Total synthesis of cytochalasin A-E

Cytochalasans are a large class of secondary metabolites produced by fungi At present, more than 300 similar compounds have been found in nature These compounds can combine with actin, change the polymerization of actin, and then affect the normal growth of cells, so they are called cytochalasin The results show that these natural products have a variety of biological activities, including antitumor, antibacterial and antiviral They can be widely used as lead compounds or tool molecules in pharmaceutical, biological and medical research Because of its rich chemical structure and biological activity diversity, cytochalasin natural products have attracted many synthetic chemists and biologists' research interests for many years Recently, Professor Tang Yefeng's research group of School of pharmacy of Tsinghua University has made important progress in the total synthesis of such natural products (angel Chem Int ed., 2018, DOI: 10.1002/anie.201808249) In recent years, Professor Zhang Yonghui of Huazhong University of science and technology has successively isolated a series of cytochalasin polymers from Aspergillus flavipes (1-13, figure 1) The natural products of these polymers are all formed by the known cytochalasin monomer aspochalasin B (14) and the polyphenol compound epicocine (15) through a series of different modes of polymerization (dimerization, trimerization or tetramerization), whose structural complexity and diversity of polymerization forms are amazing The discovery of these cytochalasin polymers greatly enriched the skeleton types of these natural products The structural novelty, complexity and diversity of these molecules not only bring great challenges to organic synthetic chemists, but also provide an excellent opportunity for the development of new strategies and new reactions In addition, some cytochalasin polymers also showed bioactivity that monomer compounds did not possess For example, asperchalasine a (8) has a strong G1 phase blocking effect on a variety of tumor cells, but has no significant effect on normal cells There is no doubt that these natural products have been found and potential biological activities have not been explored, which makes them become valuable resources for new drug research and development Figure 1: typical natural products of cytochalasin In recent years, Professor Tang Yefeng's research team has carried out a systematic and in-depth study on the total synthesis of natural products of cytochalasin and achieved a series of research results In 2016, the team completed the first full synthesis of periconiasinsa-f, a cytochalasin monomer with typical tricyclic and polycyclic skeletons (angel Chem Int ed 2016, 55, 6992 – 6996) As a further extension of the subject, and in order to solve the synthesis challenges brought by the new cytochalasin polymer, the research team has carried out a full synthesis study since the discovery of such molecules Recently, Professor Tang Yefeng's research group has made new progress in this field and successfully realized the first full synthesis of cytochalasin a-e The related papers were published on angelw Chem Int ed., and the corresponding authors were Professor Tang Yefeng and Professor Liu Gang (DOI: 10.1002 / anie 201808249), School of pharmacy, Tsinghua University Fig 2: at the beginning of the study on the hypothesis of the biogenic synthesis of asperchalalines, the author first proposed the biogenic synthesis pathway of asperchalalines A-H, and on this basis established the basic synthesis strategy of such dimers and trimers As shown in Fig 2, compounds epicocine (15) can be oxidized to obtain o-benzoquinone intermediates 16a and 16b, and both of them can be isomerized to obtain isobenzofuran 16C The latter, as an active intermediate, can act as diene to react with cytochalasin B (14) Because of the potential endo / exo and regioselectivity of the reaction, four heterodimeric natural products, asperchalalines g-h (5-7) and 17, can be theoretically obtained by path A-D After that, compounds 5 - 7 and 17 were selectively methylated to obtain the natural product asperchalalines B-E (1 - 4) In addition, compound 4 can also be further oxidized to o-benzoquinone compound 18, which then cycloaddition with the second molecule aspochalasin B to obtain the heterotrimer asperchalasine a (8) It can be seen from the above hypothesis that the primary task to realize the total synthesis of cytochalasin polymer is to construct the monomer aspochalasin B (14) efficiently Based on the previous work of the research group, the author developed a synthesis route with Diels alder reaction and RCM reaction as the key steps Starting from the known compounds, the target molecule 11-6-5 tricyclic core framework was constructed by only five steps After that, the author introduced the necessary functional groups in the c17-c20 position through the late functionalization, and finally completed the asymmetric synthesis of 14 in 11 steps (Fig 3) Fig 3: synthesis route of aspochalasin B (14) (source: angelw Chem Int ed.) Fig 4: synthesis route of heterodimer like cytochalasin (source: angelw Chem Int ed.) in obtaining monomer aspochalasin B (14) After that, the author focused on the synthesis of heterodimer like natural products In the aforementioned hypothesis of biogenic synthesis, the author assumes that the intermediate 16C of isobenzofuran is obtained by the oxidation of epicocine (15) However, in the initial attempt, the author did not get the expected heterodimerization products, only 15 self polymerization products After that, the author assumes that 16C can also be produced by dehydration of hemiacetal precursor 34 For this reason, the author designed and synthesized a series of semiacetals (such as 34, 37 - 39) These semiacetals were dehydrated in acid condition, and the corresponding isobenzofuran intermediates were formed in situ Then, they reacted with aspochalasin B by Diels alder It is gratifying to the author that all the above reactions can take place smoothly and the corresponding heterodimerization products can be obtained in a good yield (Fig 4) The results show that the steric effect of isobenzofuran precursor plays an important role in controlling the endo / exo selectivity of Diels alder reaction Free or partially protected precursors 34 and 37 were mainly converted into exo type addition products, while fully protected precursors 38 and 39 tended to form end o type products Figure 5: synthesis of heterotrimer asperchalasine a (8) (source: angelw Chem Int ed.) At the end of the study, the author removed the benzyl group of compound 40, and the product 17 obtained was directly mixed with 14 without purification and exposed to the air, then the expected oxidation reaction and biomimetic oxidation tandem [5 + 2] cycloaddition reaction took place, and the The NMR data of asperchalasine a (8) is consistent with the data of natural samples reported in literature Figure 6: summary of synthesis work (source: angel Chem Int ed.) total synthesis of natural products is a very challenging and artistic research work In this process, chemists connect each synthetic block reasonably and orderly to get the target molecules This process is like a complex and profound puzzle game, which requires the finisher to have high imagination, insight and execution In this study, the author organically integrates the inspiration of students and rational design, and vividly demonstrates this process: firstly, the author starts from two basic segments, and takes the Diels alder reaction and RCM reaction as the key steps to efficiently synthesize the tricyclic cytochalasin monomer aspochalasin B; on this basis, the author systematically studies aspochalasin B and another monomer By controlling the steric effect of the reaction precursor, four heterodimers (asperchalasine B-E) with different connection modes and stereochemistry were synthesized Finally, the first full synthesis of the heterodimer (asperchalasine a) was realized by using biomimetic oxidation tandem [5 + 2] cycloaddition reaction as the key step As the author said in the last prospect of the paper, the above research results have laid a solid foundation for the subsequent synthesis of some more complex natural products of trimer and tetramer in the cytochalasin family, and the related work is in progress Review of previous reports by Professor Tang Yefeng: research group of Professor Tang Yefeng, School of pharmacy, Tsinghua University 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, chembeangoapp, 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.