Organocatalytic Asymmetric Synthesis of Six‐Membered Carbocycle‐Based Spiro Compounds

Abstract

Well‐developed asymmetric organocatalysis has been widely incorporated in various cascade/tandem sequences, providing a simple access to structurally complex target molecules in a highly stereoselective fashion, including spirocyclic compounds. Among all types of spirocyclic skeletons, those containing a six‐membered carbocyclic ring are recognized as an important core framework with up to six consecutive stereogenic centers and this motif is commonly found in many natural products, biologically active molecules and lead compounds. This review describes the asymmetric synthesis of spirocyclic compounds containing six‐membered carbocycles using small organic molecules as catalysts.magnified image

Synthesis of γ‐Spirolactams by Birch Reduction of Arenes

“…Furthermore, their ability to form hydrogen bridges has been applied in enantioselective reactions [16] . On the other hand, the synthesis of spiro compounds requires usually many steps, [17–19] in contrast, our method offered an easy entry by Birch reduction [13] …”

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

“…In spirocyclic oxindole-based MDM2 inhibitors, the oxindole fragment occupies the Trp23-containing cleft of P53, and appropriate stereochemistry is critical for good binding affinity 73 , 74 . Therefore, we focused on asymmetric synthesis of optically pure C3-spirooxindoles 75 , 76 , 77 , 78 . We started from hydronaphthalene 79 , 80 , 81 , 82 , 83 , 84 and spirooxindole 10 , 22 , 23 , 25 , 65 because they are privileged frameworks occurring in many anti-tumor natural products and pharmaceuticals.…”

Birch Reduction of Arenes as an Easy Entry to γ‐Spirolactones

“…[6,7] On the other hand, their synthesis requires more steps, due to the adjacent quaternary carbon atom. [8][9][10] One possibility is epoxide-opening by ester or acid enolates, but strong and expensive bases had to be employed. [11,12] Thus, the Birch reduction should be an attractive alternative, because it can be performed on a large scale with cheap reagents and starting materials.…”