Protonation of alkynamide initiates polyene cyclization reaction, and efficiently constructs cis-hydronaphthalene skeleton

November 24, 2021


Overview: Prof.  Junfeng Zhao's research group from Guangzhou Medical University and Prof. Zhixiang Yu's research group from Peking University have jointly discovered a "universal" synthetic method for the efficient construction of the cis-hydronaphthalene skeleton by the polyene cyclization reaction initiated by the protonation of alkynamide. This method breaks through the limitation that the diastereoselectivity is highly dependent on the internal olefin configuration in the traditional polyene cyclization reaction, and realizes the high-efficiency construction of the easily available E-polyene with excellent diastereoselectivity, which is extremely challenging. Sexual cis-hydronaphthalene skeleton.



In Depth: Terpenoids and steroids are ubiquitous natural products with important biological activities, and their common feature is that they all have a complex polycyclic skeleton structure containing continuous multi-chiral centers. In nature, this type of complex fused-ring skeleton is constructed by a series of linear polyene cyclization reactions (referred to as polyene cyclization reactions) initiated by carbocations catalyzed by protonase. The biogenic synthesis of Hopene is such an example. The one-step polyene cyclization reaction initiated by carbocation builds 5 carbon-carbon bonds, forms 5 fused rings and contains 4 quaternary carbons. 9 consecutive chiral centers (Figure 1b). Theoretically, this reaction will produce thousands of isomers, but the enzyme almost perfectly gives only a product with a specific three-dimensional structure. The breathtaking complexity, high efficiency and high selectivity of the polyene cyclization reaction has attracted a large number of international top organic chemists such as Corey, Tamelen, Stork and Eschenmoser to imitate it through chemical means in the laboratory.


Figure 1


After more than half a century of hard work, as scientists have deepened their understanding of polyene cyclization reactions, chemists have also made great progress in the field of biomimetic polyene cyclization reactions. It has now been found that the chemoselectivity, regioselectivity and stereoselectivity of the reaction are closely related to the configuration of the olefin double bond of the ring-closure precursor and the conformation of the polyene. Based on preliminary results, summarized Stork and Eschenmoser polyene stereoselective cyclization is predictable (Stork-Eschenmoser hypothesis), that they contain polyene type olefin ( -polyenes) ring closure to give Trans - decalin product contained polyene (olefin type -polyenes) to give the CIS - decahydronaphthalene product (FIG. 1c). At present, the Stork-Eschenmoser hypothesis has been confirmed and supported by a large number of experimental results. In particular , the polyene cyclization reaction of -olefins has developed into a reliable method for constructing trans -decalin polycyclic framework, and has been widely used. In the total synthesis of terpenoids and steroidal natural products. However, the corresponding -polyenes ( Z- polyenes) strategy for constructing cis -decalin products is extremely challenging. While cis - decalin skeleton also widespread in the morphine alkaloids terpene natural products (FIG. 1a), but constructed by cyclization strategy polyene cis-The example of decalin skeleton to synthesize these natural products is very rare. This may be mainly due to the following two reasons: 1) Since the transition state energy of the two configuration products is not much different, the polyene cyclization reaction of -olefins usually produces cis -and trans -decalin products 2) Compared with the -type polyene, the construction of the cis -decalin skeleton requires the -type polyene ring-closure precursor which is more difficult to prepare . It was not until 2020 that the Gleason research group reported the first example of cis -decalin product obtained by the polyene cyclization reaction of -olefins.

The Zhao Junfeng research group of Guangzhou Medical University has been committed to the efficient synthesis of complex polycyclic compounds ( Angew. Chem. Int. Ed. , 2018 , 57 , 2115-2119; Chem. Commun. 2020 , 56 , 12817-12820) and peptide chemistry Synthesis and modification ( Chin. J. Org. Chem. 2021 , 41 , 873-887), they discovered alkynamide ( J. Am. Chem. Soc. , 2016 , 138 , 13135–13138; Angew. Chem. Int. Ed. , 2019 , 58 , 1382 – 1386; ACS Catal. 2020 , 10 , 5230-5235) and allenone ( J. Am. Chem. Soc., 2021 , 143, 10374-10381) Two types of original condensation reagents. Based on the previous work, they discovered a "universal" polyene cyclization reaction that efficiently builds the cis -decalin skeleton initiated by the protonation of alkynamide . This reaction breaks through the limitation that the diastereoselectivity is highly dependent on the internal olefin configuration in the traditional polyene cyclization reaction. Regardless of whether the central olefin is in the Z configuration or the E configuration, it can be passed through the polyene with alkynamide as the promoter. The cyclization reaction achieves the construction of the cis -decalin skeleton with high selectivity (Figure 1d). In this way, not only can the cis -decalin product be directly obtained from the E -type polyene which is easier to prepare , but also the tedious operation of separating E- and Z -olefins during the synthesis process of the ring-closure precursor polyene substrate is avoided .

In the process of studying the mechanism of the acetylenic amide condensation reagent, the author found that the acetylenic amide was protonated to form a highly active ketene imine cation, and then the ketene imine cation was captured by the carboxylate anion to form an alkenyl activated ester. The ammonolysis reaction builds an amide bond. At the same time, they also noticed that the highly active ketene imine cations can be used to initiate a series of cationic tandem reactions to construct a polycyclic skeleton. Richard Hsung of the University of Wisconsin, Evano of the University of Brussels, Belgium, and Professor Ye Longwu of Xiamen University have all in this regard. Have done a very good and beautiful job. The author therefore proposed the idea of ​​using acetylenic amide as a promoter of polyene cyclization reaction, by reacting with Bronsted acid to form a highly active ketene imine cation, thereby triggering the polyene cyclization reaction. In addition to efficiently constructing polycyclic skeletons of natural terpenoids and steroidal products, it can also provide an additional nitrogen-containing functional group, which is expected to provide a new strategy for the total synthesis of terpenoid alkaloid natural products.

Preliminary research results show that their idea is feasible. The authors use E- YCP linear olefins with alkynamide as the promoter as raw materials. Under the action of strong Bronsted acid, they can obtain excellent diastereoselectivity. The target product 2a of olefin cyclization . Surprisingly, when they characterized the tricyclic product 2a by single crystal diffraction , they found that the relative configuration of the hydronaphtho ring skeleton was cis -instead of the trans -configuration expected by the Stork-Eschenmoser hypothesis (Figure 1c, Figure 2-1). This has aroused great interest of the author. In order to explore this abnormal stereoselectivity, the author conducted experiments with the Z- YCP olefin substrate 3 with the opposite configuration . What is interesting is that they also obtained the tricyclic product of the cis -configuration. 2a (Figure 2-2). This result indicates that the polyene cyclization reaction initiated by the protonation of alkynamide is likely to proceed in a stepwise manner, and the E -and Z -YCP substrates are both reacted through the same intermediate. Fortunately, when the author uses a catalytic amount of trifluoromethanesulfonic acid (20%) for the reaction, whether it is E- YCP olefin substrate 1a or Z- YCP olefin substrate 3 or their mixtures can be highly selective The monocyclic product 4 is obtained . The important thing is compound 4Under standard cyclization reaction conditions, it can be efficiently and smoothly converted into the final tricyclic product 2a (Figure 2-3). Therefore, the author proposes that the monocyclization product 4 is a common intermediate in the reaction of Z- and E- YCP substrates. This discovery provides an innovative and convenient method for constructing the extremely challenging cis -decalin skeleton from the easily prepared E -type polyene , and is a breakthrough in the traditional polyene cyclization reaction law. The author further systematically optimized the optimal conditions of the reaction. The solvent, acid and its amount and temperature all have a significant influence on the chemical selectivity and yield of the reaction. Finally, the author found that 20 times equivalent of trifluoromethanesulfonic acid Under the action, the best reaction result can be obtained by the low temperature reaction at -40 degrees.



Figure 2


After determining the standard reaction conditions, the author investigated the universality of the reaction substrate (Figure 3). As far as the structure of the promoter alkynamide functional group is concerned, the sulfonamide group has a good tolerance for substituents. Generally speaking, electron donating substituents are better than electron withdrawing substituents ( 2a - 2e ); when the benzenesulfonamide group is replaced with methanesulfonamide, the reaction can still proceed smoothly to obtain the corresponding product ( 2f ). The YCP polyene terminator also has good compatibility with various substituents. Whether the terminator has an electron-withdrawing group or an electron-donating group on the benzene ring, the target tricyclic product can be obtained in good to excellent yields ( 2g - 2l ); In addition, the substrates substituted by heterocycles can also be compatible ( 2m - 2o ); when the terminator has substituents such as chlorine and bromine on the benzene ring, the reaction can also obtain the target product in good yield ( 2i , 2k ); when m- Br-Ph- is used as the terminator, the para-cyclization product 21 and the ortho-cyclization product 2l' can be obtained with a yield of 47% and 26%, respectively . These products containing halogen substituents provide opportunities for further conversion of products through transition metal-catalyzed coupling reactions. Unfortunately, when the terminator is a strongly electron-rich or strongly electron-deficient phenyl group, the reaction will stop at the monocyclic intermediate. For example, when using 3, 4, 5-trimethoxyphenyl with three electron-donating methoxy groups as the terminator, the author only obtained the monocyclic product 2p with a yield of 51% , and no tricyclic ring was observed. Chemical products are formed.


Figure 3


In order to further demonstrate the versatility of this method, the author investigated some E- YCP polyene substrates containing ether bonds (Figure 4). The results of the study show that E- YCP substrates containing ether bonds can also construct cis - oxahydronaphtho ring skeletons with excellent diastereoselectivity . The structure and stereochemistry of the tricyclic products are determined by the nuclear magnetic summation of the final products 6c and 6i . The single crystal diffraction experiment was confirmed. And the total carbon E -YCP similar substrate polyene, containing an ether bond E -YCP substrate polyene of the various substituents are well tolerated, both the terminator benzene electron withdrawing group, or to Electronic groups are compatible ( 6b - 6k ). Similarly, when there is a strong electron withdrawing group -NO 2 or two strong electron donating groups -OMe on the benzene ring of the terminator of E- YCP substrate , the author only obtained monocyclic products 6l and 6m , which may be due to strong absorption. The electron NO 2 substituent leads to the lack of electrons in the benzene ring of the terminator, which is not conducive to the occurrence of Friedel-Crafts alkylation reaction. For substrates 1p and 5m containing 3 or 2 methoxy groups , the reason for the formation of monocyclic products may be that the strong acid protonates the electron-rich trimethoxyphenyl group, making it difficult to participate in Friedel-Crafts alkylation reaction.


Figure 4


In order to reflect the application prospect of this method in the synthesis of complex polycyclic compounds, the author tried to further transform the polycyclic products (Figure 5) . For example, the enamide carbon-carbon double bond of cis -hydronaphthalene 2a can be smoothly reduced to obtain an amide derivative with excellent diastereoselectivity (dr>99:1) . This intermediate will be used for terpene alkaloids. The total synthesis of natural products; secondly, the tricyclic product 2a can obtain α -bromoketone 8 in good yield and diastereoselectivity under the action of NBS . Since it contains both bromine substituent and ketone carbonyl group, compound will be Become a very useful synthetic intermediate. It is worth noting that E- YCP polyene substrates can be easily obtained from Corey’s -configuration terminal alkyne polyene substrates through one-step oxidative coupling reaction, while Corey’s -configuration terminal alkyne polyene substrates The substrate can efficiently construct the trans -hydronaphthalene skeleton under the catalytic conditions of InI . After Corey's -configuration polyene substrate has a terminal alkyne converted into an alkynamide promoter, it is used for the efficient construction of the cis -hydronaphthalene skeleton under the author's reaction conditions . This means that the author and Corey’s methods combine to make cis -and trans-Hydronaphthalene skeletons can be obtained from easy-to-prepare -configuration terminal alkyne polyene substrates. This advantage will play an important role in the construction of complex polycyclic compound libraries and diverse synthetic strategies.


Figure 5


The research team of Peking University Yu Zhixiang proposed a step-by-step double-protonation reaction mechanism to understand and explain this unusual cis -diastereoselectivity (Figure 6), and performed DFT calculations on the energies of different reaction paths. They believe that the polyene substrate E- YCP ( 1a ) or Z- YCP ( 3 ) is first protonated by TfOH to obtain the highly active ketene imine cation I , and then the ketene imine cation pairs the intramolecular olefin double bond Perform electrophilic addition to obtain carbocation intermediate II . The intermediate may be directly subjected to Friedel-Crafts alkylation to obtain III' , and then deprotonated to obtain the experimentally observed cis -product 2a . Although this competition is very easy way but it did not happen, mainly because: once the carbocation intermediate II generation, which can be quickly TfOH molecular clusters in TfO - anion capture, form the intermediate II-OTf , and then through beta] - elimination reaction product was converted to monocyclic 4 . In fact, under the condition of catalytic amount of TfOH, the author did isolate compound 4 , which provided experimental support for this idea. When using an excessive amount of TfOH, compound 1a or 3 is still produced through the same processII-OTf . Only under excessive strong acid conditions, II-OTf is further protonated to obtain a double positive ion species IV , which is then Friedel-Crafts alkylated with the "terminator" benzene ring, and then deprotonated to obtain the final tricyclic product 2a . The monocyclic intermediate 4 can also undergo the same stepwise diprotonation process under standard ring closure conditions, and finally the tricyclic product 2a is obtained through the Friedel-Crafts alkylation reaction of the dicationic species IV.


Figure 6


The author first uses DFT calculations to explain why the Friedel-Crafts alkylation reaction of double positive ion species IV tends to produce cis -products (Figure 7). The calculation starts from the ketene imine cation I , the protonation product of the YCP polyene substrate 1a or 3 , and the cyclization reaction of the ketene imine cation with the intramolecular olefin double bond is easy to proceed (the energy barrier is 0.5 kcal/mol ), will get carbon ion II . After, II quickly adjacent TfO - anion is quenched to form an intermediate II-OTf ( II obtained by direct Friedel-Crafts alkylation CIS - product . 2A , desired energy barrier which is only 2.4 kcal / mol; generating Trans - The energy barrier required for the product is 8.2 kcal/mol). Subsequently, the neutral intermediate II-OTf generates 4 through the β -elimination reaction , and the energy barrier of this process is 20.3 kcal/mol. Although the free energy of II-OTf is 8.2 kcal/mol more stable than 4 , considering that the product TfOH will be rapidly consumed by 1a ,4 can still be produced. Although TfO - anion can directly deprotonate carbocation II to form 4 , and it is a process without energy barriers, because another route to intermediate II-OTf is more favorable, this route will not occur. 

When excess TfOH, II-OTf in TfO - and enamine can be protonated, TfOH then releases a molecule, to obtain a double positive ion intermediate IV . Theoretically, the intermediate can obtain cis -and trans -and cyclic products through two cyclization pathways respectively . The results show that, by the TS-IV-V transition state CIS - the reaction pathway, only 1.1 kcal / mol activation energy can be obtained free cyclized species V . However , two steps are required in the reaction pathway to generate trans -products. TS-IV-VI first generates dicationic intermediate VI from IV with an energy barrier of 13.7 kcal/mol. This step needs to absorb energy of 6.5 kcal/mol; Then TS-VI-VII migrates through the intramolecular C-C bond to generate a more stable species VII . The energy barrier of this step is 6.5 kcal/mol. The DFT calculation results show that 13.7 kcal/mol of activation free energy is required to generate trans -products, which is 12.6 kcal/mol higher than the pathway to generate cis -products. Therefore, the kinetics is not conducive to the formation of trans -products, which is consistent with the experimental results.


Figure 7


In addition, the cis -selectivity of the reaction can be explained by steric hindrance. As shown in Figure 9b, the methyl group of the imine cation and the paralyzed alkyl group in the trans -transition state TS-IV-VI have a strong 1,3-repulsive effect (the methyl hydrogen in the B and C groups and the The distance of methylene hydrogen is only 2.05 Å); the repulsion of the A and B groups in TS-IV-VI may be another influencing factor, and the distance between methyl hydrogen and methylene hydrogen is 2.30 Å . However, in the cis -transition state TS-IV-V, the A and B groups are in the trans configuration, and the A and C groups are in the staggered configuration, and the steric hindrance effect is small. Therefore, these two factors cause the activation free energy required for the trans -transition state TS-IV-VI to be 12.6 kcal/mol higher than the activation free energy required for the cis -transition state TS-IV-V.

In summary, the Zhao Junfeng research group of Guangzhou Medical University and the Yu Zhixiang research group of Peking University have jointly discovered a "universal" synthetic method for the efficient construction of cis - hydronaphthalene skeleton by the polyene cyclization reaction initiated by the protonation of alkynamide . This method breaks through the limitation that the diastereoselectivity is highly dependent on the internal olefin configuration in the traditional polyene cyclization reaction, and realizes the high-efficiency construction of the easily available E -polyene with excellent diastereoselectivity, which is extremely challenging. Sexual cis -hydronaphthalene skeleton. Since such cis -hydronaphthalene skeletons are widely present in natural products such as terpene alkaloids with important biological activity, such as morphine, this method is expected to provide new ideas and new strategies for the total synthesis of such natural products. The research team of Peking University Zhixiang Yu proposed a step-by-step two-protonation reaction mechanism model, which is supported by DFT theoretical calculations. The calculation results show that this abnormal stereoselectivity is mainly caused by the steric hindrance in the transition state. In the transition state of Friedel-Crafts alkylation reaction, the space between the substituent on the imine and the hydrogenated naphthalene skeleton that is being formed Repulsion is the fundamental reason for the excellent diastereoselectivity; at the same time, both experimental results and theoretical calculations show that excess TfOH is essential for the formation of cis -decalin, which is also a step-by-step double protonation reaction mechanism. Strong support.

This result was recently published in CCS Chemistry and has been online in the Just Published column of the official website. The author would like to use this article as a gift to celebrate the 100th anniversary of the founding of the School of Chemistry of Nankai University! This research work was funded by the National Natural Science Foundation of China and the Open Fund of the State Key Laboratory of Elemental Organic Chemistry of Nankai University.


Article Details:

Ynamide Protonation-Initiated Cis-Selective Polyene Cyclization and Reaction Mechanism

Jiasheng Yao , Chen-Long Li , Xing Fan, Zhou Wang, Zhi-Xiang Yu* and Junfeng Zhao*

Citation:CCS Chem. 2021, 3, 3133–3143