Schotten-Baumann acylation of N-debenzoyltaxol; an efficient route to N-acyl taxol analogues and their biological evaluation

Bioorganic & Medicinal Chemistry Letters
1994.0

Abstract

An efficient route to N-acyl taxol analogues is described utilizing N-debenzoyltaxol (II). Acylation of II with various acid chlorides under Schotten-Baumann conditions led to a facile one step synthesis of several N-acyl taxol analogues from a common intermediate. Taxol® (1), a complex naturally occurring diterpene isolated from the stembark of the yew tree Taxus brevifolia Nutt., has seen considerable scientific attention since its discovery in 1971. Taxol's unique microtubule assembling activity allows the molecule to exert its chemotherapeutic effects by initiating rapid polymerization of cellular tubulin, ultimately leading to the disruption of cellular mitosis. Taxol has proven to be effective in the treatment of several cancers, especially the treatment of cisplatin refractory ovarian cancers. The development of taxol analogues may prove useful in the production of more active/less toxic antitumor agents as well as lead to information on the taxol pharmacophore. In order to probe the steric and electronic microtubule binding limits of the N-acyl moiety of the taxol side chain, we have developed the following synthetic pathway. Methodology developed in our laboratory has focused on the enantioselective synthesis of (3R,4S)-3-hydroxy-4-phenyl-2-azetidinones as precursors to the N-benzoylphenylisoserine side chain of taxol. The 2-azetidinones are derived from the chiral ester-enolate imine cyclocondensation which affords the enantioenriched β-lactam precursors in 97% ee. We now report on the synthesis of N-debenzoyltaxol (II), a common intermediate utilized to synthesize a variety of N-acyl taxol analogues in one step. Advantages of this methodology also include the application of this synthetic strategy to our development of taxol photoaffinity labels, especially toward the extremely facile synthesis of radioactive taxol photolabels.

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