Asymmetric Induction in Hydrogen-Mediated Reductive Aldol Additions to α-Amino Aldehydes Catalyzed by Rhodium: Selective Formation of <i>syn</i>-Stereotriads Directed by Intramolecular Hydrogen-Bonding

Rhodium-catalyzed hydrogenation of methyl vinyl ketone and ethyl vinyl ketone in the presence of N-Boc-α-aminoaldehydes 3a−8a at ambient temperature and pressure results in reductive C−C coupling to furnish aldol adducts 3b−8b and 3c−8c, respectively, which incorporate stereotriads that embody high levels of syn-aldol selectivity accompanied by high levels of anti-Felkin−Anh control. The collective data are consistent with a catalytic mechanism involving addition of the Z(O)-rhodium enolate to the sterically less-encumbered aldehyde π-face of an intramolecularly hydrogen-bonded chelate through a Zimmerman−Traxler type transition structure. Stereochemical assignments are supported by single-crystal X-ray diffraction analysis of 5b-O-3,5-dinitrobenzoate, iso-5b, N-Me-iso-5b-O-3,5-dinitrobenzoate, and 7b. As revealed by HPLC analysis, optical purity of the stereochemically labile α-aminoaldehydes is completely preserved under the conditions of hydrogen-mediated aldol coupling. Deletion of the intramolecular hydrogen bond, as in the case of N-methyl-N-Boc-l-leucinal N-Me-5a, inverts stereoselectivity to furnish the Felkin−Anh product N-Me-iso-5b in 17% yield. Additionally, reactions performed in the presence of tert-amyl alcohol (10 equiv) exhibit markedly lower levels of anti-Felkin−Anh control (7:1 versus ≥ 20:1). The collective studies suggest that intramolecular hydrogen bonding plays a key role in both activating the α-aminoaldehyde toward addition and directing facial selectivity.在常温常压条件下，铑催化甲基乙烯基酮与乙基乙烯基酮在N-叔丁氧羰基-α-氨基醛（N-Boc-α-aminoaldehydes）3a−8a存在下的加氢反应，经还原型碳-碳偶联分别得到羟醛加成产物3b−8b与3c−8c；两类产物均含有立体三单元组（stereotriads），兼具高水平的syn-羟醛选择性与反Felkin-Anh立体控制效应。整体实验数据与如下催化机理相符：Z(O)-型铑烯醇盐（Z(O)-rhodium enolate）通过齐默曼-特拉克勒型过渡态（Zimmerman−Traxler type transition structure），进攻分子内氢键螯合环中位阻较小的醛π面发生加成反应。通过对5b-O-3,5-二硝基苯甲酸酯、iso-5b、N-Me-iso-5b-O-3,5-二硝基苯甲酸酯以及7b的单晶X射线衍射（single-crystal X-ray diffraction）分析，证实了上述立体化学归属。高效液相色谱（HPLC）分析结果显示，在加氢介导的羟醛偶联反应条件下，立体化学易变的α-氨基醛的光学纯度完全得以保留。当破坏分子内氢键时（如N-甲基-N-叔丁氧羰基-L-亮氨醛N-Me-5a），立体选择性发生反转，以17%的收率得到Felkin-Anh型产物N-Me-iso-5b。此外，在添加10当量叔戊醇（tert-amyl alcohol）的反应体系中，反Felkin-Anh立体控制效果显著降低（选择性比例从≥20:1降至7:1）。综上研究结果表明，分子内氢键在活化α-氨基醛以参与加成反应以及调控面选择性两方面均发挥关键作用。