The arylation of the immunosuppressive macrolides ascomycin and L-683,742 using pentavalent bismuth reagents is described. The in vitro activities of the aryl ether analogs are reported. The macrolide FK-506 (1) is a fungal metabolite first isolated and characterized in 1987.1 It has been shown to be a powerful immunosuppressant in vitro and in vivo, 2 being 50 to 100 times more potent than cyclosporin A - the therapy of choice for prevention of graft rejection following organ transplantation. Although structurally dissimilar, FK-506 and cyclosporin have been shown to elicit their immunosuppressive effects through a common mechanism. 3 Specifically, both bind with their cognate receptors (FKBP and cyclophilin, respectively) and those drugreceptor complexes inhibit the Ca2÷-dependent protein phosphatase calcineurin. The inhibition of calcineurin interferes with early gene transcription following T-cell activation and results in suppression of lymphocyte proliferation. More importantly, FK-506, like cyclosporin, has been shown to be effective in the prevention of organ graft rejection in the clinic. 4 Unfortunately, there are side effects associated with the clinical use of FK-506:most notably nephrotoxicity, neurotoxicity and gastric toxicity.4, 5 Research in these laboratories has focused on the derivatization of ascomycin (2) (L-683,590, FK-520) and its 31-desmethyl congener L-683,742 (3), in an effort to identify a less toxic immunosuppressant. This communication is a preliminary account of the synthesis, via novel organobismuth chemistry, and in vitro immunosuppressive activity of a new class of 31- and 32-O-aryl ethers.