci |
| collection | DOAJ |
| description | A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines. |
| first_indexed | 2024-04-13T16:08:45Z |
| format | Article |
| id | doaj.art-41de264dc36747de80b8f2e2932f053d |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-13T16:08:45Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-41de264dc36747de80b8f2e2932f053d2022-12-22T02:40:20ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462019-09-01710.3389/fchem.2019.00614474764Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-AcylazetidinesPantaleo Musci0Marco Colella1Flavio Fanelli2Flavio Fanelli3Angela Altomare4Luisa Pisano5Claudia Carlucci6Renzo Luisi7Leonardo Degennaro8Flow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy–Drug Sciences, University of Bari “A. Moro”, Bari, ItalyFlow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy–Drug Sciences, University of Bari “A. Moro”, Bari, ItalyFlow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy–Drug Sciences, University of Bari “A. Moro”, Bari, ItalyCrystallography Institute of the National Research Council (IC-CNR), Bari, ItalyCrystallography Institute of the National Research Council (IC-CNR), Bari, ItalyDepartment of Chemistry and Pharmacy, University of Sassari, Sassari, ItalyFlow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy–Drug Sciences, University of Bari “A. Moro”, Bari, ItalyFlow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy–Drug Sciences, University of Bari “A. Moro”, Bari, ItalyFlow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy–Drug Sciences, University of Bari “A. Moro”, Bari, ItalyA new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines.https://www.frontiersin.org/article/10.3389/fchem.2019.00614/fullazetidinelithiationoxazolinestereoselectivityNMR calculationsoxazolidine |
| spellingShingle | Pantaleo Musci Marco Colella Flavio Fanelli Flavio Fanelli Angela Altomare Luisa Pisano Claudia Carlucci Renzo Luisi Leonardo Degennaro Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines Frontiers in Chemistry azetidine lithiation oxazoline stereoselectivity NMR calculations oxazolidine |
| title | Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines |
| title_full | Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines |
| title_fullStr | Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines |
| title_full_unstemmed | Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines |
| title_short | Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines |
| title_sort | stereo and enantioselective addition of organolithiums to 2 oxazolinylazetidines as a synthetic route to 2 acylazetidines |
| topic | azetidine lithiation oxazoline stereoselectivity NMR calculations oxazolidine |
| url | https://www.frontiersin.org/article/10.3389/fchem.2019.00614/full |
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