Gong Liuzhu group, University of science and technology of China and Hong Xin group, Zhejiang University: palladium catalyzed asymmetric allylic C c-h-bond alkylation of 1,4-diene and acridolide

The author of the paper: Lin Huachen's asymmetric allyl alkylation is one of the most important methods for asymmetric catalytic formation of C-C bond, which usually requires the use of highly active allyl reagents, such as allyl carbonate, allyl halides, etc Compared with the classical allylic alkylation, allylic C c-h-bond alkylation has better atom and step economy However, there are relatively few asymmetric reports about this kind of reaction Recently, Gong Liuzhu group of University of science and technology of China and Hong Xin group of Zhejiang University reported palladium catalysis 1, Asymmetric allylic C c-h-bond alkylation of 4-diene and acridolide yields branched chain products with cis double bonds with very good regioselectivity and stereoselectivity, and a new hydrocarbon bond activation mode based on electron pair proton synergistic transfer is found by DFT calculation The results were published online in J am Chem SOC (DOI: 10.1021 / JACS 8b13582) Figure 1 Condition screening (source: J am Chem SOC.) the author first used acridolide 1a and 1,4-diene 2A as template substrates, and through a series of reaction condition screening (Figure 1), found that PD (DBA) 2 as palladium source, L5 as chiral ligand, 2,5-dmbq as exogenous oxidant, toluene as solvent, substrates 1a and 2A reacted at 25 ℃ for 20 The target product 3AA can be obtained in 99% yield and 99% ee per hour Under the optimal reaction conditions, the applicability of the substrate was investigated (Fig 2) Alkyl substituted 1,4-diene substrates can participate in the reaction well (3ab-3al), and can tolerate a variety of active functional groups, such as alkyl chloride, ester group, amide, alcohol hydroxyl, aromatic heterocycle, etc Aryl substituted 1,4-diene can also participate in the reaction well, but the product is not very stable, so it needs to be converted into stable methyl ester (3am '- 3aq') In addition, the acridolide with different substituents on the aromatic ring can obtain the target product (3ba - 3Ga) with excellent regioselectivity and stereoselectivity The acridolide with different alkyl substituents can also obtain the alkylation product (3HA - 3KA) with medium to good yield and good stereoselectivity Figure 2 Substrate range (source: J am Chem SOC.) it is worth noting that this method can provide key chiral intermediates 3lr and 3LS for asymmetric catalytic synthesis of lepadiformine marine alkaloids (Figure 3) Acridolide 3 is reduced by NaBH 4 to obtain chiral primary alcohol, which is oxidized by DES Martin reagent to obtain chiral aldehyde 4 4 reacts with p-ylide to get olefin 5, 5 reacts with ring closing and double decomposition to get cyclohexadiene 6 The double bond was reduced by Pd (OH) 2 / H 2, the benzyl group was removed, and the amide was reduced by LiAlH 4 to get alcohol 7 Finally, the product 9 can be obtained by deprotection, reductive amination and cyclization Among them, 9B is the natural product lepadiformine C In addition, 9 is the intermediate compound of synthesis lepadiformine A and B reported in the literature Figure 3 Total synthesis of lepadiformine (source: J am Chem SOC.) next, by designing a series of mechanism verification tests and combining the theoretical calculation and simulation results of Hongxin research group of Zhejiang University, the author proposes a new carbon hydrogen bond activation mode based on electron pair proton cooperative transfer (Figure 4) From complex 12, allylic hydrocarbon bond was activated by transition state ts13 to produce PD (II) intermediate 14 It is confirmed that the double electron transfer and proton transfer involved in the activation process of hydrocarbon bond are synergetic by the internal reaction coordinate calculation structure By deprotonation and isomerization of acridolide, π - allylpalladium intermediate 18 with s-trans geometry can be formed 18 can undergo the transition state TS19 isomerization to s-cis geometry π - allylpalladium intermediate 22 Due to the influence of nucleophile geometry and coordination mode, the product 3BB can be obtained from the transition state ts23 with relatively low energy barrier The rate determining step in the whole reaction process is the allylic hydrocarbon bond activation process, which is consistent with the kinetic experimental results Figure 4 DFT calculation results (source: J am Chem SOC.) recently published in J am Chem SOC (DOI: 10.1021 / JACS 8b13582) The first authors of this paper are Lin Huachen, Ph.D student of University of science and technology of China, Xie Peipei, Ph.D student of Zhejiang University, and Gong Liuzhu, Wang Pusheng, Ph.D student of University of science and technology of China And Hong Xin from Zhejiang University The above research work was supported by the Ministry of science and technology and the National Natural Science Foundation of China.