Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group
One approach to enhance the bioavailability and half-life of peptides in vivo is through N-methylation of one or more of the amino acids within the peptide sequence. However, commercially available Fmoc-N-Me-AA-OHs are limited and often expensive. In this study, a solid-phase synthesis method for Fm...
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MDPI AG
2023-11-01
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| Series: | Methods and Protocols |
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| Online Access: | https://www.mdpi.com/2409-9279/6/6/110 |
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| author | Tanya Román Gerardo Acosta Constanza Cárdenas Beatriz G. de la Torre Fanny Guzmán Fernando Albericio |
| author_facet | Tanya Román Gerardo Acosta Constanza Cárdenas Beatriz G. de la Torre Fanny Guzmán Fernando Albericio |
| author_sort | Tanya Román |
| collection | DOAJ |
| description | One approach to enhance the bioavailability and half-life of peptides in vivo is through N-methylation of one or more of the amino acids within the peptide sequence. However, commercially available Fmoc-N-Me-AA-OHs are limited and often expensive. In this study, a solid-phase synthesis method for Fmoc-N-Me-AA-OH was developed using a 2-chlorotrityl chloride (2-CTC) resin as a temporary protective group for the carboxylic acid strategy. Two strategies for the alkylation step were compared, employing either dimethyl sulfate or methyl iodide in the Biron−Kessler method. In this work we tested the protocol with two amino acids: Fmoc-Thr(tBu)-OH and Fmoc-βAla-OH. The first one is an alpha amino acid, very hindered and with the amine group directly influenced by the electronic effects of the carboxy group, whereas in Fmoc-βAla-OH, the presence of a methylene group weakens this influence due to the intervening carbon atoms. The desired amino acids, Fmoc-N-Me-Thr(tBu)-OH and Fmoc-N-Me-βAla-OH, were synthesized by both strategies with high yield and purity. |
| first_indexed | 2024-03-08T20:29:40Z |
| format | Article |
| id | doaj.art-203517f06e2548ecb63761c5a85f4ebc |
| institution | Directory Open Access Journal |
| issn | 2409-9279 |
| language | English |
| last_indexed | 2024-03-08T20:29:40Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Methods and Protocols |
| spelling | doaj.art-203517f06e2548ecb63761c5a85f4ebc2023-12-22T14:28:07ZengMDPI AGMethods and Protocols2409-92792023-11-016611010.3390/mps6060110Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting GroupTanya Román0Gerardo Acosta1Constanza Cárdenas2Beatriz G. de la Torre3Fanny Guzmán4Fernando Albericio5Núcleo Biotecnología Curauma, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, ChileDepartment of Organic Chemistry and CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Barcelona, 08028 Barcelona, SpainNúcleo Biotecnología Curauma, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, ChileKwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South AfricaNúcleo Biotecnología Curauma, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, ChileDepartment of Organic Chemistry and CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Barcelona, 08028 Barcelona, SpainOne approach to enhance the bioavailability and half-life of peptides in vivo is through N-methylation of one or more of the amino acids within the peptide sequence. However, commercially available Fmoc-N-Me-AA-OHs are limited and often expensive. In this study, a solid-phase synthesis method for Fmoc-N-Me-AA-OH was developed using a 2-chlorotrityl chloride (2-CTC) resin as a temporary protective group for the carboxylic acid strategy. Two strategies for the alkylation step were compared, employing either dimethyl sulfate or methyl iodide in the Biron−Kessler method. In this work we tested the protocol with two amino acids: Fmoc-Thr(tBu)-OH and Fmoc-βAla-OH. The first one is an alpha amino acid, very hindered and with the amine group directly influenced by the electronic effects of the carboxy group, whereas in Fmoc-βAla-OH, the presence of a methylene group weakens this influence due to the intervening carbon atoms. The desired amino acids, Fmoc-N-Me-Thr(tBu)-OH and Fmoc-N-Me-βAla-OH, were synthesized by both strategies with high yield and purity.https://www.mdpi.com/2409-9279/6/6/1102-CTC resinN-methylationalpha and beta amino acids |
| spellingShingle | Tanya Román Gerardo Acosta Constanza Cárdenas Beatriz G. de la Torre Fanny Guzmán Fernando Albericio Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group Methods and Protocols 2-CTC resin N-methylation alpha and beta amino acids |
| title | Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group |
| title_full | Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group |
| title_fullStr | Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group |
| title_full_unstemmed | Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group |
| title_short | Protocol for Facile Synthesis of Fmoc-N-Me-AA-OH Using 2-CTC Resin as Temporary and Reusable Protecting Group |
| title_sort | protocol for facile synthesis of fmoc n me aa oh using 2 ctc resin as temporary and reusable protecting group |
| topic | 2-CTC resin N-methylation alpha and beta amino acids |
| url | https://www.mdpi.com/2409-9279/6/6/110 |
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