Direct Catalytic Asymmetric Synthesis of <i>anti</i>-1,2-Amino Alcohols and <i>syn</i>-1,2-Diols through Organocatalytic <i>anti</i>-Mannich and <i>syn</i>-Aldol Reactions

Chiral 1,2-amino alcohols and 1,2-diols are common structural motifs found in a vast array of natural and biologically active molecules. Efficient enantioselective syntheses of ketones containing syn- or anti-1,2-amino alcohols and 1,2-diols have been reported using metal-based strategies. To date, however, approaches involving organocatalysis have been limited to the syntheses of the syn-1,2-amino alcohols and anti-1,2-diols. Herein we disclose simple and efficient routes to highly enantiomerically enriched anti-1,2-amino alcohols and syn-1,2-diols through direct asymmetric Mannich, Mannich-type, and aldol reactions involving unmodified α-hydroxyketones in reactions catalyzed by primary amine-containing amino acids. These reactions exploit (Z)-enamines of α-hydroxyketones in their bond-forming transition states. This study compliments and extends our bioorganic approach to asymmetric synthesis in these two versatile synthon classes. Significantly, these reactions are practical, tolerate wet solvent, and exploit commercially available amino acids, such as threonine and tryptophan, and their derivatives as catalysts. These results provide additional support for our original hypothesis suggesting that amino acid catalysis played a key role in prebiotic chemistry facilitating the asymmetric synthesis of the molecules of life.手性1,2-氨基醇（chiral 1,2-amino alcohols）与1,2-二醇（1,2-diols）是广泛存在于大量天然产物及生物活性分子中的常见结构基元。此前已有研究采用金属基策略，实现了含顺式或反式1,2-氨基醇与1,2-二醇结构的酮类化合物的高效对映选择性合成。然而迄今为止，涉及有机催化的合成方法仅局限于顺式1,2-氨基醇（syn-1,2-amino alcohols）与反式1,2-二醇（anti-1,2-diols）的合成。本文报道了一条简便高效的合成路径：以含伯胺的氨基酸为催化剂，通过未修饰α-羟基酮（α-hydroxyketones）参与的直接不对称曼尼希（Mannich）、类曼尼希（Mannich-type）及羟醛缩合（aldol）反应，可制备高对映体富集的反式1,2-氨基醇（anti-1,2-amino alcohols）与顺式1,2-二醇（syn-1,2-diols）。此类反应在成键过渡态中利用了α-羟基酮的（Z）-烯胺中间体。本研究丰富并拓展了我们针对这两类通用合成子的生物有机不对称合成策略。值得注意的是，此类反应具备良好的实用性，可耐受含水溶剂，且催化剂为商业化易得的氨基酸（如苏氨酸（threonine）与色氨酸（tryptophan））及其衍生物。上述结果进一步支持了我们最初的假说：氨基酸催化在益生元化学中发挥了关键作用，推动了生命分子的不对称合成。