Organocatalytic stereoisomerization versus alkene isomerization: Catalytic asymmetric synthesis of 1-hydroxy-trans -2,5-diphenylphospholane 1-oxide

The potential for an organocatalytic asymmetric stereoisomerization or alkene isomerization as atom-economic reaction with minimal structural change was investigated. The McCormack cycloaddition of 1,4-diarylbuta-1,3-dienes with (dialkylamino)dichlorophosphane and aluminum trichloride gives meso-2,5-diaryl-1-(dialkylamino)-1-oxo-2,5-dihydro-1H-phospholes, which were identified as suitable substrates for asymmetric isomerization to (1R,5R)-2,5-diaryl-1-(dialkylamino)-1-oxo-4,5-dihydro-1H-phospholes in the presence of bifunctional organocatalysts (cinchona alkaloids, Takemoto catalyst) in up to 91% ee and quantitative yield. The substrate range and the mechanism of the catalysis were studied. The reaction involves proton abstraction by the base, but a primary deuterium KIE is absent. Enriched (1R,5R)-1-(diethylamino)- 1-oxo-2,5-diphenyl-4,5-dihydro-1H-phosphole was hydrolyzed to (5R)-1-hydroxy-1-oxo-2,5-diphenyl-4,5-dihydro-1H-phosphole, which was hydrogenated diastereoselectively under dissolving metal conditions to give (2R,5R)-1-hydroxy-1-oxo-2,5-diphenylphospholane (Fiaud's acid) in preference to meso-1-hydroxy-1-oxo-2,5-diphenylphospholane. An asymmetric catalytic total synthesis of Fiaud's acid, which is a building block for chiral phospholane synthesis, has been realized in five steps from thiophene, using nickel-catalyzed Wenkert arylation, McCormack cycloaddition, asymmetric dihydro-1H-phosphole isomerization, hydrolysis, and diastereo-selective hydrogenation.