Taking into account the importance in medicinal- and agro-chemistry of optically active isothiazole derivatives, we became interested in the asymmetric preparation of 3-aminosubstituted isothiazole 1-oxides [1]. A solution of 1 in CH2Cl2 with an equimolecular amount of (-)-2b was irradiated at 400W, 80°C. Sulfoxide 3 was produced in 80% overall yield and 50% ee together with little amount of sulfone (8%) after 1h. (-)-2a gave much slower reactions. In order to determine the absolute configuration (AC) of the new 3-aminosubstituted isothiazole Soxides, we simulated [2,3] the ECD spectrum of (+)-3-aminomethyl isothiazole S-oxide, (+)-3b in the range 380-200 nm, both in the gas phase and ethanol at the TDDFT/B3LYP/aug-cc-pVDZ level of calculation. To this end we used (S)-3b which exists almost as a single conformer at the DFT/B3LYP/6-31G* level of calculation. In Figure are reported the experimental (black line) ECD spectrum of (+)-3b and predicted ECD spectra of (S)-3b, taking into account the first 30 excited states both in the gas phase and ethanol. In the gas phase (green line), even if the positions and intensities of predicted ECD bands do not perfectly match the experimental data, the experimental spectrum shows a sequence of negative, positive, negative Cotton effects which is reproduced in the theoretical spectrum, indicating the (+)/(S) correlation. Including the ethanol effect (red line), significantly improves the agreement between calculated and experimental data, strongly supporting the (+)/(S) configurational correlation. We can conclude that (+)-3b possesses (S) AC and therefore the chiral auxiliaries (-)- 2b induces the preferential formation of the (S) antipode in the above asymmetric oxidation reaction. 1. Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pocar, D. “Chemistry of biologically active isothiazoles”, in Topics in Heterocyclic Chemistry, 9 (Bioactive Heterocycles III), 2007, 179-264. Publisher: Springer GmbH, 2. Frisch, M.J. et al., Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, USA, 2003, http://www.gaussian.com/. 3. see, for instance: Tartaglia, S.; Padula, D.; Scafato, P.; Chiummiento, L.; Rosini, C. J

Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides / F. Clerici, A. Casoni, G. Celentano, A. Contini, S. Pellegrino, G. Mazzeo, C. Rosini. ((Intervento presentato al 12. convegno International Conference on Circular Dichroism ISBC, Interdisciplinary Symposium on Biological Chirality tenutosi a Brescia nel 2009.

Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides

F. Clerici
Primo
;
A. Casoni
Secondo
;
G. Celentano;A. Contini;S. Pellegrino;
2009

Abstract

Taking into account the importance in medicinal- and agro-chemistry of optically active isothiazole derivatives, we became interested in the asymmetric preparation of 3-aminosubstituted isothiazole 1-oxides [1]. A solution of 1 in CH2Cl2 with an equimolecular amount of (-)-2b was irradiated at 400W, 80°C. Sulfoxide 3 was produced in 80% overall yield and 50% ee together with little amount of sulfone (8%) after 1h. (-)-2a gave much slower reactions. In order to determine the absolute configuration (AC) of the new 3-aminosubstituted isothiazole Soxides, we simulated [2,3] the ECD spectrum of (+)-3-aminomethyl isothiazole S-oxide, (+)-3b in the range 380-200 nm, both in the gas phase and ethanol at the TDDFT/B3LYP/aug-cc-pVDZ level of calculation. To this end we used (S)-3b which exists almost as a single conformer at the DFT/B3LYP/6-31G* level of calculation. In Figure are reported the experimental (black line) ECD spectrum of (+)-3b and predicted ECD spectra of (S)-3b, taking into account the first 30 excited states both in the gas phase and ethanol. In the gas phase (green line), even if the positions and intensities of predicted ECD bands do not perfectly match the experimental data, the experimental spectrum shows a sequence of negative, positive, negative Cotton effects which is reproduced in the theoretical spectrum, indicating the (+)/(S) correlation. Including the ethanol effect (red line), significantly improves the agreement between calculated and experimental data, strongly supporting the (+)/(S) configurational correlation. We can conclude that (+)-3b possesses (S) AC and therefore the chiral auxiliaries (-)- 2b induces the preferential formation of the (S) antipode in the above asymmetric oxidation reaction. 1. Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pocar, D. “Chemistry of biologically active isothiazoles”, in Topics in Heterocyclic Chemistry, 9 (Bioactive Heterocycles III), 2007, 179-264. Publisher: Springer GmbH, 2. Frisch, M.J. et al., Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, USA, 2003, http://www.gaussian.com/. 3. see, for instance: Tartaglia, S.; Padula, D.; Scafato, P.; Chiummiento, L.; Rosini, C. J
Settore CHIM/06 - Chimica Organica
Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides / F. Clerici, A. Casoni, G. Celentano, A. Contini, S. Pellegrino, G. Mazzeo, C. Rosini. ((Intervento presentato al 12. convegno International Conference on Circular Dichroism ISBC, Interdisciplinary Symposium on Biological Chirality tenutosi a Brescia nel 2009.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/146380
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