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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.

The development of new protocols for peptide bond formation which avoid side reactions, including epimerization, are very important. The acyl azide method for the preparation of peptides is very good at maintaining chiral integrity, however; acyl azides are considered to be highly unstable and potentially explosive intermediates. Thus, the acyl azide method is underutilized by the synthetic community. Acyl azides were safely generated and reacted in situ within a continuous-flow system. The acyl azide was generated by using nitrous acid in water, and efficiently extracted into the organic phase containing the amine nucleophile for peptide coupling. The protocol has been used to prepare a number of dipeptides (5 examples) without epimerization (

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.

Strategies for the generation of noroxymorphone from 14-hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone and nalmefene, as well as mixed agonists-antagonists like nalbuphine. The transformation requires removal of the N-methyl group from the naturally occurring opiates and a double bond hydrogenation. The pivotal reaction step thereby is a N-methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3-oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and various phenol protection groups were explored. The most direct route consumes only H2, O2 and H2O as stoichiometric reagents and produces only H2O as by-product. Challenges inherent in gas-liquid reactions with oxygen as oxidant were addressed by developing a continuous flow process.

The palladium-catalyzed N-demethylation of the opioid alkaloids oxymorphone 3,14-diacetate and 14-hydroxymorphinone 3,14-diacetate to their nor-derivatives with oxygen as the terminal oxidant has been investigated. Palladium(II) acetate forms colloidal palladium(0) particles upon heating in N,N-dimethylacetamide. The palladium(0) particles are effective catalysts for the aerobic N-demethylation of these opiate alkaloids. Demethylation of 14-hydroxymorphinone 3,14-diacetate with pure oxygen as oxidant in a continuous flow reactor provided the demethylated product with excellent selectivity after residence times of only 10–20 min with 2.5–5 mol % palladium acetate as catalyst on a laboratory scale. Scale-up of the oxidation in a 100 mL flow reactor (combination of FlowPlate A6 and coiled tube to enhance the gas–liquid mass transfer), hydrogenation in a packed bed reactor, and subsequent hydrolysis afforded the desired noroxymorphone in high quality and good yield on a kg scale. The reaction sequence consume...

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.

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.