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SYNTHESIS

CHIRAL LIGANDS: ENANTIOPURE STEREOISOMERS OF 1-PHENYL-2-(3,5-DISUBSTITUTED ISOXAZOLIN-5-YL) ETHANOLS AND ABSOLUTE CONFIGURATIONAL ASSIGNMENT BY 1H-NMR. SYNTHESIS. chiral centers. SEPARATION OF STEREOISOMERS DIASTEREOISOMERS:

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SYNTHESIS

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  1. CHIRAL LIGANDS: ENANTIOPURE STEREOISOMERS OF 1-PHENYL-2-(3,5-DISUBSTITUTED ISOXAZOLIN-5-YL) ETHANOLS AND ABSOLUTE CONFIGURATIONAL ASSIGNMENT BY 1H-NMR SYNTHESIS • chiral centers SEPARATION OF STEREOISOMERS DIASTEREOISOMERS: Separation procedures: column chromatography or TLC on silica gel; eluent: diethylether/petroleum ether (gradient) mixture (±) M (±)m (±)M (±)m (±)M (±)m d.p.(%) 100 100 100 100 97 84 ENANTIOMERS Separation procedure: preparative chiral HPLC, UVdetection Cornelia Uncutaa, Emeric Barthaa, Anca Tanasea, Catalin I. Tanasea, Anca Hirtopeanua, Daniela Vulugaa, Nicolas Vanthuyneb and Christian Rousselb a Center of Organic Chemistry C D Nenitzescu, Bucharest, Romania b UMR Chirotechnologies: Catalyse et Biocatalyse, Universite Paul Cezanne Aix-Marseille III, Marseille, France (+)M (-)M (+)m (-)m (+)M (-)M (+)m (-)m (+)M (-)M (+)m (-)m e.p.(%)100 100 100 100 99.8 99.8 98.0 99.8 99.8 99.5 99.3 99.8 r.t. (min) 12.7 18.1 21.85 26.3 12.4 10.8 13.4 11.1 5.9 8.5 8.3 10.1 Conditions A A A A B B B B C C C C r.p. +51.6 -53.8 +35.1 -33.8 +22 -23 +100 -102 +25 -25 +108 -110 (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, (CHCl3, c=0.98) c=1) c=.099) c=1) c=0.68) c=0.28) c=0.41) c=0.33) c=0.15) c=0.18) c=0.14) c=0.36) Absolute config. (1R, 3S) (1S, 3R) (1S, 3S) (1R, 3R) (1S, 3R) (1R, 3S) (1R, 3R) (1S, 3S) (1S, 3R) (1R, 3S) (1R, 3R) (1S, 3S) LEGEND: d.p. = diastereomeric purity (by 1H-NMR) Column Elution e.p. = enantiomeric purity (by analytical chiral HPLC) A: Chiralpak AD r.t. = retention time B: Chiralcel OJ (hexane/2-PrOH, 80/20, 1mL/min, 25°C) r.p. = rotatory power [α]D25 C: Chiralpak AS ABSOLUTE CONFIGURATION ASSIGNMENT Stereisomers of compound 1 Stereoisomers of compounds 2 and 3 Unambigous assignment based on X-ray analysis (cf .C. Uncuta, G. B. Caraman, C. I. Tanase, E. Bartha, V. Ch. Kravtsov, Y. A. Simonov, J. Lipkowski , N. Vanthuyne and C. Roussel,” Synthesis and Absolute Configuration Assignment of 5-Amino-1,3,5-triphenyl-pentane-1, 3-diol stereoisomers”, Chirality, 2005, 17, 1-10) Assignment at C-1: based on derivatization with α-methoxyphenylacetic acid (MPA), racemic and (+) S, followed by 1H-NMR analysis. Empirical rule: 1-Ph signals upfield shifted in the ester with “l” (like) compared to “u” (unlike) descriptor for the stereogenic centers at C-1 and in the MPA moiety. Assignment at C-3: based on diastereoselectivity in the reduction with NaBH4 Empirical rule: The prevailing alcohol has “u” (unlike)descriptor for the stereogenic centers C-1 and C-3. Financial suport: CERES PROGRAMME, Romanian Ministry of Education and Research

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