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Title: The development and application of magnesium amide bases in asymmetric synthesis
Author: Bennie, Linsey S.
ISNI:       0000 0004 2743 9689
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2012
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Using a structurally-simple and readily-available C2-symmetric magnesium bisamide, superb conversions and selectivities were achieved for the asymmetric deprotonation of a range of prochiral ketones at both -78°C (up to 95:5 er) and -20°C (up to 90:10 er). The synthesis of a selection of optically-pure pseudo-C2-symmetric amines from readily available starting materials was then undertaken, in order to allow the preparation of novel bisamides for use in asymmetric deprotonation processes involving 4-substituted cyclohexanones. Pleasingly, selectivities as high as 96:4 er could be achieved at -78°C; these are some of the highest selectivities ever recorded for these substrates. Furthermore, at -20°C, excellent selectivities and conversions were recorded for a number of our novel magnesium bisamide bases. It is important to note that this is in marked contrast to the typically low temperatures required by the equivalent lithium amide bases. A computational modelling stud y was also undertaken. Through our theoretical calculations, we have shown that the energy of the pathway which would lead to the (S)-enantiomer of the enol silane, the major product of our reactions using the (R,R)-configuration of the bisamide, is lower than the alternative pathway which would deliver the (R)-enantiomer. Furthermore, in general, the magnitude of the difference in activation energies between the (R)- and (S)-selective pathways correlates well with our experimental enantioselectivities. A number of possible approaches towards an asymmetric deprotonation protocol, employing a sub-stoichiometric quantity of enantiopure amine, were explored. Initially, employing Hauser bases ((TMP)MgCl or (HMDS)MgCl) as the bulk organometallic reagent alongside a fluorinated amine delivered disappointing results. Attention was then focused on a recycling protocol employing di-tert-butylmagnesium as the bulk magnesium source. At first, attempts to develop a recycling transformation using a C2-symmetric amine alongside di-tertbutylmagnesium at -78°C resulted in no conversion to the silyl enol ether product. This was later shown to be due to poor reactivity between the C2-symmetric amine and di-tertbutylmagnesium at -78°C. Moreover, when the reaction temperature was increased, no enantioenrichment of the silyl enol ether product was observed. A more acidic fluorinated amine was then employed in an attempt to increase the reactivity of the system. However, low conversions were achieved after 16 h at -78°C, and poor enantioselectivities were obtained at more elevated temperatures. Even when an extended reaction time of 48 hours was employed, the silyl enol ether product was obtained in similar yield to that achieved previously. 1H NMR studies were then employed to confirm that no alkylmagnesium amide formation occurred at -78°C. Moreover, attempts to develop an efficient recycling procedure using an alternative electrophile (diphenylphosphoryl chloride) and a chiral aminoalcohol were unsuccessful. A range of bridged bicyclic ketones were then prepared in order to probe their application in magnesium amide-mediated asymmetric deprotonation reactions. Initial studies were performed using a simple oxabicyclic substrate and our C2-symmetric bisamide. Pleasingly, after a short period of optimisation, the enantioenriched silyl enol ether was obtained in unprecedented yield and enantioselectivity. Attention was then turned to the analogous thiabicyclic ketone substrate. When performing the asymmetric deprotonation of this novel substrate under the previously optimised conditions at -78°C, an outstanding level of enantioselection was observed (99:1 er), and the silyl enol ether product was obtained in good yield. Having achieved such impressive results at -78°C, the efficiency of the transformation at room temperature was probed. Pleasingly, the enantioenriched silyl enol ether was obtained in excellent enantioselectivity (94:6 er) and yield, without the requirement for s ubambient temperatures. This is in marked contrast to the results achieved using the corresponding lithium amide, which delivered the silyl enol ether with a lower level of enantioselectivity (93:7) at -78°C. Impressive results could also be achieved when the analogous alkylmagnesium amide was applied to the desymmetrisation of the thiabicyclic substrate. Studies within the area of magnesium base chemistry have been extended to the enantioselective total synthesis of the bicyclic eicosanoid, (-)-mucosin. The synthetic strategy which has been devised involves a magnesium base-mediated enantioselective deprotonation as the key transformation. As such, the required meso-ketone substrate has been prepared efficiently using a series of simple synthetic transformations. With the mesoketone in hand, conversion to the racemic enol silane has been achieved by utilising carboncentred magnesium base chemistry. In addition, preparation of the required allylic bromide electrophile has been completedin a short number of synthetic steps using readily available starting materials, and the racemic enol silane and allylic bromide coupling partners were reacted to give the required -substituted ketone in moderate yield. Efforts were then focused on the development of an asymmetric method for the preparation of the enol silane intermediate, delivering the optically-enriched enol silane in high enantioselectivity using our C2-symmetric magnesium bisamide (93:7 er) or the C2-symmetric lithium amide (94:6 er) at - 78°C.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available