Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation.

We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2 O2 ) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeII catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including . CF3 , . C4 F9 , . CH2 CN, and . CH2 CO2 Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3 I and C4 F9 I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.

Novel riboswitch-binding flavin analog that protects mice against Clostridium difficile infection without inhibiting cecal flora.

Novel mechanisms of action and new chemical scaffolds are needed to rejuvenate antibacterial drug discovery, and riboswitch regulators of bacterial gene expression are a promising class of targets for the discovery of new leads. Herein, we report the characterization of 5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione (5FDQD)-an analog of riboflavin that was designed to bind riboswitches that naturally recognize the essential coenzyme flavin mononucleotide (FMN) and regulate FMN and riboflavin homeostasis. In vitro, 5FDQD and FMN bind to and trigger the function of an FMN riboswitch with equipotent activity. MIC and time-kill studies demonstrated that 5FDQD has potent and rapidly bactericidal activity against Clostridium difficile. In C57BL/6 mice, 5FDQD completely prevented the onset of lethal antibiotic-induced C. difficile infection (CDI). Against a panel of bacteria representative of healthy bowel flora, the antibacterial selectivity of 5FDQD was superior to currently marketed CDI therapeutics, with very little activity against representative strains from the Bacteroides, Lactobacillus, Bifidobacterium, Actinomyces, and Prevotella genera. Accordingly, a single oral dose of 5FDQD caused less alteration of culturable cecal flora in mice than the comparators. Collectively, these data suggest that 5FDQD or closely related analogs could potentially provide a high rate of CDI cure with a low likelihood of infection recurrence. Future studies will seek to assess the role of FMN riboswitch binding to the mechanism of 5FDQD antibacterial action. In aggregate, our results indicate that riboswitch-binding antibacterial compounds can be discovered and optimized to exhibit activity profiles that merit preclinical and clinical development as potential antibacterial therapeutic agents.

Generation of Broad-Spectrum Antifungal Drug Candidates from the Natural Product Compound Aureobasidin A.

The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 µg/mL. The approach is readily adaptable to large-scale synthesis and industrial production.

New process for the preparation of methyl carbonates.

The methyl carbonate of HOBt was developed for the conversion of alcohols to carbonates. This method is superior to the use of methyl chloroformate or methyl pyrocarbonate, especially with more hindered alcohols. The reagent is a stable solid that is easily prepared on a multigram scale. [reaction: see text]

A practical synthesis of cabergoline.

Cabergoline is an N-acylurea derived from 9,10-dihydrolysergic acid, which is a potent prolactin inhibitor. It is marketed by Pharmacia as Dostinex for the treatment of hyperprolactinemia and is currently under active development for the treatment of a variety of CNS disorders. In the existing process, the N-acylurea is formed by the reaction of an amide with a large excess of ethyl isocyanate at elevated temperatures. An improved process was developed that eliminates this hazardous reaction. The amide is reacted with phenyl chloroformate and then with ethylamine, which provides a mild and efficient means of forming the unsymmetrical N-acylurea.