JACS: the Sarpong group of the University of California, Berkeley completed the synthesis of pentacyclic (-) - ambiguine p

Figure 1 is an indole alkaloid Among them, ambiguines a (1) and H (2) contain four ring skeletons, while other ambiguines have fused five ring skeletons and characteristic seven membered rings Some members of the hapalindole family, such as fischerindoles and welwitindolinones, have a wide range of biological activities, including anti microbial, anti fungal, insecticidal, anticancer and phytotoxicity At present, the researchers have only studied the preliminary biological activity of ambiguines, but have not carried out a comprehensive study Therefore, the synthesis of pentacyclic ambiguities is of great significance to reveal the biological functions of these natural products Baran and Maji team reported the total synthesis of four ring ambiguines H (2) in 2007 and 2018 respectively, but five ring ambiguines (3-11) has not been synthesized so far The challenge lies in the construction of seven membered rings (E-rings) in five ring ambiguines Recently, the Richmond Sarpong group of the University of California, Berkeley, reported the total synthesis of (- - ambiguine P (11) (DOI: 10.1021 / JACS 8b13388) in j.am Chem SOC (photo source: J am Chem SOC.) inverse synthesis analysis of ambiguine P (scheme1): ambiguine P and its pentacyclic homologues can be produced by the General intermediate 14 through later oxidation and / or chlorination, while pentacyclic isocyanide 14 can be obtained from 15 through alkylation of formyl and conversion of cyano to isocyano; C12 of 15 The primary amide in 16 can be used as the guiding group to introduce the chiral center For the construction of pentacyclic framework, the author used the easily available starting material (19-21) to construct 18 rapidly by copper catalyzed cross coupling and 1,2-addition, and then successively functionalized indole C3, C2 and C4 sites In order to construct a seven membered ring with a five ring skeleton, the author carried out cobalt mediated Nicholas alkylation at C2 of 18, and then Friedel crafts cyclization at C4 to construct a C-ring (photo source: J am Chem SOC.) the key to the synthesis of natural products of pentacyclic ambiguine is the enantioselective α - functionalization of C12 Because the stereochemistry of C15 makes it CIS configuration and trans configuration is needed, the author tries to overcome this problem by using 16 amide oriented α - functionalization Scheme 2: first of all, the C3 functionalized indole 22 was obtained from indole (20) and (s) - carvone (21) by Cu (II) - mediated oxidative coupling according to Baran's method Then, the ketene carbonyl group and propargyl alcohol 19 were added 1,2-and oxidized by Babler dauben to obtain ketene 18 Then, we cyclized Nicholas at C2 of indole ring to form a seven membered ring, and obtained 23 Then, we alkyled Friedel crafts at C4 of indole ring to form an E ring, and obtained 17 Then 17 introduces cyano group by conjugation addition with cyanide Finally, the author uses Bu 3snh to reduce and remove the cobalt group to obtain pentacyclic 24 (photo source: J am Chem SOC.) the synthesis of ambiguine P (scheme3): after obtaining the pentacyclic intermediate 24, the author attempts to construct the C12 chiral center with cyano as the guiding group Firstly, the mixture of 25 and 16 was obtained by RH (I) - catalyzed cyanohydrolysis of 24, which was treated by nahmds / methyl formate to obtain hemiacetaldehyde amine, and then reduced by sodium borohydride to obtain hemiacetaldehyde amine 26, which was introduced into the C12 chiral center 26 15 was obtained by ring opening and Barton McCombie deoxidization, then secondary alcohols were produced by tmsch 2Li treatment, and 28 was obtained by addition of cyano group with microwave and ppts After that, TMS was removed to produce primary amide and vinyl group, Peterson's olefinization and cyanohydrolysis were carried out to obtain amide 29, tertiary amine 30 and pseudoindole 31 were obtained by Hofmann rearrangement, and pentacycloisonitrile 14 was obtained by formylation dehydration Finally, SeO 2 was used to remove isonitriles and allylic oxidation was carried out to obtain the non enantiomeric mixture ambiguineP (11) (dr=1.5:1) (photo source: J am Chem SOC.) conclusion: Richmond Sarpong group took indole 22 with C3 functional group as raw material and completed the first full synthesis of pentacyclic ambiguine P through 20 steps The highlights of the synthesis are as follows: firstly, Nicholas reaction is used to alkylate at C2 position to build a fused seven membered ring; secondly, amide guided functionalization is used to introduce quaternary carbon chiral center at C12 position to quickly build a five ring framework In addition, the universal late intermediate prepared by the author is also suitable for the synthesis of other pentacyclic ambiguities.