Preparation of (8S)-8-fluoroerythronolide A and (8S)-8-fluoroerythronolide B, potential substrates for the biological synthesis of new macrolide antibiotics

Leaving Groups Prolong the Duration of 20S Proteasome Inhibition and Enhance the Potency of Salinosporamides

“…Complete conversion of the β-lactone hydrolysis product of 13 to the cyclic ether end product was slow but steady over 5 days (Figure e). Intramolecular displacement of fluoride to form cyclic ethers has been reported previously. , …”

Snapshots of the Fluorosalinosporamide/20S Complex Offer Mechanistic Insights for Fine Tuning Proteasome Inhibition

“…The ability of the proteasome active site to catalyze the uncommon reaction of fluoride displacement from an sp 3 carbon demonstrates the effectiveness of the free base (Thr1NH 2 ). The analogous intramolecular fluoride elimination reaction for 3 ( Ia → Ia′ , Scheme ) is exceedingly slow in aqueous buffer (≥5 days at pH 7.3, 37 °C), and independent reports of intramolecular displacement of fluoride to form cyclic ethers required vigorous conditions. − The kinetics of the more facile chloride elimination from 1 in aqueous buffer have been reported previously; the reaction rate was pH-independent from pH 4.5 to pH 6.5 and increased at pH > 7 . While the p K a of C-3OH is not known, it is reasonable to expect it to be similar to that of other tertiary alcohols (>14).…”

“…However, it is difficult to predict the behavior of fluorine substrates (so-called “flustrates”) . Moreover, fluoride elimination from sp 3 carbons rarely occurs and reportedly only under vigorous conditions (e.g., reflux in the presence of acid or base). − The notoriously poor LG ability of fluorine suggested that this halogen might remain intact when bound to the proteasome and that its “intermediate” potency and proteasome inhibition/recovery profile might be rooted in other unique properties of fluorine (vide supra), including its potential to act as a hydrogen bond acceptor . Establishing the basis for the unusual behavior of 3 would thus offer critical insights for fine-tuning proteasome inhibition.…”

Selective Fluorinations by Reagents Containing the OF Group

“…He reacted CF 3 OF with silyl enol ethers at -70 °C and got in one step the corresponding R-fluorocarbonyl derivatives in 70-90% yield (Scheme 29). Toscano used erythromycin internal enol ether to prepare by this way fluoroerythromycin 52 with outstanding biological properties (Scheme 30). It should be noted that CF 3 OF reacts with the enol moiety faster than with a free hydroxyl group so the latter does not have to be protected if large excess of the hypofluorite could be avoided.…”