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Ustiloxin D and phomopsin A are potent antimitotic agents that bind to tubulin and interfere with cellular microtubule function. A synthetic strategy has been developed to allow access to both of the natural products as well as a variety of variants of the ustiloxin and phomopsin family members in order to provide sufficient quantities for biological studies. Herein we report the enantioselective total synthesis of ustiloxin D using a longest linear sequence of 20 steps. Four of the five stereocenters were set using catalytic asymmetric methodologies. In particular, Evans's new Al-catalyzed asymmetric aldol reaction facilitated access to both syn and anti products corresponding to the different benzylic stereochemistries found in ustiloxins and phomopsins. In addition, due to its high functional group tolerance, Trost's Pd-mediated etherification was used to construct the chiral tertiary alkyl-aryl ether. Taken together, these synthetic strategies allow us to use densely functionalized intermediates to realize an efficient synthesis of ustiloxin D.

The immunosuppressants FK506 and rapamycin bind to the same immunophilin, FK506 binding protein (FKBP), and inhibit distinct signal transduction pathways in T lymphocytes. A nonnatural immunophilin ligand, 506BD, which contains only the common structural elements of FK506 and rapamycin, was synthesized and found to be a high-affinity ligand of FKBP and a potent inhibitor of FKBP rotamase activity. Whereas 506BD does not interfere with T cell activation, it does block the immunosuppressive effects of both FK506 and rapamycin. Thus, the common immunophilin binding element of these immunosuppressants, which is responsible for rotamase inhibition, is fused to different effector elements, resulting in the inhibition of different signaling pathways. Inhibition of rotamase activity is an insufficient requirement for mediating these effects.