Synthesis, conformational analysis, and biological evaluation of heteroaromatic taxanes

Gunda I. Georg, Geraldine C.B. Harriman, Michael Hepperle, Jamie S. Clowers, David G. Vander Velde, Richard H. Himes

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Abstract

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 (56) displayed cytotoxicity against B16 melanoma cells similar to paclitaxel.

Original languageEnglish (US)
Pages (from-to)2664-2676
Number of pages13
JournalJournal of Organic Chemistry
Volume61
Issue number8
DOIs
StatePublished - Apr 19 1996

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    Georg, G. I., Harriman, G. C. B., Hepperle, M., Clowers, J. S., Vander Velde, D. G., & Himes, R. H. (1996). Synthesis, conformational analysis, and biological evaluation of heteroaromatic taxanes. Journal of Organic Chemistry, 61(8), 2664-2676. https://doi.org/10.1021/jo951961c