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Title: Enantioselective desymmetrisation of imides using oxazaboroilidine catalysts derived from cis-amino-indan-2-ol
Author: Kutama, Ibrahim U.
ISNI:       0000 0004 5356 3018
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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By repeating and optimizing procedure from earlier work in this group, three N-substituted meso-anthracene-maleimides have been prepared in excellent yields 88 - 94%. These compounds were successfully desymmetrised to the corresponding 3-methoxy ?-lactams, using B-OMe oxazaborolidine catalyst derived from cis-1-amino-indan-2-ol. Under the optimized conditions, improved yields and excellent enantioselectivities of 95 - >99% of the methoxy-lactams were obtained. Desymmetrisation of the N-PMP substrate gave one enantiomer of the product but proceeded by rapid conversion of the hydroxy-lactam intermediate to the over-reduced pyrrolidine compound. Investigation in to the correlation between this high selectivity and the formation of the over reduced product revealed that an in-situ stereoablative process by the (1R, 2S) version of the B-OMe catalyst serves to upgrade the enantioselectivity. This desymmetrisation methodology has been employed for the total synthesis of natural product, pyrrolam A which was obtained in six steps from the desymmetrised material in 48% overall yield and 94% ee. By adapting literature methodology, N-PMP glutarimide and a number of N-benzyl glutarimides have been successfully synthesised via the corresponding glutaric anhydrides in moderate yields (52 - 87%). Desymmetrisation of N-PMP-3-phenyl glutarimide to the corresponding d-lactam using B-OMe and B-Me oxazaborolidine catalysts derived from cis1-amino-indan-2-ol gave excellent selectivity but low yields of the products with both catalysts due to the formation of over reduced piperidine product. Further investigation revealed an in-situ stereoablative process causes an upgrade of ee in both (1R, 2S) and (1S, 2R) versions of B-Me oxazaborolidine catalyst, with matched and mismatched enantioselectivity with the two enantiomers of the catalyst. The N-Bn substrates were successfully desymmetrised, using B-Me oxazaborolidine catalyst, to the corresponding dlactams in moderate yields (20 - 61%) and high enantioselectivities (54 - 92%). Desymmetrisation of a representative N-Bn substrate with the prolinol oxazaborolidine catalyst under the same conditions gave poor yield and enantioselectivity of the product (13% yield, 13% ee). Functionalisation of a representative N-Bn desymmetrised product gave various (3S, 4R)- disubstituted 2-piperidinones in good yields and excellent diastereoselectivity. Subsequent reduction of the 2-piperidinones gave (3S, 4R)-disubstituted piperidines which are important structural motifs in many biologically active natural products and pharmaceuticals.
Supervisor: Jones, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available