Monguchi Daiki
Institute for Chemical Research, Kyoto University, Japan.
Yakugaku Zasshi. 2006 Aug;126(8):617-27. doi: 10.1248/yakushi.126.617.
Optically active alpha,alpha-disubstituted alpha-amino acids belong to an important class of unnatural amino acids. Since the synthesis of such amino acids involves the creation of a quaternary stereocenter, methods for their synthesis have been extensively studied. We have reported that N-t-butoxycarbonyl(Boc)-N-methoxymethyl(MOM)-amino acid derivatives undergo asymmetric alpha-alkylation in up to 93% ee. Original chiral information on an amino acid is preserved in axially chiral enolate intermediates, and thus asymmetric induction is achieved without the aid of external chiral sources (i.e., memory of chirality). Recently, we have reported a new protocol for the asymmetric cyclization of amino acid derivatives, which enables straightforward synthesis of cyclic amino acids with a tetrasubstituted carbon center from the usual alpha-amino acids in up to 98% ee. Here we report the asymmetric construction of highly substituted chiral nitrogen heterocycles via intramolecular conjugate addition of chiral enolates generated from N-Boc-N-alkylylamino acid derivatives. This method is applicable to the asymmetric construction of pyrrolidine, piperidine, tetrahydroisoquinoline, and indoline derivatives with contiguous quaternary and tertiary stereocenters.
光学活性的α，α-二取代α-氨基酸属于一类重要的非天然氨基酸。由于此类氨基酸的合成涉及季碳立体中心的构建，其合成方法已得到广泛研究。我们曾报道，N-叔丁氧羰基（Boc）-N-甲氧基甲基（MOM）-氨基酸衍生物能以高达93%的对映体过量（ee）进行不对称α-烷基化反应。氨基酸上的原始手性信息保留在轴手性烯醇盐中间体中，因此无需借助外部手性源即可实现不对称诱导（即手性记忆）。最近，我们报道了一种氨基酸衍生物不对称环化的新方法，该方法能从普通α-氨基酸直接合成具有四取代碳中心的环状氨基酸，对映体过量高达98%。在此，我们报道通过分子内共轭加成由N-Boc-N-烷基氨基氨基酸衍生物生成的手性烯醇盐来不对称构建高度取代的手性氮杂环。该方法适用于具有相邻季碳和叔碳立体中心的吡咯烷、哌啶、四氢异喹啉和吲哚啉衍生物的不对称构建。
