Isothiourea-promoted enantioselective catalysis

: from point chirality in flow to planar chirality in acylative dynamic kinetic resolutions

Abstract

Lewis base organocatalysis, particularly the use of chiral isothioureas, has been widely investigated by the Smith group and shown to be effective in various annulation and acylation reactions. This thesis explores the versatility of isothiourea catalysis in addressing two distinct synthetic challenges:

(1) The transition from homogeneous to heterogeneous systems via the application of polymer-supported isothiourea catalysed in heterocyclic synthesis.
(2) The expansion from point chirality to planar chirality via the isothiourea catalysed enantioselective synthesis of macrocyclophanes.

In the first part of this work, a packed bed reactor incorporating a polymer-supported isothiourea HyperBTM derivative was developed to promote the enantioselective annulation reaction in flow. Utilizing an α,β-unsaturated acyl ammonium intermediate, the reaction of α-azol-2-ylacetophenones and -acetamides with alkyl, aryl, and heterocyclic α,β-unsaturated anhydrides delivered a range of products in good to excellent yields with high enantiopurity (up to 97:3 er). The robustness of this immobilized catalyst was demonstrated through a 15 mmol scale-up, affording the target heterocyclic product in 68% overall yield with 98:2 er after recrystallization. 

The second and third part of this thesis addresses the effective isothiourea catalysed acylative kinetic (KR) and dynamic kinetic resolution (DKR) approaches to the generation of a range of planar chiral para- or metacyclophanes with excellent levels of enantioselectivity. For configurationally stable planar chiral paracyclophanols bearing 12- and 13-membered ansa-chains, effective KR was achieved using (R)-BTM and isobutyric anhydride, with selectivity factors (s) reaching up to 50. Application to configurationally labile macrocyclic phenols with 14 to 18 membered ansa-chains allows their effective acylative DKR, generating the desired products with excellent enantioselectivity (up to 95% yield and 98:2 er). Furthermore, this acylative DKR strategy was successfully expanded to configurationally labile metacyclophanols with 11- to 19-membered ansa-chains affording products with excellent levels of enantioselectivity (up to 98% yield and 96:4 er).

Date of Award	2 Jul 2026
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew Smith (Supervisor)