A series of dioxolane analogues based on dexoxadrol ((4S,6S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane) and etoxadrol ((2S,4S,6S)-2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane) were prepared and tested for their ability to displace [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP (1-(1-phenylcyclohexyl)piperidine) binding sites in rat brain tissue homogenates. Qualitative structure-activity relationships within this series were explored through modifications of the three major structural units of dexoxadrol, the piperidine, 1,3-dioxolane, and aromatic rings of the molecule. N-Alkyl derivatives of dexoxadrol were found to be inactive, as were those analogues where the dioxolane ring was modified. Phenyl-substituted etoxadrol analogues were compared to similarly substituted PCP analogues and distinct differences were found in their structure-activity relationships suggesting that the aromatic rings in these two drug classes interact differently with the PCP binding sites. The replacement of the phenyl ring in etoxadrol by either a 2- or 3-thienyl ring led to compounds with affinity comparable to etoxadrol, and the replacement of the ethyl moiety on etoxadrol's dioxolane ring with propyl (7) or isopropyl (8) led to compounds which were more potent than etoxadrol or PCP. The most potent compound was (2S,4S,6S)-2-ethyl- 2-(1-chlorophenyl)-4-(2-piperidyl)-1,3-dioxolane (11), where a chlorine moiety was placed in the ortho position in the aromatic ring of etoxadrol. Its potency was comparable with TCP in vitro.
f)-Fredericamycin A 1 is synthesized using 5-exo-digonal radical closure of selenide 15 (Scheme 2), and an unusual procedure for both selective demethylation of the advanced intermediate 22 and adjustment of the stereochemistry in the pentadienyl side chain.
Rosaramicin, a macrocyclic lactone isolated from the fermentation broth of Micromonospora rosaría NRRL-3718, is a potent broad spectrum antibiotic of considerable clinical interest.3 This natural product is characteristic of its class and provides an interesting test of an anti-selective aldol method developed in these laboratories.4
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