DpenPhos/Rh(I)催化的β-脱氢氨基酸酯的不对称氢化反应

DpenPhos/Rh(I) Catalyzed Asymmetric Hydrogenation of Dehydro-β-Amino Acid Esters

本文研究了一类结构可调手性单齿亚磷酰胺配体DpenPhos在Rh(I)催化的E和Z型β-脱氢氨基酸酯的不对称催化氢化反应中的应用.经过系统的反应条件和配体结构优化,发现N原子上含有H的亚磷酰胺配体与Rh(I)形成的催化剂通常比N原子上不含H的配体表现出更高的反应活性.在E型β-脱氢氨基酸酯的不对称氢化反应中,催化剂(R,R)-3k/Rh(I)表现突出,可以实现底物的常压催化氢化,取得了92%～96%的对映选择性,催化剂用量可降低至0.2 mol%;对于Z型β-脱氢氨基酸酯的不对称氢化反应,则(R,R)-3l/Rh(I)为最优催化剂,可以获得92%～98%ee值的氢化产物,特别是对于β-芳基取代衍生物的氢化反应,相应氢化产物的ee值可以达到96%～98%.该类催化剂为天然或非天然光学活性β氨基酸的合成提供了一个简便、高效的方法.

Enantiomerically pure β-amino acids and their derivatives are very important chiral building blocks for the syn- thesis offl-peptides, β-lactams, and many important biologically active compounds. Among various methods developed for their synthesis, catalytic asymmetric hydrogenation of the corresponding dehydro-Ⅰ-amino acid esters represents one of the most efficient and environmentally benign approaches, in which the Rh（Ⅰ） catalysts containing chiral phosphorous ligands play a central role. Although a variety of Rh（I） complexes of bidentate or monodentate ligands have been discovered for asymmetric hydrogenation of dehydro-Ⅰ-amino acid esters, some challenging issues still remain in terms of efficiency, enan- tioselectivity, and substrate scope. In the present work, a variety of Rh（Ⅰ） complexes of modular monodentate phosphoramid- ire ligands, DpenPhos, have been systematically investigated for the asymmetric hydrogenation of （E）- or （Z）- β-substituted dehydro- β-amino acid esters. It was found that the presence of a N-H moiety in the phosphoramidite ligand is critically im- portant for achieving high activity of the catalysis. Both （Z）- and （E）-geometrical isomers of the β-acetamido acrylic acid esters can be hydrogenated in the presence of DpenPhos/Rh（Ⅰ） catalysts to form the same enantiomers, albeit slightly different conditions were required to attain optimal enantioselectivities. （R,R）-3k/Rh（Ⅰ） （1 mol%） was disclosed to be optimal for the hydrogenation of （E）β-alkyl substituted dehydro-β-amino acid esters in dichloromethane under a relatively low pressure of hydrogen （0.5 MPa）, affording the corresponding β-amino acid esters with 92%-96% ee. The reaction still proceeded smoothly without significant sacrifice of activity or enantioselectivity either at a catalyst loading of 0.2 mol% or 0.1 MPa pressure of H2. For the hydrogenation of more challenging （Z）-β-alkyl or aryl substituted dehydro-β-amino acid esters, （R,R）-3FRh（Ⅰ） in combination with the dichloromethane/isopropanol （V/V=2/1） mixed solvent system turned out to be the best in terms of enantioselectivity and catalytic activity, giving a variety of β-alkyl or aryl substituted β-amino acid esters in 〉 99% yields with excellent optical purities （92%-98% ee）.