Synthesis of the Hexahydropyrrolo-[3,2-c]-quinoline Core Structure and Strategies for Further Elaboration to Martinelline, Martinellic Acid, Incargranine B, and Seneciobipyrrolidine

Abstract

Natural products are rich sources of interesting scaffolds possessing a plethora of biological activity. With the isolation of the martinella alkaloids in 1995, namely martinelline and martinellic acid, the pyrrolo[3,2-c]quinoline scaffold was discovered. Since then, this scaffold has been found in two additional natural products, viz. incargranine B and seneciobipyrrolidine. These natural products have attracted attention from synthetic chemists both due to the interesting scaffold they contain, but also due to the biological activity they possess. This review highlights the synthetic efforts made for the preparation of these alkaloids and formation of analogues with interesting biological activity.

Metal‐Free Rapid Diastereoselective Construction of Isocryptolepine Core via Elecrophilic Dearomatization ‐ Inramolecular Michael Addition Sequence

“…Martinelline alkaloids are known for their antimicrobial activity and high binding affinity to bradykinin, α1-adrenergic, and muscarinic receptors. [7] Numerous works were devoted to isocryptolepine high antiparasitic properties against trypanosoma, leishmania and plasmodium species as well as chloroquine resistant plasmodium species, antifungal and cytotoxic activities. [8][9][10][11][12][13] It is necessary to admit that plants containing pyrrolo[3,2-c]quinoline alkaloids were used in folk medicine for eye-infection and malaria treatment.…”

“…Pyrrolo[3,2‐ c ]quinoline group includes alkaloids of martinelline family (martinelline, martinnelic acid, seneciobipyrrolidine, incarganine B) and isocryptolepine (Figure 1b). Martinelline alkaloids are known for their antimicrobial activity and high binding affinity to bradykinin, α1‐adrenergic, and muscarinic receptors [7] . Numerous works were devoted to isocryptolepine high antiparasitic properties against trypanosoma, leishmania and plasmodium species as well as chloroquine resistant plasmodium species, antifungal and cytotoxic activities [8–13] .…”

Photocatalytic [2+2+m] Cyclization of 2‐Cyanoaryl Acrylamides with 2‐Bromocarbonyls Involving C(sp3)−H Functionalization

“…As a part of our ongoing research toward the iminyl radical-involved construction of N-heterocycles, [8g,12] we herein report a novel photocatalytic [2 + 2 + 2] cyclization of 2-cyanoaryl acrylamides with 2-benzyl-2-bromocarbonyls, providing a mild, facile, and straightforward approach to streamline the assembly of structurally diverse functionalized benzo [1,6]naphthyridinones that are frequently found in natural alkaloids [13] and bioactive molecules [14] (Scheme 1C). Additionally, [2 + 2 + 1] cyclization of 2-cyanoaryl acrylamides using more simple starting material 2-bromocarbonyls was also realized through this photocatalytic system, providing alternative, mild, and green access to functionalized pyrrolo [3,2-c]-quinolines that widely exist in many natural products [15] as well as bioactive molecules. [16] Notably, this transformation enabled the selective formation of two distinct CÀ C bonds, one CÀ N bond, and one quaternary carbon center in a one-pot operation.…”

“…Finally, the base effect on the reaction efficiency was examined. It should be noted that using LiOH as the base led to the highest yield of 3 aa than other bases (entries [11][12][13][14][15][16]. Several control experimental results indicated that base, photocatalyst, and visible light were requisite for this transformation (entries [17][18][19].…”