Abstract
Carbometalation of oxazolidinone (Ox)-substituted ynamides is used to generate highly substituted Ox-divinyl (and aryl vinyl) ketones for use in Nazarov cyclizations. The Ox-group serves as a remarkably effective chiral activating group, enabling the torquoselective Nazarov cyclization of these sterically congested substrates to be performed under mild conditions. It also serves as a charge-stabilizing group in the intermediate oxyallyl cation, suppressing undesired [1,2]-sigmatropic shifts of neighboring substituents and facilitating the regio- and stereoselective incorporation of nucleophiles to yield cyclopentanoids containing up to three contiguous all-carbon quaternary (4°) stereocentres.
Highlights
The enantioselective synthesis of quaternary (4) stereocentres is a major challenge in organic synthesis, hindering access to sp3-rich scaffolds in drug discovery and natural products synthesis.[1,2]
All other divinyl and aryl vinyl ketones 5 shown in Table 1 were accessed by reaction of 9 (M 1⁄4 MgBr) with the corresponding aldehyde followed by Dess–Martin periodinane oxidation of the crude alcohols (Method B) giving 5c–j in yields of 31–91%
Carbometalation of Ox-ynamides affords direct access to highly substituted Ox-divinyl and -aryl vinyl ketones, which undergo exceptionally facile Nazarov cyclizations leading to 4-stereocentre-containing cyclopentanoids
Summary
The enantioselective synthesis of quaternary (4) stereocentres is a major challenge in organic synthesis, hindering access to sp3-rich scaffolds in drug discovery and natural products synthesis.[1,2] problematic is the enantioselective formation of multiple 4-stereocentres, which requires control over both relative and absolute stereochemistry.The Nazarov cyclization offers inherent control over relative stereochemistry through conservation of orbital symmetry and constitutes an attractive route to multistereocentre-containing cyclopentanoids.[3]. Tius and co-workers[6] reported chiral Brønsted acid-catalyzed Nazarov cyclizations of divinyl ketones 1 (Scheme 1a) leading to cyclopentenols 3 containing two new vicinal 4-stereocentres (R1–3 s H) with high enantioselectivities (o en er > 97 : 3).
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