Louis C. Morrill

Organocatalytic Functionalization of Carboxylic Acids: Isothiourea-Catalyzed Asymmetric Intra- and Intermolecular Michael Addition−Lactonizations

Tetramisole promotes the catalytic asymmetric intramolecular Michael addition-lactonization of a variety of enone acids, giving carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric intermolecular Michael addition-lactonization of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee).

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,β-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.

Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study

HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using α,α-di-deuterio 4-fluorophenylacetic acid, consistent with rate determining deprotonation of an intermediate acyl isothiouronium ion.

Catalytic asymmetric α-amination of carboxylic acids using isothioureas

HBTM-2.1 promotes the direct asymmetric α-amination of carboxylic acids with N-aryl-N-aroyldiazenes at low catalyst loadings (as low as 0.25 mol%), giving either 1,3,4-oxadiazin-6-ones or N-protected α-amino acid derivatives (upon ring opening) with exquisite enantiocontrol (typically ≥99% ee).

Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights

N-heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of α-aroyloxyaldehydes with β-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-β-trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.

Isothiourea-Mediated Asymmetric Functionalization of 3-Alkenoic Acids

Isothiourea HBTM-2.1 promotes the catalytic asymmetric α-functionalization of 3-alkenoic acids through formal [2 + 2] cycloadditions with N-tosyl aldimines and formal [4 + 2] cycloadditions with either 4-aryltrifluoromethyl enones or N-aryl-N-aroyl diazenes, providing useful synthetic building blocks in good yield and with excellent enantiocontrol (up to >99% ee). Stereodefined products are amenable to further synthetic elaboration through manipulation of the olefinic functionality.

Isothiourea-Mediated Stereoselective C-Acylation of Silyl Ketene Acetals

Isothiourea DHPB promotes the diastereoselective C-acylation of silyl ketene acetals with anhydrides or benzoyl fluoride, giving 3-acyl-3-aryl or 3-acyl-3-alkylfuranones in excellent yields and stereoselectivities (up to 99:1 dr).

Asymmetric Isothiourea‐Catalysed Formal [3+2] Cycloadditions of Ammonium Enolates with Oxaziridines

A highly enantioselective Lewis base-catalysed formal [3+2] cycloaddition of ammonium enolates and oxaziridines to give stereodefined oxazolidin-4-ones in high yield is described. Employing an enantioenriched oxaziridine in this process leads to a matched/mis-matched effect with the isothiourea catalyst and allowed the synthesis of either syn- or anti-stereodefined oxazolidin-4-ones in high d.r., yield and ee. Additionally, the oxazolidin-4-one products have been derivatised to afford functionalised enantioenriched building blocks.

Isothiourea-catalysed asymmetric C-acylation of silyl ketene acetals

Screening of a range of chiral isothioureas and acyl donors to promote the asymmetric C-acylation of silyl ketene acetals indicates that C(2)-aryl-dihydropyrimidobenzothiazole-derived isothioureas and propionic anhydride give optimal reactivity and enantioselectivity in this process. Under optimised conditions 3-acyl-3-aryl or 3-acyl-3-alkylfuranones are prepared in good yields and moderate to excellent enantioselectivities (up to 98% ee; ee=enantiomeric excess).

Isothiourea-Mediated Asymmetric O- to C-Carboxyl Transfer of Oxazolyl Carbonates: Structure–Selectivity Profiles and Mechanistic Studies

The structural motif within a series of tetrahydropyrimidine-based isothioureas necessary for generating high asymmetric induction in the asymmetric Steglich rearrangement of oxazolyl carbonates is fully explored, with crossover and dynamic (19)F NMR experiments used to develop a mechanistic understanding of this transformation.