Bifunctional Thiourea Organocatalyst Enables a Halocyclization and Spiroketalization Cascade

Key words

halocyclization - spirocyclization - hydrogen-bond donor catalysis - dynamic kinetic resolution - cascade reaction

Significance

Tse, Yeung, and co-workers report an enantio- and diastereoselective domino halocyclization and spiroketalization of styryl keto acids. In the presence of an electron-rich bifunctional thiourea organocatalyst and the appropriate electrophilic halogen source, the corresponding spirocyclic products are obtained in good to excellent yields and with excellent diastereo- and enantioselectivities. The method can be extended toward an enantio- and diastereoselective chloro-dispiroketalization. Additionally, the authors demonstrate its applicability in the synthesis of structural analogues of danshenspiroketallactone, a naturally occurring­ monobenzannulated 5,5-spiroketal.

Comment

The reported method expands the toolbox of catalytic asymmetric electrophilic halocyclizations, which previously focused on polyenes as substrates to provide fused-ring systems (R. C. Samanta, H. Yamamoto J. Am. Chem. Soc. 2017, 139, 1460). Mechanistic studies suggest that the transformation involves a dynamic kinetic resolution of the hemiketal form of the starting material, followed by activation of the halogen and asymmetric halocyclization. Intriguingly, an electron-rich thiourea catalyst is required for high enantioselectivities as opposed to its commonly used electron-deficient congeners. The authors propose that electron-donating substituents lead to an enhanced interaction between the halogen source and the sulfur atom of the thiourea.

Publikationsverlauf

Artikel online veröffentlicht:
20. Januar 2021