The specific goal of this proposal is the synthesis of a series of increasingly challenging lignan natural products culminating in the efficient preparation of two antitumor prototypes: steganacin and podophyllotoxin. Development of such sequences should prove especially useful for exploration of structure-activity relationships among analogs to these promising agents. Dianion intermediates exhibit extraordinary reactivity towards electrophiles. Preliminary studies have demonstrated that carboxylic acid dianions can be either dimerized or iodinated simply by varying the stoichiometry of added I2. Building upon this simple transformation, numerous symmetrically- and unsymmetrically-submitted succinic acid derivatives (including anhydrides, lactones, and amides) become readily available. Key synthetic steps to be explored in the generation of both steganacin and podophyllotoxin include reaction of amide dianions with 2-iodocarboxylates, selective reduction of the resulting acid-amide products, and intramolecular photochemically-driven iodination using N-iodoamide precursors.
| Belletire, J L; Fry, D F; Fremont, S L (1992) The role of dianion coupling in the synthesis of dibenzylbutane lignans. J Nat Prod 55:184-93 |
| Belletire, J L; Ho, D M; Fry, D F (1990) Stereoselectivity questions in the synthesis of wikstromol. J Nat Prod 53:1587-92 |
