Studies Towards The Asymmetric Synthesis Of Indole Alkaloids Rhazinoline、Strictamine And Ajmaline

Total synthesis of monoterpene indole alkaloids(MIAs)is an important research field in natural products chemistry.MIAs exhibit diverse bioactivities and structural complexity.According to the features of the monoterpenoid scaffolds,this kind of natural products are categorized into three groups,including corynanthe,aspidosperma and iboga.Among the corynanthes,the representative akuammiline alkaloids rhazinoline,strictamine,and the representative ajmaline alkaloids ajmaline have posed great synthetic challenges caused by their caged polycyclic skeletons and complex stereochemistry.This research focuses on the asymmetric total synthesis of the above three natural products,which comprises two parts: 1)Asymmetric total synthesis of the akuammiline alkaloids rhazinoline and strictamine;2)Construction of the ABCF ring system of the ajmaline alkaloid ajmaline.All of the above synthesis are based on the photocatalytic radical cascade reaction developed by our group.The first part: asymmetric total synthesis of rhazinoline and strictamine.Using chiral aldehyde ester 329 as starting material,the β-tetrahydrocarboline skeleton was assembled via Type II photocatalytic radical cascade reaction.Then the C7–C16 bond was constructed by Tsuji-Trost reaction,affording the ABCD tetracyclic compound 325.After a synthetic sequence involving the opening the C ring through reduction and constructing the E ring via a reductive Heck reaction,the key tetracyclic compound 350 a with the α-C16 methyl ester group was obtained in a highly stereoselective manner.Finally,the C ring was constructed through the N-alkyl reaction,leading to the completion of the first asymmetric total synthesis of rhazinoline in 24 steps for the longest linear sequence.Next,starting from intermediate 353,the first generation of strictamine was achieved.Specifically,after the installation of an exocyclic at C16 of 353 and subsequent borohydride-oxidation reaction,the single isomer 374 with the β-C16 hydroxylmethyl group and the core skeleton was prepared,which was converted into strictamine through simple transformations.In the improved second-generation synthesis of stricatmine,the common ABD tricyclic intermediate 338 was employed as the substrate of the vital Ni-mediated reductive Heck reaction.,in which the E ring was smoothly constructed with a terminal double bond introduced at C16.The resulting intermediate was further transformed into compound 374 successfully,thus realizing the more efficient and concise synthesis of strictamine in 21 steps for the longest linear step.The second part research focus on the assembly of the ABCF ring system of ajmaline.Starting from the product 328 of the Type II photocatalytic radical cascade reaction,intensive investigations on constructing the F ring was performed.Firstly,compound 441 was obtained through Wittig reaction.While the Tsuji-Trost reaction and free radical coupling reaction of C17-CHO with Δ2,7 double bond or Δ6,7 double bond of 441 failed to give the desired compound,using compound 466 as the substrate,the C-7 and C-17 were successfully connected via a [3+2] cycloaddition to construct ABCF tetracyclic system of ajmaline,which paved the way for the subsequent work.