Yao S, Saaby S, Hazell RG, Jorgensen KA
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University, Denmark.
Chemistry. 2000 Jul 3;6(13):2435-48. doi: 10.1002/1521-3765(20000703)6:13<2435::aid-chem2435>3.0.co;2-z.
A catalytic enantioselective aza-Diels-Alder reaction of imines has been developed. The reaction of N-tosyl alpha-imino ester with different dienes including activated, non-activated, cyclic, and acyclic dienes has been investigated in the presence of various chiral Lewis acids. A series of phosphino-oxazoline ligands have been synthesized and evaluated for the reaction. It was found that the combination of phosphino-oxazoline ligands with copper(I) salts gives the best results for the activated dienes, while BINAP-copper(I) complexes are good catalysts for all the dienes studied. In the case of activated acyclic dienes the aza-Diels-Alder products can be obtained in higher than 80% isolated yield and 96% ee, while for the unactivated cyclic dienes the exo diastereomer is formed as the major product in up to 95 % ee. For an activated cyclic conjugated diene, 2-trimethylsilyloxy-1,3-cyclohexadiene, the reaction proceeds as a Mannich-type addition reaction giving optically active gamma-oxo alpha-amino acid derivatives in good yields and up to 96% ee. The reaction of an unactivated acyclic diene, 2,3-dimethyl-1,3-butadiene, with the N-tosyl alpha-imino ester gives both the aza-Diels-Alder and aza-ene products, in a ratio of 9:1 favoring the aza-Diels-Alder product. Furthermore, a series of different imines have been synthesized and investigated as possible substrates for the present catalytic enantioselective aza-Diels-Alder reaction in order to obtain mechanistic insight. All imines studied gave moderate to high ee. Particularly, the reaction of the N-phenyl and N-p-methoxyphenyl substituted glyoxylate imines with Danishefsky's diene proceeded well affording the corresponding aza-Diels-Alder product in high yield with up to 91% ee at room temperature. The present catalytic enantioselective reaction of imines provided an effective route to optically active nonproteinogenic alpha-amino acids. The products of the catalytic enantioselective aza-Diels-Alder reaction of the cyclic dienes can be used for the preparation of key compounds such as natural products and compounds of pharmaceutical interest. The absolute configurations of five products have been solved by X-ray structural analysis, and it is found that the absolute configuration of the aza-Diels-Alder adduct is dependent on the substituent on the imine nitrogen atom. It turned out that the N-tosyl glyoxylate imine and N-p-methoxyphenyl glyoxylate imine give the aza-Diels-Alder adduct with opposite absolute configuration using the same enantiomer of the catalyst. On the basis of the results the mechanistic aspects for the reactions are discussed.
已开发出一种催化对映选择性亚胺的氮杂狄尔斯-阿尔德反应。在各种手性路易斯酸存在下，研究了N-甲苯磺酰基α-亚胺酯与不同二烯（包括活化的、未活化的、环状和非环状二烯）的反应。合成了一系列膦基恶唑啉配体并对该反应进行了评估。发现膦基恶唑啉配体与铜（I）盐的组合对活化二烯给出了最佳结果，而联萘二苯膦-铜（I）配合物对所有研究的二烯都是良好的催化剂。对于活化的非环状二烯，氮杂狄尔斯-阿尔德产物可以以高于80%的分离产率和96%的对映体过量获得，而对于未活化的环状二烯，外型非对映体作为主要产物形成，对映体过量高达95%。对于活化的环状共轭二烯2-三甲基甲硅烷氧基-1,3-环己二烯，反应以曼尼希型加成反应进行，以良好的产率和高达96%的对映体过量得到光学活性的γ-氧代α-氨基酸衍生物。未活化的非环状二烯2,3-二甲基-1,3-丁二烯与N-甲苯磺酰基α-亚胺酯的反应给出氮杂狄尔斯-阿尔德和氮杂烯产物，比例为9:1，有利于氮杂狄尔斯-阿尔德产物。此外，合成了一系列不同的亚胺并作为当前催化对映选择性氮杂狄尔斯-阿尔德反应的可能底物进行研究，以获得机理见解。所有研究的亚胺都给出了中等至高的对映体过量。特别地，N-苯基和N-对甲氧基苯基取代的乙醛酸亚胺与达尼谢夫斯基二烯的反应在室温下顺利进行，以高产率得到相应的氮杂狄尔斯-阿尔德产物，对映体过量高达91%。当前亚胺的催化对映选择性反应为光学活性的非蛋白ogenicα-氨基酸提供了一条有效途径。环状二烯的催化对映选择性氮杂狄尔斯-阿尔德反应的产物可用于制备关键化合物，如天然产物和具有药物意义的化合物。通过X射线结构分析确定了五种产物的绝对构型，发现氮杂狄尔斯-阿尔德加合物的绝对构型取决于亚胺氮原子上的取代基。结果表明，使用相同对映体的催化剂，N-甲苯磺酰基乙醛酸亚胺和N-对甲氧基苯基乙醛酸亚胺给出具有相反绝对构型的氮杂狄尔斯-阿尔德加合物。基于这些结果讨论了反应的机理方面。
