title: Total synthesis of indoline alkaloids: A cyclopropanation strategy.
abstract: Indoline alkaloids constitute a large class of natural products; their diverse and complex structures contribute to potent biological activities in a range of molecules. Designing an appropriate strategy for the total synthesis of indoline alkaloids is a difficult task that depends on being able to efficiently assemble the core architectures. The best strategies allow access to a variety of different indoline alkaloid structures in a minimum of steps. The cyclopropanation of simple olefins and the subsequent synthetic transformation of the resulting cyclopropyl intermediates has been intensively studied in recent decades. In contrast, the cyclopropanation of enamines, especially for the construction of complex nitrogen-containing ring systems, remained relatively unexplored. Previous success with the cyclopropanation of simple indoles to form stable indolylcyclopropanocarboxylates encouraged us to explore the assembly of indoline alkaloid skeletons with cyclopropanation as a key reaction. Theoretically, indolylcyclopropanocarboxylates are doubly activated by a vicinally substituted amino group and carboxyl group; that is, they are typical donor-acceptor cyclopropanes. Accordingly, they tend to yield an active iminium intermediate, which can undergo inter- and intramolecular nucleophilic reactions to form the core structure of indoline alkaloids with an expanded ring system. In this Account, we summarize our efforts to develop a cascade or stepwise reaction of cyclopropanation/ring-opening/iminium cyclization (the CRI reaction) on tryptamine derivatives for assembling indoline alkaloid skeletons. With the CRI approach, three types of indoline alkaloid skeletons have been efficiently constructed: (i) hexahydropyrrolo[2,3-b]indoline (type I), (ii) tetrahydro-9a,4a-iminoethano-9H-carbazole (type II), and (iii) tetrahydroquinolino[2,3-b]indoline (type III). The effects of substituents on tryptamine derivatives were carefully investigated for inter- and intramolecular CRI reactions during construction of type I and type II skeletons. These results provided a basis for the further design and synthesis of complex natural products containing nitrogen. The usefulness of the CRI reaction is well demonstrated by our total synthesis of structurally intriguing indoline alkaloids such as N-acetylardeemin, minfiensine, vincorine, and communesin F. In addition, we highlight advances by other groups in construction of the three types of skeletons as well as their total syntheses of these indoline alkaloids. Discussion of the total syntheses of these indoline alkaloids focuses on comparing the individual synthetic strategies for forming the ring systems embedded in the final products. We also describe the total synthesis of perophoramidine, which has the same type III skeleton as communesin F. The observation of a retro Diels-Alder reaction during our synthesis of communesin F inspired the hetero Diels-Alder reaction on which our total synthesis of perophoramidine was based.
authors.affiliation: Department of Medicinal Natural Products, Key Laboratory of Drug Targeting and Novel Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Song
authors.forename: Yong
authors.initials: Y
authors.lastname: Qin
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry; D003500:Cyclization; D003521:Cyclopropanes / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D014748:Vinca Alkaloids / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000470:Alkaloids; D001688:Biological Products; D002227:Carbazoles; D003521:Cyclopropanes; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D011744:Pyrimidinones; D014748:Vinca Alkaloids; C522025:communesin F; C504098:minfiensine; C543267:vincorine; C080891:5-N-acetylardeemin; C057812:indoline