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Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2022-10-04 , DOI: 10.1021/acs.accounts.2c00513
Anna-Carin C Carlsson 1 , Staffan Karlsson 1 , Rachel H Munday 2 , Matthew R Tatton 3
Affiliation  

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.

中文翻译:

对映体纯生物活性阻转异构体的合成和分离方法

阻转异构现象是一种立体化学现象,由含有旋转受限 σ 键的分子表现出来。与经典的点手性相反,这两种阻转异构立体异构体以动态混合物的形式存在,并且可以相互转化而无需破坏和重组键。尽管此功能增加了结构的复杂性,但阻转异构体已成为药物化学项目中的常见目标。它们的轴向手性(例如,来自轴向手性联芳基图案)提供了独特的 3D 结构。通常希望在早期发现阶段通过非选择性反应获得阻转异构体的两种对映体,因为它允许药物化学团队从两个方向探索结构活性关系。然而,一旦选择了单一的阻转异构体,就会出现几个问题。首先,在某些条件下,纯的单一阻转异构体可能会相互转化为不需要的立体异构体。其次,阻转异构体的分离非常重要,如果选择盐拆分方法,通常需要使用色谱法或添加剂的昂贵手性固定相。其他选择可以是使用酶或手性催化剂的动力学拆分。然而,除了通常与后两种方法相关的高成本之外,可以获得的最大收率仅为所需阻转异构体的 50%。理想的方法是对映选择性地安装手性阻转异构轴或采用动态动力学拆分方法。理论上,这两种方法都有可能提供定量产率的单一阻转异构体。该帐户将讨论我们在早期药物开发项目之一中开发阻转异构候选药物的拆分/分离和不对称合成方法所经历的成功/失败和挑战。讨论了药物开发阶段不同阶段的不同方法的适用性。根据可用的规模和时间,有时首选通过色谱法分离阻转异构体的混合物,而不对称或拆分方法需要长期供应。讨论了色谱法的使用对分离效率和溶剂消耗的影响,具体取决于底物的性质。
更新日期:2022-10-04
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