JACS: the Sarpong group of the University of California, Berkeley, uses the C-C bond activation strategy to complete the synthesis of (- - xishacorene B

The construction of C-C bond is very important in the synthesis of terpenoids and other complex organic molecules When developing the strategy of total synthesis of terpenoids, chemists usually focus on new C-C bond construction methods For example, when cheap and easily available chiral reagents are combined with new C-C bond construction methods, the C-C bond activation of carvone will generate new skeleton structure, thus expanding the range of complex product molecules (1 → 3, figure 1a) In addition, it has been reported in the literature that after the conversion of epoxy carvone 4 to dihydroxylated pinene derivative 5, the natural product nuclear structure 6 was obtained by cross coupling with vinyl or aryl halides via PD (0) catalysis (Figure 1b) Xishacorene B (7, figure 1c) is a new diterpenoid compound (org Lett 2017, 19, 4183) isolated by Guo Yuewei, a researcher of Shanghai Institute of medicine, Chinese Academy of Sciences, from the soft coral sinualia polydactyla along the Xisha Islands in 2017 The preliminary results of biological screening showed that it can be used as a promoter of T lymphocyte proliferation induced by concanavalin A Therefore, these molecules have the potential to become new small molecular Immunoenhancers Recently, the Richmond Sarpong group of the University of California, Berkeley, used the C-C bond activation strategy to complete the synthesis of (-) - xishacorene B from raw material (R) - carvone through ten steps The related papers were published on J am Chem SOC (DOI: 10.1021 / JACS 8b05832) (photo source: J am Chem SOC.) inverse synthesis analysis and coupling reaction optimization of xhacoreneb (Figure 1c): xhacoreneb (7) can be traced back to bicyclic [3.3.1] nonane 8, and 8 can be synthesized from cyclobutanol 5 and vinyl iodine 9 Firstly, the cross coupling reaction between cyclobutanol 5 and vinyl iodine 9 was optimized (Table 1) According to Uemura's report, the coupling mechanism may involve: PD (0) complex is inserted into 9 to obtain PD (II) species, which is exchanged by ligands to form alkenyl PD alkoxide 11; at this time, β - C elimination / C-C bond activation will lead to the cracking of cyclobutanol to produce alkyl palladium intermediate 12, and then 12 is eliminated to obtain 13, completing the catalytic cycle PD (pcy3) 2 is the best palladium complex, the reaction temperature is 30-40 ℃, and cyclobutanol 5 with free hydroxyl is the ideal substrate When the amount of vinyl iodide 9 is 1.5 equivalent, the yield of coupling reaction is the highest; when the amount of vinyl iodide 9 and reaction temperature are reduced, the yield is decreased Compared with 1,4-dioxane, benzene is a better solvent; when EtOAc is used as solvent, the acylation of free hydroxyl group can be completed in one step, so as to realize in-situ acyl protection (photo source: J am Chem SOC.) the optimized reaction conditions can be extended to the coupling of compound 5 with a series of vinyl halides (Figure 2), and the corresponding adducts can be obtained in a good to extremely good yield Vinyl iodide can only be coupled at a lower reaction temperature, while vinyl bromide needs a higher temperature In order to construct a bicyclic framework, the author tried to use the coupling product shown in Figure 2 to carry out Mukaiyama type hydrogen atom transfer (HAT) reaction, and discussed the conditions for the cyclization of hat The final reaction conditions were as follows: first, HBr / AcOH was used to treat electron rich double bond to introduce tribromide, and then two cyclized products (Table 2) were obtained under free radical conditions (AIBN, n-Bu 3snh, 80 ℃) In addition, the change of catalyst system, silane reagent and solvent can lead to competitive side reactions (image source: J am Chem SOC.) (image source: J am Chem SOC.) next, the author obtained 34 (scheme 1, a) by 13 Bromination and hydroxylation, and then 34 was cyclized by free radicals to obtain the diastereomer mixture 35 (D.R is 1.1:1) in 92% yield After [3.3.1] tricyclic intermediate 35 was obtained, two ester groups and ketone carbonyl groups were reduced by LiAlH 4 to obtain triol 8, which was selectively converted to corresponding iodide 36 by DCC · Mei treatment At high temperature, the elimination of C9 terminal group iodine and the formation of vinyl group occurred after 36 t-BuOK treatment The author speculates that in this reaction, C12 hydroxy substituted C15 iodide was etherified by Williamson to obtain oxyheterocyclobutane intermediate 39, and alcohol 40 was obtained after C12 hydroxy elimination Xishacorene B (7) was prepared by PCC oxidation and HWE olefinization, but the reported data were different from that of natural products (synthesis product: - 19.5; natural product: - 11.3) The author speculates that this may be due to the poor solubility of 7 in methanol due to its strong lipophilicity In the end, the author realized the synthesis of C1 isomer 36 (scheme 1b) of 7 by using bicyclic intermediate 43 in the same way (photo source: J am Chem SOC.) conclusion: Sarpong group completed the synthesis of (-) - xishacorene B through ten steps reaction with (R) - carvone as raw material, and proved the practicability of C-C bond activation / cross coupling sequence reaction in the construction of complex molecular skeleton Carvone was converted into pinene derivatives by two steps, which laid a foundation for cross coupling In this paper, various kinds of [3.3.1] bicyclic skeletons were constructed by PD catalyzed C-C cleavage / coupling of cyclobutanol and free radical mediated C-C bond formation At the same time, a new method for the synthesis of complex molecular framework is provided by activating inert C-C bond Professor Richmond Sarpong's research direction: Based on the new synthesis methodology, the total synthesis of natural products is mainly aimed at the complex structure of polycyclic alkaloids.