Biomimetic Total Synthesis of Ervitsine and Indole Alkaloids of the Ervatamine Group via 1,4-Dihydropyridines

Abstract

Addition of the enolate derived from 2-acetylindole 1a to pyridinium salt 2 followed by in situ trapping of the initially formed 1,4-dihydropyridine 3a with Eschenmoser's salt gives tetracycle 5a. Subsequent elaboration of the exocyclic methylene and E-ethylidene substituents leads to N a-methylervitsine (17a). A similar sequence from the N a-protected 2-acetylindole 1c establishes the first total synthesis of the 2-acylindole alkaloid ervitsine. Alternatively, dihydropyridine 3a is trapped with BrSePh to give the tetracyclic selenide 7a, which is then converted to N a-methylervitsine by way of selenoxide 20. The synthesis of the alkaloids of the ervatamine group starts with the addition of the enolate derived from 2-acetyl-1-benzylindole (1g) to pyridinium salt 24 and the conversion of the resulting 1,4-dihydropyridine to 3,5-diacylated dihydropyridine 26g. Chemoselective reduction of the vinylogous amide moiety of 26g, followed by deprotection of the indole ring and LiEt3BH reduction leads to diol 37b. On sequential treatment with Eschenmoser's salt, methyl iodide, NaCNBH3, and MnO2, 37b is converted to the tetracyclic 2-acylindole 39, from which the first total synthesis of 19,20-didehydroervatamine and 20-epiervatamine is accomplished by manipulation of the 1-hydroxyethyl chain. The above syntheses can be considered as biomimetic, as cyclization of the key intermediates I and II mimics the key steps of the biosynthesis of the title alkaloids.

Lewis Acid Mediated Aminobenzannulation Reactions of δ‐Ketoalkynes: Synthesis of 1‐Aminocarbazoles and 9‐Aminopyrido[1,2‐a]indoles

“…2-Acyl-N-propargyl-1H-indole 1a was prepared from readily accessible 2-acyl-1H-indole [23] 8a and propargyl bromide under PTC (phase-transfer catalysis) conditions, followed by, for compounds 1b-e, functionalization of the terminal alkyne under Sonogashira conditions. [1] Table 1.…”

“…2-Acylindoles 8a,b are known compounds and were prepared as reported in ref. [23,24] 2-Acyl-N-propargyl indoles 1a-c,e are known compounds. [1] Compound 1d is new and was prepared as reported in ref.…”

A Synthetic Entry to Ervatamine Alkaloids − Synthesis of (±)-6-Oxo-16-episilicine and (±)-6-Oxosilicine

“…Tetrahydropyridyl esters 5f,g, with a two-carbon substituent at C-20, had proved to be valuable synthetic intermediates in our synthesis of ervatamines. [7] However, 5f and g, in oxosilicine synthesis were found to be less satisfactory because epimerization at C-20 occurred to some extent under the cyclization conditions, so further synthetic use of the resulting tetracycles 6f,g was abandoned. Tetracycle 6g was alternatively obtained by debenzylation of 6f with AlCl 3 in C 6 H 6 .…”

“…When we started our studies, 6-oxosilicine, isolated from several Hazunta species, [4] was the only alkaloid of this group with a known total synthesis. [5,6] We have recently reported [7] straightforward biomimetic syntheses of two alkaloids of the ervatamine group (19,20-didehydroervatamine, 20-epiervatamine) and the biogenetically related alkaloid ervitsine via 4-[(2-indolyl)carbonylmethyl]-1,4-dihydropyridines (A), either through the corresponding 3,5-diacyldihydropyridines or by electrophile-promoted cyclization via a dihydropyridinium cation, respectively. Here we wish to further illustrate the potential and synthetic flexibility of 3,5-diacyl-4-[(2-indolyl)carbonylmethyl]-1,4-dihydropyridines.…”

Friedel-Crafts Reaction of Indoles with Nitroalkenes Catalyzed by Mesoporous Material MCM-41

“…Friedel-Crafts 反应有所报道, 如 CeCl 3 •7H 2 O/NaI 化合 物 [7] , 硫脲及其衍生物 [14,15] , Zn(II), Cu(II)与唑啉络合 物 [6,16,17] , BINOL 的磷酸衍生物 [18] 等. 此外, 本课题组对 吲哚与硝基烯烃的 Friedel-Crafts 反应也做了一些研究 工作, 如 Yb(OTf) 3 催化剂 [19] 、Cu(II)-席夫碱络合物 [20] 、 的苯环上连有 N(CH 3 ) 2 时, 反应产率有所下降(表 3, Entry 9).…”