Asynt reports that the Cresswell group, led by Dr. Alexander J. Cresswell at the University of Bath (UK), demonstrated the synthesis of new spirocyclic tetraiodonaphthyridines (THNs) expanding the chemical space of these important scaffolds for drug discovery.
Image credit: Asynt
Presented at the recent Automated Synthesis Forum in Oxford, UK, and supported by promising unpublished work, the team uses a combination of photochemistry with flow chemistry to achieve significant results. This work demonstrates a novel hydroaminoalkylation (HAA) of halogenated vinylpyridines, catalyzed by photoredox, followed by either an intramolecular N-arylation via SNAr, or a palladium-catalyzed CN bond formation in continuous flow to enable an automated synthesis of α- alkylated and 1,2,3,4-tetrahydro-1,8-spirocyclic
The key step in the synthesis, the photocatalyzed reaction (HAA), was performed using Uniqsis PhotoSyn from Asynt. This high power LED photoreactor lamp unit for continuous flow applications is equipped with a high efficiency 420 nm LED array (716 individual diodes) which was mounted in a Cold Coil with a 5 mL PFA coil and cooled to -0.5 °C using a Huber CC-805 cooler. The ability to maintain a low temperature with a light intensity of 350 W at 420 nm was a key factor in the success of this reaction, capabilities that only PhotoSyn possesses compared to other solutions on the market.
Tetrahydronaphthyridines (THNs) are semi-saturated bicycles that fuse a piperidine with a pyridine, two of the most popular N-heterocycles used in medicinal chemistry. These bicyclic compounds possess saturated N-heterocycles fused to (hetero)aromatic units that afford eight different structural isomers through the placement of the two THN nitrogen atoms. These structural motifs can be found in the MC4R antagonist PF-07258669 in phase 1 clinical trials by Pifzer and in the development of the selective FGFR4 inhibitor Roblitinib by Novartis. THNs and their isomers can be used in a number of biosteres increasing their importance.
In addition to demonstrating the optimization of the reaction leading to the automated, continuous flow synthesis of THNs from primary amines, the team—using an autosampler—demonstrated both a library synthesis and that the process is applicable to a range of amines, including cyclic amines and of multiple functional groups – all with good to excellent yields.
Further extending this work, the researchers applied their methodology to a concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist, previously synthesized in 15 steps. The industrial route, while 11 steps in the longer linear sequence, is enantioselective, compared to a racemic synthesis in this case. However, this shows how dramatically the synthesis of complex spirocyclic amines can be improved when a photoredox cancellation strategy from unprotected amines is used.
In summary, the researchers developed an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-
