The tetramisole-promoted catalytic enantioselective [2,3]-sigmatropic rearrangement of quaternary ammonium salts bearing a (Z)-3-fluoro-3-arylprop-2-ene group generates, after addition of benzylamine, a range of β-fluoro-β-aryl-α-aminopentenamides containing a stereogenic tertiary fluorine substituent. Cyclic and acyclic nitrogen substituents as well as various aromatic substituents are tolerated, giving the β-fluoro-β-aryl-α-aminopentenamide products in up to 76% yield, 96:4 dr, and 98:2 er.

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst–substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst–substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation−π interactions over C–H···π is responsible for diastereoselectivity.

A tandem relay catalytic protocol using both Pd and isothiourea catalysis has been developed for the enantioselective synthesis of α-amino acid derivatives containing two stereogenic centers from readily accessible N,N-disubstituted glycine aryl esters and allylic phosphates. The optimized process uses a bench-stable succinimide-based Pd precatalyst (FurCat) to promote Pd-catalyzed allylic ammonium salt generation from the allylic phosphate and the glycine aryl ester. Subsequent in situ enantioselective [2,3]-sigmatropic rearrangement catalyzed by the isothiourea benzotetramisole forms syn-α-amino acid derivatives with high diastereo- and enantioselectivity. This methodology is most effective using 4-nitrophenylglycine esters and tolerates a variety of substituted cinnamic and styrenyl allylic ethyl phosphates. The use of challenging unsymmetrical N-allyl-N-methylglycine esters is also tolerated under the catalytic relay conditions without compromising stereoselectivity.

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.

The isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangement of N,N-diallyl allylic ammonium ylides is explored as a key part of a route to free functionalised α-amino esters and piperidines. The [2,3]-sigmatropic rearrangement proceeds with excellent diastereo- and enantiocontrol (>95:5 dr, up to 97% ee), with the resultant N,N-diallyl α-amino esters undergoing either mono- or bis-N-allyl deprotection. Bis-N-allyl deprotection leads to free α-amino esters, while the mono-deprotection strategy has been utilized in the synthesis of a target functionalised piperidine.Download high-res image (176KB)Download full-size image

An enantioselective N-heterocyclic carbene catalysed formal [3+2] cycloaddition has been developed for the synthesis of oxazolindin-4-one products. The reaction of oxaziridines and α-aroyloxyaldehydes under N-heterocyclic carbene catalysis provides the formal cycloaddition products with excellent control of the diastereo- and enantioselectivity (12 examples, up to >95:5 dr, >99:1 er). A matched-mismatched effect between the enantiomer of the catalyst and oxaziridine was identified, and preliminary mechanistic studies have allowed the proposal of a model to explain these observations.Download high-res image (106KB)Download full-size image

AbstractA new general concept for α,β-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,β-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,β-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

AbstractA new general concept for α,β-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,β-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,β-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

The catalytic enantioselective 6-exo-trig Michael addition-lactonization of enone-acid substrates to form cis-chromenones with high diastereo- and enantiocontrol was developed using the commercially available isothiourea tetramisole. An acidic workup proved necessary to minimize product epimerization and maximize product er, providing cis-chromenones in excellent yield, and with excellent diastereo- and enantioselectivity.

The diastereo- and enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofuran derivatives (15 examples, up to 96:4 dr, 95:5 er) via intramolecular Michael addition has been developed using keto–enone substrates and a bifunctional tertiary amine–thiourea catalyst. This methodology was extended to include non-activated ketone pro-nucleophiles for the synthesis of 2,3-disubstituted indane and 3,4-disubstituted tetrahydrofuran derivatives.

Tailoring the functionality of self-assembled monolayers (SAMs) can be achieved either by depositing prefunctionalized molecules with the appropriate terminal groups or by chemical modification of an existing SAM in situ. The latter approach is particularly advantageous to allow for diversity of surface functionalization from a single SAM and if the incorporation of bulky groups is desired. In the present study an organocatalytic isothiourea-mediated Michael addition–lactonization process analogous to a previously reported study in solution is presented. An achiral isothiourea, 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole (DHPB), promotes the intermolecular Michael addition–lactonization of a trifluoromethylenone terminated SAM and a variety of arylacetic acids affording C(6)-trifluoromethyldihydropyranones tethered to the surface. X-ray photoelectron spectroscopy, atomic force microscopy, contact angle, and ellipsometry analysis were conducted to confirm the presence of the substituted dihydropyranone. A model study of this approach was also performed in solution to probe the reaction diastereoselectivity as it cannot be measured directly on the surface.

[2,3]-Sigmatropic rearrangement processes of allylic ylides or their equivalents can be applied to a variety of different substrates and generate products of wide interest/applicability to organic synthesis. This review describes the development and applications of stereoselective [2,3]-rearrangement reactions in which a substoichiometric amount of a catalyst is used in either the formation of the reactive intermediate or the [2,3]-rearrangement step itself.Keywords: allylic ammonium ylides; allylic N-oxides; allylic oxonium ylides; allylic sulfonium ylides; allylic sulfoxides; O-propargylic oximes; stereoselective catalysis; [2,3]-rearrangement

Hydrazone-carboxylic acids undergo intramolecular cyclization in the presence of pivaloyl chloride, iPr2NEt, and catalytic DABCO to form a range of substituted fused tricyclic 2,3-dihydro-1,3,4-oxadiazoles in high yields.

Triazolinylidenes promote γ-selective C-carboxylation (up to 99:1 regioselectivity) in the O- to C-carboxyl transfer of furanyl carbonates in contrast to DMAP that promotes preferential α-C-carboxylation with moderate regiocontrol (typically 60:40 regioselectivity). The generality of this process is described and a simple mechanistic and kinetic model postulated to account for the observed regioselectivity

The exploration and expansion of the scope of the isothiourea-mediated synthesis of dihydropyridinones is presented. The use of ketimines derived from α,β-unsaturated γ-ketoesters as the Michael acceptor in a Michael addition/lactamisation cascade gives access to a range of dihydropyridinones with high enantioselectivity. The nature of the N-sulfonyl group present on the ketimine is extensively investigated, with further studies into derivatisation of the dihydropyridinone core also reported.

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

α,β-Unsaturated trichloromethyl ketones are suitable α,β-unsaturated amide and ester equivalents in N-heterocyclic carbene (NHC)-catalyzed redox hetero-Diels–Alder reactions with azolium enolates generated from α-aroyloxyaldehydes. The initially formed syn-dihydropyranone products can be isolated or can undergo ring-opening with benzylamine followed by aminolysis of the resulting CCl3 ketone to form a range of diamides with high diastereo- and enantioselectivity (up to >95:5 dr and >99% ee).

This tutorial review highlights the organocatalytic Lewis base functionalisation of carboxylic acids, esters and anhydrides via C1-ammonium/azolium enolates. The generation and synthetic utility of these powerful intermediates is highlighted through their application in various methodologies including aldol-lactonisations, Michael-lactonisations/lactamisations and [2,3]-rearrangements.

Benzotetramisole promotes the catalytic asymmetric [2,3]-rearrangement of allylic quaternary ammonium salts (either isolated or prepared in situ from p-nitrophenyl bromoacetate and the corresponding allylic amine), generating syn-α-amino acid derivatives with excellent diastereo- and enantioselectivity (up to >95:5 dr; up to >99% ee).

The asymmetric synthesis of tri- and tetrasubstituted trifluoromethyl dihydropyranones via an NHC-catalyzed redox process, introducing methyl, benzyl, and aryl substituents to the C(5) position, is presented. Their substrate-controlled derivatization into δ-lactones and cyclic hemiacetals containing stereogenic trifluoromethyl groups is also described.Keywords: asymmetric organocatalysis; cycloaddition; dihydropyranones; N-heterocyclic carbenes; trifluoromethyl; δ-lactones

A one-pot isothiourea-mediated Michael addition/lactonization/thiol elimination cascade sequence for the formation of 4,6-disubstituted and 3,4,6-trisubstituted 2-pyrones from (phenylthio)acetic acids and α,β-unsaturated trifluoromethyl ketones is described. The synthesis of a COX-2 inhibitor and the wide-ranging derivatization of the 2-pyrone moiety to trifluoromethyl substituted aromatics and heteroaromatics is also disclosed.

Isothiourea HBTM-2.1 catalyzes the asymmetric Michael addition/lactonization of aryl- and alkenylacetic acids using α-keto-β,γ-unsaturated phosphonates as α,β-unsaturated ester surrogates, giving access to a diverse range of stereodefined lactones or enantioenriched functionalized diesters upon ring-opening.

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,β-unsaturated ketimines is described. Incorporation of the valuable 2-sulfonate group allows derivatization to a range of di-, tri-, and tetrasubstituted pyridines.

Readily prepared 2-arylacetic anhydrides act as convenient ammonium enolate precursors in isothiourea (HBTM-2.1)-mediated catalytic asymmetric intermolecular Michael addition–lactonisation processes, giving diverse synthetic building blocks in good yield with high diastereo- and enantiocontrol (up to 98:2 dr and >99% ee).

Isothiourea HBTM-2.1 catalyses the Michael addition–lactonisation of 2-aryl and 2-alkenylacetic acids and α,β-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 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.

The isothiourea HBTM-2.1 (5 mol %) catalyzes the asymmetric formal [2 + 2] cycloaddition of both arylacetic acids (following activation with tosyl chloride) and preformed 2-arylacetic anhydrides with N-sulfonylaldimines, generating stereodefined 2,3-diaryl-β-amino esters (after ring-opening) and 3,4-diaryl-anti-β-lactams, respectively, with high diastereocontrol (up to >95:5 dr) and good to excellent enantiocontrol. Deprotection of the N-tosyl substituent within the β-lactam framework was possible without racemization by treatment with SmI2.

The in situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts derived from NHC addition to a range of substituted benzaldehydes is probed. Equilibrium constants for the formation of these 3-(hydroxybenzyl)azolium salts, as well as rate constants of hydrogen–deuterium exchange (kex) at C(α) of these intermediates for a range of N-aryl triazolinylidenes is reported. These combined studies give insight into the preference of N-pentafluorophenyl NHCs to participate in benzoin and Stetter reaction processes.

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.

The asymmetric annulation of a range of α,β-unsaturated acyl ammonium intermediates, formed from isothiourea HBTM 2.1 and anhydrides with either 1,3-dicarbonyls, β-ketoesters or azaaryl ketones gives either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields (up to 93%) and high enantioselectivity (up to 97% ee).

Telescoped and one-pot olefination/asymmetric functionalization approaches to disubstituted pyrrolidines (dr up to 99:1, up to 99% ee) have been developed using commercially available tetramisole (0.1 to 5 mol %). Using OTMS-quinidine as the Lewis base gives preferential access to an anti-configured pyrrolidine in high enantioselectivity.

Asymmetric α-amination through an N-heterocyclic carbene (NHC)-catalyzed redox reaction of α-aroyloxyaldehydes with N-aryl-N-aroyldiazenes to form α-hydrazino esters with high enantioselectivity (up to 99% ee) is reported. The hydrazide products are readily converted into enantioenriched N-aryl amino esters through samarium(II) iodide mediated N–N bond cleavage.

Chiral N-heterocyclic carbenes (NHCs) promote the asymmetric formal [4 + 2] cycloaddition of alkylarylketenes with β,γ-unsaturated α-ketocarboxylic esters and amides. Divergent diastereoselectivity is observed in this process, with γ-aryl-β,γ-unsaturated α-ketocarboxylic esters and amides giving preferentially syn-dihydropyranones (up to 68:32 dr syn:anti, up to 98% ee), while γ-alkyl-derivatives generate anti-dihydropyranones (up to 18:82 dr syn:anti, up to 75% ee).

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.

A chiral NHC catalyzes the asymmetric formal [2 + 2] cycloaddition of alkylarylketenes with both electron-deficient benzaldehydes and 2- and 4-pyridinecarboxaldehydes to generate stereodefined β-lactones. In the benzaldehyde series, optimal product diastereo- and enantiocontrol is observed using 2-nitrobenzaldehyde (up to 93:7 dr (syn:anti) and 93% ee). Substituted 2- and 4-pyridinecarboxaldehydes are also tolerated in this process, generating the corresponding β-lactones in good yield and enantioselectivity, although the diastereocontrol in these processes is highly dependent upon the aldehyde substitution. These processes are readily scalable, allowing multigram quantities of the β-lactone products to be prepared. Derivatization of these products, either through ring opening into the corresponding stereodefined β-hydroxy and β-amino acid derivatives without loss of stereochemical integrity or via cross-coupling, is demonstrated.

Second-order rate constants have been determined for deuteroxide ion-catalyzed exchange of the C(3)-proton for deuterium, kDO (M–1 s–1), of a series of 20 triazolium salts in aqueous solution at 25 °C and ionic strength I = 1.0 (KCl). Evidence is presented that the rate constant for the reverse protonation of the triazol-3-ylidenes by solvent water is close to that for dielectric relaxation of solvent (1011 s–1). These data enabled the calculation of carbon acid pKa values in the range 16.5–18.5 for the 20 triazolium salts. pD rate profiles for deuterium exchange of the triazolium salts reveal that protonation at nitrogen to give dicationic triazolium species occurs under acidic conditions, with estimates of pKaN1 = −0.2 to 0.5.

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).

The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of enantioselectivity (90–99% ee) via a pericyclic cascade process.

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).

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ∼50% conversion). Low catalyst loadings (0.10–0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

The O- to C-carboxyl transfer of oxazolyl carbonates promoted by triazolinylidenes, generated in situ with NEt3, shows a markedly different rate and chemoselectivity profile to the same reaction promoted by triazolinylidenes generated using KHMDS. The mechanism of these pathways has been probed through extensive crossover studies to understand this process. The use of NEt3 as a base allows domino multi-step reaction sequences to be developed, although chiral NHCs only generate modest levels of asymmetric induction (<15% ee) in these domino reaction processes.

The evaluation of a range of enantiomerically pure NHCs, prepared in situ from imidazolinium or triazolium salt precatalysts, to promote the catalytic enantioselective Steglich rearrangement of oxazolyl carbonates to their C-carboxyazlactones, is reported. Modest levels of enantioselectivity (up to 66% ee) are observed using oxazolidinone derived NHCs.N1,N2-Bis((S)-1-phenylethyl)imidazolinium tetrafluoroborateC19H23BF4N2Ee 100%[α]D20=+7.8 (c 0.5, CHCl3)Souce of chirality: (S)-α-methylbenzylamineAbsolute configuration: (S,S)N1,N2-Bis((S)-1-phenylethyl)imidazolium tetrafluoroborateC11H21BF4N2Ee 100%[α]D20=+7.8 (c 0.5, CHCl3)Source of chirality: (S)-α-methylbenzylamineAbsolute configuration: (S,S)(S)-1-Benzyl-3-(2-tert-butylphenyl)-5-isopropyl-4,5-dihydro-1H-imidazolium tetrafluoroborateC23H31BF4N2Ee 100%[α]D20=-0.7 (c 1.4, CHCl3)Source of chirality: l-valineAbsolute configuration: (S)(3S,7S)-3,7-Diisopropyl-2,3,7,8-tetrahydroimidazo[4,3-b:5,1-b′]bis(oxazole)-4-ium trifluoromethanesulfonateC14H21F3N2O5SEe 100%[α]D20=+54.6 (c 0.5, CH2Cl2)Source of chirality: l-valineAbsolute configuration: (S,S)(5aR,10bS)-2-Phenyl-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]-oxazinium tetrafluoroborateC18H16BF4N3OEe 100%[α]D20=+300.4 (c 0.5, MeCN)Source of chirality: (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-olAbsolute configuration: (5aR,10bS)(5aS,6R,9S,9aR)-6,11,11-Trimethyl-2-phenyl-5a,6,7,8,9,9a-hexahydro-4H-6,9-methano-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborateC19H24BF4N3OEe 100%[α]D20=+28.8 (c 0.5, CHCl3)Source of chirality: D-camphorAbsolute configuration: (5aS,6R,9S,9aR)(S)-5-Benzyl-2-phenyl-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-2-ium tetrafluoroborateC18H18BF4N3OEe 100%[α]D20=-18.1 (c 0.8, MeOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)(S)-5-Benzyl-2,6,6-triphenyl-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-2-ium tetrafluoroborateC30H26BF4N3OEe 100%[α]D20=+3.0 (c 0.5, MeOH)Source of chirality: l-valineAbsolute configuration: (S)(R)-5-Benzyl-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborateC18H18BF4N3Ee 100%[α]D20=+8.7 (c 1.04, MeCN),Source of chirality: l-phenylalanineAbsolute configuration: (S)(S)-5-((tert-Butyldimethylsilyloxy)diphenylmethyl)-2-phenyl-2,5,6,7-tetrahydropyrrolo[2,1-c][1,2,4]triazolium tetrafluoroborateC30H36BF4N3SiOEe 100%[α]D20=-108.4 (c 0.5, MeCN),Source of chirality: l-pyroglutamic acidAbsolute configuration: (S)(S)-6,6-Dimethyl-2-phenyl-5-isopropyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-2-ium tetrafluoroborateC15H20BF4N3OEe 100%[α]D20=-5.0 (c 1.0, MeCN)Source of chirality: l-valineAbsolute configuration: (S)(S)-5-Benzyl-6,6-dimethyl-2-phenyl-5,6-dihydrooxazolo[2,3-c][1,2,4]triazol-2-ium tetrafluoroborateC19H20BF4N3OEe 100%[α]D20=-73.0 (c 0.5, MeCN)Source of chirality: l-phenylalanineAbsolute configuration: (S)

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).

The synthesis of a range of C2-symmetric imidazolinium salts from (1R,2R)-cyclohexane-1,2-diamine, and an evaluation of the reactivity and asymmetric induction of the derived NHCs as catalysts for the asymmetric synthesis of β-lactams, is reported. In this series, optimal enantioselectivity (up to 70% ee) is observed using N-benzyl or N-1-naphthylmethyl-substituted NHCs, consistent with a chiral relay effect operating to dictate the stereochemical outcome of this reaction.(3aR,7aR)-1,3-Dimethyl-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC9H17BF4N2Ee 100%[α]D20=-144.2 (c 1.1, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Diethyl-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC11H21 BF4N2Ee 100%[α]D20=-107.8 (c 1.1, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Dineopentyl-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC17H33BF4N2Ee 100%[α]D20=-22.0 (c 1.0, CH2Cl2)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Bis(4-methoxybenzyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC23H29BF4N2O2Ee 100%[α]D20=-85.5 (c 1.1, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Bis(4-(trifluoromethyl)benzyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC23H23BF7N2Ee 100%[α]D20=-30.2 (c 1.1, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Bis(naphthalene-1-ylmethyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC29H29BF4N2Ee 100%[α]D20=-71.2 (c 0.9, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Bis(naphthalene-2-ylmethyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC29H29BF4N2Ee 100%[α]D20=-82.9 (c 1.1, CH2Cl2)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Bis(2,4,6-trimethylbenzyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC27H37BF4N2Ee 100%[α]D20=-21.5 (c 0.6, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Dibenzyl-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium chlorideC21H25BF4N2Ee 100%[α]D20=-62.2 (c 1.0, CHCl3)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Diphenyl-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC19H21BF4N2Ee 100%[α]D20=+66.2 (c 0.6, MeOH)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Di-o-tolyl-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC21H27BF4N2Ee 100%[α]D20=+47.1 (c 0.5, CH2Cl2)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(3aR,7aR)-1,3-Bis(2-isopropylphenyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-3-ium tetrafluoroborateC25H35BF4N2Ee 100%[α]D20=+20.6 (c 0.5, CH2Cl2)Source of chirality: (1R,2R)-trans-cyclohexane-1,2-diammonium (S)-tartrateAbsolute configuration: (R,R)(S)-3,3-Diphenyl-4-(2-furanyl)-1-tosylazetidin-2-oneC26H21NO4SEe 70%[α]D20=+28.1 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(R)-3,3,4-Triphenyl-1-tosylazetidin-2-oneC26H23NO3SEe 56%[α]D20=+15.8 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-3,3-Diphenyl-4-(4-bromophenyl)-1-tosylazetidin-2-oneC28H22NO3SBrEe 55%[α]D20=+14.7 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-3,3-Diphenyl-4-(2-phenylvinyl)-1-tosylazetidin-2-oneC30H25NO3SEe 42%[α]D20=+59.6 (c 0.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-3,3-Diphenyl-4-(4-methoxyphenyl)-1-tosylazetidin-2-oneC29H25NO4SEe 23%[α]D20=+2.9 (c 0.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(3R,4S)-3-Ethyl-3,4-diphenyl-1-tosylazetidin-2-oneC24H23NO3SEe 29%[α]D20=-14.0 (c 0.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)(3R,4R)-3-Ethyl-4-(furan-2-yl)-3-phenyl-1-tosylazetidin-2-oneC22H21NO4SEe 26%[α]D20=+35.6 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)(3R,4S)-3-Ethyl-4-(naphthalen-1-yl)-3-phenyl-1-tosylazetidin-2-oneC28H25NO3SEe 12%[α]D20=-0.3 (c 0.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)(3R,4S)-3-Ethyl-4-(naphthalen-2-yl)-3-phenyl-1-tosylazetidin-2-oneC28H25NO3SEe 54%[α]D20=-145.9 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)

The synthesis of a range of imidazolinium salts derived from acyclic 1,2-diamines, and an evaluation of the reactivity and asymmetric induction of the corresponding NHCs as catalysts for the asymmetric synthesis of β-lactams, is reported. An N-methyl-substituted NHC derived from (1R,2R)-1,2-diphenylethanediamine shows optimal reactivity and enantioselectivity in this series, in contrast to that observed with NHCs derived from (1R,2R)-cyclohexane-1,2-diamine.(S)-3-(2,5-Dimethylphenyl)-5-isopropyl-1-methyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC15H23BF4N2Ee 100%[α]D20=+38.7 (c 0.5, CHCl3)Source of chirality: l-valineAbsolute configuration: (S)(S)-1-Benzyl-3-(2-tert-butylphenyl)-5-isopropyl-4,5-dihydro-1H-imidazolium tetrafluoroborateC23H31BF4N2Ee 100%[α]D20=-0.7 (c 1.4, CHCl3)Source of chirality: l-valineAbsolute configuration: (S)Bis((S)-3,4-dibenzyl-1-(2-tert-butylphenyl)-4,5-dihydro-1H-imidazol-3-ium) tetrafluoroborateC27H31BF4N2Ee 100%[α]D20=+3.9 (c 1.03, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (S)(S)-1,3,4-Tribenzyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC24H25BF4N2Ee 100%[α]D20=+16.8 (c 0.53, MeOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)(4R,5R)-1,3-Dimethyl-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC17H19BF4N2Ee 100%[α]D20=+253 (c 0.59, CHCl3)Source of chirality: (1R,2R)-1,2-diphenylethane-1,2-diamineAbsolute configuration: (R,R)(4R,5R)-1,3-Dibenzyl-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC29H27BF4N2Ee 100%[α]D20=+147 (c 0.25, CHCl3)Source of chirality: (1R,2R)-1,2-diphenylethane-1,2-diamineAbsolute configuration: (R,R)(4R,5R)-4,5-Di-tert-butyl-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium iodideC13H27IN2Ee 100%[α]D20=-63.1 (c 0.42, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,R)(4R,5R)-1,3-Dibenzyl-4,5-di-tert-butyl-4,5-dihydro-1H-imidazol-3-ium bromideC25H35BrN2Ee 100%[α]D20=-82.8 (c 1.09, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,R)(4R,5R)-1,3-Dibenzyl-4,5-di-tert-butyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC25H35BF4N2Ee 100%[α]D20=-155.2 (c 0.53, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,R)(4S,5S)-4,5-Diphenyl-1,3-bis((R)-1-phenylethyl)-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC31H31BF4N2Ee 100%[α]D20=-216 (c 0.98, CHCl3)Source of chirality: (1S,2S)-1,2-diphenyl-N1,N2-bis((R)-1-phenylethyl)ethane-1,2-diamineAbsolute configuration: (R,S,S,R)(4R,5R)-4,5-Diallyl-1,3-bis((S)-1-phenylethyl)-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborateC25H31BF4N2Ee 100%[α]D20=-33.1 (c 1.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S,R,R,S)(S)-4-(Furan-2-yl)-3,3-diphenyl-1-tosylazetidin-2-oneC26H21NO4SEe 58%[α]D20=+31.2 (c 1.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(3S,4S)-3-Ethyl-4-(furan-2-yl)-3-phenyl-1-tosylazetidin-2-oneC22H21NO4SEe 33%[α]D20=-30.0 (c 0.1, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (S,S)(R)-4-(4-Bromophenyl)-3,3-diphenyl-1-tosylazetidin-2-oneC28H22BrNO3SEe 47%[α]D20=+17.6 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

The reaction of a chiral N-phenylnitrone derived from Garner’s aldehyde with alkylarylketenes generates 3-alkyl-3-aryloxindoles directly in excellent yields and with good to excellent levels of enantioselectivity (up to 90% ee).

Cascade reaction sequences incorporating N-heterocyclic carbene-based organocatalysis have been developed that allow the direct preparation of a range of (±)-4-phenoxycarbonylazlactones in good isolated yields (66–84%) from the corresponding N-p-anisoyl amino acids.

N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding β-lactams in good to excellent isolated yields; chiral NHCs give β-lactams in high e.e. after crystallisation.

The structural requirements of amidines necessary to act as efficient O- to C-carboxyl transfer agents are delineated and the scope of this process outlined through its application to a range of oxazolyl, benzofuranyl and indolyl carbonates.

•FabA is a promising drug target in Gram-negative bacteria.•High-throughput coupled assay for FabA using a substrate analogue has been developed.•New class of non-covalent inhibitor has been identified using the assay.•The compound inhibits the biological activity of FabA.•Crystal structure of the compound bound to FabA has been determined.Eukaryotes and prokaryotes possess fatty acid synthase (FAS) biosynthetic pathways that comprise iterative chain elongation, reduction, and dehydration reactions. The bacterial FASII pathway differs significantly from human FAS pathways and is a long-standing target for antibiotic development against Gram-negative bacteria due to differences from the human FAS, and several existing antibacterial agents are known to inhibit FASII enzymes. N-Acetylcysteamine (NAC) fatty acid thioesters have been used as mimics of the natural acyl carrier protein pathway intermediates to assay FASII enzymes, and we now report an assay of FabV from Pseudomonas aeruginosa using (E)-2-decenoyl-NAC. In addition, we have converted an existing UV absorbance assay for FabA, the bifunctional dehydration/epimerization enzyme and key target in the FASII pathway, into a high-throughput enzyme coupled fluorescence assay that has been employed to screen a library of diverse small molecules. With this approach, N-(4-chlorobenzyl)-3-(2-furyl)-1H-1,2,4-triazol-5-amine (N42FTA) was found to competitively inhibit (pIC50 = 5.7 ± 0.2) the processing of 3-hydroxydecanoyl-NAC by P. aeruginosa FabA. N42FTA was shown to be potent in blocking crosslinking of Escherichia coli acyl carrier protein and FabA, a direct mimic of the biological process. The co-complex structure of N42FTA with P. aeruginosa FabA protein rationalises affinity and suggests future design opportunities. Employing NAC fatty acid mimics to develop further high-throughput assays for individual enzymes in the FASII pathway should aid in the discovery of new antimicrobials.Download high-res image (103KB)Download full-size image

The catalytic enantioselective 6-exo-trig Michael addition-lactonization of enone-acid substrates to form cis-chromenones with high diastereo- and enantiocontrol was developed using the commercially available isothiourea tetramisole. An acidic workup proved necessary to minimize product epimerization and maximize product er, providing cis-chromenones in excellent yield, and with excellent diastereo- and enantioselectivity.

Isothiourea-catalyzed annulations between 2-acyl benzazoles and α,β-unsaturated acyl ammonium intermediates are selectively tuned to form either lactam or lactone heterocycles in good yields (up to 95%) and high ee (up to 99%) using benzothiazole or benzoxazole derivatives, respectively. Computation gives insight into the significant role of two 1,5-S⋯O interactions in controlling the structural preorganization and chemoselectivity observed within the lactam synthesis with benzothiazoles as nucleophiles. When using benzazoles the absence of a second stabilizing non-bonding 1,5-S⋯O interaction leads to a dominant C–H⋯O interaction in determining structural preorganization and lactone formation.

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.

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.

The in situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts derived from NHC addition to a range of substituted benzaldehydes is probed. Equilibrium constants for the formation of these 3-(hydroxybenzyl)azolium salts, as well as rate constants of hydrogen–deuterium exchange (kex) at C(α) of these intermediates for a range of N-aryl triazolinylidenes is reported. These combined studies give insight into the preference of N-pentafluorophenyl NHCs to participate in benzoin and Stetter reaction processes.

Readily prepared 2-arylacetic anhydrides act as convenient ammonium enolate precursors in isothiourea (HBTM-2.1)-mediated catalytic asymmetric intermolecular Michael addition–lactonisation processes, giving diverse synthetic building blocks in good yield with high diastereo- and enantiocontrol (up to 98:2 dr and >99% ee).

Cascade reaction sequences incorporating N-heterocyclic carbene-based organocatalysis have been developed that allow the direct preparation of a range of (±)-4-phenoxycarbonylazlactones in good isolated yields (66–84%) from the corresponding N-p-anisoyl amino acids.

The diastereo- and enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofuran derivatives (15 examples, up to 96:4 dr, 95:5 er) via intramolecular Michael addition has been developed using keto–enone substrates and a bifunctional tertiary amine–thiourea catalyst. This methodology was extended to include non-activated ketone pro-nucleophiles for the synthesis of 2,3-disubstituted indane and 3,4-disubstituted tetrahydrofuran derivatives.

The O- to C-carboxyl transfer of oxazolyl carbonates promoted by triazolinylidenes, generated in situ with NEt3, shows a markedly different rate and chemoselectivity profile to the same reaction promoted by triazolinylidenes generated using KHMDS. The mechanism of these pathways has been probed through extensive crossover studies to understand this process. The use of NEt3 as a base allows domino multi-step reaction sequences to be developed, although chiral NHCs only generate modest levels of asymmetric induction (<15% ee) in these domino reaction processes.

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

The structural requirements of amidines necessary to act as efficient O- to C-carboxyl transfer agents are delineated and the scope of this process outlined through its application to a range of oxazolyl, benzofuranyl and indolyl carbonates.

N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding β-lactams in good to excellent isolated yields; chiral NHCs give β-lactams in high e.e. after crystallisation.

The exploration and expansion of the scope of the isothiourea-mediated synthesis of dihydropyridinones is presented. The use of ketimines derived from α,β-unsaturated γ-ketoesters as the Michael acceptor in a Michael addition/lactamisation cascade gives access to a range of dihydropyridinones with high enantioselectivity. The nature of the N-sulfonyl group present on the ketimine is extensively investigated, with further studies into derivatisation of the dihydropyridinone core also reported.

Isothiourea HBTM-2.1 catalyses the Michael addition–lactonisation of 2-aryl and 2-alkenylacetic acids and α,β-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.

Triazolinylidenes promote γ-selective C-carboxylation (up to 99:1 regioselectivity) in the O- to C-carboxyl transfer of furanyl carbonates in contrast to DMAP that promotes preferential α-C-carboxylation with moderate regiocontrol (typically 60:40 regioselectivity). The generality of this process is described and a simple mechanistic and kinetic model postulated to account for the observed regioselectivity

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).

This tutorial review highlights the organocatalytic Lewis base functionalisation of carboxylic acids, esters and anhydrides via C1-ammonium/azolium enolates. The generation and synthetic utility of these powerful intermediates is highlighted through their application in various methodologies including aldol-lactonisations, Michael-lactonisations/lactamisations and [2,3]-rearrangements.

Chiral N-heterocyclic carbenes (NHCs) promote the asymmetric formal [4 + 2] cycloaddition of alkylarylketenes with β,γ-unsaturated α-ketocarboxylic esters and amides. Divergent diastereoselectivity is observed in this process, with γ-aryl-β,γ-unsaturated α-ketocarboxylic esters and amides giving preferentially syn-dihydropyranones (up to 68:32 dr syn:anti, up to 98% ee), while γ-alkyl-derivatives generate anti-dihydropyranones (up to 18:82 dr syn:anti, up to 75% ee).

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ∼50% conversion). Low catalyst loadings (0.10–0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

The asymmetric annulation of a range of α,β-unsaturated acyl ammonium intermediates, formed from isothiourea HBTM 2.1 and anhydrides with either 1,3-dicarbonyls, β-ketoesters or azaaryl ketones gives either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields (up to 93%) and high enantioselectivity (up to 97% ee).

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.