Zelaszczyk D, Kieć-Kononowicz K
Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland.
Curr Med Chem. 2007;14(1):53-65. doi: 10.2174/092986707779313480.
Beta-blockers are a very important group of drugs widely used for the treatment of cardiovascular diseases. All aryloxyaminopropanols are chiral and show different stereoselectivity in their pharmacodynamic and pharmacokinetic properties for each enantiomer. The more potent beta-adrenoceptor blocking activity is generally associated with (S)-enantiomers. Most beta-blocking agents are sold as racemates although (R)-enantiomers not only show in some cases lack of activity but might be responsible for undesirable effects. Among reports on the direct enzymatic resolution of the most representative beta-blocker propranolol, the most interesting is N-acetylation method with commercially available lipases to yield (S)-N-acetylpropranolol. Another type of the one-step (S)-isomer biocatalytic preparation from racemic mixture of propranolol is the biodegradation with the fungus. Biocatalytic methods of obtaining homochiral beta-blockers that are focused on production of versatile precursors are widely described in literature. The strategies based on the use of glycidol and derivatives as C-3 synthones have been shown to be extremely useful for the introduction of the 2-propanol chain on the aromatic system. Halohydrins are the established intermediates in the preparation of optically active beta-blockers. Its resolution by esterhydrolases has been used as a standard alternative in preparation of the homochiral propranolol. Additionally, the enzymatic resolution of the following intermediates was reported: 1-azido-3-aryloxy-2-propanols, 4-(1-aryloxy)-3-hydroxybutyric acid esters, glycerol and cyanohydrin derivatives. However, even the highly enantioselective lipase-catalyzed process can only provide 50% of the starting racemate in an optically active form. An alternative method such as a reduction of a prochiral ketone by various strains of yeast might quantitatively provide an enantiomeric product with a yield greater than 50%. The reported substrates for microbial reductions were: 1-halo-aryloxypropan-2-ones and 1-acetoxy-aryloxypropan-2-ones.
β受体阻滞剂是一类非常重要的药物，广泛用于治疗心血管疾病。所有芳氧基氨基丙醇都是手性的，其对映体在药效学和药代动力学性质上表现出不同的立体选择性。更强效的β肾上腺素能受体阻断活性通常与（S）-对映体相关。大多数β受体阻滞剂以消旋体形式出售，尽管（R）-对映体在某些情况下不仅显示缺乏活性，而且可能导致不良影响。在关于最具代表性的β受体阻滞剂普萘洛尔的直接酶法拆分的报道中，最有趣的是用市售脂肪酶进行N-乙酰化方法以生成（S）-N-乙酰普萘洛尔。另一种从普萘洛尔外消旋混合物一步制备（S）-异构体的生物催化方法是用真菌进行生物降解。文献中广泛描述了以生产通用前体为重点的获得纯手性β受体阻滞剂的生物催化方法。已证明基于使用缩水甘油及其衍生物作为C-3合成子的策略对于在芳环系统上引入2-丙醇链非常有用。卤代醇是制备光学活性β受体阻滞剂的既定中间体。其通过酯水解酶的拆分已被用作制备纯手性普萘洛尔的标准替代方法。此外，还报道了以下中间体的酶法拆分：1-叠氮基-3-芳氧基-2-丙醇、4-（1-芳氧基）-3-羟基丁酸酯、甘油和氰醇衍生物。然而，即使是高度对映选择性的脂肪酶催化过程也只能以光学活性形式提供50%的起始消旋体。诸如用各种酵母菌株还原前手性酮的替代方法可能定量提供产率大于50%的对映体产物。报道的微生物还原底物为：1-卤代-芳氧基丙-2-酮和1-乙酰氧基-芳氧基丙-2-酮。
