Stereoselective construction of four ring fused skeleton of calyciphylline a alkaloids

The author of the paper: danyan calyciphyline a alkaloids, whose structure is characterized by a fused five ring or six ring system containing more than six stereocenters, and a plurality of chiral centers are ortho all carbon substituted chiral centers (Figure 1) Due to the low content of these alkaloids in nature and the limited amount of isolation, no further study has been carried out on their biological activities Because of their interest in biological activities and complex structures, organic chemists have shown great enthusiasm for the synthesis of calycipryline a alkaloids So far, more than 15 studies on the synthesis of these alkaloids have been reported Recently, the yoshiharu Iwabuchi research group of Northeastern University of Japan reported the stereoselective construction of the four ring fused framework of ABCD (DOI: 10.1021 / ACS Orglett 8b01087) containing ortho all carbon substituted chiral centers in the class a alkaloids of calyciphilline The highlight of this study is that the central A-ring was constructed by the pinacol coupling reaction mediated by SMI 2, and another adjacent all carbon substituted chiral center was introduced by semipinacol rearrangement reaction to realize the construction of C-C bond with large steric hindrance (photo source: Organic letters) based on the understanding of this kind of molecular structure, the author proposed the following synthesis design route (scheme 1): BCD tricyclic lactam 7 was used as the synthesis starting intermediate, which was previously reported as the synthesis intermediate of other Daphniphyllum alkaloids In this paper, we propose to construct ketal-8 from compound 7 by intramolecular reduction free radical coupling reaction, and construct A-ring of calyciphylline a alkaloids at the same time It is a great challenge to construct all carbon substituted chiral centers at C8 and C5 positions In this paper, we propose to prepare ketene 10 from diol 9 by a series of simple transformations, and then 1, After 2-addition, the endo alcohol was syn selective epoxidated to produce epoxy alcohol 11, and then the compound 12 was rearranged to obtain allyl and hydroxyl groups at C8 and C9, respectively, which established the structural basis for the construction of E-ring and F-ring The specific synthesis route is as follows: firstly, the construction of A-ring is studied The key intramolecular pinacol coupling was explored (Table 1) The results showed that Mg could not stimulate the reaction, AIBN and bu3snh could not realize the C-C bond connection between the two carbonyls, but would lead to the reduction of aldehyde group, and smi2 could successfully prepare a single enantiomeric tetracycline glycol 9 In addition, the coupling product 9 was not formed after HMPA and LiCl were added into the reaction The reason may be that the addition of HMPA and LiCl can reduce the interaction between SMI 2 and carbonyl (photo source: Organic letters) after obtaining tetracyclic compound 9, the author began to try to construct C8 all carbon substituted chiral center The synthesis of semipinacol rearrangement precursor epoxy alcohol 11 is shown in the figure (scheme 3): diol 9 is oxidized by 5-f-azado / NO x to obtain α - hydroxyketone 16, and then α - hydroxyketone is dehydrated under the action of martinsulfurane to obtain alkene 10 and cyclopropane 17 (4:1) The spectral data of alkene 10 and bonjoch report (org Lett 2017, 19, 878) In the presence of CECL 3, allyl magnesium bromide was introduced into allyl group at C1 to obtain allyl alcohol 18, which was a single enantiomer Then, allyl alcohol 18 was epoxidated stereoselectively with vanadium catalyst to obtain epoxy alcohol 11 (photo source: Organic letters) after obtaining the key precursor 11, the author explored the key Marson semipinacol rearrangement reaction (Table 2), and found that when using concentrated hydrochloric acid as Br? Nsted Acid, no reaction occurred; then screened several Lewis acids, and found that when using BF 3 · OET 2, the product 12 could be obtained in medium yield Finally, the author found that the single stereoisomer 12 can be obtained with high yield by using the reaction conditions reported by lipshutz (Tetrahedron lett 1981, 22, 4603) The stereochemical structure of the compound was confirmed by X-ray crystallography (Figure 2) Conclusion: the author has developed a stereoselective method for the construction of the four ring fused structure of the calciphylline a alkaloid ABCD containing six chiral centers (including ortho all carbon substituted chiral centers) This study provides some useful solutions for the realization of C-C bond bonding in the high steric resistance region of complex molecules.