A new route to chiral beta-lactams
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In previous work it had been discovered that subjecting the spiro-isoxazolidine formed by the 1,3-dipolar cycloaddition of C,N-diphenylnitrone and (2S)-2-t-butyl-5-methylene-1,3-dioxolan-4-one to FVP resulted in the formation of the β-lactam (4R)-1,4-diphenylazetidin-2-one. The main aim of this project was to optimise this process and to investigate the scope and generality of this new synthetic route to chiral β-lactams. Firstly, the 1,3-dipolar cycloaddition reactions involving (2S)-2-t-butyl-5-methylene-1,3-dioxolan-4-one were repeated with a range of different nitrones. The resulting spiro-isoxazolidines were initially formed as a mixture of two diastereomers, with the major cycloadduct isolated by recrystallisation. FVP of each spiro-isoxazolidine gave rise to a mixture of different products, which in all cases included the desired β-lactam. The β-lactams were isolated in yields of 14−31% using preparative TLC and the e.e was found to be in the range of 86.6−99.1%. The relatively low yields obtained were the result of the fragmentation of the initially formed β-lactam and the competition between fragmentation of the spiro-isoxazolidine and 1,3-dipolar cycloreversion. The 1,3-dipolar cycloaddition reactions of C-aryl-N-phenylnitrones and (Z)-(2S)-2-t-butyl-5-methoxycarbonylmethylene-1,3-dioxolan-4-one were then carried out. After isolating the major trans diastereomer, FVP was carried out to form a mixture of the trans and cis diastereomers of the expected β-lactam. The presence of the cis-β-lactam is the result of epimerisation at the C-3 position of the initially formed trans β-lactam. Isolation of the β-lactam from the mixture of products formed by FVP was again achieved using preparative TLC. The isolated yields of the β-lactams were all less than 20% as a result of 1,3-dipolar cycloreversion of the spiro-isoxazolidine being a major competing process that occurs when they are subjected to FVP. Having synthesised a range of 1,4-disubstiuted β-lactams with (4R) stereochemistry, attention was turned to the synthesis of the opposite (4S) enantiomer series. This involved repeating the 1,3-dipolar cycloaddition reactions with (2R)-2-t-butyl-5-methylene-1,3-dioxolan-4-one as the dipolarophile. Subjecting the major diastereomers of these spiro-isoxazolidines to FVP formed the expected (4S)-β-lactams, which were isolated in similar yields to their (4R) counterparts. The e.e. of the products formed were all greater than 99%, with chiral stationary phase HPLC confirming the formation of the opposite enantiomer.
Thesis, MPhil Master of Philosophy
Embargo Date: 2017-11-05
Embargo Reason: Thesis restricted in accordance with University regulations. Electronic copy restricted until 5th November 2017
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