Catalytic enantio- and diastereoselective domino halocyclization and spiroketalization

Abstract

Asymmetric domino electrophilic halocyclizations are highly useful in the synthesis of structurally complex and pharmaceutically important compounds. Although some studies aimed at catalytic and enantioselective polyene cyclizations are documented, the chiral products have been limited to fused rings. Here, we report an efficient and highly enantio- and diastereoselective halocyclization and spiroketalization of olefinic keto-acids. Instead of electron-deficient thiourea, in this study electron-rich thiourea catalysts are crucial for high enantioselectivity. The resulting spiro compounds are privileged cores of many drugs and natural products. Our experimental and computational studies revealed that the reaction proceeded via a double dynamic–kinetic resolution mechanism. We anticipate that this work will stimulate the synthesis of other multifunctional compounds via electrophilic halocyclization. Domino asymmetric electrophilic halocyclization is useful for the synthesis of polycyclic pharmaceutical compounds, but remains limited to the generation of fused rings. Now, the scope is extended to complex spirocycle products by a catalytic protocol involving an electron-rich thiourea catalyst.