Organocatalytic Diastereo- and Enantioselective Michael Addition Reactions of 5-Aryl-1,3-dioxolan-4-ones

Abstract

5-Aryl-1,3-dioxolan-4-one heterocycles derived from mandelic acid derivatives and hexafluoroacetone have been identified as new and effective pro-nucleophiles in highly diastereo-and enantioselective Michael addition reactions to nitro olefins catalyzed by bifunctional epi-9-amino-9-deoxy cinchona alkaloid derivatives. Diastereoselectivities up to 98% and enantioselectivities up to 89% for a range of nitro olefins and 5-aryl-1,3-dioxolan-4-ones under mild reaction conditions are reported.Single enantiomer bifunctional organocatalysts derived from cinchona alkaloids or cyclohexane diamine have emerged as powerful tools for the enantioselective formation of carbon-carbon and carbon-heteroatom bonds. 1 Their ready preparation and ability to impart high enantiocontrol in the addition of carbon-and heteroatom-centered nucleophiles to a variety of electrophiles have all contributed to the pace of the field. 2,3 While most efforts have concentrated on the development of the range of electrophilic components, less attention has been devoted to expanding the pool of carboncentered pro-nucleophiles attuned to this type of catalysis.To address this, we have been searching for new and synthetically Versatile pro-nucleophilic entities that would partake in highly stereoselective reactions mediated by metalfree bifunctional catalysts that our group, and others, have developed. One family of heterocycles, the 1,3-dioxolan-4-ones, was particularly attractive owing to the simplicity of their structure combined with their ready synthesis (Scheme 1). We postulated that the tunability arising from possible structural and electronic variations to the group at the 5-position and the acetal function could provide the necessary acidity/nucleophilicity profile for some derivatives to partake in enantioselective Lewis base/Brønsted acid bifunctional organocatalyst mediated additions to electrophiles

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

“…As described in our previous communication [61], the employment of bifunctional catalyst 9 [54–55] in a highly stereoselective two-stage one-pot cascade led to the formation of enantiomerically highly enriched spirocycle (+)- 1a (Scheme 8). In a repeat of the process but with the intention of targeting a piperidin-2-one ring-containing polycyclic scaffold, cyclic imine 5a was added at the second stage.…”

“…Not only could this approach allow the rapid generation of structural complexity, but the products would be amenable to further synthetic transformations. Furthermore, the γ-nitro ester starting materials are accessible in an enantioenriched form by using an organocatalytic Michael addition methodology, which was developed by our group and others [54–59]. In pursuit of this we have successfully harnessed the power of the nitro-Mannich/lactamisation cascade in a formal synthesis of (3 S ,4 R )-paroxetine [60], in the construction of architecturally complex polycyclic alkaloid structures [61] and more recently as a key complexity building step in the total synthesis of nakadomarin A [62–65].…”

Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea organocatalysts

“…Dixon and co-workers 29 added acidic 5-aryl-1,3-dioxolanone heterocycles derived from mandelic acid derivatives and hexafluoroacetone to nitrostyrenes in the presence of the cinchonine-derived catalyst 14. The products of these reactions are highly versatile and can be easily converted to a range of a-hydroxy acid derivatives.…”

Cinchona‐Catalyzed Nucleophilic Conjugate Addition to Electron‐Deficient CC Double Bonds

“…Soon afterward, various types of carbon [40][41][42][43][44], oxygen [45], and phosphorous [46] Michael donors were successfully employed in the thiourea-catalyzed addition to nitroalkenes. In the presence of the bifunctional epi-9-amino-9-deoxy cinchoninebased thiourea catalyst 79a, the 5-aryl-1,3-dioxolan-4-ones 138 bearing an acidic a-proton derived from mandelic acid derivatives and hexafluoroacetone were identified by Dixon and coworkers as effective pronucleophiles in diastereo-and enantioselective Michael addition reactions to nitrostyrenes 124 [40]. While the diastereoselectivity obtained exceeded 98%, the enantiomeric excess recorded was in the range of 60-89% (Scheme 9.47).…”