Development of Catalytic Asymmetric Synthesis of Optically Active beta-Hetero-alpha-amino Acids

光学活性的α-氨基酸连接在β-碳原子上，不仅是许多生物活性多肽的重要组成部分，也是合成有用化合物的手性构件。在这项研究中，作者开发了一些新的催化不对称合成光学活性的β-杂-α-氨基酸。β-杂-α-乙酰丙酸酯的立体选择性合成以相应的β-酮-α-乙酰氨基丙烯酸酯为原料，合成了β-位含杂取代基的α-乙酰胺基丙烯酸酯。这两种几何异构体都有可能以完美的立体选择性制备。β-杂-α-乙酰氨基丙烯酸酯的催化不对称氢化。得到的β-杂-α-乙酰氨基丙烯酸酯在作者研制的具有反络合手性双膦陷阱的手性铑催化剂上具有高的对映体选择性(最高达97%ee)。从(E)-和(Z)-底物上分别获得了具有完全立体专一性和高对映体选择性的苏氨酸和红血球-β-杂α-氨基酸。环状β-杂-α-氨基酸的催化不对称合成TRAP-Rh催化剂对四氢吡嗪-2-甲酰胺的不对称加氢反应也很有效，得到的(S)-哌嗪-2-(N-叔丁基)甲酰胺的ee高达97%，这对合成HIV蛋白酶抑制剂Crixivan是非常重要的。有趣的是，两种手性催化剂都有可能获得高对映体过量的对映体。

Optically active alpha-amino acids attached a hetero atom on the beta-carbon atom are important as not only constituents of many biologically active peptides but also chiral building blocks for syntheses of useful compounds. In this study, the author developed some new catalytic asymmetric syntheses of optically active beta-hetero-alpha-amino acids.1. Stereoselective Synthesis of beta-Hetero-alpha-acetamldoacrylates. alpha-Acetamidoacrylates bearing a heterosubstituent at the beta-position were synthesized from the corresponding beta-keto-alpha- acetamidoacrylates. Both of the geometrical isomers were possible to be prepared with perfect stetreoselectivity.2. Catalytic Asymmetric Hydrogenation of beta-Hetero-alpha-acetamidoacrylates. The beta-hetero-alpha- acetamidoacrylates thus obtained were hydrogenated with high enantioselectivity (up to 97% ee) by a chiral rhodium catalyst possessing a trans-chelating chiral diphosphine TRAP, which had been developed by the authors. threo- and erythro-beta-Hetero-alpha-amino acids were obtained with complete stereospecificity and high enantioselectivity from the (E)- and (Z)-substrates, respectively.3. Catalytic Asymmetric Synthesis of Cyclic beta-Hetero-alpha-amino acids. The TRAP-rhodium catalysts were also effective for asymmetric hydrogenations of tetrahydropyrazine-2-carboxamides, giving (S)-piperazine-2-(N-tert-butyl)carboxamides with up to 97% ee, which are important for the synthesis of HIV protease inhibitor Crixivan. Of interest is that both of the enantiomers with high enantiomeric excess were possible to be obtained by two chiral catalysts derived from a single chiral source.