Continuous flow synthesis of arylhydrazines via nickel/photoredox coupling of tert-butyl carbazate with aryl halides.

Nickel/photoredox catalyzed C-N couplings of hydrazine-derived nucleophiles provide a powerful alternative to Pd-catalyzed methods. This continuous-flow photochemical protocol, optimized using design of experiments, achieves these couplings in short residence times, with high selectivity. A range of (hetero)aryl bromides and chlorides are compatible and understanding of process stability/reactor fouling has been discerned.

Batch- and Continuous-Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines-A Concise Synthesis of Noroxymorphone.

14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas-liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process.

Synthesis of enantiomerically-pure [13C]aristeromycylcobalamin and its reactivity in dioldehydratase, glyceroldehydratase, ethanolamine ammonia-lyase and methylmalonyl-CoA mutase reactions.

We describe a novel enantioselective synthesis of aristeromycin, the carbocyclic analogue of adenosine. The seven-step synthesis is also suitable for the preparation of specifically-labelled [6'-(13)C]aristeromycin. Both the unlabelled and (13)C-labelled product was coupled to vitamin B(12) to form aristeromycylcobalamin. This carbocyclic analogue of coenzyme B(12) was examined for its coenzymic activity with several adenosylcobalamin-dependent enzymes. For glyceroldehydratase and dioldehydratase, the reaction rate (k(cat)) was 38 and 44 % of that measured with adenosylcobalamin as coenzyme. In contrast, aristeromycylcobalamin showed no detectable activity with methylmalonyl-CoA mutase and ethanolamine ammonia-lyase. Instead, it was a weak inhibitor of the former and a strong inhibitor of the latter enzyme. The slower turnover rate with glyceroldehydratase raised the hope of detecting the 6'-deoxyaristeromycyl radical intermediate. Comparison of the EPR spectra of the intermediates in the glyceroldehydratase reaction, which used adenosyl- and aristeromycylcobalamines, respectively, as coenzyme, revealed a significant shift and this suggests a different geometric position of these cofactors at the binding site during the cleavage of the carbon-cobalt bond. However, we found no evidence for the existence of a 6'-deoxyaristeromycyl radical during the reaction with [6'-(13)C]aristeromycylcobalamin. We conclude that the lifetime of this radical is still too short to be observed.