The enantioselective total synthesis of (+) - corymine and (−) - deformylcorymine by Li Chaozhong, Shanghai Institute of Organic Chemistry

Akuammiline alkaloids are a family of monoterpenoid indole alkaloids with pentacyclic structure Their representative structures include aspidophyline a (1), prcrinine (2), strictamine (3), vincoline (4), etc These compounds show many pharmacological activities, so they become the synthetic target of chemists The other two key members of the akuammiline alkaloid family are corymine (5) and deformylcorymine (6) Recently, Li Chaozhong's research group reported the synthesis of (±) - corymene from n-nitrophenyltryptamine in 21 steps, among which propargyl clarison rearrangement is the key step to construct c15-c20 bond with stereospecificity The strategy of (±) - deformylcorymin synthesis by 19 steps of indole-3-one was reported by the research group of ancestral linkage However, up to now, there are no reports of asymmetric total synthesis of these compounds Recently, the team of Li Chaozhong, researcher of Shanghai Institute of organic chemistry, Chinese Academy of Sciences, reported the enantioselective total synthesis of (+ - corymene and (− - deformylcorymene Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 0c00302) (source: inverse synthesis analysis of J am Chem SOC.) (+) - corymine is shown in scheme 1 The tetrahydropyran ring of corymene can be installed by stereoselective reduction of ketone 7 The structure of 7-azacycloheptane can be constructed by stereoselective nickel mediated stereospecific 7-endo cyclization of ketene 8 Pyrrolyl and cyclohexenyl skeletons can be established by intramolecular nucleophilic nitrogen addition and malonate carbon addition of imino ketone a The C2 side chain in a can be introduced by Suzuki coupling of 3H indole-2-trifluoromethylsulfonate derived from hydroxyindole B Finally, the enantioselective addition of 3-bromoindole-c to Malonate Catalyzed by copper was obtained (source: J am Chem SOC.) the synthesis route starts from the allylation of n-ns-tryptamine (9) and (z) - 11,2-dibromobutyl-2-ene to allylic alkenylbromide 10 In the mixed solution of t-buoh-thf, 3-bromoindole 11 is obtained by NBS and water treatment The two-step yield is 95% After screening the conditions of copper catalyzed asymmetric addition reaction, the author found that the target product (-) - 12 can be obtained with 65% yield and 91% ee value by using copper bis (oxazoline) complex [Cu] as catalyst, N, n-diisopropylacetamine as base and 11 reacting with dimethyl malonate (source: J am Chem SOC.) (-) - 12 reacted with trifluoromethylsulfonic anhydride to produce intermediate 13, which reacted with 9 - (3,3-diethyloxy-propyl) - 9-BBN (14) to obtain 2-alkylation product (-) - 15 (scheme 3) in 54% yield under the catalysis of PD (PPH 3) 4 Then, (-) - 15 was oxidized by MnO 2 to produce iminone (-) - 16, the yield was 65% The compound (-) - 16 was treated with etona at room temperature, and then p-methylthiol was added directly to the resulting mixture to construct [6.5.0] bicyclic framework in one step, and a tetracyclic product (-) - 18 was provided in the form of a mixture of two diastereomers in 66% yield Then (-) - 18 reacted with meerwein reagent (me3o · BF 3) at room temperature, and then treated with trimethylsilyltrifluoromethane sulfonate N-methylation and EtOH elimination were completed in one step, and the required compound (+) - 8 was obtained in 72% yield (source: J am Chem SOC.) the last key step in the synthesis of corymene is the construction of seven membered azacyclononane ring (scheme 4) Through a large number of screening conditions, the author found that in the presence of Ni (COD) 2, Nai and Mg (OTF) 2, (+) - 8 can obtain the cyclized product (-) - 7 in a moderate yield Then the author used KBH 4 to stereoselective reduce (-) - 7 to get alcohol (-) - 19 The natural product (+ - corymene ((+) - 5) was obtained by the lactonization promoted by cesium carbonate and dibal-h reduction of compound 19 in 82% yield One ester group was selectively removed from (-) - 19 by LiCl treatment, and (- - deformylcorymene (-) - 6 of single stereoisomer was obtained in 71% yield (source: J am Chem SOC.) the above synthesis strategy can also be extended to the total synthesis of other akuammiline alkaloids Deformylcorymene reacts with CS 2 and methyl iodine to form corresponding xanthate, which is then treated with tris (trimethylsilyl) silane and AIBN to obtain (- - 10-d emerhoxyvincorine ((-) - 20) in 82% yield (source: J am Chem SOC.) (-) - 7 can also be successfully obtained by continuous dibal-h reduction and O-acetylation (-) - 3-epi-dihydrocoryne17-acetate ((-) - 22, scheme 5) In addition, (-) - 7 was refluxed in LiCl and DMF to obtain a chemically selective de esterification product (-) - 23, which was reduced by SMI 2 and resulted in the cleavage of seven carbon nitrogen bonds The intermediate was further reduced by triethylsilane and BF 3 · et 2O to (- - 2 (s) - cathafoline ((-) - 24) (source: J am Chem SOC.) conclusion: through reasonable route design, the author realized the first asymmetric total synthesis of akuammiline alkaloids (+ - corymine and (−) - deformylcorymine through 11 steps of reaction with commercially available n-nitrophenyltryptamine The key steps of this route are: (a) the enantioselective addition of 3-bromoindole with Malonate Catalyzed by copper successfully established the C 7 quaternary carbon chiral center; (b) the formation of cyclohexyl and pyrrolidine ring by nucleophilic C C-and N-addition step; (c) the construction of azacycloheptane ring by 7-endo cyclization of alkenyl bromide mediated by Ni (COD) 2 The strategy is also extended to the synthesis of (- - 10 demethoxyvincorine (13 steps), (-) - 2 (s) - cathafoline (11 steps) and (- - 3-epi-dihydrocor-ymine17-acetate (12 steps) in the akuammiline family.