Advances in the application of N-sulfinyl auxiliaries to the synthesis of pyrrolidines and α-amino acid derivatives

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.

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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.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Stockman, Robert
Keywords: Pyrrolidines, α-Amino acid derivatives, N-sulfinyl
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 60592
Depositing User: O'Connor, Daniel
Date Deposited: 18 Aug 2020 10:20
Last Modified: 23 Nov 2023 09:20

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