During our research and development of the anthracycline anti-tumor drug candidate, doxazolidine, need emerged for a mild, chemoselective aryl amidation reaction to efficiently synthesize a series of related tripartite prodrugs. Incorporation of the Katzenellenbogen spacer, a self-immolative p-amidobenzyloxycarbonyl moiety, is common in tripartite prodrug design as its use facilitates prodrug "activation" by providing spatial separation between the drug- and enzymatically-labile, "targeting"-portions of the molecule. Proteolysis of the anilide bond, followed by rapid 1,6-elimination of the iminoquinone methide and spontaneous decarboxylation of the liberated carbamic acid, allows for targeted, localized release of the active therapeutic in the diseased tissue conferred via specific dysregulated enzyme expression/secretion (Scheme 1). Previous syntheses required these constructs to be assembled by step-wise acylation of the aniline, followed by derivatization of the benzyl alcohol and subsequent coupling to the drug. However, a more convergent synthesis of such structurally related prodrugs, which differ only in the targeting-groups used, was envisioned to proceed through a common pre-assembled, spacer-drug intermediate. Installation of the respective targeting groups could then be postponed until the final step of the synthesis, assuming a suitable transformation for anilide-bond formation could be found. We report use of the traceless Staudinger ligation of an advanced aryl azide intermediate 1 with various phosphinophenyl esters 2a-b in the synthesis of a series of peptidyl- and carbamate peptidyl-prodrugs 3a-b (Scheme 2). Synthetic advantages and limitations to the method are presented, along with structural modifications to the target compounds that may be adopted to overcome these limitations. In vitro data used to screen the prodrug library and select a lead compound for more extensive biological testing is also presented.

Synthesis of tripartite prodrugs via N → C amidative-installation of the Katzenellenbogen-spacer: Application of the traceless Staudinger ligation

249th National Meeting (2015)

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