Biotransformations in the Synthesis of Enantiopure Bioactive Molecules
Biotransformations in the Synthesis of Enantiopure Bioactive Molecules
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对映体纯生物活性分子合成中的生物转化
DOI：
10.1002/chin.199834322
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Carl R. Johnson
中科院分区：
文献类型：
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作者：
Carl R. Johnson
认识到手性在自然界中起着至关重要的作用，促进了对映选择性合成的努力。虽然酶在不对称合成中的应用的概念早已被认识，但直到最近这些催化剂才引起非专业人员的注意。区分外消旋底物的对映体的能力具有公认的制备价值。5酶促拆分可获得两种对映异构体，如果需要这两种对映异构体，则这是理想的。然而，如果仅需要一种对映异构体，则50%转化率构成最大产率。酶也能够区分前手性和内消旋化合物的对映体基团。与外消旋材料的动力学拆分相反，这些转化的理论产率为100%。近年来，内消旋化合物的酶促去对称化反应得到了广泛的应用，并成为合成对映体纯化合物的一种非常有效的方法。6.我将在此概述我们实验室的工作，涉及酶和发酵在去对称化和拆分中的应用，用于生产对映体纯中间体，以及后者在合成各种生物活性靶分子中的应用。脂肪酶的分子结构很像丝氨酸蛋白酶，由丝氨酸、组氨酸和天冬氨酸（或谷氨酸）组成的催化三联体。这种机制首先将酯（或其他酰基衍生物）的酰基转移到丝氨酸残基的羟基上，形成酰化酶。酰基随后被转移到外部亲核试剂，酶返回到其预酰化状态，重新开始该过程。各种亲核试剂可以参与该过程：水导致水解，醇导致酯化或酯交换，胺导致酰胺化，过氧化氢导致形成过酸（其可以环氧化可用的烯烃）。蛋白质的形状性质在酶活性位点内产生亲水性或亲脂性口袋7，这导致对映体、非对映体或化学选择性。这种选择性可以在酰基酶中间体的形成过程中或在随后的亲核攻击中或两者中表现出来（图1）。一般来说，细胞产生脂肪酶来水解细胞外脂肪。由于天然底物是水不溶性的，脂肪酶特别被构造成在水/有机界面处起作用。由于这个原因，脂肪酶似乎是最适合在有机溶剂中操作的酶; 8在这种情况下，界面是在不溶性酶与其必需的水合水和含有酰化剂（如乙酸异丙烯酯）和待酰化底物的有机溶剂之间（图2）。作为形状选择性结合的结果，酶促酯水解可以与相应的酶促酯形成对映互补，例如，（RS）-乙酸酯的水解可以导致（R）-乙酸酯和（S）-醇的形成，而Carl R.约翰逊1937年出生于弗吉尼亚州夏洛茨维尔，在附近的弗吉尼亚州橙子镇长大。他于1958年获得弗吉尼亚医学院药学学士学位，在那里他被已故的Walter Hartung介绍到有机化学研究。他获得了博士学位。与纳尔逊J.伦纳德在伊利诺伊大学于1962年。在与EJ Corey一起在哈佛大学担任NSF博士后研究员一段时间后，他于1962年秋季加入韦恩州立大学，担任化学系的杰出教授和系主任。他对职业的贡献...
Recognition that chirality plays a crucial role in nature has fostered much effort in enantioselective synthesis. Although the concept of enzyme applications1-4 to asymmetric synthesis has been long recognized, it is only recently that these catalysts are attracting the attention of the nonspecialist. The ability to discriminate between enantiomers of a racemic substrate is of well-recognized preparative value. 5 An enzymatic resolution gives access to both enantiomers, which is desirable if both are required. However, if only one enantiomer is needed, a 50% conversion constitutes the maximum yield. Enzymes are also capable of differentiating enantiotopic groups of prochiral and meso compounds. In contrast to the kinetic resolution of a racemic material, the theoretical yield of these conversions is 100%. The enzymatic desymmetrization of meso compounds has gained popularity in recent years and constitutes a highly effective approach for the synthesis of enantiomerically pure compounds. 6 I will present here an overview of work from our laboratory involving the use of enzymes and fermentations in desymmetrizations and in resolutions for the production of enantiopure intermediates and the use of the latter in the synthesis of a variety of bioactive target molecules. The molecular machinery of lipases is much like that of the serine proteases and consists of a catalytic triad of amino acidssserine, histidine, and aspartic (or glutamic) acid. This machinery first transfers the acyl group of an ester (or other acyl derivative) to the hydroxyl group of the serine residue to form the acylated enzyme. The acyl group is subsequently transferred to an external nucleophile with return of the enzyme to its pre-acylated state to start the process over again. A variety of nucleophiles can participate in this process: water results in hydrolysis, an alcohol results in esterification or transesterification, an amine results in amidation, hydrogen peroxide results in the formation of a peracid (which can epoxidize an available olefin). The shape nature of the protein creates hydrophilic or lipophilic pockets7 within the enzyme active site which result in enantio-, diastereo-, or chemoselectivity. This selectivity can be manifested during formation of the acyl-enzyme intermediate or in the subsequent nucleophilic attack or both (Figure 1). In general, cells produce lipases to hydrolyze extracellular fats. Because the natural substrates are water insoluble, lipases are especially structured to act at a water/organic interface. For this reason lipases appear to be optimum among the enzymes to operate in organic solvents; 8 in this case the interface is between the insoluble enzyme with its essential water of hydration and the organic solvent containing an acylating agent, eg, isopropenyl acetate, and a substrate to be acylated (Figure 2). As a consequence of shape selective binding, enzymatic ester hydrolysis can be enantiocomplementary to the corresponding enzymatic ester formation, eg, hydrolysis of an (RS)-acetate may result in the formation of the (R)-acetate and (S)-alcohol whereas exposure of theCarl R. Johnson was born in Charlottesville, VA, in 1937 and grew up in the nearby town of Orange, VA. He received a BS degree in pharmacy in 1958 from the Medical College of Virginia where he was introduced to organic chemistry research by the late Walter Hartung. He received his Ph. D. with Nelson J. Leonard at the University of Illinois in 1962. After a brief period as an NSF Postdoctoral Fellow at Harvard University with EJ Corey, he joined the faculty at Wayne State University in Fall 1962 where he is Distinguished Professor and Chair of the Department of Chemistry. His service to the profession has …