This Communication describes a cascade reaction sequence that leads to highly functionalized cyclohexenones starting from reaction of cyclobutenones with alpha-lithio-alpha,beta-unsaturated sulfones and amides. The hexatriene-cyclohexadiene cyclization steps presumed to be involved in these transformations are among the most facile hexatriene electrocyclizations reported thus far.
The scale-up of a prototype HCV protease inhibitor (1) from gram-scale in the laboratory to kilogram-scale in the pilot plant is described. Key features of the optimization included synthesis of bulk quantities of exomethylene proline intermediate 6, separation the diastereomers of spirocycle 2 without chromatography, isolation of the precursor to 1 to purge by-products which might raise genotoxic structural alerts, and purification of an amorphous drug substance via a crystalline acetic acid solvate.
[reaction: see text] Chemoselective cyclizations of divinyl ketones to cyclohexenones mediated by a sterically demanding Lewis acid and an amine base have been accomplished under mild reaction conditions. The extension of this methodology to the synthesis of eight-membered rings is also demonstrated.
Remarkably Facile Hexatriene Electrocyclizations as a Route to FunctionalizedCyclohexenones via Ring Expansion of Cyclobutenones. -Functionalized cyclohexenones are synthesized by nucleophilic addition/4π-ring opening /6π-ring closing cascade reactions between cyclobutanones and α-lithio-α,β-unsaturated sulfones and amides. The new method tolerates nucleophiles containing aromatic, heteroaromatic and tert-alkyl substituents. -(MAGOMEDOV*, N. A.; RUGGIERO, P. L.; TANG, Y.; J.
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