Design and Effective Synthesis of the First 4-Aza-2,3-didehydropodophyllotoxin Rigid Aminologue: A N-Methyl-4-[(3,4,5-trimethoxyphenyl)amino)]-1,2-dihydroquinoline-lactone

Abstract

The first N1-alkyl-4-amino-1,2-dihydroquinoline-lactone has been prepared by a five-step sequence in a 51% overall yield via the corresponding furo[3,4-b]quinolin-1(3H)-one. A new practical synthesis of this intermediate was carried out using versatile, commercially available starting materials and constitutes the shortest and highest yielding route. These synthetic pathways could be widened with a view toward the preparation of different substituted derivatives, which could be considered as rigid aminologues of 4-aza-2,3-didehydropodophyllotoxins.

Total synthesis of structures proposed for quinocitrinines A and B and their analogs. Microwave energy as efficient tool for generating heterocycles

“…In the first step a microwave assisted Friedlander 10 condensation between substituted 2-amino-benzaldehydes 3 and optically active substituted SS-tetramic acids 4 (obtained from the corresponding natural amino acids 11 ) led to intermediates fused tricyclic quinolines 5a-h which were N-methylated using methyl triflate 12 at room temperature leading to 6a-h. Finally, compounds 7 were obtained after cleavage of the O-methyl group in 6h (R1=OMe, R2= iBu) using BBr3 at room temperature 13 for 7 days or under microwave irradiation for 120 min.…”

“…Methylation of the intermediate was performed in dry dichloromethane using methyl triflate under nitrogen at room temperature as previously reported 12 , the Boc group was completely cleaved during the reaction likely due to the presence of the Lewis acid and/or to the strong inductive electron withdrawing effect generated by the presence of the quinolinium cation. A further epimerization of C-11 in intermediate 6h was observed by NMR (see Figure 2b).…”

“…The methylation reaction was performed according to a previous reported procedure 12 . Briefly, 60 ml dry CH2Cl2 was added to quinoline 5a-h (1.31 mmol) in 100 ml round bottom flask.…”

Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular‐Disrupting Agents

“…Amino analogue 11 was synthesized according to our previously reported procedure. [15] Two structurally relevant synthetic intermediates of this process, quinoline 26 [15] and imine 27 [15] (Figure 3), were also biologically evaluated.…”

“…Compounds 11,26, and 27 were prepared as previously described. [15] (9RS)-4-Methyl-6,7-(methylenedioxy)-9-(3,4,5-trimethoxybenzyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one (5). An equimolar mixture (1 mmol) of tetronic acid 15, aldehyde 13, [17] and aniline 14 in EtOH (10 mL) was held at reflux for 1 h. The resulting solid was removed by filtration and recrystallized from MeOH to afford 5 as a white powder (217 mg, 50 %): R f = 0.…”