Figure 6. I: Fully optimized structure (B3LYP/LANL2DZ&6-31G* level) of (S)-A. The hydrogen atoms have been omitted for clarity. The carbon atoms of the azomethine ylide moiety have been highlighted with asterisks. Bond distances and dihedrals are given in Ǻ and deg., respectively. The molecular surface (Probe radius: 1.4 Ǻ) is also included. II: View over the Si face of (S)-A along the axis determined by the Ag and P2 atoms.
Scheme 6. Model reaction used in the computational studies. The hydrogen atoms highlighted in blue, green and red correspond to a phenyl, a methoxy and a methyl group in the reaction depicted in Scheme 1.
In previous work on chiral Ag-based catalysts we have observed a clear preference for the endo-cycloadducts because of the electrostatic interaction between the nitrogen atom of maleimide and the silver atom.e Therefore, we considered the formation of the diastereomeric endo-cycloadducts C and D via transition structures TS1 and TS2, respectively. The main geometric features and the relative energies of these transition structures are reported in Figure 7. It is found that the Gibbs activation energies are larger than the total activation energies because of the unfavourable entropic balance on going from the reactants to the saddle points, thus resulting in larger reaction times. As expected both TS1 and TS2 are quite asynchronous, TS1 being ca. 2 kcal/mol more stable than TS2. In this latter transition structure there is an appreciable steric clash between one of the phenyl groups of the phosphine moiety of (S)-16 and the dipolarophile B. This results in a larger distortion of the (S)-16 moiety in TS2 with respect to (S)-A. As a result, exclusive formation of endo-(S,S,S,R)-C is predicted, in full agreement with the experimentally observed formation of cycloadducts endo described across the text. The same trend is found for the cycloadducts endo-(S,S,S,R)-C and endo-(S,R,R,S)-D, the latter being ca. 1.3 kcal/mol less stable than the former. Moreover, the slightly positive values of the Gibbs reaction energies associated with the formation of these catalyst-bound cycloadducts are compatible with the catalyst turnover since there is no inhibition of the catalyst by the product of the cycloaddition step. These calculations support that NMM is the best dipolarophile due to the coordination of the nitrogen atom to the metal centre. On the other hand, the presence of a bulkier substituent in this nitrogen atom blocks the endo-approach reducing the enantioselection, such as occurred with NPM.In summary, our calculations are in full agreement with the experimental findings and provide a rationale for the excellent asymmetric induction and catalytic efficiency of species similar to (S)-16. Figure 7. Fully optimized structure (B3LYP/LANL2DZ&6-31G* level) of TS1 and TS2, leading to endo-(S,S,R)-C and endo-(S,R,R,S)-D, respectively. The hydrogen atoms have been omitted for clarity. Bond distances and dihedrals are given in Ǻ and deg., respectively. Numbers in parentheses and in square brackets are the relative total and Gibbs free energies respectively, computed at the B3LYP/LANL2DZ&6-31G*+ZPVE level.
Evaluating all the data described in the main text, the employment of the complex generated by the 1:1 mixture of chiral Binap and AgClO4 is very stable and can be manipulate without any special care. It was efficient in the catalyzed 1,3-DC using maleimides and aryliminoesters, however other dipolarophiles did not work satisfactorily. The whole catalytic mixture can be recovered from the reaction mixture and reused without any loss of efficiency. The TS responsible of the enantiodiscrimination is, as expected, quite asynchronous, an appreciable steric clash between one of the phenyl groups of the phosphine moiety of (S)-16 and the dipolarophile being the crucial interaction.
4. Experimental section
All reactions were carried out in the absence of light. Anhydrous solvents were freshly distilled under an argon atmosphere. Aldehydes were also distilled prior to use for the elaboration of the iminoesters. Melting points were determined with a Reichert Thermovar hot plate apparatus and are uncorrected. Only the structurally most important peaks of the IR spectra (recorded on a Nicolet 510 P-FT) are listed. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were obtained on a Bruker AC-300 using CDCl3 as solvent and TMS as internal standard, unless otherwise stated. Optical rotations were measured on a Perkin Elmer 341 polarimeter. HPLC analyses were performed on a JASCO 2000-series equipped with a chiral column (detailed for each compound in the main text), using mixtures of n-hexane/isopropyl alcohol as mobile phase, at 25 ºC. Low-resolution electron impact (EI) mass spectra were obtained at 70eV on a Shimadzu QP-5000 and high-resolution mass spectra were obtained on a Finnigan VG Platform. HRMS (EI) were recorded on a Finnigan MAT 95S. Microanalyses were performed on a Perkin Elmer 2400 and a Carlo Erba EA1108. Analytical TLC was performed on Schleicher & Schuell F1400/LS silica gel plates and the spots were visualized under UV light (=254 nm). For flash chromatography we employed Merck silica gel 60 (0.040-0.063 mm).
4.2. 1,3-Dipolara cycloaddition of iminoesters 6 and dipolarophiles. General procedure.
A solution of the imino ester (1 mmol) and dipolarophile (1 mmol) in toluene (5 mL) was added to a suspension containing (R)- or (S)-Binap (0.05 mmol, 31 mg) and AgClO4 (0.05 mmol, 10 mg) in toluene (5 mL). To the resulting suspension triethylamine (0.05 mmol, 7 L) was added and the mixture stirred at room temperature and in the absence of the light for 16-48 h (see main text). The precipitate was filtered and the complex was recovered. The organic filtrate was directly evaporated and the residue was purified by recrystallization or by flash chromatography yielding pure endo-cycloadducts.
The solid was washed with warm toluene twice and then dissolved in DCM in order to transfer the catalytic complex into the flask. After evaporation of DCM the resulting solid was ready to catalyze a new batch.
4.2.1. Methyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate12aa.Error: Reference source not founda,Error: Reference source not found 4.2.2. Ethyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate12ab.
Acknowledgments. This work This work has been supported by the DGES of the Spanish Ministerio de Educación y Ciencia (MEC) (Consolider INGENIO 2010 CSD2007-00006, CTQ2007-62771/BQU, and CTQ2004-00808/BQU), Generalitat Valenciana (CTIOIB/2002/320, GRUPOS03/134 and GV05/144), and by the University of Alicante. M. G. Retamosa thanks University of Alicante for a predoctoral fellowship. The authors also thank the SGI/IZO-SGIker UPV/EHU for generous allocation of computational resources an Prof. V. Ratovelomanana-Vidal for her generous gift of (S)-SynPhos (S)-11.
Corresponding authors. Fax: +34-96-5903549;
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For correspondence on computational studies.
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