Natural products containing heteroaromatics

Current interest in the synthesis of natural products containing heteroaromatic moieties as building blocks for pharmaceutical industries, material science, and supramolecular chemistry has resulted in considerable effort in developing new synthetic methods [101]. 

Natural products containing pyrazole rings are practically nonexistent. It seems that the evolution of organisms has produced few enzymes capable of forming an N-N bond. However, a methanol extract of the sponge Tedania anhelans yielded the two unusual heteroaromatic acids, pyrazole-3(5)-carboxylic acid 905 and 4-methylpyrazole-3(5)-car-boxylic acid 906, which are reported for the first time as natural products <1997JNP802>. 

Thus, radical addition reactions provide a useful means of functionalising pyridines, quinolines and isoquinolines, particularly when it is reasonable to employ the heteroaromatic base in excess. Intramolecular variants of the reaction are devoid of that limitation and have been widely exploited in the synthesis of nitrogen-containing heteroaromatics. The mildness of the reaction conditions have found favour in natural products total synthesis and medicinal chemistry programs. These bare testament to the reactions worth and have raised its stature from academic curiosity to useful synthetic tool. 

A common strategy employed to effect selectivity is exploitation of inherent substrate reactivity and utilization of activated C-H bonds. Heteroaromatic compounds represent common motifs in both natural products and medicinal agents and contain certain C-H bonds that are intrinsically more reactive than others. By using heteroaromatic motifs as the Ar-H unit, the inherent differences in reactivity of C-H bonds around the motif can be exploited to achieve selectivity. 

Several total syntheses of pyridine containing natural products have been described via the inverse electron demand Diels-Alder reaction of 1-azadiene bearing electron-withdrawing groups and subsequent elimination to form the heteroaromatic ring. In this process, all the stereo-genic centers created during the cycloaddition are destroyed. However, application of the inverse electron demand Diels-Alder reaction for the stereoselective C-N bond formation in total syntheses of natural products is also documented. 

---