Biological Chemistry Department, Instituto de Química Avanzada de Cataluña, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
Institut für Anorganische Chemie, J.-W.-Goethe-Universität, Frankfurt/Main, Germany.
J Am Chem Soc. 2020 Nov 18;142(46):19754-19762. doi: 10.1021/jacs.0c09994. Epub 2020 Nov 4.
The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing -dialkyl, -cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.
季碳原子的拥挤性质阻碍了它们的制备，尤其是当需要立体控制时。在这里，我们报告了一种具有广泛底物范围的生物催化方法，用于创建具有这种结构特征的季碳原子中心，导致不同的化合物类别的化合物。关键步骤包括金属依赖的 3-甲基-2-氧代丁酸羟甲基转移酶（KPHMT）及其变体催化的 3,3-二取代 2-氧代酸对醛的醛醇加成。由此产生的 3,3,3-三取代 2-氧代酸被转化为 2-氧代内酯和 3-羟基酸，并直接转化为尿苷酸衍生物，所有这些都带有 -二烷基、-环烷基和螺环季碳原子。此外，这些反应中的一些使用外消旋亲核试剂的单个对映异构体来提供立体纯的季碳原子。这些酶的显著的底物耐受性和立体控制表明它们具有合成结构复杂分子的潜力。
