Recently, the Gui Jinghan research team of the Shanghai Institute of Organics cooperated with the Hongxin research team of Zhejiang University to complete the synthesis of natural products bufospirostenin A and ophiopogonol A by using free radical fragmentation reaction and cross

The steroidal natural products rearranged by

skeleton have attracted widespread attention from synthetic chemists due to their novel and unique chemical structure. Among them, bufospirostenin A and ophiopogonol A are complex steroidal natural products with a 5/7/6/5/5/6 hexagonal skeleton separated by Jinan University Ye Wencai's research group and Shenyang Pharmaceutical University Li Ning's research group. Preliminary studies show that bufospirostenin A has 21% and 43% inhibitory activities on ATPase at concentrations of 12.5 and 25 μM, respectively. Southern University of Science and Technology Li Chuangchuang's research group, Shanghai Institute of Organic Gui Jinghan's research group and Peking University Yang Zhen's research group successively reported the synthesis research of bufospirostenin A. Recently, the Gui Jinghan research team of the Shanghai Institute of Organics cooperated with the Hongxin research team of Zhejiang University to complete the synthesis of natural products bufospirostenin A and ophiopogonol A by using free radical fragmentation reaction and cross-ring Prins cyclosynthesis reaction. A total of 7 reactions were carried out. The relevant work was published in the Journal of the American Chemical Society (J. Am. Chem. Soc. 022, 44, 17769–17775).

Figure 1. Structure of steroidal natural products bufospirostenin A and ophiopogonol A. (Image source: J. Am. Chem. Soc.) The flexibility and ring tension effect of ring compounds in

makes their conformational control extremely challenging. For example, the cross-ring Prins cyclosynthesis reaction of cyclodecene is a very convenient method to prepare 5/7 ring unit (Figure 2), but the currently reported cross-ring ring reaction can only be obtained from the cross-conformation realizes the preparation of trans-ring skeleton 4, while there is no relevant report from parallel conformation 3 to selectively obtain cis-ring skeleton 5. Therefore, the author hopes to develop a conformational control method to achieve cis-selective cross-circuit cyclosynthesis reaction, thereby providing a simple and efficient route for the synthesis of natural products bufospirostenin A and ophiopogonol A.

Figure 2. Cross-cyclocyclic reaction of cyclodecene. (Picture source: J. Am. Chem. Soc.)

Author from diosgenin acetate (diosgenin) Acetate) set out (Figure 3), and the lactone 9 was successfully prepared by using the oxidative degradation reaction developed by the Mukaiyama hydration reaction and the oxidation degradation reaction developed by the research group of Tian Weisheng 0 . Afterwards, the authors tried to use the cross-ring Prins cyclosynthesis reaction to construct 5/7 cis-fused units in natural products, but after trying a series of Lewis acids and Brønsted acids, they found that 8% of the target cis-cyclogenic product 1 was obtained only when PTSA or TfOH was used. This experimental result is consistent with the results reported in the literature: that is, trans-cyclogenic product is easy to generate, while cis-cyclogenic product is difficult to obtain. Analysis of X-ray single crystal diffraction structure of compound 0–12, the author believes that in the reaction, the enone 0 mainly exists in parallel conformation with lower energy 7 (Figure 3B). The conformation is easily isomerized into cross conformation with slightly higher energy 8. The latter reaction is more rapid, and mainly generates trans-ring product 2. Therefore, the author tried to lock the conformation 7 at low temperature, that is, preventing it from isomerizing into conformation isomer 8, and at the same time, adding strong Lewis acid to activate the substrate so that 7 is the reaction conformation, and mainly obtains the target cis-ring product 1.After a lot of experiments, the authors found that using BBr3 to perform cross-ring Prins cyclosynthesis reaction at –78 °C can obtain 43% cis-ring product 1 (Fig. 3B, line 9). Adding Cs2CO3 to the system can reduce the interference of HBr in the system. Intermediate 1 undergoes dehydration, regioselective Mukaiyama hydration and spirocyclic ketalization reactions to obtain the natural product bufospirostenin A, with a total of 7 steps of reaction (Figure 3). Using the same strategy, the authors completed the synthesis of the natural product ophiopogonol A in 7-step reaction from dioxins (Figure 4).

Figure 3. Synthesis of natural product Bufospirostenin A. (Image source: J. Am. Chem. Soc.)

Figure 4. Synthesis of natural product Ophiopogonol A. (Image source: J. Am. Chem. Soc.)

In order to clarify the effect of Lewis acid on the cross-cyclic cyclosynthesis reaction, the authors conducted theoretical calculations for the two systems of Me2AlCl/0 °C and BBr3/–78 °C respectively (Figure 5). The calculation results show that under Me2AlCl/0 °C, the Lewis acid-substrate complex INT1 can isomerize to form higher energy INT5. The latter has a lower energy barrier to carbonyl-ene reaction, so it mainly generates trans-ring product 2 (Fig. 5A); in BBr3/–78 Under °C, the conformational isomerization between INT8 and INT12 has the highest reaction energy barrier, so the lower energy INT8 undergoes the Prins reaction pathway, mainly generating cis-ring product 1 (Fig. 5B). The difference in reaction potential energy surfaces explains the different results of Me2AlCl and BBr3-mediated cyclosynthesis reactions in stereoselectivity, and reveals the key role of conformational isomerization in the stereoselectivity control of the mid-cyclocyclic reactions.

Figure 5. Theoretical calculation of cross-ring ring reaction. (Picture source: J. Am. Chem. Soc.)

In summary, the author completed the simple synthesis of bufospirostenin A and ophiopogonol A by developing the free radical fragmentation-cross-ring Prins ring integration strategy, starting from cheap and easy-to-get steroid industrial raw materials. This fragmentation-cycle integration strategy provides a new idea for the synthesis of other natural products with 5/7 ring skeletons. At the same time, the calculation results show that the rate of conformation isomerization plays a decisive role in the reaction pathway and stereoselectivity.