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Studies on the asymmetric synthesis of an [alpha]-hydroxyphenethylamine

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dc.contributor.advisor McCleland CW, Prof en
dc.contributor.author Black SL en
dc.date.accessioned 2016-09-22T13:19:00Z
dc.date.available 2016-09-22T13:19:00Z
dc.date.submitted 1998 en
dc.identifier.uri http://hdl.handle.net/20.500.11892/157457
dc.description.abstract The possibility of an enantioselective synthesis of (R)-salbutamol has been investigated. Our strategy has focussed on the reduction of an appropriately ring-substituted co- bromoacetophenone with borane in the presence of a chiral methionine-derived oxazaborolidine catalyst, followed by manipulation of the ring substituents and replacement of the bromo group by t-butylamine. <br><br> Initially, the efficacy of the catalyst in the reduction was explored by using ca- bromoacetophenone as the substrate. (R)-2-Bromo-l-phenylethanol was obtained with an optical purity of ca. 45%. Attention was then turned to salbutamol for which methyl 5-acetylsalicylate (95) served as a convenient starting material. Protection of the hydroxy group as a benzyl ether was effected and the acetyl group was then monobrominated to give methyl 2-benzyloxy-5-bromoacetylbenzoate (97). <br><br> The ketone (97) was reduced with BH<sub>3</sub> in the presence of a racemic form of the catalyst (94). Excess BH<sub>3</sub> was subsequently added to reduce the ester group. The resulting 2-bromo-l-(4-benzyloxy-3-hydroxymethylphenyl) ethanol (99) was aminated with t-butylamine and the benzyloxy group removed through hydrogenolysis, to give salbutamol (1) in an overall yield of 40%. <br><br> Asymmetric reduction of the ketone (97) was then effected with the optically active (S)- catalyst (94) derived from L-methionine. Only partial reduction of the ketone was observed to take place, while the optical yield was estimated from HPLC analysis to be about 60%. <br><br> Computer modelling of the reduction process was also carried out at the molecular mechanics and semiempirical MO levels of approximation. The energetics of complexation of both o-bromoacetophenone and its substituted analogue (97) with the chiral BH<sub>3</sub> oxazaborolidine adduct, as well as the enantioselectivity of the hydride transfer step were explored. Calculations show that the complexes which could form between the catalyst and the ester carbonyl group are likely to be more stable than those involving the ketone carbonyl group, although the rate of hydride transfer to the ester is predicted to be slower. <br><br> These theoretical results would account for the relatively low conversions and enantioselectivities observed for the reduction of (97) if the catalyst in fact binds preferentially to the wrong carbonyl group. en
dc.language English en
dc.title Studies on the asymmetric synthesis of an [alpha]-hydroxyphenethylamine en
dc.type Masters degree en
dc.description.degree MSc en

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