Probing the reactivity of α,β-unsaturated acyl ammonium intermediates in organocatalysis

Abstract

The research described in this thesis focuses on probing the reactivity of α,β-unsaturated acyl
ammonium intermediates and the use of theses reactive intermediates in a new concept:
aryloxide-facilitated catalyst turnover in α,β-unsaturated acyl ammonium catalysis.

Chapter 2: Initially, the concept of aryloxide-facilitated catalyst turnover was used in a novel
isothiourea-catalysed transfer hydrogenation reaction of α,β-unsaturated p-nitrophenyl esters.
An efficient synthetic procedure was successfully developed, which was demonstrated to be
applicable to a range of α,β-unsaturated PNP esters (15 examples, 38−98% yield), typically
with electron withdrawing β-substituents proving most reactive. Attempts to perform the
reaction enantioselectively showed that in principle α,β-unsaturated acyl ammonium
intermediates generated from α,β-unsaturated PNP esters and a chiral isothiourea catalyst can
react enantioselectively.

Chapter 3: Following on the established new concept in α,β-unsaturated acyl ammonium
catalysis, enantioselective Michael addition of nucleophiles to α,β-unsaturated PNP esters has
been further explored using the aryloxide-facilitated catalyst turnover strategy. This new
method was applicable for a range of malonates and malonate derivatives as pro-nucleophiles,
resulting in generally good yields with excellent enantioselectivities (14 examples, up to 86%
yield, > 99:1 er). This work demonstrated for the first time that simple nucleophiles could be
applied in stoichiometric quantities in enantioselective a,b-unsaturated acyl ammonium
catalysis.

Chapter 4: A detailed variable time normalisation kinetic analysis (VTNKA) was performed to
investigate the kinetics of the enantioselective Michael addition of malonates to
α,β-unsaturated PNP esters, using ¹⁹F{¹H} NMR spectroscopic analysis. The order with respect
to α,β-unsaturated ester, malonate and catalyst were found to be first order, but zero order with
respect to base, indicating the turnover-limiting step is likely to be the Michael addition of
malonate to the α,β-unsaturated acyl ammonium intermediate.

Date of Award	29 Jul 2020
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew David Smith (Supervisor)