This grant will continue development of a major research program to undertake fundamental studies in the chemistry of recently discovered, biologically active antibiotics. The proposed research will investigate preparation of dioxaspiroketal antibiotics which demonstrate a number of valuable biological effects. Examples include: (1) Milbemycin alpha 1; the most potent member of a novel group of macrocyclic lactones with high pesticidal and antihelminthic activity evoked by unprecedented interference of GABA-mediated neurotransmission in invertebrates. (2) Breynolide; the aglycone of the sulfide-containing antibiotic, breynin, demonstrating significant in vivo hypocholesterolemic activity in mammals. (3) Additionally, synthetic approaches will be initiated toward linearol, a hemiketal of the new dolastane family of marine natural products which have displayed antimicrobial and antileukemic activities.
