The overall objective of this research program is the development of efficient procedures for the construction of architecturally novel antitumor agents. Specific aims for the 14-18 years will be to complete the total synthesis of breynogenin and stubomycin. The structure of breynogenin closely resembles that of the aglycone of phyllanthoside, and as such is an ideal synthetic target in that it will provide additional analogs of the phyllanthoside-phyllanthostatin class of antitumor agents. (Note that during the 10-13 year of this program, we completed the first, and to this date the only, total syntheses of three of the four members of the phyllanthoside-phyllanthostatin family.) Stubomycin, on the other hand, possesses a novel macrocyclic lactam skeleton; it has been reported to display potent anitumor activity against the sarcoma 180, IMC-carcinoma and meth-A tumor cell lines. As new tragets in the antitumor area, we have chosen calyculin A and the trienomycins A, B and C. Our interest in calyculin A stems from the (6.5) spiroketal system, common to the phyllanthocin-breynogenin aglycones. Calyculin A displays both potent inhibitory activity against the development of starfish embryos (0.01 mu g /mL) and strong cytotoxic activity against the L1210 cell line (IC50 1.75 x 10-3 mu g/mL). The trienomycins, all of which display strong cytotoxic activity against HeLa S3 cells in vitro, represent a natural extension of our stubomycin work. In addition to the above quite specific synthetic goals, a more general underlying and long range aim of this research program is the development of a better understanding of the molecular architecture responsible for the antitumor properties of these and related system. Thus, as we develop our method of procedure for each of the above targets, we will also introduce various analog systems which will be amenable to construction and subsequent testing, such that in the end we will be able to dissect out the critical structural feature or features responsible for the observed antitumor properties. Once such features are identified, the design of new and possibly more effective antitumor drugs should be feasible.