Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich , 8093 Zürich, Switzerland.
Acc Chem Res. 2016 Dec 20;49(12):2807-2821. doi: 10.1021/acs.accounts.6b00461. Epub 2016 Dec 12.
The preparation of enantioenriched chiral compounds by kinetic resolution dates back to the laboratories of Louis Pasteur in the middle of the 19th century. Unlike asymmetric synthesis, this process can always deliver enantiopure material (ee > 99%) if the reactions are allowed to proceed to sufficient conversion and the selectivity of the process is not unity (s > 1). One of the most appealing and practical variants is acylative kinetic resolution, which affords easily separable reaction products, and several highly efficient enzymatic and small molecule catalysts are available. Unfortunately, this method is applicable to limited substrate classes such as alcohols and primary benzylamines. This Account focuses on our work in catalytic acylative kinetic resolution of saturated N-heterocycles, a class of molecules that has been notoriously difficult to access via asymmetric synthesis. We document the development of hydroxamic acids as suitable catalysts for enantioselective acylation of amines through relay catalysis. Alongside catalyst optimization and reaction development, we present mechanistic studies and theoretical calculation accounting for the origins of selectivity and revealing the concerted nature of many amide-bond forming reactions. Immobilization of the hydroxamic acid to form a polymer supported reagent allows simplification of the experimental setup, improvement in product purification, and extension of the substrate scope. The kinetic resolutions are operationally straight forward: reactions proceed at room temperature and open to air conditions, without generation of difficult-to-remove side products. This was utilized to achieve decagram scale resolution of antimalarial drug mefloquine to prepare more than 50 g of (+)-erythro-meflqouine (er > 99:1) from the racemate. The immobilized quasienantiomeric acyl hydroxamic acid reagents were also exploited for a rare practical implementation of parallel kinetic resolution that affords both enantiomers of the amine products in high enantiopurity. The success of this process relied on identification of two cleavable acyl groups alongside implementation of flow-chemistry techniques to ensure reusability of the resolving agents. The work discussed in this Account has laid foundations for new catalyst design as well as development of desymmetrization and dynamic kinetic resolution processes. In the meantime, as all the requisite reagents are commercially available, we hope that hydroxamic acid promoted acylative kinetic resolution will become a method of choice for preparation of saturated N-heterocycles in enantiopure form.
通过动力学拆分制备对映体富集的手性化合物可以追溯到 19 世纪中叶路易斯·巴斯德（Louis Pasteur）的实验室。与不对称合成不同，如果反应进行到足够的转化率并且过程的选择性不是单一的（s > 1），则该过程始终可以提供对映体纯的物质（ee > 99%）。最吸引人且实用的变体之一是酰基动力学拆分，它提供了易于分离的反应产物，并且有几种高效的酶和小分子催化剂可供使用。不幸的是，该方法适用于有限的底物类别，例如醇和伯苄胺。本专题重点介绍了我们在饱和 N-杂环的催化酰基动力学拆分方面的工作，该类分子通过不对称合成难以获得。我们记录了羟肟酸作为通过接力催化对胺进行对映选择性酰化的合适催化剂的发展。除了催化剂优化和反应开发外，我们还提出了机理研究和理论计算，以说明选择性的起源，并揭示许多酰胺键形成反应的协同性质。羟肟酸的固定化形成聚合物支撑试剂，可以简化实验装置，改善产物纯化，并扩展底物范围。动力学拆分操作简单：反应在室温下进行，并在空气条件下进行，没有生成难以去除的副产物。这用于实现抗疟药甲氟喹的工业规模拆分，以从外消旋体中制备超过 50 g 的（+）-erythro-甲氟喹（er > 99：1）。固定化的准对映体酰基羟肟酸试剂还被用于罕见的实际平行动力学拆分的实现，该拆分以高对映体纯度提供胺产物的两种对映体。该过程的成功依赖于识别两种可裂解的酰基基团，同时实施流动化学技术以确保拆分试剂的可重复使用性。本专题讨论的工作为新的催化剂设计以及解对称化和动态动力学拆分过程的发展奠定了基础。同时，由于所有必需的试剂都可商购，我们希望羟肟酸促进的酰基动力学拆分将成为制备对映体纯饱和 N-杂环的首选方法。
