Novel applications of magnesium base systems in preparative organic chemistry and asymmetric synthesis

Student thesis: Doctoral Thesis

Abstract

During this research project the synthesis of sp³-rich azepanes was envisioned using our asymmetric deprotonation strategy as a key step build in chirality. First a series of chiral enol phosphates were prepared in good to high yields with high enantioselectivities (up to 99:1) using a C₂-symmetric magnesium base developed in the Kerr group. Thereafter a series of trisubstituted alkenes were synthesized by a cross coupling strategy using phenylmagnesium bromide and to our delight, after a detailed optimisation, the desired products were obtained with high to excellent yields. The scope of the nucleophilic coupling partner was also successfully expanded for primary and secondary alkyl Grignard reagents, which are known to be more challenging coupling partners and the desired products were obtained in high to excellent yields. When the primary alkyl cross coupled products were used as substrates the desired 7-membered azepanes were obtained after a one pot ozonolysis-reductive amination sequence, with good yields and high ers in a diastereoselective manner. Neither in the cross coupling step nor in the tandem ozonolysis-reductive amination erosion of the enantioselectivity was not observed. In the case of the secondary and aryl coupled products, with identical conditions the ring closure does not occur, and the corresponding aliphatic ε-amino ketones could be obtained with moderate to good yields in an enantiomerically enriched fashion. Further optimisation of the reaction conditions allowed us to prepare the desired chiral azepanes even with these challenging substrates.In parallel with this a series of conformationally locked cyclobutanones were synthesised and desymmetrised with a C₂-symmetric magnesium base, developed in our group.The enol phophates were isolated with significantly lower enantiomeric ratios (57:43 to 59:41) than the previously reported values (95:5 to 99:1). In order to explain the observed differences a Kumada coupling reaction was developed for the cross coupling of enol phosphates with phenylmagnesium bromide. The products were obtained in moderate to high yields and separation of these products revealed that the enantioselectivity of the products was identified incorrectly previously. In addition the structure of the C₂-symmetric magnesium base was also investigated by DOSY NMR and revealed that under standard conditions a mixed alkylmagnesium amide forms instead of the previously assumed bisamide. With these results in hand, a novel mixed magnesium amide system was identified computationally as an efficient base, for the asymmetric deprotonation of cyclobutanones. Finally, the desired amine was prepared through a three step synthetic sequence.
Date of Award1 Apr 2018
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorWilliam Kerr (Supervisor) & Nicholas Tomkinson (Supervisor)

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