Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

Abstract

An analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients (APIs) approved by the FDA reveals a preference for 1,4-substituted (para), 1-substituted (mono), 1,2,4-substituted, and 1,2-substituted (ortho) arenes. Notably, these substitution patterns are widely commercially available and readily accessible by electrophilic aromatic substitution (SEAr), but more highly substituted and contra-electronic substitution patterns are severely underrepresented in drug substances. Finally, structural variation decreases with increasing substitution and there is a strong reliance on natural product scaffolds in drugs with more highly substituted benzenoid rings.

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

“…Consequently 1,2,3,4-substituted benzenoids are underrepresented in pharmaceuticals. [5] Between the two trisubstituted retrosynthetic precursors, 1,2,4-substituted arene, A,a re more commercially and synthetically accessible than the congested 1,2,3-substituteda rene, B (Scheme 1B). However, for both arenes (A and B)r egioselectivity remains ak ey chal-lenge in common approaches,i ncluding electrophilic aromatic substitution (S E Ar) and transition metal catalyzedC ÀHf unctionalization.…”

“…Notwithstanding the many useful methods that have accrued for arene functionalization [3] and ring construction, [4] installing each substituent in its precise location requires careful consideration of both regiocontrol and functional group compatibility over several synthetic steps, and general methods are lacking. Consequently 1,2,3,4‐substituted benzenoids are underrepresented in pharmaceuticals [5] . Between the two trisubstituted retrosynthetic precursors, 1,2,4‐substituted arene, A , are more commercially and synthetically accessible than the congested 1,2,3‐substituted arene, B (Scheme 1 B).…”

Aryl(TMP)iodonium Tosylate Reagents as a Strategic Entry Point to Diverse Aryl Intermediates: Selective Access to Arynes

“…Polysubstituted aryl­(TMP)­iodonium salts lead to several medicinally relevant densely functionalized benzenoid substitution patterns (Scheme ). Substitution at the meta and para positions relative to the iodonium lead to 1,2,3,4-substituted oxabicyclic arenes in high yield ( 3l – 3o , Scheme ). Additionally, aryl­(TMP)­iodonium salts with substitution at the meta and ortho′ positions resulted in the distinct 1,2,3,4-substituted oxabicyclic arene products 3p and 3q (Scheme ).…”

Synthesis of 4,4-Dimethyl-1,6-heptadiyne and Alcyopterosin O

“…Eight additional publications on the synthesis of illudalane sesquiterpenes have appeared since the beginning of 2018, as these targets increasingly attract attention for natural product synthesis. Among the challenges they typically pose is the need to construct a penta- or hexasubstituted benzenoid ring system and a neopentylene ring fusion within the indane core. Alkyne cyclotrimerization has figured prominently in previous approaches, as has the use of 4,4-dimethyl-1,6-heptadiynesneopentylene-tethered 1,6-diynesas key building blocks.…”

“…This synthesis of alcyopterosin O overcomes the traditional challenges of the illudalane sesquiterpenes highlighted above (cf. Figure ): construction of a highly substituted benzenoid and neopentylene ring fusion. For example, Zhang’s 2019 synthesis of granulolactone features intermolecular [2+2+2] cyclotrimerization of symmetrical diyne 1 to deliver a desmethyl variant of granulolactone, with five additional steps required to introduce the final arene methyl group regioselectively .…”