Asymmetric [3+2] cycloaddition reactions: new chemistry for solid phase

Allen, Jacqueline Y. (2003) Asymmetric [3+2] cycloaddition reactions: new chemistry for solid phase. (PhD thesis), Kingston University,


The aim of this project was to investigate new asymmetric chemistry for solid phase syntheses where in comparison to solution phase reactions very few solid phase reactions are in general use. The first part of the project involved the synthesis and radical cleavage of a Barton ester to provide a traceless linker on the final reaction product. The synthesis of the Barton ester from benzoylglycine was not successful as the acid chloride derivative of benzolyglycine appeared to undergo a facile cyclisation reaction. In contrast the acid chlorides of both indole-3-acetic acid and N-methylindole-3-acetic acid' were successfully reacted with N-hydroxypyridine-2-thione to give Barton esters and immediate radical cleavage gave the corresponding indole derivatives. The yields of the indole reactions remained low despite our attempts at optimisation and it was therefore concluded that a pyridine-z-thione ester was an unstable linker for successful solid phase chemistry. The second part of the project involved the synthesis of isoxazolidines using [3 + 2] cycloaddition reactions. These compounds have been shown to be useful intermediates in the synthesis of natural products, antibiotics and other medicinally important compounds. Initially model [3 + 2] cycloaddition reactions were carried out to investigate the regio- and stereoselectivity of the reaction. Analysis of several IH_NMR spectra showed broad resonance splitting patterns, attributed to the inversion of the trivalent nitrogen atom, which was investigated by high temperature IH_NMR. Reactions with the N-(methylene)methylamine N-oxide nitrone simplified spectral analysis. Asymmetric [3 + 2] cycloaddition reactions were then carried out between the N-(benzylidene)methylamine N-oxide (and the nitro, chloro and bromo derivatives) with the acryloyl and crotonyl acylated Evans' chiral auxiliaries. The reaction between N-(p-nitrobenzylidene )methylamin~ N-oxide and the acryloyl chiral auxiliary derivative was unsuccessful due to polymerisation of the chiral auxiliary, whilst those between the nitrones and the crotonyl chiral auxiliary derivative gave regiochemical data "but the stereochemical data could not be determined due to the overlapping of resonances on the IH_NMR spectrum. Analysis of the IH_NMR spectra of alternative [3 + 2] cycloaddition products from reactions with the nitrone N-(methylene)methylainine N-oxide were again thwarted by inversion of the nitrogen atom whereas in a [3 + 2] cycloaddition reaction between N-(p-nitrobenzylidene)-methylamine N-oxide and the methacryloyl chiral auxiliary derivative an X-ray analysis of the major diastereomer was obtained. This confirmed the absolute stereochemistry to be (S)-( - )-4:.benzyl-N-[ (S)-5-carbonyl-N,5-dimethyl-(R)-3-(p-nitrophenyl)isoxazolidine ]-2-oxazolidinone (SSR). An attempt was then carried out to transfer this chemistry on to solid supports using Merrifield resin. Purification of the resulting isoxazolidine led to an interesting decarboxylation reaction. Finally, initial investigations into [3 + 2] cycloaddition reactions with electron poor 1,2-disubstituted alkynes were carried out.

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