N- to C-sulfonyl photoisomerisation of dihydropyridinones: a synthetic and mechanistic study.

The scope and limitations of a photoinitiated N- to C-sulfonyl migration process within a range of dihydropyridinones is assessed. This sulfonyl transfer proceeds without erosion of either diastereo- or enantiocontrol, and is general across a range of N-sulfonyl substituents (SO2R; R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-NO2C6H4, Me, Et) as well as C(3)-(aryl, heteroaryl, alkyl and alkenyl) and C(4)-(aryl and ester) substitution. Crossover reactions indicate an intermolecular step is operative within the formal migration process, although no crossover from C-sulfonyl products was observed. EPR studies indicate the intermediacy of a sulfonyl radical and a mechanism is proposed based upon these observations.

Exploiting the Imidazolium Effect in Base-free Ammonium Enolate Generation: Synthetic and Mechanistic Studies.

N-Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition-cyclization reactions using different α,ß-unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the "imidazolium" effect in ammonium enolate formation and have highlighted key differences with traditional base-mediated processes.

Enantioselective isothiourea-catalysed trans-dihydropyridinone synthesis using saccharin-derived ketimines: scope and limitations.

The catalytic enantioselective synthesis of a range of trans-dihydropyridinones from aryl-, heteroaryl- and alkenylacetic acids and saccharin-derived ketimines with good to excellent stereocontrol (15 examples, up to >95 : 5 dr, up to >99 : 1 er) is reported. After extensive optimisation, HyperBTM proved the optimal isothiourea catalyst for this transformation at -78 °C, giving trans-dihydropyridones with generally excellent levels of diastereo- and enantioselectivity.

Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies.

The catalytic enantioselective synthesis of a range of cis-pyrrolizine carboxylate derivatives with outstanding stereocontrol (14 examples, >95 : 5 dr, >98 : 2 er) through an isothiourea-catalyzed intramolecular Michael addition-lactonisation and ring-opening approach from the corresponding enone acid is reported. An optimised and straightforward three-step synthetic route to the enone acid starting materials from readily available pyrrole-2-carboxaldehydes is delineated, with benzotetramisole (5 mol%) proving the optimal catalyst for the enantioselective process. Ring-opening of the pyrrolizine dihydropyranone products with either MeOH or a range of amines leads to the desired products in excellent yield and enantioselectivity. Computation has been used to probe the factors leading to high stereocontrol, with the formation of the observed cis-steroisomer predicted to be kinetically and thermodynamically favoured.

Enantioselective Synthesis of 3,5,6-Substituted Dihydropyranones and Dihydropyridinones using Isothiourea-Mediated Catalysis.

The scope of dihydropyranone and dihydropyridinone products accessible by isothiourea-catalyzed processes has been expanded and explored through the use of 2-N-tosyliminoacrylates and 2-aroylacrylates in a Michael addition-lactonization/lactamization cascade reaction. Notably, to ensure reproducibility it is essential to use homoanhydrides as ammonium enolate precursors with 2-aroyl acrylates, while carboxylic acids can be used with 2-N-tosyliminoacrylates, delivering a range of 3,5,6-substituted dihydropyranones and dihydropyridinones with high enantioselectivity (typically >90 % ee). The derivatization of the heterocyclic core of a 3,5,6-substituted dihydropyranone through hydrogenation is also reported.

Synthesis of di-, tri-, and tetrasubstituted pyridines from (phenylthio)carboxylic acids and 2-[aryl(tosylimino)methyl]acrylates.

An isothiourea-catalyzed Michael addition-lactamization followed by the sulfide oxidation-elimination/N- to O-sulfonyl transfer sequence for the formation of 2,3,5- and 2,3-substituted pyridine 6-tosylates from (phenylthio)acetic acids and α,ß-unsaturated ketimines is described. Incorporation of the valuable 2-sulfonate group allows derivatization to a range of di-, tri-, and tetrasubstituted pyridines.

Organocatalytic Michael addition-lactonisation of carboxylic acids using α,ß-unsaturated trichloromethyl ketones as α,ß-unsaturated ester equivalents.

Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and α,ß-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high diastereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative.

Isothiourea-mediated one-pot synthesis of functionalized pyridines.

Acids to bases: The synthesis of 2,4,6-trisubstituted pyridines from (phenylthio)acetic acid and a range of α,ß-unsaturated ketimines is reported. This process proceeds by intermolecular Michael addition/lactamization, thiophenol elimination, and N- to O-sulfonyl migration, giving 2-sulfonate-substituted pyridines which are readily derivatized to generate structural diversity.