Highly Efficient Synthesis Of 3,3-Disubstituted Oxindoles Base On P-QMs Derived From Isatins

The 3,3-disubstituted oxindoles as important structural motifs present in numerous pharmaceutical compounds and bioactive natural products.The development of efficient methods for the design and synthesis of these compounds has attracted chemists’ attentions and become as a hot field in the synthetic chemistry.In addition,the research on this area has accelerated the development of total synthesis of natural products.Recently,p-QMs(para-quinone methides)has been largely applied in organic synthesis for constructing functionalized molecules,particularly for asymmetric catalysis.In general,p-QMs was utilized for the 1,6-conjugate addition reactions,in which,the remote stereoselectivities could be efficiently realized using organocatalysis and metal-catalysis.Although the research on the p-QMs have evolved rapidly over the past years,the applications of p-QMs for efficiently constructing 3,3-disubstituted oxindoles have remained elusive.Furthermore,previous studies on p-QMs were generally derived from aldehydes,while ketones derived p-QMs received little attentions.Based on these results,we have creatively designed and synthesized a new family of p-QMs derived from isatins,which were utilized for the efficient preparation of 3-aryl-3-substituted oxindoles,spiro-3,3’-substituted oxindoles and 3-thiophenyl oxindoles.And the research provided new avenues for the synthesis of 3,3-disubstituted oxindoles.These works were shown below:(1)The Rauhut-Currier reaction is an effective method for the construction of C-C bond between two activated olefins.Moreover,this reaction stands out as a simple but efficient strategy for the synthesis of valuable compounds.In the first part of this thesis,a remote cross Rauhut-Currier reaction utilizing vinyl ketones and para-quinone methides derived from isatins was realized,which was successfully catalyzed using bifunctional phosphines,furnishing chiral 3,3-disubstituted oxindoles in excellent enantioselectivities and high yields.The mechanistic studies demonstrated the key role of the alkyl hydrogen of the vinyl ketones,which conceivably interacted with the para-quinone methide carbonyl group via the hydrogen bond,offering a new insight for the design of novel asymmetric reactions(2)Dearomatization reactions have emerged as an important tool for synthesizing valuable compounds and can efficiently transform aromatic compounds into three-dimensional molecules.Gold catalysis is an important tool for constructing functionalized molecules and has attracted significant interest in organic chemistry.However,its applications in dearomatization reactions have remained largely unexplored.In the second part,we report the first example of the efficient synthesis of spirocyclohexadienones via the dearomazation of phenols involving allenoates catalyzed by Au(I).Moreover,we also realize the intermolecular remote Rauhut-Currier reaction between allenoates and p-QMs catalyzed by nucleophilic phosphines,which efficiently afforded the phenolic compounds bearing the allenoates in a short time(3)Cysteine is a key molecule for exactly modifying proteins owing to the low abundance in natural proteins and the reactivity of the thiol functional group.The cysteine bioconjugation is an important way to modify the protein.It is of great significance in the exploration of protein tracing and drug delivery.In the third part of this article,we reported the kinetic resolution of 3-phenylthio substituted oxindole in the presence of chiral phosphate catalysis with perfect enantioselectivity.And a structure of disulfide was obtained for the modification of cysteine at the same time.