TY - GEN

T1 - Elucidating the mechanism of the palladium-catalysed decarboxylative asymmetric allylic alkylation of alpha-sulfonyl anions

AU - Bowen, Eleanor

PY - 2020

Y1 - 2020

N2 - This research project focused on the investigation of the palladium-catalysed decarboxylative asymmetric allylic alkylation (Pd-DAAA) reaction of α-anions of a 5-membered sulfone, sulfolane, bearing a range of ketone and ester anion stabilising substituents, in the presence of the (S,S)-ANDEN Phenyl Trost ligand. In the first instance, the synthesis of the prerequisite substrates for the Pd-DAAA reaction, namely a sulfone bearing allyl ester and phenyl ester substituents, and a sulfone bearing allyl ester and phenyl ketone substituents, was optimised.A mechanistic study followed, and it was discovered that substrates containing a 2-methyl substituted allyl ester were less reactive than their non-substituted counterparts, making these intermediates unsuitable for enolate crossover studies. Instead, 2 H-labelling of the allylic ester was achieved in good yield with 93% deuterium incorporation at the terminal alkene position. Enolate crossover reactions of both ester and ketone deuterated and non-deuterated substrates showed significant crossover, suggesting that an outer-sphere alkylationmechanism operates for both ester and ketone substrates.Relative stereochemistry determination experiments were attempted to conclusively establish the mechanism of the Pd-DAAA of cyclic sulfones, using cis-5-phenyl-2-cyclohexen-1-ol as the allylic stereochemical label. Although benzyl ester and phenyl ketone precursors were successfully prepared, they were found to be unreactive in the Pd-DAAA process, even over an extended reaction time with temperatures up to 120 °C. Optimisation of the Pd-DAAA of cyclic sulfones was explored by testing the use of additives, in an effort to increase the observed enantioselectivity. Ultimately, no increase in enantioselectivity was observed as compared to previously optimised additive-free conditions. Using these conditions, the substrate scope of the Pd-DAAA reaction was substantially broadened for a range of not only 5- but also 6-membered cyclic sulfones with varying ester and ketone substituents, affording novel enantioenriched alkylated products with 10-94% ee.

AB - This research project focused on the investigation of the palladium-catalysed decarboxylative asymmetric allylic alkylation (Pd-DAAA) reaction of α-anions of a 5-membered sulfone, sulfolane, bearing a range of ketone and ester anion stabilising substituents, in the presence of the (S,S)-ANDEN Phenyl Trost ligand. In the first instance, the synthesis of the prerequisite substrates for the Pd-DAAA reaction, namely a sulfone bearing allyl ester and phenyl ester substituents, and a sulfone bearing allyl ester and phenyl ketone substituents, was optimised.A mechanistic study followed, and it was discovered that substrates containing a 2-methyl substituted allyl ester were less reactive than their non-substituted counterparts, making these intermediates unsuitable for enolate crossover studies. Instead, 2 H-labelling of the allylic ester was achieved in good yield with 93% deuterium incorporation at the terminal alkene position. Enolate crossover reactions of both ester and ketone deuterated and non-deuterated substrates showed significant crossover, suggesting that an outer-sphere alkylationmechanism operates for both ester and ketone substrates.Relative stereochemistry determination experiments were attempted to conclusively establish the mechanism of the Pd-DAAA of cyclic sulfones, using cis-5-phenyl-2-cyclohexen-1-ol as the allylic stereochemical label. Although benzyl ester and phenyl ketone precursors were successfully prepared, they were found to be unreactive in the Pd-DAAA process, even over an extended reaction time with temperatures up to 120 °C. Optimisation of the Pd-DAAA of cyclic sulfones was explored by testing the use of additives, in an effort to increase the observed enantioselectivity. Ultimately, no increase in enantioselectivity was observed as compared to previously optimised additive-free conditions. Using these conditions, the substrate scope of the Pd-DAAA reaction was substantially broadened for a range of not only 5- but also 6-membered cyclic sulfones with varying ester and ketone substituents, affording novel enantioenriched alkylated products with 10-94% ee.

U2 - 10.17635/lancaster/thesis/942

DO - 10.17635/lancaster/thesis/942

M3 - Master's Thesis

PB - Lancaster University

ER -