A six-step synthesis of salbutamol from methyl salicylate with an overall yield of 17% has been completed, although the yield was not optimised. In the process, Zn(BH4)2 was found to selectively reduce a ketone carbonyl group in the presence of an ester unit. In contrast, borane was found to reduce both the ketone and ester carbonyl groups. Reduction of phenacyl bromide with borane in the presence of chiral catalysts based on (R)-alaninol and (R,S)-ephidrine resulted a measure of enantioselectivity in the product. However, the configuration of the alcohol obtained in the case of (R)-alaninol was contrary to expectations based both on experimental trends observed elsewhere as well as our own theoretical predictions. The asymmetric reduction of methyl 5-bromoacetyl-2-benzyloxybenzoate was accomplished with both borane and Zn(BH4)2 in the presence of a range of chiral catalysts. Optically active products were obtained in all cases, although the optical rotations were significantly smaller in the case of Zn(BH4)2. Unfortunately, we were not successful in determining the enantiomeric excesses of these reactions. The use of a NMR lanthanide shift reagent resulted in a complex spectrum that was impossible to interpret unambiguously. This presumably arises from the presence of several Lewis base sites in the product at which complexation with the shift reagent can take place. It was also not possible to determine the optical rotation of salbutamol itself owing to the relatively small amount of material obtained. A conformational analysis of salbutamol, where NMR data was correlated with molecular modelling results, was successfully carried out and revealed a strong preference for that conformer family characterised by O–C–C–N and Ar–C–C–N torsion angles of ca. 60º and 180º, respectively. Interestingly, these conformers are found to be stabilised by OH…N rather than NH…O hydrogen bonding. This study has also confirmed the effectiveness of the MMFF94 force field for conformational analysis studies in compounds of this kind. Lastly, a relatively simple method for modelling the BH3/oxazaborolidine reduction of ketones at the PM3 semiempirical MO level of approximation was devised. This approach has provided insights into the mechanism of the reaction and has furthermore enabled us to predict the enantioselectivities likely to result from various catalysts and ketones. In comparing our theoretical and experimental findings, an anomalous result was observed in the case of (R)-alaninol; this will have to be investigated further, particularly at the experimental level. However, we believe that our approach provides a sound basis for aiding the design and screening of new, potentially better catalysts.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nmmu/vital:11065 |
| Date | January 2003 |
| Creators | Bena, Luvuyo Clifford |
| Publisher | University of Port Elizabeth, Faculty of Science |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis, Masters, MSc |
| Format | 91 leaves, pdf |
| Rights | Nelson Mandela Metropolitan University |
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