- Synergistic Catalysis for the Asymmetric [3+2] Cycloaddition of Vinyl Aziridines with α,β-Unsaturated Aldehydes
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The first asymmetric [3+2] cycloaddition of vinyl aziridines with α,β-unsaturated aldehydes, based on synergistic catalysis, is disclosed. This methodology allows the formation of attractive pyrrolidine structures in good yields (up to 84 %), moderate diastereoselectivity, and high enantioselectivity values (up to >99 % ee). Additionally, a tricyclic pyrrolidine core structure found in biologically active molecules was synthesized in a one-pot fashion by using the presented reaction concept. Finally, a mechanistic proposal is outlined.
- N?sborg, Line,Tur, Fernando,Meazza, Marta,Blom, Jakob,Halskov, Kim S?holm,J?rgensen, Karl Anker
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- Oxetanes in drug discovery: Structural and synthetic insights
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An oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups. The magnitude of these changes depends on the structural context. Thus, by substitution of a gem-dimethyl group with an oxetane, aqueous solubility may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degradation in most cases. The incorporation of an oxetane into an aliphatic chain can cause conformational changes favoring synclinal rather than antiplanar arrangements of the chain. Additionally spirocyclic oxetanes (e.g., 2-oxa-6-aza-spiro[3.3]heptane) bear remarkable analogies to commonly used fragments in drug discovery, such as morpholine, and are even able to supplant the latter in its solubilizing ability. A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously documented, thus providing the foundation for their broad use in chemistry and drug discovery.
- Wuitschik, Georg,Carreira, Erick M.,Wagner, Bj?rn,Fischer, Holger,Parrilla, Isabelle,Schuler, Franz,Rogers-Evans, Mark,Müller, Klaus
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supporting information; scheme or table
p. 3227 - 3246
(2010/08/19)
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- Oxetanes as promising modules in drug discovery
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(Chemical Equation Presented) Ring the changes: Introduction of an oxetane ring results in remarkably improved physico- and biochemical properties of the underlying scaffold. The oxetane ring confers enhanced solubility, reduces the metabolic degredation, lipophilicity, and amphiphilicity, and modulates the basicity of a nearby amine group.
- Wuitschik, Georg,Rogers-Evans, Mark,Mueller, Klaus,Fischer, Holger,Wagner, Bjoern,Schuler, Franz,Polonchuk, Liudmila,Carreira, Erick M.
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p. 7736 - 7739
(2007/10/03)
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