Synthesis, Conformational Analysis, and Biological Evaluation of Heteroaromatic Taxanes

• Published in: Journal of organic chemistry Vol. 61; no. 8; pp. 2664 - 2676
• Main Authors: Georg, Gunda I, Harriman, Geraldine C. B, Hepperle, Michael, Clowers, Jamie S, Vander Velde, David G, Himes, Richard H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.04.1996; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; ROUTE; ASYMMETRIC-SYNTHESIS; STAUDINGER REACTION; ACTIVE TAXOL ANALOGS; ENOLATE IMINE CONDENSATION; TAXOTERE; N-TRIMETHYLSILYL IMINES; C-13 SIDE-CHAIN; EFFICIENT; BETA-LACTAMS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo951961c

The asymmetric syntheses of heteroaromatic 3-[(tert-butyldimethylsilyl)oxy]-2-azetidinones 12−16 via chiral ester enolate−imine cyclocondensation chemistry are described. The azetidinones contain heteroaromatic moieties which, in certain cases, contribute to a decrease in enantioselectivity due to possible alternate coordinations in the transition states. The (3R,4S)-3-[(tert-butyldimethylsilyl)oxy]-4-heteroaryl-2-azetidinones were subsequently converted to the heteroaromatic taxanes 31−36 and 43−45. Conformational analyses of the 3‘-(2-pyridyl) analogue 31 and 3‘-(2-furyl) analogue 43 indicate they have solution conformational preferences virtually identical to paclitaxel and docetaxel. Heteroaromatic N-acyl paclitaxel analogues 47−51 were prepared from N-debenzoylpaclitaxel via Schotten−Baumann acylation. The majority of the 14 analogues displayed good to excellent activity in a microtubule assembly assay in comparison to paclitaxel. The analogues were also tested for cytotoxicity against B16 melanoma cells. 3‘-Dephenyl-3‘-(2-pyridyl)paclitaxel (31), 3‘-dephenyl-3‘-(2-furyl)paclitaxel (34), N-BOC-3‘-dephenyl-3‘-(2-furyl)paclitaxel (43), 3‘-dephenyl-3‘-(2-furyl)-N-(hexanoyl)paclitaxel (44), and N-debenzoyl-N-(3-furoyl)paclitaxel (51) were found to be more cytotoxic than paclitaxel against this cell line. 3‘-Dephenyl-3‘-(4-pyridyl)paclitaxel (33) and N-debenzoyl-N-(2-furoyl)paclitaxel (50) displayed cytotoxicity against B16 melanoma cells similar to paclitaxel.