Asymmetric Construction And In Vitro Antitumor Activity Study Of Chiral α-CF₃ Spiro [benzo [b] Thiophen-hydroxyindole-pyrrolidine]

Medicinal chemistry aims to design and synthesis novel,highly purified bioactive molecules that meet specific criteria and have the potential to become safe and effective drugs.For many applications,drug discovery begins with the screening of chiral compound libraries generated from a variety of off-the-shelf building blocks.Asymmetric synthesis has enabled the assembly of stereochemically diverse molecules that were once impossible to synthesize,facilitating the publication of many recent findings in medicinal chemistry.Spirocyclic oxindole frameworks have significant antitumor biological activity as MDM2 receptor inhibitors and promising applications in drug synthesis intermediates,pesticides,dyes and materials.Therefore,it is an attractive target molecule in organic synthesis.Fluorine atoms and fluorinated groups are widely found in the fields such as materials science,agricultural and medicinal chemistry and in bioactive molecules.The trifluoromethyl（CF₃）group as the most important and commonly used fluorinated functional group is of increasing interest in medical and organic chemistry due to its ability to improve molecular properties such as p Ka,metabolic stability,lipophilicity,and even cell membrane permeability.In particular,cyclic compounds with chiral trifluoromethylated chiral centers are found in many bioactive molecules,lead compounds and marketed drugs.We have therefore developed two novel regionally distinct trifluoromethyl-containing synthetic blocks using acid-controlled catalysis,which were applied to agent-catalyzed enantioselective[3+2]cycloaddition using asymmetric organocatalytic chemistry.The reactions of unsaturated olefins derived from oxindoles with 1,3-dipoles containing trifluoromethyl were used to obtain variousα-CF3-containing [benzo[b]thiophene-hydroxyindolyl-pyrrolidine] compounds in only one step.It has four adjacent chiral centers,including two adjacent spiral seasonal carbon centers.The target molecules were obtained in yields up to 96% and ee values up to 99%.Our reactions on substrates containing various substituents and regionally different 1,3-dipoles demonstrate the universality of the reaction as well as the versatility of this target molecule.The smooth execution of three gram-scale reactions proved its ability to be produced on a large scale.In addition,we conducted preliminary tests on the antitumor activity of a portion of the target molecule,which produced some inhibition of three tumor cells at certain concentrations.The cycloaddition reaction not only successfully utilizes the new 1,3-dipole to introduce trifluoromethyl in an asymmetric manner into sulfur-containing spirooxindole compounds with multi-chiral centers,but also provides important guidance for the introduction of trifluoromethyl into sulfur-containing heterocyclic compounds and the control of stereoselectivity in the construction of multi-chiral spirooxindole compounds.