Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivatives have been primarily synthesized by manipulating the natural product. As a consequence of major innovations in the subscience of synthetic methodology, the capacity of synthesis to deal with molecules of considerable complexity has increased dramatically. In this paper, we show by example some total syntheses which draw from strategy-enabling advances in methodology. Moreover, we show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself.

Cancer cells may be distinguished from normal cells by cell surface displays of aberrant levels and types of carbohydrate domains. Accordingly, these tumor associated carbohydrate antigens (TACAs) represent promising target structures for the design of anticancer vaccines. Over the past 20 years, our laboratory has sought to use the tools of chemical synthesis to develop TACA-based anticancer vaccine candidates. We provide herein a personal accounting of our laboratory’s progress toward the long-standing goal of developing clinically viable fully synthetic carbohydrate-based anticancer vaccines.

Several novel, fully synthetic, carbohydrate-based antitumor vaccines have been assembled. Each construct consists of multiple cancer-related antigens displayed on a single polypeptide backbone. Recent advances in synthetic methodology have allowed for the incorporation of a complex oligosaccharide terminating in a sialic acid residue (i.e., GM2) as one of the carbohydrate antigens. Details of the vaccine synthesis as well as the results of preliminary immunological investigations are described herein.