Professor Zhou Ling group of Northwest University: Series asymmetric PRINS reaction catalyzed by chiral phosphoric acid

The introduction PRINS cyclization provides an important way for the construction of polysubstituted tetrahydropyran, furan derivatives and complex natural molecules However, there are few studies on asymmetric PRINS reactions, especially the series PRINS cyclization The difficulty lies in the regioselectivity and stereoselectivity control of onium ions and carbon positive ions after cyclization, as well as the need to avoid some rearrangement reactions Recently, a series of trans tetrahydropyrfuran tetrahydroquinoline derivatives have been synthesized for the first time by a series of asymmetric PRINS cyclization reaction based on the design of chiral phosphoric acid catalyst and substrate The related results were recently published in org Lett (DOI: 10.1021 / ACS Orglett 9b02714) Fig 1 chiral phosphoric acid catalyzed series asymmetric PRINS cyclization (source: org Lett.) introduction to Professor Zhou Ling's research group, Professor Zhou Ling's research group was founded in September 2012 In May, the research direction is organic synthesis methodology, organic catalysis, etc some progress has been made in the catalytic substitution of Nitrogen Heterocyclic Carbene, asymmetric reaction catalyzed by chiral phosphoric acid, and oxidative dehydrogenation cycloaddition reaction Prof Zhou Ling graduated from Lanzhou University in 2002 with a bachelor's degree and obtained a doctor's degree in organic chemistry from Lanzhou University in 2007 From 2007 to 2009, he served as the research and development leader of Barcelona Pharmaceutical (China); from 2009 to 2011, he was engaged in postdoctoral research at the National University of Singapore Since 2012, he has served as a professor / doctoral supervisor in Northwest University He has published more than 40 research papers in J am Chem SOC., angelw Chem Int ed., chem SCI., org Lett., chem Commin And has been cited more than 1000 times Presided over and undertaken projects such as National Natural Science Foundation and Shaanxi Provincial Outstanding Youth Fund In 2012, he was selected as a special expert of Shaanxi Province; in 2013, he was supported by the outstanding young academic backbone program of Northwest University; in 2014, he was awarded "Thieme Chemistry Journals Award"; in 2017, he was awarded the first outstanding youth fund of Shaanxi Province Leading scientific research achievements: the series asymmetric PRINS reaction catalyzed by chiral phosphoric acid PRINS cyclization is an important method for the synthesis of oxygen-containing heterocycles, and has been continuously used in the synthesis of complex natural products So far, PRINS cyclization catalyzed by Lewis acid and Bronsted acid has been reported one after another, but asymmetric PRINS cyclization is relatively rare The difficulty lies in the control of the regioselectivity and stereoselectivity of the onium ions and the carbonium ions after cyclization, as well as the need to avoid some rearrangement reactions Recently, a series of tetrahydropyrans (THPS) and tetrahydrofurans (THFs) compounds have been constructed by the research group of Professor list of Mapuche Institute in Germany by means of the asymmetric PRINS reaction with a series of independently developed diaminodiphosphate (IDP) with strong acidity and large steric hindrance Fig 2 asymmetric PRINS cyclization (source: org Lett.) chiral tetrahydroquinolines (THQs) derivatives are a kind of very important nitrogen-containing heterocyclic compounds, which have many biological activities and wide applications THQs of fused ring also have unique biological activities and potential medical value (J Med Chem 2013, 56, 3656) There are also many challenges for the synthesis of chiral THQs At present, most methods are based on Diels alder reaction, Povarov reaction and hydrogenation reduction to construct THQs derivatives However, the mechanism of these reactions suggests that only h a and H B CIS products can be obtained, because the cycloalkenes used are CIS How to obtain THQs products of chiral H A and H B Trans is an unsolved problem (as shown in Fig 2b) The research group has made progress in the asymmetric [3 + 2] cycloaddition of o-alkenylphenol catalyzed by chiral phosphoric acid (org Lett 2018, 20, 2929; chem SCI 2019, 10, 6777), and the de aromatization of 2-naphthol compounds (chem - EUR J 2017, 23, 5381) Based on the understanding of the mechanism of PRINS cyclization, it is found that the enantioselectivity (trans vs CIS) of the product depends on the corresponding six membered ring (6-endo-trig) or five membered ring transition state (5-endo-trig) of the substrate and intermediate Based on the previous research and the understanding of the mechanism, the author designed a series reaction of PRINS cyclization and azamichael addition, and efficiently constructed two new heterocycles, three new chemical bonds (C-O, C-C, C-N) and three adjacent chiral centers For the first time, the asymmetric synthesis of trans tetrahydropyrfuran tetrahydroquinoline derivatives was realized (Fig 2b) As shown in) 5-o-hydroxyphenyl-4-ene-1-pentanol (1a) and 3,5-dibromo-o-aminobenzaldehyde (2a) were selected as template substrates When diphenyl phosphate (DPP) was selected as catalyst for the first time, a 3-A racemate with 46% yield was obtained Next, the best reaction conditions (Table 1 entry 15) were determined through the screening of the chiral phosphoric acid catalyst (CPA), substrate and catalyst equivalence ratio, and the product 3a of THQs was obtained with high yield, high enantioselectivity and single non enantioselectivity Table 1 screening of asymmetric PRINS cyclization reaction conditions (source: org Lett.) under the best reaction conditions, the author expanded the range of substrates For 1A substrates, THQs products (90-98% ee) can be obtained by better reaction results, either with electron absorption group or with electron group modification At the same time, the product 3A (451 mg, 95% yield, 98% ee) was also synthesized In addition, the absolute configurations of ent-3a, 3b-3d and 3G are confirmed by X-ray single crystal diffraction (as shown in Figure 3) Fig 3 1A substrate extension (source: org Let.) for 2A substrate (as shown in Fig 4), excellent results (3l-3u) can be obtained in 3-position single substitution and 3-position and 5-position double substitution, while 3W (yield: 52%, 90% ee) of 4-methyl substitution product is far lower than 3V (yield: 99%, 98% ee) of 3, 4-dimethyl substitution product ) When the author selected 4-bromo, 5-bromo, 6-bromo or 6-methyl monosubstituted 2A substrate and compared it with 3l, it was found that the yield of 3x was reduced, and the yield of 3Y was greatly reduced, while the target product was not obtained by 6-bromo and 6-methyl monosubstituted o-aminobenzaldehyde substrates The great difference may be caused by electronic effect and steric hindrance In addition, the product 3Z (yield 96%, 99% ee) was obtained at 60 ℃ Fig 4 2A substrate expansion (source: org Lett.) in order to better understand the reaction process, the author conducted the following control experiments (as shown in Fig 5) Under the standard reaction conditions, the target product 3AA was not obtained when the methyl protected 1AA was selected for reaction (Fig 5a) The experimental results show that substrate 1A may undergo the process of de aromatization When 1A with Z / E ratio of 1:1 was selected for the experiment, the product 3a with yield of 50% and EE value of 98% was obtained, and the substrate of z-1a was recovered with recovery of 49% (Fig 5b) The experimental results are in accordance with the author's initial assumption: it is possible that due to the influence of steric hindrance, the six element transition state formed by z-1a is difficult to carry out PRINS reaction Similar to the above reasons, when substrate 4 is selected for reaction, compound 5 with yield of 75%, Dr value of 5:1 and EE value of 95% is obtained (Fig 5C) In addition, when the author selects excessive substrate 1 (2.4 equivalent) and p-cyanobenzaldehyde 2AA for experimental study, the racemic compound 6 with high yield can be obtained, and the chiral compound 6 with medium to excellent enantioselectivity can also be obtained; moreover, the structure of the derivative compound 7d is confirmed by X-ray single crystal diffraction (Fig 5d) The capture results of compound 6 confirmed the possibility of PRINS cyclization step by step Fig 5 control experiment (source: org Lett.) the author proposed the following reaction mechanism (Fig 6) At first, the intermediate a was obtained by intermolecular nucleophilic addition reaction between compound 1a and 2L under the action of chiral phosphoric acid, and then the intermediate a lost a molecule of water to obtain the intermediate B of onium ion Under the catalysis mode of chiral phosphate ion, intermediate B undergoes PRINS cyclization through phenol dearylation and favorable six membered ring chair transition state to form intermediate C at this time, H A and H B have the lowest potential resistance Because of the steric hindrance, the transition state intermediate B 'formed by Z - 1A is not conducive to the PRINS reaction In the end, the intermediate C undergoes the intramolecular azamichael addition reaction, and the product 3L is generated, and the CPA catalyst is released to complete a catalytic cycle Fig 6 reaction mechanism (source: org Lett.) finally, the author tried asymmetric PRINS reaction with compound 2-hydroxy-1-naphthaldehyde 8 as an example The yield of compound 9 was 83% and the EE value was 82% (as shown in Figure 7) Fig 7 the results of series asymmetric PRINS cyclization (source: org Lett.) in which 2-hydroxy-1-naphthaldehyde was involved were recently published in org Lett (DOI: 10.1021/acs.orglett 9b02714) Sun huairi, a postgraduate of Northwest University, Zhao Qingyang, an associate professor of Zhongshan University, and Zhou Ling, a professor of Northwest University, were the first authors of the paper Thanks to the support of NSFC (216721702160217221203148), Shaanxi Provincial Outstanding Youth Fund (2018jc-020), natural science basic research plan (2018jm2029), and China Postdoctoral Science Fund (2018m643705) Today, when sun huairi (left) and Zhao Qingyang (right) pay more and more attention to figures and scientific research in the 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 website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.