ABSTRACT
An enantioselective isothiourea-catalysed [2 + 2] cycloaddition of C(1)-ammonium enolates with pyrazol-4,5-diones is used to construct spirocyclic ß-lactones in good yields, excellent enantioselectivity (99 : 1 er) but with modest diastereocontrol (typically 70 : 30 dr). Upon ring-opening with morpholine or alternative nucleophilic amines and alcohols ß-hydroxyamide and ß-hydroxyester products are generated with enhanced diastereocontrol (up to >95 : 5 dr). Control experiments show that stereoconvergence is observed in the ring-opening of diastereoisomeric ß-lactones, leading to a single product (>95 : 5 dr, >99 : 1 er). Mechanistic studies and DFT analysis indicate a substrate controlled Dynamic Kinetic Asymmetric Transformation (DyKAT) involving epimerisation at C(3) of the ß-lactone under the reaction conditions, coupled with a hydrogen bond-assisted nucleophilic addition to the Si-face of the ß-lactone and stereodetermining ring-opening. The scope and limitations of a one-pot protocol consisting of isothiourea-catalysed enantio-determining [2 + 2] cycloaddition followed by diastereo-determining ring-opening are subsequently developed. Variation within the anhydride ammonium enolate precursor, as well as N(1) and C(3) within the pyrazol-4,5-dione scaffold is demonstrated, giving a range of functionalised ß-hydroxyamides with high diastereo- and enantiocontrol (>20 examples, up to >95 : 5 dr and >99 : 1 er) via this DyKAT.
ABSTRACT
The development of enantioselective synthetic methods capable of generating vicinal stereogenic centres, where one is tetrasubstituted (such as either an all-carbon quaternary centre or where one or more substituents are heteroatoms), is a recognised synthetic challenge. Herein, the enantioselective conjugate addition of a range of carbo- and heterocyclic α-substituted ß-ketoesters to α,ß-unsaturated aryl esters using the isothiourea HyperBTM as a Lewis base catalyst is demonstrated. Notably, divergent diastereoselectivity is observed through the use of either cyclopentanone-derived or indanone-derived substituted ß-ketoesters with both generating the desired stereodefined products with high selectivity (>95 : 5 dr, up to 99 : 1 er). The scope and limitations of these processes are demonstrated, alongside application on gram scale. The origin of the divergent substrate selectivity has been probed through the use of DFT-analysis, with preferential orientation driven by dual stabilising CHâ¯O interactions. The importance of solvation with strongly polar transition-states is highlighted and the SMD solvation model is demonstrated to capture solvation effects reliably.
ABSTRACT
DFT calculations on the full catalytic cycle for manganese catalysed enantioselective hydrogenation of a selection of ketones have been carried out at the PBE0-D3PCM //RI-BP86PCM level. Mn complexes of an enantiomerically pure chiral P,N,N ligand have been found to be most reactive when adopting a facial coordination mode. The use of a new ligand with an ortho-substituted dimethylamino-pyridine motif has been calculated to completely transform the levels of enantioselectivity possible for the hydrogenation of cyclic ketones relative to the first-generation Mn catalysts. In silico evaluation of substrates has been used to identify those likely to be reduced with high enantiomer ratios (er), and others that would exhibit less selectivity; good agreements were then found in experiments. Various cyclic ketones and some acetophenone derivatives were hydrogenated with er's up to 99 : 1.
ABSTRACT
A range of modern density functional theory (DFT) functionals have been benchmarked against experimentally determined metal hydride bond strengths for three first-row TM hydride complexes. Geometries were found to be produced sufficiently accurately with RI-BP86-D3(PCM)/def2-SVP and further single-point calculations with PBE0-D3(PCM)/def2-TZVP were found to reproduce the experimental hydricity accurately, with a mean absolute deviation of 1.4 kcal/mol for the complexes studied.