Professor Yang Hua group of Central South University: Domino cyclization reaction based on 3-oxindole skeleton polarity matching

Because of its structure specificity and reaction diversity, methylene indole oxide has attracted more and more attention in the field of synthetic chemistry and pharmaceutical chemistry, and its application in the construction of multicyclic skeleton has been continuously expanded However, most of the reports in this field focus on the cyclization reaction of methylene oxindole-3 double bond, and there are relatively few reports on the ring opening of five membered lactam For a long time, Professor Yang Hua's research group of Central South University has been devoted to the development of Diels alder cyclization, domino cyclization and Michael addition reaction catalyzed by organic small molecules (J org Chem., 2016, 81, 8001-8008; J org Chem., 2017, 82, 3895-3900; J ORG Chem., 2017, 82, 12202-12208; org Lett., 2018, 20, 7535-7538; J org Chem , 2018 , 83 , 12284-12290 ）。 Recently, the research group has developed a novel "one pot" reaction, in which the polar matching 3-hydroxy-oxindole and methylene oxindole derived from 3-oxindole are enantioselective Michael addition / intramolecular ring opening / internal acylation tandem cyclization under the catalysis of formamide Under mild conditions, the strategy efficiently and economically constructs the framework of indospiroquinolinone The results were published in org Lett (DOI: 10.1021 / ACS Orglett 9b00477) Professor Yang Hua's cutting-edge scientific research achievements: Based on the polarity matching of 3-oxindole skeleton, the organic catalytic ring recombination domino cyclization reaction has been widely concerned because of its complex structure and extensive biological activity However, how to construct the multi ring skeleton with high enantioselectivity and high speed in the way of atomic economy and step economy has always been a challenging topic Reasonable design of domino cyclization reaction can provide an effective solution and significantly improve the bonding efficiency and cyclization efficiency 3-hydroxy-indole oxide and methylene-indole oxide are derived from 3-indole oxide They are two kinds of valuable and widely used synthetic monomers, which have been widely used in synthetic chemistry Due to its chemical and electronic specificity, 3-hydroxy-oxindole has two active nucleophilic sites, while methylene oxindole has several potential sites, and their reactivity just matches Specifically, in the methylene indole oxide, the chemically inert lactam ring opening will make it possible to recombine the ring skeleton, which provides an interesting strategy for the construction of new heterocyclic compounds with high difficulty So far, it is still a challenge to synthesize polycyclic indole spiro compounds by the series reaction of methylene indole oxide ring opening The polarity match of methylene indole oxide and 3-hydroxyindole oxide Under the catalysis of organic catalyst, the framework of indole oxyspiroquinolinone can be selectively constructed by designing a reasonable domino cyclization reaction (Fig 1) Figure 1 Polar matching design to construct indole oxyspiro ring (source: org Lett.) the author first optimized the reaction conditions with methylene indole oxide and 3-hydroxyindole oxide as raw materials Under the optimal conditions, the target product indole oxyspironolone was obtained with 92% yield, > 99% enantioselectivity and 89:11 non enantioselectivity In order to investigate the substrate application scope of this method, the authors investigated a series of 3-hydroxy-oxyindole (Fig 2) and methylene-oxyindole (Fig 3) with different substituents, all of which can react smoothly We also investigated the enantioselective open-loop series reaction of methylene indole and 3-aminoindole (Fig 4) A new polycyclic indole spiro ring was obtained with 84% yield, 71% enantioselectivity and 93:7 non enantioselectivity, which proved that this method has good universality Fig 2 Substrate expansion of 3-hydroxy-oxindole (source: org Lett.) Fig 3 Substrate expansion of methyleneoxindole (source: org Lett.) Fig 4 Series reaction of methyleneoxindole and 3-amino-oxindole (source: org Lett.) finally, Based on the experimental results and the absolute configuration of the main isomers, a possible double activation mechanism of the catalyst is proposed Initially, 3-hydroxy-oxindole was deprotonenolized by the tertiary amine of the catalyst formamide to produce an efficient Michael donor At the same time, as Michael receptor, methylene indole oxide is guided by the formamide group through the interaction of hydrogen bond Therefore, enolized 3-hydroxy-indole oxide attacks methylene indole oxide on the re surface, and enantioselectively generates intermediate a Then, the key intermediate lactone B was formed by the intramolecular ring opening of lactam Finally, under the promotion of TsOH · H 2O, the intermediate B undergoes intramolecular amidation to produce polycyclic indole spiro Fig 5 Possible reaction mechanism (source: org Lett.) to sum up, the author has developed Michael addition / intramolecular ring opening / internal amidation "one pot" series reaction of enantioselectivity of 3-hydroxy-oxyindole and methylene-oxyindole derived from polarity matching under the catalysis of formamide Under mild conditions, the strategy can efficiently and economically construct the framework of three consecutive chiral centers, with excellent yield (up to 97%) and enantioselectivity (up to > 99% ee), and medium to good enantioselectivity (up to > 95:5 DR) This achievement was recently published in org Lett (DOI: 10.1021 / ACS Orglett 9b00477) The first author of this paper is Ren Jiwei, a doctoral student in the school of chemistry and chemical engineering of Central South University The corresponding authors are Professor Yang Hua, Professor Chen Xiaoqing and associate professor Xiang Fuyue The above research work was supported by the Ministry of science and technology, the National Natural Science Foundation of China and the natural science foundation of Hunan Province Ren Jiwei (first author): a review of previous reports: Professor Yang Hua's research group of Central South University: explanation and regulation of stereospecific reverse reaction in asymmetric organic catalytic condensation of indigo and cyclohexanone hydroxyaldehyde CBG information interview with Professor Yang Hua of Central South University Today, science and technology elements are increasingly valued in economic life, China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.