Professor Liu Bo, School of chemistry, Sichuan University, research group: divergent total synthesis of natural products of aconitine sesquiterpene dimer

As one of the most representative natural metabolites isolated from the family Chloranthaceae, dioscorea sesquiterpenes has attracted wide attention due to its complex structure and excellent biological activity Up to now, several research groups have reported on the synthesis of sesquiterpenoids Recently, Professor Liu Bo's research group of Sichuan University made a new breakthrough, and completed the total synthesis research of natural products of eight aconitine sesquiterpene dimers with divergent strategy (Fig 1, NAT Commin 2019, 10, 1892) Once published, this work was selected as the highlight work by Nat Commin., which is the second generation synthesis of aconitine sesquiterpene dimers by the research group Fig 1 A brief introduction to Professor Liu Bo's research group Professor Liu Bo's research group is mainly interested in the synthesis of complex natural products of terpenes With the aid of biomimetic synthesis strategy, it focuses on the combination of series reaction and one pot multi-component reaction to carry out the research work of high-efficiency and full synthesis of target molecules and related synthesis methodology He has undertaken the research work of National Natural Science Foundation of China (key projects, general projects, excellent youth fund), the "973" plan of the Ministry of science and technology, and the new century excellent talents support plan of the Ministry of education Prof Liu Bo, Professor of the school of chemistry, Sichuan University, winner of the National Excellent Youth Fund Graduated from Southwest Normal University in 1998 with a Bachelor of Science degree In 2001, he received a master of Science degree from Chengdu Institute of organic chemistry, Chinese Academy of Sciences, under the guidance of researcher Feng Xiaoming and researcher Jiang Yaozhong In 2004, he received his Ph.D in science from Shanghai Institute of organic chemistry, Chinese Academy of Sciences, under the guidance of researcher Zhou Weishan From September 2004 to March 2007, he was engaged in postdoctoral research in Southwest Medical Center of the University of Texas He was mainly engaged in transition metal catalyzed reaction research and total synthesis of natural products His tutor was Prof Jef K de brabander Since June 2007, he has worked in the school of chemistry, Sichuan University Professor Liu Bo has published more than 60 SCI papers in J am Chem SOC., angel Chem Int ed., org Lett., chem Commun., EUR J chem And other professional journals Some of the research results were selected as most read articles of org Lett And J am Chem SOC., which were included in the website of chemistry specialty organization highlights, and included and positively evaluated by brsmbog Com and chemlogs Net, as well as synfacts Professor Liu Bo won the following Awards: New Century Excellent Talents support program of the Ministry of Education (2009), excellent youth fund of National Natural Science Foundation (2013), Thieme Chemistry Journal Award (2014), ACP letureship awards to Japan & Malaysia (2014), ACP letureship awards to Taiwan (2015) ）, Weishan natural product synthesis award of China Chemical Society (2015), ACP letureship awards to Singapore (2016), etc Frontier scientific research achievements: Professor Liu Bo's research group began to study the synthesis of natural products of aconitine sesquiterpenoids in 2008 (Figure 2) In the first few years, it focused on the synthesis of aconitine sesquiterpenoids monomer, and then turned to the study of the total synthesis of [4 + 2] dimer After years of efforts, it has achieved A series of achievements are as follows: (1) in 2011, the synthesis of aconitine sesquiterpene monomer was realized (org Lett 2011, 13, 5406); (2) in 2013, the high-efficiency synthesis of natural products bolivianine and isobilivinine of aconitine sesquiterpene was completed for the first time by using bionic simulation (j.am Chem SOC 2013, 135, 9291; chem EUR J 2014, 20, 2613; CCL In 2017, 28, 113); (3) in 2015, a rhodium catalyzed intramolecular cyclopropanization reaction was developed to construct the 3 / 5 / 6 bicyclic framework of the urane, laying a good foundation for the rapid synthesis of such natural products (CC 2015, 51, 6179); (4) in 2017, the total synthesis of shizukol D and sarglablide J, the natural products of aconitine sesquiterpene dimer, was realized for the first time (angel Chem Int ed., 2017, 56, 637); (5) this year, based on the work in 17 years, the divergent total synthesis of aconitine sesquiterpene dimer was realized (NAT Commun., 2019, 10, 1892) Fig 2 research process of synthesis of natural product monomer and dimer of aconitine of Professor Liu Bo's research group For [4 + 2] type aconitine sesquiterpene dimer, it can be divided into type 1, type 2 and type 3 types according to different substituents on B ring (as shown in Fig 3) Among them, Professor Liu Bo's research group has completed the total synthesis of type 2 natural products shizukaol D and sargradrolide J (angel Chem Int ed., 2017, 56, 637) Peng Xiaoshui's research group has realized the total synthesis of type 1 natural products shizukaol A and type 2 natural products shizukaol e (nature commun., 2018, 9, 4040) However, there is no successful report on the total synthesis of type 3 natural products Considering that this kind of natural products also have a variety of excellent biological activities, and that type 3 is similar to type 1 and type 2 in terms of structure, Professor Liu Bo's research group envisages whether to start from type 1 Natural products and realize type 2 and type through several derivative steps Unfortunately, the direct functionalization of B-ring in type 1 natural products resulted in no need of enantiomers Therefore, it will be of great significance to develop a general strategy to construct the natural products of the above three types of diomers After a lot of detailed research, they found that pyridine promoted in-situ formation of diene precursor can realize the construction of type 3 natural product skeleton, and then synthesized a number of natural products of active aconitine type sesquiterpene dimer Fig 3 the structure of three kinds of [4 + 2] type dimers and their related biogenic synthesis pathway Considering that furadiene is unstable and difficult to separate, Professor Liu Bo's research group used the strategy of acid mediated in-situ diene formation to realize the synthesis of these natural products in the previous synthesis of type 2 natural products (Fig 4) However, they found that the exo / endo isomerization process would take place in the type 1 natural products with double substitution of Gemini, for example, the conversion of bolivianine to isobolivianine could be realized under the condition of acid Therefore, they speculated whether a common alkali promoted strategy could be developed to construct the above three types of natural products of aconitine sesquiterpene [4 + 2] After studying the structure of type 3 natural products, they found that sarglablide I can be selected as a common intermediate of natural products to achieve the divergent synthesis of other type 3 natural products It should be noted that in the strategy of [4 + 2] reaction realized by alkali, the preparation of diene precursor is shorter than that of the previous acid promoted cycloaddition reaction (12 steps vs 17 steps) Fig 4 evolution progress from acid promoted Diels alder reaction to current strategy For the synthesis of diene precursor, Professor Liu Bo's research group took commercially available chiral reagent (+) - Verbenone as the starting material (Fig 5) After SEO 2 oxidation and BF 3 OET 2 catalytic ring opening, it was oxidized with 3A [3 + 2] in the presence of can The furan ring was constructed by cycloaddition, and then further converted to hydrazone by allylic oxidation Then the 3 / 5 / 6 framework structure was constructed by improving the rhodium catalyzed intramolecular cyclopropanization (chem Commun 2015, 51, 6179) developed by the research group Finally, the diene precursor 7 was obtained by allylic oxidation, esterification and NaBH 4 reduction Fig 5 synthesis of furandiene precursor In addition, for the synthesis of amphiphilic diene, the research team tried to build a stereochemistry correct hydroxyl intermediate compound on C4 site based on the known intermediate 8, but they tried a variety of strategies without success For example, in the osmium catalyzed dihydroxylation or Sharpless asymmetric dihydroxylation, compound 8 is the product with stereochemistry opposite, while in the PR é Vost trans dihydroxylation, it is the allyl compound or mixture (Fig 6) Fig 6 synthesis attempt of amphiphilic diene Finally, they found that the target compound 14 can be obtained by ozone breaking reaction of compound 8 without any reductant during post-treatment At this time, a small amount of differential isomerization by-product 15 will be accompanied Then they tried to use vinyl metal reagents with large steric hindrance to achieve ketone carbonyl addition while inhibiting C5 isomerization, resulting in all by-products of isomerization 15 (Fig 7) After that, they found that the addition of compound 14 can be realized by using vinyl lithium with small steric hindrance as nucleophilic reagent, which can not only obtain the target product 16, but also inhibit the isomerization process The results show that the temperature of the reaction has an obvious effect on the experimental results The alkenylated products were broken into aldehydes by ozonation, then reduced to compound 9, then deprotected, aldol condensed to lactone precursor, and finally converted to amphiphilic fragment 18 by aldol condensation Fig 7 synthesis of amphiphilic 18 They will get furandiene precursor 7 to generate furandiene compound 19 in situ under the condition of pyridine, and [4 + 2] cycloaddition reaction with amphiphilic 18 can occur smoothly under the condition of heating This reaction has achieved good surface selectivity, regional selectivity and end O-type selectivity (Fig 8) It should be pointed out that they can get the optimal yield by carefully adjusting the reaction temperature In addition, the formation of furadiene intermediates in situ by compound 7 is accompanied by the rearrangement of cope Fig 8 the [4 + 2] intermediate 21 obtained by the key Homo activated Diels alder reaction optimization can be obtained through the removal of glycol protection, ester reduction and furan oxidation ring opening to obtain the common natural product intermediate sarglablide I which can be subsequently derived After selective esterification, sarglablide I can generate natural products multistalide B and shizukaol C respectively (Fig 9) Fig 9 Total Synthesis of sarglablide I, multistalide B and shizukaol C dimers of aconite sesquiterpene In addition, sarglablide I, a natural product, can be selectively esterified with 26, and the 27 produced can be desilicated to protect shizukaol I In addition, 27 can be further selectively esterified with 29, and then chlorojaponide C can be produced by desilication protection Previous biological activity studies showed that the natural product has excellent antimalarial activity, with IC 50 reaching 1.1nm Cytotoxic studies showed that the compound has high selectivity factor (Si = 4900), which indicated that The compound is a potential anti malaria candidate drug molecule (Figure 10) Fig 10 total synthesis of shizukaol I and chloroajaponilide C dimers of aconite