Here we report the use of aryl azides in the traceless Staudinger ligation for the installation of a Katzenellenbogen spacer derived from p-azidobenzyl alcohol, and its application in prodrug synthesis.  Compounds incorporating the p-amidobenzyloxy carbonyl moiety have previously been assembled by step-wise acylation of the analine nitrogen and subsequent coupling via the mixed p-nitrophenyl carbonate to yield the prodrug.  However, in cases where a final deprotection reaction is then required to generate the enzymatically active substrate, the sensitivity of the substrate to the deprotection conditions may preclude efficient synthesis.  We demonstrate that p-azidobenzyloxy carbamates allow for chemoselective amidative-installation of the Katzenellenbogen spacer via a Staudinger ligation, thereby obviating the need for a final deprotection reaction.  Given the prominent use of the self-immolative spacer in prodrug design, we feel this transformation provides a valuable alternative route to delicate therapeutics such as prodrugs of the anthracycline doxazolidine.

Aryl azides in the traceless Staudinger ligation: Applications to prodrug synthesis

243rd National Meeting (2012)

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