Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Atropisomerism is a stereochemical phenomenon exhibited by molecules containing a rotationally restricted σ bond. Contrary to classical point chirality, the two atropisomeric stereoisomers exist as a dynamic mixture and can be interconverted without the requirement of breaking and reforming a bond. Although this feature increases structural complexity, atropisomers have become frequent targets in medicinal chemistry projects. Their axial chirality, e.g., from axially chiral biaryl motifs, gives access to unique 3D structures. It is often desirable to have access to both enantiomers of the atropisomers via a nonselective reaction during the early discovery phase as it allows the medicinal chemistry team to probe the structure activity relationship in both directions. However, once a single atropisomer is selected, it presents several problems. First, the pure single atropisomer may interconvert to the undesired stereoisomer under certain conditions. Second, separation of atropisomers is nontrivial and often requires expensive chiral stationary phases using chromatography or additives if a salt resolution approach is chosen. Other options can be kinetic resolution using enzymes or chiral catalysts. However, apart from the high cost often associated with the two latter methods, a maximum yield of only 50% of the desired atropisomer can be obtained. The ideal approach is to install the chiral atropisomeric axis enantioselectively or employing a dynamic kinetic resolution approach. In theory, both approaches have the potential to provide a single atropisomer in quantitative yield. This Account will discuss the successes/failures and challenges we have experienced in developing methods for resolution/separation and asymmetric synthesis of atropisomeric drug candidates in one of our early phase drug development projects. Suitability for the different methods at various stages of the drug development phase is discussed. Depending on the scale and time available, a separation of a mixture of atropisomers by chromatography was sometimes preferred, whereas asymmetric-or resolution approaches were desired for long-term supply. With the use of chromatography, the impact on separation efficiency and solvent consumption, depending on the nature of the substrate, is discussed. We hope that with this Account the readers will get a better view on the challenges medicinal and process chemists meet when designing new atropisomeric drug candidates and developing processes for manufacture of a single atropisomer.

DBU Promoted Polysubstituted Arene Formation via a Michael Addition/Cyclization/Elimination Cascade Reaction

“…Recently, the enantioselective construction of axially chiral biaryls has attracted much attention, as their widely existence in natural products [ 48 , 49 ] and bioactive molecules [ 50 , 51 , 52 ], as well as in chiral ligands [ 53 , 54 ] and chiral organo-catalysts [ 55 , 56 , 57 ]. In this context, the successful synthesis of the ortho -brominated product 7ka encouraged us to test the possibility of the enantioselective synthesis of this stable atropisomer.…”

Carbene-Catalyzed Atroposelective Construction of Chiral Diaryl Ethers

“…Axially chiral biaryl compounds frequently exist as materials, as biologically active chemicals, and also as chiral ligands or organocatalysts . Due to the importance of this structural motif, catalytic atroposelective biaryl scaffold synthesis has been extensively studied, with recent advances .…”

Atropselective Organocatalytic Synthesis of Chiral Compounds Containing Nitrogen along the Axis of Chirality

“…Included in this group are atropisomers, which are non-superimposable stereoisomers because their rotation about a single bond is restricted due to clashes in the steric bulk of large substituents in close proximity. The restriction in rotation may also arise from dipole-dipole interactions or from other electrostatic interactions [2].…”

“…As new methods to obtain atropisomers are being developed, e.g., catalytic enantioselective synthesis [2,16], as well as ways to analyze the, e.g., variable temperature NMR for atropisomer mixtures, determination of rotational energy barriers (ΔErot) by density In medicinal chemistry, the need to identify atropisomerism has been long recognized to be of great importance in drug discovery, since as it happens with other types of stereoisomers; atropisomers may display quite different properties, such as in vitro inhibition, crystallization, in vivo racemization rates, and absorption, distribution, metabolism, excretion, and toxicity properties [13]. Atropisomerism used to be looked at as a "lurking menace", which could not only be present unknowingly, but could also increase the cost of pharmaceutical research and development [14].…”

“…As new methods to obtain atropisomers are being developed, e.g., catalytic enantioselective synthesis [2,16], as well as ways to analyze the, e.g., variable temperature NMR for atropisomer mixtures, determination of rotational energy barriers (∆E rot ) by density func-tional theory (DFT) calculations and quantum mechanical calculations, which give a good estimate of the half-life for interconversion of the two forms, atropisomers, are being looked at more favorably [14]. Experimental methods including segmented flow technologies are also used to investigate the kinetics of interconversion [2].…”