Hoge Garrett
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
J Am Chem Soc. 2003 Aug 27;125(34):10219-27. doi: 10.1021/ja034715o.
Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two convergent methods. The first method relies on the chiral alkylation of 1-((-)-menthoxy)phospholaneborane using a s-BuLi/(-)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized via this method because only one antipode of sparteine is available in nature. The second route relies on the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity (77-95% ee) under low H(2) pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors, 39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure (30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pressure. Increasing the pressure of H(2) caused a significant increase in enantiomeric excess for low catalyst loading reactions. Several studies were undertaken to further investigate the enantioselectivity dependence on both pressure and catalyst loading.
一种P-手性1,2-双膦基乙烷配体的两种对映体通过两种汇聚方法合成。第一种方法依赖于使用s-BuLi/(-)-鹰爪豆碱衍生的手性碱对1-((-)-薄荷氧基)膦硼烷进行手性烷基化。由于自然界中仅存在鹰爪豆碱的一种对映体，因此通过该方法只能合成催化剂的一种对映体。第二条路线依赖于甲基膦硼烷和手性1,4-二醇的组合。配体的任何一种对映体均可通过第二条路线由1,4-二醇的相应对映体制备。在低氢气压力（30 psi）下，使用催化剂前体36对乙酰氨基丙烯酸衍生物进行不对称氢化反应，可获得中等至良好的对映选择性（77 - 95% ee）。CI-1008（普瑞巴林）前体39和40的不对称氢化反应，在高催化剂负载量（1 mol%）和低压（30 psi）下可获得良好的对映选择性（92%）。在此压力下，对映体过量值随催化剂负载量急剧下降。对于低催化剂负载量的反应，提高氢气压力会导致对映体过量值显著增加。开展了多项研究以进一步考察对映选择性对压力和催化剂负载量的依赖性。
