Synthetic Efforts toward Akuammiline Alkaloids from Tetracyclic 6,7-Seco Derivatives

Abstract

The addition of enolates derived from indole-3-acetic esters 1−3 to pyridinium salts 4, 23, and 24, followed by acid cyclization of the resulting 1,4-dihydropyridines, leads to tetrahydro-1,5-methanoazocino[3,4-b]indoles 5−7, 25−27, which have been subsequently elaborated into 4E-ethylidene(or 4α-ethyl)-hexahydro-1,5-methanoazocino[3,4-b]indoles. Closure of the six-membered C ring of akuammiline alkaloids by formation of C-6/C-7 bond from appropriately N (b) -substituted derivatives of these tetracyclic ABDE substructures has been extensively investigated. In the N-unsubstituted indole series, both cyclization of thionium ions generated either by Pummerer reaction from sulfoxide 16 or by DMTSF treatment of dithioacetal 36 and photocyclization of chloroacetamide 47 occur upon the indole nitrogen to give pentacycles 18, 38, and 49, respectively. When the indole nitrogen is blocked by a substituent, the thionium ions derived from sulfoxides 17 and 43 and dithioacetals 37 and 44 do not cyclize and lead to different products depending on the reaction conditions, whereas chloroacetamides 48 and 51 undergo a reductive photodehalogenation. Attempted radical cyclization of seleno derivatives 53, 55, and 56 under a variety of conditions gives the corresponding reduced products. Finally, attempted photoisomerization of 1-acylindole 62 leads to the N (b) -methyl tetracycle 63.

Formal Total Synthesis of (±)‐Strictamine by [2,3]‐Sigmatropic Stevens Rearrangements

“…Over the past decades, akuammilinea lkaloids have interested the synthetic community owing to their unique chemical structure and biological activity. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In particular,s trictamine (1)w as first synthesized in 2015 and 2016 by the groups of Garg (enantioselective), [18] Zhu (racemic), [19] Ohno (formal), [20] and ours (formal). [21] Biosynthetically,s trictamine (1)b elongs to the group of monoterpenoid indole alkaloids, which are derived from (E)-geissoschizine (4).…”

“…[21] Biosynthetically,s trictamine (1)b elongs to the group of monoterpenoid indole alkaloids, which are derived from (E)-geissoschizine (4). [22][23][24][25][26][27][28][29] In contrastt oo ther monoterpenoid indole alkaloids, the akuammiline alkaloids are defined by one CÀCb ond between carbon atomsC -7 and C-16,l eading to av ery compact cage-like structure (methanoquinolizidine 2)r eminiscento fa damantane (3). In contrastt oa damantane (3), which harbors four six-membered rings in ac hair conformation,t he methanoquinolizidine system 2 consists of two six-membered rings in ab oat conformationa nd only one in ac hair conformation.…”

“…The retrosynthetic analysis starts with formation of the indolenine unit as av ery sensitive structurem otif. The indoleninei si ntroduced by reduction of the nitro group to aniline followed by intramolecular condensation with the ketone of compound 5.T he methanoquinolizidine system 2 is built by two consecutive steps:i ntramolecular 1,4-addition of vinyl iodide 5 to the a,b-unsaturated ester and [2,3]-sigmatropic Stevens rearrangement [34][35][36] of ylide 6.…”

“…Ylide 6 is established by deprotonation of the ammonium salt resulting from N-alkylation of tertiary amine 7 and iodide 8.T ertiary amine 7 is assembled by intramolecular NÀHi nsertion of the a-diazo carbonyl group of pyrrolidine 9.T he key transformation of the synthesis is the Stevens [2,3]-sigmatropic rearrangement (6 to 5).…”

Tandem dinucleophilic cyclization of cyclohexane-1,3-diones with pyridinium salts

“…The tetrahydropyridine scaffold is inherent for pharmacologically relevant representatives [18–24]. At the same time, heterocyclic systems containing an annulated pyridinium core, such as quinolinium and isoquinolinium salts, are of considerable importance as building blocks for the synthesis of various alkaloid frameworks [10,25–35]. …”