Enantiodivergent [4+2] Cycloaddition of Dienolates by Polyfunctional Lewis Acid/Zwitterion Catalysis

Abstract Diels–Alder reactions have become established as one of the most effective ways to prepare stereochemically complex six‐membered rings. Different catalysis concepts have been reported, including dienophile activation by Lewis acids or H‐bond donors and diene activation by bases. Herein we report a new concept, in which an acidic prodiene is acidified by a Lewis acid to facilitate deprotonation by an imidazolium–aryloxide entity within a polyfunctional catalyst. A metal dienolate is thus formed, while an imidazolium–ArOH moiety probably forms hydrogen bonds with the dienophile. The catalyst type, readily prepared in few steps in high overall yield, was applied to 3‐hydroxy‐2‐pyrone and 3‐hydroxy‐2‐pyridone as well as cyclopentenone prodienes. Maleimide, maleic anhydride, and nitroolefin dienophiles were employed. Kinetic, spectroscopic, and control experiments support a cooperative mode of action. High enantioselectivity was observed even with unprecedented TONs of up to 3680.


General Remarks
All reactions were performed in oven-dried glassware (stored in an oven, at 150 °C) and under a positive pressure of nitrogen, unless otherwise indicated. Technical grade solvents (dichloromethane (DCM), petroleum ether (PE), ethyl acetate (EE), diethylether (Et2O), tetrahydrofuran (THF) and toluene) were distilled before use. Dry solvents like DCM, Et2O, toluene, THF and acetonitrile were taken from solvent purification systems (MBraun MB SPS-800). Purchased chemicals were used without further purification. Analytical thin layer chromatography (TLC) was performed with silica gel 60F-254 TLC plates and compound spots were visualized by fluorescence quenching under UV light (254 nm) or by staining with KMnO4/NaOH. Purification by flash-chromatography was performed on silica gel 60 (40-63 μm particle size), using a forced flow of eluent. All catalytic reactions were performed in oven dried Schlenk vials under a positive pressure of nitrogen unless otherwise indicated. In reactions where low temperatures were necessary a cryostatic temperature regulator was used. n-Heptane and i-propanol for HPLC were purchased in HPLC-quality and used without further purification.
NMR data were recorded on Bruker Avance spectrometers operating at Larmor frequencies of 700, 500, 400 or 300 MHz ( 1 H), 176, 125, 100 or 75 MHz ( 13 C) and 376 MHz ( 19 F). Chemical shifts δ are referred in terms of ppm. J-Coupling constants are given in Hz. The following abbreviations classify the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets) and br (broad signal). Infrared spectra were recorded by the IR service of the University of Stuttgart on an FT-IR spectrometer (Bruker Alpha FT-IR) with an ATR unit and the signals are given by wavenumbers (cm -1 ). Optical rotation was measured on a Perkin Elmer 241 Polarimeter operating at the sodium D line (λ = 589 nm) and mercury lines (λ1 = 578 nm and λ2 = 546 nm) with a 100 mm path cell length. Melting points were measured using a melting point apparatus (Büchi 535) in open glass capillaries. Mass spectra were measured on a Finnigan MAT 95 for CI and EI and a Bruker MicroTOFQ for ESI and obtained from the MS service of the University of Stuttgart. The UV-Vis spectra were recorded with a Lambda 365-Spectrometer (PerkinElmer). Single crystal X-ray analysis was performed by Dr. Wolfgang Frey, University of Stuttgart, on a Bruker Kappa APEXII Duo (Cu Kα 1.54178Å and Mo Kα 0.71073 Å). Enantiomeric excesses (ee) were determined by high performance liquid chromatography (HPLC) or NMR spectroscopy using the (R)-BINOL. The applied method is given in the description of the corresponding product.

General Procedures (GP)
General Procedure for the Imine-Synthesis (GP1) The corresponding ligands were synthesized following the literature procedure. 6 The corresponding aldehyde (1.0 equiv.) and the corresponding amine (1.0 equiv.) were dissolved in dry DCM (5 mL / mmol) in the presence of molecular sieves (4 Å) under nitrogen atmosphere and the reaction mixture was stirred for 18 h. After that, the reaction mixture was filtered through celite, the filter cake washed with dry DCM (5 mL/1 mmol) and the solvent removed under reduced pressure. The resulting yellow solid was dissolved in a small amount of dry DCM (0.2 mL/mmol) and added to n-pentane (2 mL/mmol). The formed precipitate was filtered to afford the pure ligand as a yellow solid.

General Procedure for the Metal Complexation (GP2)
Based on a literature protocol, 6 the corresponding ligand (1.0 equiv.) was dissolved in dry acetonitrile (5 mL / 0.01 mmol) and the corresponding metal source (Cu(acac)2, 1.0 equiv.) was added and the mixture was stirred at 60 °C for 16 h. The solution was filtered over celite and the filter cake washed with DCM. Subsequently, the solvent was removed under reduced pressure. The residue was dissolved in a small amount of DCM and the product was precipitated by adding n-pentane to the solution. The suspension was centrifuged, the supernatant solution was decanted off and the residue was then dried under high vacuum to afford the corresponding pre-catalyst.

General Procedure for the Activation of the Complexes (GP3)
Based on a literature protocol, 6 the complexes were dissolved in a solvent mixture of DCM/THF/Et3N (66/33/1) and the solution was filtered over a small silica pad in a glass frit and eluted with the same mixture. The volatiles were removed under reduced pressure and the product (activated catalyst) was dissolved in a small amount of DCM (0.1 mL), precipitated in n-pentane (5 mL), filtered and dried under high vacuum for 2 h. The activated catalyst could be used without further purification in the catalytic DA reactions.

General Procedure for Catalytic Diels−Alder Reactions of 3-Hydroxypyrones (GP4)
To an oven-dried Schlenk vial containing activated catalyst C1 (0.005 mmol, 5 mol%) and Nsubstituted maleimide 2 (0.105 mmol, 1.05 equiv.) dry THF (0.1 mL) was added. The solution was placed in a cryobath at −40 °C and allowed to stir for 10 min under nitrogen atmosphere. The corresponding diene 1 (0.1 mmol, 1.0 equiv.) was then added using a syringe pump over a period of 12 h as a stock solution (in 0.1 mL THF) followed by additional solvent (0.05 mL) to avoid a loss of the material on the glass wall. After the addition period was completed the reaction mixture was stirred for six hours. Afterwards the reaction mixture was filtered through a short pad of silica to remove the catalyst using a mixture of petroleum ether/ethyl acetate 1:1 as eluent. The crude product was purified by flash column chromatography (PE : EE = 2:1) to yield the pure product.

General Procedure for Catalytic Diels−Alder Reactions of 3-Hydroxypyrones in Control Experiments (GP5)
To an oven-dried Schlenk vial containing the corresponding catalyst (C2-C5) (0.05 mmol, 5 mol%), the corresponding base (0.0025 mmol, 2.5 mol%) and maleimide 2B (0.105 mmol, 1.05 equiv.) THF (0.1 mL) was added. The reaction mixture was placed in a cryobath at −40 °C and allowed to stir for 10 min under nitrogen atmosphere. The diene 1a (0.1 mmol, 1.0 equiv.) was then added using a syringe pump over the period of 12 h as a stock solution (in 0.1 mL THF, plus additional solvent 0.05 mL to avoid loss of the material on the glass wall. After the addition period was completed the reaction mixture was stirred for additional 10 hours. Afterwards the reaction mixture was filtered through a short pad of silica to remove the catalyst using a mixture of petroleum ether/ethyl acetate (1:1) as eluent. The crude product was purified by flash column chromatography (PE : EE = 2:1) to yield the pure product.

General Procedure for the Catalytic Diels−Alder Reactions of 3-Hydroxypyridones (GP6)
To an oven-dried Schlenk vial containing activated catalyst C1 (0.005 mmol, 5.0 mol%), and maleimide 2B (0.105 mmol, 1.05 equiv.) 0.1 mL of dried THF was added at room temperature. The solution was allowed to stir for 10 min under nitrogen atmosphere. The corresponding diene 4 (0.1 mmol, 1.0 equiv.) was then added using a syringe pump over the period of 12 h as a stock solution (in 0.1 mL THF) followed by additional solvent (0.05 mL) to avoid a loss of the material on the glass wall. After the addition period was completed the reaction mixture was stirred for additional six hours. Afterwards the reaction mixture was filtered through a short pad of silica to remove the catalyst using a mixture of petroleum ether/ethyl acetate 1:1 as eluent. The crude product was purified by flash column chromatography (PE : EE = 2:1) to yield the pure product.

General Procedure for the Cycloaddition Reaction with Enone (8) (GP7)
The activated catalyst C1a-(S,S) was added as a stock solution (0.05 mL) in anhydrous THF to a catalysis tube containing N-benzylmaleimide 2B (18.7 mg, 0.10 mmol, 1.0 equiv.) or nitroolefin 10 (14.9 mg, 0.1 mmol, 1.0 equiv.) and enone 8 (18.4 mg, 0.12 mmol, 1.2 equiv.) under nitrogen atmosphere. The reaction mixture was stirred for 20 h. Afterwards the reaction mixture was diluted with a solvent mixture of petroleum ether/ethyl acetate (1/1, 2 mL), filtered through a small pad of silica to remove the catalyst from the reaction mixture and the crude product was eluted with additional petroleum ether/ethyl acetate (1/1, 10 mL). After removal of solvent under reduced pressure, the crude product was purified via column chromatography with petroleum ether/ethyl acetate as eluent (4/1) to yield the pure product.

General Procedure for the Determination of ee values with (R)-BINOL (GP8)
To an NMR tube filled with 0.4 mL of saturated CDCl3 solution of (R)-BINOL was added the corresponding cycloaddition product (1.0 mg, dissolved in 0.1 mL of CDCl3). The 1 H NMR spectra were recorded at 500 or 700 MHz. The enantiomeric excesses were determined by integration of characteristic signals of the () and ()-enantiomers. 7

4-Chloro-3-hydroxy-2-pyrone (1c)
To a solution of 3-hydroxy-2-pyrone 1a (0.40 g, 3.57 mmol) in DMF (10 mL) was added NCS (0.71 g, 5.36 mmol, 1.50 equiv.) portionwise over the period of 15 min. The reaction mixture was stirred for 16 h at room temperature and diluted with 10 mL of H2O and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. The residue was purified by column chromatography (using DCM as eluent) to afford pyrone 1c (261.5 mg, 1.78 mmol, 50%) as a yellow crystalline solid. The NMR spectra is in agreement to the one reported in the literature. 8

C55H44ClCuF5N4O5S
[b] Endo/exo ratios determined by 1 H NMR using the crude product.
[c] The enantiomeric excess of the endo-isomer was determined by 1 H NMR using saturated CDCl3 solution of (R)-(+)-binaphthol. 7 A minus sign indicates that the antipode of the enantiomer depicted was generated in excess.

H NMR Titration Experiments
Catalyst C1b (0.51 mg, 0.00052 mmol, 1.0 equiv.) was dissolved in THF-d8 (0.2 mL) and filled in the NMR-tube. The hydroxypyrone 1a (0, 1.0, 2.0 and 10.0 equiv.) was added directly to the tube and after shaking for one minute at 20 ºC the 1 H NMR spectra was recorded ( Figure  S1). Figure S1. 1 H-NMR titration experiments. The blue curve shows the spectrum of C1b in THF-d8 at 20 °C. For the red curve, 1.0 equiv. of 1a were added. For the green and purple curve, 2.0, and 10.0 equiv. of 1a were added, respectively. The yellow curve shows the spectra of pre-catalyst of C1b.

Kinetic Experiments Probing Catalyst Robustness and Product Influence
Blackmond's reaction progress kinetic analysis (RPKA) was performed using 1 H-NMR spectroscopy for monitoring the complete course of the catalytic reaction. By the so-called "same excess" protocol, the catalyst robustness and a possible product inhibition under the reaction conditions was assessed. 14 The model reaction of 1a and 2B was examined at 20 °C in THF-d8 using 3.0 mol% of C1b. The experiments were performed starting from three different points. The different initial concentrations for the reactants 1a and 2B and the catalyst for the kinetic experiments are summarized in Table S1. Table S1: Different initial concentrations of hydroxypyrone 1a, maleimide 2B and product 3aB in "sameexcess"-experiments and "product addition" for investigation of possible product inhibition and catalyst stability. The reactions were performed by adding a solution of the catalyst C1b, 1,2-diphenylethane (internal standard, 0.02 mmol), hydroxypyrone 1a, maleimide 2B in tetrahydrofuran-d8 (0.5 mL) to an NMR sample tube. The reaction mixture was analysed by 1 H NMR spectroscopy at −20 °C to monitor the conversion of 2B in dependence of time. First, the progress of a reference reaction was monitored with the indicated initial substrate concentrations ( Table 1, Experiment B1). The second experiment was done with the initial substrate concentrations which were equal to those of the reference reaction when 50% conversion was reached (Experiment B2). The third measurement was done with the same initial conditions like in the second reaction, but with the addition of product 3aB (Experiment B3). These experiments could provide information of either catalyst deactivation or product inhibition. The difference between the reactions B2 and B3 compared to B1 is that when the latter reaction reached 50% of conversion, the catalyst was not fresh anymore because it has undergone a number of turnovers already, whereas in B2 and B3 the catalyst is fresh at the starting point. Figure  S3 presents a comparison of kinetic profiles of these three reactions. Time adjustment was done by simple shifting the data of reactions B2 and B3 to the point where the concentrations are the same as for reference reaction B1. Since the reaction progress from this point onward is almost identical as the time shift of the B2 curve shows, it appears that no significant catalyst decomposition occurs during the reaction. Additionally, an overlay of the reaction profiles B3 with B1 was found demonstrating that the product 3aB does not inhibit the catalyst. Figure S3. Probing catalyst stability and product influence on the catalytic reaction.

Kinetic Experiments-Determination of Reaction Orders Using Variable Time Normalization Graphical Analysis (VTNA)
The orders of all reaction components were determined using the variable time normalization graphical analysis method (VTNA) described by Burés. 15,16 Four reactions E1-E4 with different initial concentrations of each component, catalyst C1b, hydroxypyrone 1a and maleimide 2B, were performed and monitored via 1 H NMR. The different initial concentrations for the components used in the kinetic experiments are summarized in the Table S3. The corresponding experiments E1-E4 were performed by adding a solution of the catalyst C1b, 1,2-diphenylethane (internal standard, 0.02 mmol), hydroxypyrone 1a, maleimide 2B in THF-d8 (0.5 mL) to an NMR sample tube at 20 °C as shown in Table S3. The reaction mixture was analysed by 1 H NMR spectroscopy at 20 °C to monitor the conversion of 1a and 2B and the yield of 3aB in dependence of time ( Figure S4). Figure S4. Conversion of 1a and 2B and the yield of 3aB in dependence of time.

S64
The reaction progress profiles of all four experiments E1-E4 are plotted in Figure S5 and were investigated using VTNA. The order in each component can be determined by systematically changing each exponent of the normalized time axis, with the intention to obtain a linear overlay of all reaction profiles in the plot. The best fit for the normalization of the time scale axis was achieved for partial orders of 0.07 for 3-hydroxy-2-pyrone 1a, When the normalization is applied to all the components, the result is a plot with a straight line with a slope equal to kobs. The slope, kobs of the reaction and was found to be kobs= 1.8·10 4 L 2.02 mol -2.02 s -1 . The plot of this time normalized reaction profiles is shown in Figure S6. All processed data are given in α = 1.95, β = 0.07, γ = 1.00.

Investigation of a Possible Non-Linear-Effect
Examination of linear or non-linear effects was done under the conditions described in GP4 using 5.0 mol% of catalyst C1b with six different enantiomeric excesses (Table S4), which were prepared by mixing the corresponding amounts of pure enantiomers of the catalysts C1b. The plot of ee(3aB) as a function of ee(C1b) showed a positive non-linear effect which might be an indication of the relevance of catalyst dimers ( Figure S7). Table S4. Enantiomeric excess of the catalyst C1b and the product 3aB.

Crystallographic Data
Catalyst C6 CCDC 1995950 contains the supplementary crystallographic data for compound C6. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.