The asymmetric synthesis of enol phosphates and their application in total synthesis

  • Muralikrishnan Rajamanickam

Student thesis: Doctoral Thesis

Abstract

The synthesis of a wide range of highly valuable enol phosphate products has been carried out. The use of carbon centred magnesium bases, previously developed in the group has allowed the formation of kinetic enol phosphate products under room temperature conditions. By applying specific quench conditions such as the reverse addition quench condition yields up to 95% were obtained while using di-tertbutylmagnesium base. Interestingly acetophenone derivatives required the use of di-mesitylmagnesium base to access the corresponding enol phosphate compounds. Such enol phosphates can also be obtained under an enantioenriched fashion with the use of chiral magnesium bisamide bases. Previously studied C2- and pseudo C2-symmetric magnesium amide bases were synthesised and the process optimised to obtain up to 95% yield and 95:5 of selectivity on the benchmark substrate. A novel co-addition quench protocol was developed to access high reactivity and selectivity at mild temperature conditions (-20 °C).The high stability of enol phosphate products allowed a detailed study of the chiral magnesium amide bases. Such study allowed the development of a practical methodology towards chiral alkyl-magnesium amide bases allowing similar results to chiral magnesium bisamide bases with half the amount of chiral amine. Further investigations of the reactive species in solution through DOSY NMR techniques were also carried out. Finally the sum of knowledge gained through synthesis and application of enolphosphates allowed the total synthesis of a natural product (+)-Sporochnol. The key transformation of the synthesis consisted on the desymmetrisation of a prochiral ketone to generate an enantioenriched enol phosphate followed by a Kumada cross coupling reaction.The novel Kumada coupling reaction was initially developed for the synthesis of (+)-Sporochnol.With the success encountered in such methodology we further developed the reaction, which, ultimately allowed the cross coupling of unactivatedenol phosphate compounds with alkyl Grignard reagents at room temperature using commerically available and air stable PEPPSI catalysts.
Date of Award1 Apr 2015
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorWilliam Kerr (Supervisor) & (Supervisor)

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