Huang you, Professor of Nankai University Research Group: synthesis of chroman and tetrahydroquinoline with alkynyl substituted quaternary carbon center by continuous domino 1,6-addition / cyclization catalyzed by organophosphine

The quaternary carbon centers with alkynyl groups in the lead are widely found in medicine and bioactive molecules, which have important synthetic value At present, most of the synthesis methods are based on an existing alkynyl or TERT carbon substrate Therefore, it is of great value to develop a synthesis method for in-situ formation of alkynyl quaternary carbon centers Recently, Professor Huang You's research group of Nankai University has developed a domino cyclization strategy (Figure 1) of p-benzoquinone and α - substituted diacetate catalyzed by organophosphine, realizing the efficient synthesis of chroman and tetrahydroquinoline compounds with alkynyl quaternary carbon center (org Lett., DOI: 10.1021 / ACS Orglett 8b03819) Fig 1 domino cyclization of p-benzoquinone and α - substituted diacetate (source: org Lett.) Zhu Yannan, Ph.D student of Professor Huang you, was admitted to Shandong Normal University in 2012 and received his Bachelor of Science Degree in 2016 In the same year, he was admitted to Nankai University and studied for master's degree from Professor Huang you In 2018, he became a doctoral student and engaged in the research of organic phosphine catalytic reaction Frontier scientific research achievements: the synthesis of chroman and tetrahydroquinoline chroman with alkynyl substituted quaternary carbon centers by continuous domino 1,6-addition / cyclization catalyzed by organophosphine and tetrahydroquinoline compounds widely exist in medicine and bioactive molecules, which have important application value (Fig 2) At the same time, the alkynyl substituted quaternary carbon center is a kind of very important drug structure unit Most of the synthesis strategies of this kind of structure have some defects, such as the expensive catalyst, various additives, and need to rely on an existing alkynyl or tertiary carbon substrate Recently, the research group of Professor Huang you of Nankai University has developed the domino cyclization reaction based on dienyl ester catalyzed by organophosphine On the basis of highly efficient synthesis of a chroman or tetrahydroquinoline heterocycle, at the same time, an alkynyl quaternary carbon center has been formed in situ The reaction can be realized at room temperature, with short reaction time and wide range of substrates The highest separation yield can reach 97% and Dr value > 20:1 This work was published in the Journal of organic chemistry, org Lett (DOI: 10.1021 / ACS Orglett 8b03819) Zhu Yannan, Ph.D student of School of chemistry, Nankai University, was the first author, and Wang Dan, master's degree student, participated in the project Fig 2 natural products and bioactive molecules with chroman, tetrahydroquinoline structure or alkynyl quaternary carbon center (source: org Lett.) the authors first used unsubstituted p-benzoquinone 1a and α - acetoxymethylbenzenoate 2A as template substrates to screen alkali, phosphine catalyst and solubilizer respectively, and found that 2.4 equivalent When CS 2CO 3 is used as base and 20 mol% of (2-brc 6h 4) PPH 2 is used as catalyst, the substrate can react in THF, the highest yield can be 96% to obtain the cyclized product 3a, and the reaction can be completed in 1 h at room temperature Under the optimal reaction conditions, the applicability of the substrate was investigated (Fig 3) For the dienyl ester substrate, benzyl ester (3a-3e) with different electronic substituents and aliphatic ester group (3f-3j) with different volume can participate in the reaction well With the increase of steric hindrance, the enantioselectivity of the reaction increases It is worth noting that when the γ - position of the dienyl ester is linked with a substituent, the reaction can realize the construction of the non terminal alkynyl quaternary carbon center, and the corresponding products 3K and 3L can still be obtained in a good yield For the p-benzoquinone substrate, the corresponding domino cyclization product (3m - 3W) can be obtained with good to excellent yield, no matter whether there are electron donor or electron acceptor on the benzene ring or heterocyclic p-benzoquinone The tert butyl of phenol in p-benzoquinone can also be replaced by isopropyl or methyl tert butyl The corresponding products, 3x and 3Y, can also be obtained in good yields In addition to hydroxy substituted p-benzoquinone, amino substituted p-benzoquinone can also successfully complete the reaction (5a - 5d) Although the Dr value is significantly reduced, the two enantiomers can be easily separated by column chromatography The absolute configuration of 3W and 5aa (trans isomer of 5A) can be confirmed by X-ray single crystal diffraction Fig 3 substrate development of dienyl ester and p-benzoquinone (source: org Lett.) in order to prove the practicability of this method, the author carried out gram scale preparation experiment and product derivation Figure 4 shows that the reaction can achieve gram scale preparation under the same conditions, and the target product 3G can be obtained with 85% yield and a single non enantiomer The alkynyl group in the product 3G can be derivatized by click reaction and NBS bromination respectively, and the corresponding products 6G and 7g can be obtained The ester group in product 3G can be converted into corresponding alcohol 8g under the reduction of LiAlH 4 It should be noted that a single enantiomer product 9A can be obtained by Sonogashira coupling with iodobenzene when the ratio of enantiomers is only 2:1 In addition, different kinds of chiral phosphine catalysts have been used to study the asymmetric reaction, but no ideal results have been obtained Fig 4 gram level experiment and product derivatization (source: org Lett.) further, the author studied the mechanism of the domino cyclization reaction through control experiment (Fig 5) First of all, if the ortho hydroxy group of benzene ring in p-benzoquinone is protected by methyl, the reaction can not take place, only the reaction intermediate enyne 11a (EQ 1) generated by dienyl ester 2A can be obtained Alkyne 11a (EQ 2) could not be produced from dienyl ester 2A without the presence of phosphine catalyst Under the joint action of alkali and phosphine catalyst, p-benzoquinone 1A can react directly with alkyne intermediate 11a, but the final cyclization product 3A can only be obtained in 43% yield; if only alkali and no phosphine catalyst are added, p-benzoquinone 1a and alkyne 11a can only get 3A (EQ 3) in micro yield The above control experiments show that the reaction is realized by two steps Firstly, the intermediate of alkyne is formed in situ by alkenyl ester, and then the cyclization reaction between alkyne and p-benzoquinone takes place Both steps require the participation of phosphine catalyst and base, and the yield can be significantly improved by the strategy of in situ formation of alkyne Fig 5 control experiment (source: org Lett.) based on the above experimental results, the author proposed the possible reaction mechanism (Fig 6) Firstly, the phosphine catalyst attacks the β - carbon atom of the dienyl ester 2a, and the resulting intermediate removes one molecule of acetoxy anion to form the amphiphilic intermediate II Then, II dephosphonate catalyst under the action of alkali to generate enyne 11a, so the first catalytic cycle is completed In the second catalytic cycle, the phosphine catalyst attacks the active alkenyl group of enyne 11a to form nucleophilic intermediate III Then, the 1,6-conjugated addition of p-benzoquinone 1A was carried out by III, and the intermediate V was formed by proton transfer Finally, the target product 3A was formed by intramolecular cyclization of V, and the phosphine catalyst was released Fig 6 possible reaction mechanism (source: org Lett.) Summary: this method is based on the domino cyclization process catalyzed by p-benzoquinone and dienyl ester On the basis of efficient synthesis of a chroman or tetrahydroquinoline heterocycle, at the same time, an alkynyl quaternary carbon center is generated in situ The reaction conditions are mild and the operation is simple, which provides a convenient and efficient strategy for the synthesis of new chromophores or tetrahydroquinolines The research was supported by the National Natural Science Foundation of China (21672109, 21871148, 214720797, 21172115, 20972076), Tianjin Natural Science Foundation (15jcybjc20000, 10jcybjc04000, 05yfjmjc00600) and Nankai University A review of previous reports: Professor Huang You's research group of Nankai University: efficient synthesis of six and seven membered nitrogen heterocyclic compounds by diverse domino cyclization of thiohilide; Professor Huang You's research group of Nankai University: DBU catalyzed desymmetric cyclization of cyclohexanenone 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, chembeango app, 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.