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.

Keywords: Diversity-Oriented Synthesis; amino acetophenones; aurones; azocanes; coumarins; flavones; natural products; quinolones.

Figure 1

Chemical structures reported in this review. (A) General structures of the targeted natural products; (B) Structures of the starting blocks and natural product analogs prepared.

Scheme 1

Synthesis of the starting blocks.

Scheme 2

Synthesis of 5- and 7-aminoflavones.

Scheme 3

Synthesis of 2-aryl-4-quinolones starting from aminodimethoxyacetophenones.

Scheme 4

Access to chemical diversity through the alkylation of 4-quinolones.

Figure 2

Structural analogy between 3-phenylcoumarin and 3-phenyl-2-quinolone and the structure of a natural coumarin.

Scheme 5

Synthesis of 3-aryl-2-quinolones.

Scheme 6

Synthesis of epoxychalcones.

Scheme 7

Synthesis of azaaurones.

Figure 3

Naturally occurring compounds containing the azocane ring.

Scheme 8

Synthesis of highly functionalized azocanes.

Scheme 9

Mechanism of formation of the benzoazocane 29.