Atropisomerism in the Pharmaceutically Relevant Realm

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: Atropisomerism is a conformational chirality that occurs when there is hindered rotation about a σ-bond. While atropisomerism is exemplified by biaryls, it is observed in many other pharmaceutically relevant scaffolds including heterobiaryls, benzamides, diarylamines, and anilides. As bond rotation leads to racemization, atropisomers span the gamut of stereochemical stability. LaPlante has classified atropisomers based on their halflife of racemization at 37 °C: class 1 (t 1/2 < 60 s), class 2 (60 s < t 1/2 < 4.5 years), and class 3 (t 1/2 > 4.5 years). In general, class-3 atropisomers are considered to be suitable for drug development.

Synthesis, conformational stability and molecular structure of 4-aryl- and 4,5-diaryl-1,8-bis(dimethylamino)naphthalenes

“…40,41 First, atropisomerism is a fundamentally important element of chirality in nature. 42 Atropisomers can vary greatly in their biological activities and functions. 43,44 Based on such conformationally stable compounds, it would be possible to create, for example, chiral ligands for asymmetric synthesis.…”

Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone–Atorvastatin Prodrug

“…The troubles arise from their difficult synthesis and kinetic axial control in a biological environment [ 2 ]. However, atropisomers have been found in naturally occurring compounds and their increase in activity and selectivity towards the respective enzymes has undoubtedly been evident [ 3 , 4 , 5 , 6 , 7 ].…”

“…Herein, we have reported a library of atorvastatins with structural modifications at position 3 of pyrrole to develop an additional chiral axis with a racemization barrier bigger than 30 kcal/mol (Class III atropisomers in the Laplante terminology [ 4 , 5 ]), yielding consequently diastereomeric drugs with potentially different pharmacological effects. DFT calculations and kinetic experiments were used to evaluate the rotational racemization barrier in atorvastatin-model compounds lacking the chiral chain ( Section 2.1 and Section 2.3 ).…”

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

“…For example, natural products with the heterobiaryl skeleton, such as Ancistrocladinium A , Rivularin D 3 , Murrastifoline F , and Marinopyrrole A , were isolated from marine blue-green alga Rivularia firma , Murraya koenigii , and actinomycete strain CNQ-418, and some of these products exhibit excellent activities in antimicrobial bioassays ( Figure 1 A) [ 14 , 15 , 16 ]. In addition, axial heterobiaryl compounds are also present in many FDA-approved drugs, and they have been proven to have a positive contribution to pharmacokinetics including absorption, distribution, metabolism, excretion, and potency via interaction with the target protein, which made heterobiaryl molecules more and more prevalent in drug discovery and drug development ( Figure 1 B) [ 17 , 18 , 19 , 20 , 21 ]. In addition, axially chiral heterobiaryl subunits, such as isoquinoline containing phosphine and atropisomeric isoquinoline N -oxide, have been successfully employed as powerful chiral ligands to construct various chiral molecules through transition-metal catalyzed asymmetric transformation ( Figure 1 C) [ 22 , 23 , 24 , 25 , 26 , 27 ].…”