Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives
Pyrrolidines are widely prevalent in pharmaceuticals, catalysis and agrochemicals. The (3+2) cycloaddition of azomethine ylides with alkenes is one of the most powerful methods for pyrrolidine synthesis. This reaction creates 2 σ-bonds and up to 4 new stereocentres in one reaction. Methods for the s...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2020
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| Online Access: | https://eprints.nottingham.ac.uk/60592/ |
| _version_ | 1848799782489817088 |
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| author | O'Connor, Daniel |
| author_facet | O'Connor, Daniel |
| author_sort | O'Connor, Daniel |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Pyrrolidines are widely prevalent in pharmaceuticals, catalysis and agrochemicals. The (3+2) cycloaddition of azomethine ylides with alkenes is one of the most powerful methods for pyrrolidine synthesis. This reaction creates 2 σ-bonds and up to 4 new stereocentres in one reaction. Methods for the stereoselective synthesis of pyrrolidines which possess functionality in the 2- and 5-positions have been extensively developed; however, methods for the stereoselective synthesis of pyrrolidines without substituents in the 2- and 5-position are sparse.
We investigated the synthesis of pyrrolidines via the (3+2) cycloaddition of N-sulfinyl azomethine ylides and electron-deficient alkenes with the aim of controlling the stereochemistry in the 3- and 4-positions. We synthesised (S)-2-methyl-N,N-bis((trimethylsilyl)methyl)propane-2-sulfinamide and subjected this to photoredox catalysis and discovered this generates sulfinyl radical by lysis of the nitrogen-sulfur bond. The sulfinyl radical added to the alkene yielding a sulfoxide product.
We were successful in forming azomethine ylides via acid catalysis of suitable N-sulfinyl precursors. These reacted with electron-deficient alkenes to provide access to N-sufinyl pyrrolidines. This reaction did not lead to stereochemical control in the 3- and 4- positions of the pyrrolidines. This was due to racemisation of the auxiliary under the reaction conditions giving a 1:1 mixture of diastereomers.
During our efforts to improve the yields of the reactions towards pyrrolidines, serendipitously, we discovered a 1,3-migration reaction of N-sulfinyl-α-aminoesters to sulfinyl amines. This discovery has so far led to an efficient synthesis of both enantiomers of tert-leucine ethyl ester, racemic 1-adamantyl glycine and racemic cyclohexyl glycine and has potential to lead to the synthesis of many unnatural α-amino acids. Initial mechanistic considerations and studies point to this being a radical chain mechanism. |
| first_indexed | 2025-11-14T20:41:08Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-60592 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:41:08Z |
| publishDate | 2020 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-605922025-02-28T14:54:55Z https://eprints.nottingham.ac.uk/60592/ Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives O'Connor, Daniel Pyrrolidines are widely prevalent in pharmaceuticals, catalysis and agrochemicals. The (3+2) cycloaddition of azomethine ylides with alkenes is one of the most powerful methods for pyrrolidine synthesis. This reaction creates 2 σ-bonds and up to 4 new stereocentres in one reaction. Methods for the stereoselective synthesis of pyrrolidines which possess functionality in the 2- and 5-positions have been extensively developed; however, methods for the stereoselective synthesis of pyrrolidines without substituents in the 2- and 5-position are sparse. We investigated the synthesis of pyrrolidines via the (3+2) cycloaddition of N-sulfinyl azomethine ylides and electron-deficient alkenes with the aim of controlling the stereochemistry in the 3- and 4-positions. We synthesised (S)-2-methyl-N,N-bis((trimethylsilyl)methyl)propane-2-sulfinamide and subjected this to photoredox catalysis and discovered this generates sulfinyl radical by lysis of the nitrogen-sulfur bond. The sulfinyl radical added to the alkene yielding a sulfoxide product. We were successful in forming azomethine ylides via acid catalysis of suitable N-sulfinyl precursors. These reacted with electron-deficient alkenes to provide access to N-sufinyl pyrrolidines. This reaction did not lead to stereochemical control in the 3- and 4- positions of the pyrrolidines. This was due to racemisation of the auxiliary under the reaction conditions giving a 1:1 mixture of diastereomers. During our efforts to improve the yields of the reactions towards pyrrolidines, serendipitously, we discovered a 1,3-migration reaction of N-sulfinyl-α-aminoesters to sulfinyl amines. This discovery has so far led to an efficient synthesis of both enantiomers of tert-leucine ethyl ester, racemic 1-adamantyl glycine and racemic cyclohexyl glycine and has potential to lead to the synthesis of many unnatural α-amino acids. Initial mechanistic considerations and studies point to this being a radical chain mechanism. 2020-07-24 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/60592/1/Daniel%20O%27Connor%20Thesis%20Final.pdf O'Connor, Daniel (2020) Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives. PhD thesis, University of Nottingham. Pyrrolidines α-Amino acid derivatives N-sulfinyl |
| spellingShingle | Pyrrolidines α-Amino acid derivatives N-sulfinyl O'Connor, Daniel Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| title | Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| title_full | Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| title_fullStr | Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| title_full_unstemmed | Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| title_short | Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| title_sort | advances in the application of n-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives |
| topic | Pyrrolidines α-Amino acid derivatives N-sulfinyl |
| url | https://eprints.nottingham.ac.uk/60592/ |