Diversity-Oriented Synthesis: Amino Acetophenones as Building Blocks for the Synthesis of Natural Product Analogs

Abstract

Diversity-Oriented Synthesis (DOS) represents a strategy to obtain molecule libraries with diverse structural features starting from one common compound in limited steps of synthesis. During the last two decades, DOS has become an unmissable strategy in organic synthesis and is fully integrated in various drug discovery processes. On the other hand, natural products with multiple relevant pharmacological properties have been extensively investigated as scaffolds for ligand-based drug design. In this article, we report the amino dimethoxyacetophenones that can be easily synthesized and scaled up from the commercially available 3,5-dimethoxyaniline as valuable starting blocks for the DOS of natural product analogs. More focus is placed on the synthesis of analogs of flavones, coumarins, azocanes, chalcones, and aurones, which are frequently studied as lead compounds in drug discovery.

Linking the Autotaxin-LPA Axis to Medicinal Cannabis and the Endocannabinoid System

“…Indeed, inhibitors might need to be taken several times a day to maintain ATX inhibition and subsequently reduce LPA production. The development of cannabinoid-inspired ATX inhibitors might be interesting from this point of view since their lipidic structure allows potential deposits in fatty tissues and lipid carrier proteins to prolong the limited inhibition following their administration [ 44 , 66 , 67 ].…”

Gram Scale Synthesis of Membrane-Active Antibacterial 4-Quinolone Lead Compound

“…Isolated compound 16 (0.22 g, 61%) as a yellow solid: R f = 0.4 (30% EtOAc/ 13 C{ 1 H}NMR (151 MHz, DMSO-d 6 ) δ 165.5, 157.5, 149.0 (q, J = 34.5 Hz), 148.6, 145.0 (q, J = 4.5 Hz), 138.4,134.7 (q, J = 3.0 Hz), 131.2 (q, J = 31.5 Hz), 124.4 (q, J = 270.0 Hz), 123.6 (q, J = 271.0 Hz),121.1 (q, J = 274.5 Hz), 120.1 (q, J = 4.5 Hz), 117.0 (q, J = 33.0 Hz), 115.7, 113.0 (q, J = 3.0 Hz), 112.4, 99.5, 57.9; 19 q, J = 34.5 Hz), 146.3 (q, J = 4.5 Hz), 143.1, 135.6, 126.7, 125.7 (q, J = 234.0 Hz), 125.2 (q, J = 270.0 Hz), 123.6 (q, J = 7.5 Hz), 122.8 (q, J = 259.5 Hz), 119.5 (q, J = 4.5 Hz), 119. (18). Aqueous HBr (48%, 0.12 mL, 1.75 mmol, 4.50 equiv) was added to a stirring solution of quinoline 17 (0.18 g, 0.39 mmol, 1.00 equiv) in acetic acid (2 mL).…”

“…To test this hypothesis, we carried out alkylation of quinoline derivative 4 to prevent this tautomerism. Compound 4 , upon treatment with alkylating agents (methyl iodide and benzyl bromide) in the presence of potassium carbonate in DMF, provided the alkylated derivatives 7 (7:1 inseparable mixture of regioisomers) and 8 (6:1 inseparable mixture of regioisomers) in 89% and 85% yields, respectively . We then attempted to prepare the desired azido derivative 9 via CuI-promoted azidation of methyl ether protected quinoline 7 ( 7 :1 inseparable mixture of regioisomers) under various conditions (Scheme B) but these led, instead, to the formation of 5-amino-4-quinolone 11 in up to 68% yield. ,, Attempts at transforming benzyl ether protected quinoline 8 to the respective azide also led to the formation of the 5-amino-4-quinolone 11 .…”

Cu-Catalyzed Tandem C–N and C–C Bond Formation Leading to 4(1H)-Quinolones: A Scaffold with Diverse Biological Properties from Totally New Raw Materials in a Single Step

“…Owing to such diverse pharmacophore properties, development of new synthetic methods for constructing 4-quinolones continues to gain the attention of synthetic organic chemists worldwide . As a result, a significant amount of research has been carried out on developing various methodologies for constructing 2-substituted-4-(1 H )-quinolones from different raw materials (Scheme a–c). ,− Traditional methods such as Conrad–Limpach, Camps, and Niementowski reactions have been the most frequently used methods for accessing 4-quinolones . However, they have some inherent issues like starting material’s potential instability due to incompatible groups in the same molecule (amine and carbonyl in ortho -amino acetophenone, the key raw material for Camps’ type reactions) or regioselectivity (Conrad–Limpach), or in some cases requiring harsh cyclization conditions (sometimes as high as 250 °C).…”

“…with toxic “CO” gas for carbonylation . Our careful literature search revealed that, still in a medicinal chemistry lab, the traditional two-step protocol involving cyclization of acylated 2-aminoacetophenones (Camps’ cyclization) is the most frequently used procedure. ,, This could probably be attributed to relatively simpler reaction conditions in Camps’ cyclization, though it restricts the scope of starting materials to 2-aminoacetophenones with two incompatible functional groups (amine and carbonyl) that can potentially pose stability issues on large scales. Therefore, to further accelerate the development of newer 4-(1 H )-quinolone-based bioactive compounds, finding simpler alternative methods from different starting materials continues to remain a topic of interest for modern synthetic organic chemists.…”