Synthetic Studies On The Total Synthesis Of "Post-Iboga" Natural Products

"Post-Iboga" indole alkaloids have aroused the interest of many synthetic chemists because of their unique and rare skeleton structure and remarkable analgesic and anti-tumor biological activities.These indole alkaloids generally contain[6/5/7/6/6]five-ring fused skeleton,which is distributed around the aza-[3.3.1]bridge ring skeleton containing the C16 all-carbon quaternary carbon chiral center.As we all know,the construction of all-carbon quaternary carbon chiral centers has always been a difficult problem in the field of organic synthesis,and the construction of bridged ring skeletons containing all-carbon quaternary carbon chiral centers has brought great challenge to the synthesis of natural products of this family.Therefore,it is of great significance to develop a new method for efficient and rapid construction of an aza-[3.3.1]bridged ring skeleton containing a C16 all-carbon quaternary carbon chiral center,and apply it to the total synthesis of the natural products of this family.The main work of this paper includes two parts:Part I:Establishment of the asymmetric Michael/aldol cascade reaction to construct the aza-[3.3.1]bridged ring skeletonAn asymmetric Michael/aldol cscade reaction between the tryptamine derivatives and acrolein was successfully developed to construct the aza-[3.3.1]bridged cycle containing full carbon chiral quarter carbon in the bridgehead.In this method,the quaternary ammonium salts of cinchona alkaloids were used as the phase-transfer-catalyst.The yield and enantioselectivity of the aza[3.3.1]bridged cycle target compounds were up to 69%(2 steps)and 99%under the condition optimization.It was found that the method was not only suitable for the substrate with electron donating substituents in different positions of indole ring,but also tolerant to various substituents on Phth protection group.The screening of different structures of acrolein receptor showed that ?-substituted acrolein could also afford high yield and enantioselectivity.Part ?:Asymmetric total synthesis of "Post-Iboga" indole alkaloidsThe asymmetric Michael/aldol cascade reaction between the phthaloyl-protected cyano-containing tryptamine derivative and 2-ethylacrolein was successfully applied to construct the chiral aza-[3.3.1]bridged cyclic lactam ketone containing ethyl group at C20 position on gram scales.Subsequently,by applying the key reactions including the Saegusa oxidation,intramolecular SN2' nucleophilic substitution reaction,the participation of Raney Ni in cyano reduction,I2/KOH-mediated oxidative esterification of aldehyde group,the catalyst-controlled highly stereoselective hydrogenation to install the C20 side-chain,the first asymmetric total syntheses of(-)-demethoxychippiine,(-)-3-O-methyl-demethoxychippiine(taberhaine B),and(-)-3-hydroxy-3,4-secocoronaridine were achieved with a linear step of 13-14 steps,in 3.5%-5.6%overall yield.In addition,an analogue demethoxytabercarpamine I and two diastereoisomers including 20-epi-demethoxychippiine and 20-epi-3-O-methyl-demethoxychippiine were also achieved.After that,the asymmetric Michael/aldol cascade reaction between the phthaloyl-protected cyano-containing tryptamine derivative and acrolein was used again to construct the chiral aza-[3.3.1]bridged cyclic lactam ketone.Next,by applying the one-pot oxidation/lactamization ring closure,Saegusa oxidation,Pd-catalyzed Stille coupling and Barton-McCombie radical dihydroxylation,an efficient enantioselective total synthesis of(+)-Tronocarpine was accomplished in 11 steps with 5.6%overall yield.