Nazarov reactions of aryl and heteroaryl vinyl ketones provide synthetic pathways to a variety of heterocycle-fused cyclopentanones, and have been applied to the synthesis of numerous natural products. However, under typical aromatic Nazarov conditions using Lewis or Bronsted acids, aryl vinyl ketones substituted with 2-furyl and 2-benzofuryl rings do not cyclize. Our research has shown that aryl vinyl ketones with 2-furyl and 2-benzofuryl groups can be successfully cyclized utilizing flow photochemistry under mild conditions. Through this photo-Nazarov reaction, various heterocycle-fused cyclopentanones have been synthesized, including the fused tricyclic motif embedded in the core of the biologically-active marine alkaloid nakadomarin A. However, the 1,2,5,6-tetrahydropyridine carboxylic acid used as starting material to synthesize the requisite aryl vinyl ketones is costly ($80/g), prompting us to explore an alternative, cost-effective route to nakadomarin-inspired aryl vinyl ketones, starting from methyl nicotinate (&lt;$1/g). Development and optimization of this route, making use of a Fowler reduction/ester hydrolysis/Stille cross-coupling reaction sequence is described. The relationship between nitrogen protecting group and photo-Nazarov cyclization efficiency is also discussed.<br/>

Photo-Nazarov reactions of heterocyclic aryl vinyl ketones: Development of a cost-effective route to cyclization substrates

255th National Meeting (2018)

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