SYNTHESIS OF MACROLIDES, STEROIDS, CYCLOPENTANOIDS ETC.

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The aim of this proposal is to develop facile synthetic entries into various classes of biologically active molecules. We are examining the question of whether tailor-made transition metal complexes may serve as templates to control selectivity in a way reminiscent of enzymes. The first section deals with the development and understanding of metal catalyzed cyclizations at high substrate concentration and with high control stereochemistry to form medium and large ring carbo- and heterocycles whose biological functions include antibiotic and antifungal activity. Some example are: 1) a 9-membered carbocyclic ring such as pachyaldehyde, a representative of a family of antimicrobial marine natural products, 2) a 10- membered macrolide such as the antibiotic cephalosporilide C, 3) an 11-membered carbocyclic ring such as the antibiotic aspochalasin B, 4) a 12-membered metal bridged aryl cyclic ether such as the PG synthetase inhibitor arnebinol, 5) the 14 - membered macrolide portion of the cytochalasin antibiotics, 6) The 17-membered para bridged antibiotic lankacidin C, and 7) The 36-membered ring system of amphotericin B, a clinically important antifungal compound. Cyclopentanes are a structural type of exploding biological significance. Delicate selectivity in cyclizations will be explored in the case of the antifungal terpene chokol C, the antimicrobials udoteatrial and petiodial, the antibiotics enterocine and merulidial, the pharmacologically important picrotaxane neurotoxins, the anticonvulsant anisatin, the antibiotics punctatin A and mellodonal, and retigeranic acid. Mimicking enzymes with transition metal templates is examined to improve selectivity in cycloadditions to five-membered rings. Enzymes use substrate structural features remote from the reaction center to control conformation and thus selectivity; the specific introduction of such remote binding sites will be developed for controlling cycloadditions. Especially relevant is use of gamma -alkoxy -alpha, beta -unsaturated sulfones for 1) asymmetric cyclopentenone annulation, 2) carbacyclin and prostaglandin synthesis, and 3) a synthesis of ginkgolide A, a PAF inhibitor. The third section encompasses steroids and related terpenes using related methodology. A short asymmetric synthesis of the A ring and a totally new metal catalyzed reaction for forming the CD rings of the clinically important Vitamin D metabolites will examined. Closely related chemistry offers a simple strategy to the novel and clinically important antifungal sicannin. The fourth section extends these new synthetic concepts to the beta-lactam antibiotics.