Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
J Am Chem Soc. 2021 Feb 24;143(7):2930-2937. doi: 10.1021/jacs.0c13034. Epub 2021 Feb 10.
Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CHR versus CHR). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1-1.2 equiv) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an -hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.
手性二烷基碳宾胺在有机化学、药物化学和生物化学等领域都非常重要，可用作生物活性分子、手性配体和手性催化剂等。然而，大多数用于合成二烷基碳宾胺的催化不对称方法并不能普遍适用于两个烷基大小相似的胺（如 CHR 与 CHR）。在此，我们报道了两种温和的方法，用于催化对映体选择性合成保护的二烷基碳宾胺，均使用手性镍催化剂将烷基锌试剂（1.1-1.2 当量）与外消旋体偶联，具体而言，偶联物为 α-邻苯二甲酰亚氨基烷基氯或保护的α-氨基酸的 -羟基邻苯二甲酰亚胺（NHP）酯。这些方法用途广泛，可提供带有各种官能团的二烷基碳宾胺衍生物。对于 NHP 酯的偶联，我们进一步描述了一种一锅法变体，其中 NHP 酯原位生成，可使从市售氨基酸衍生物一步生成对映体富集的保护的二烷基碳宾胺；我们通过将其应用于一系列有趣的目标分子的高效催化对映选择性合成，证明了该方法的实用性。
