Asymmetric Protonation of Enolates with Optically Active Imides as Proton Sources

前手性金属烯烃类化合物的不对称质子化反应是合成光学活性羰基化合物的有效途径。尽管一些基团对这一过程的持续进展做出了重要贡献，但这些反应大多是含极性基团的烯醇酸盐的反应，包括氨基、羟基或苯基，关于2-甲基环己酮等单酮的不对称诱导反应的报道很少。我们已经报道过具有不对称2-恶唑啉环的新型手性质子源(S，S)-或(R，R)-亚胺，它可以很容易地由Kemp的三羧酸和(1R，2S)-或(1S，2R)-2-氨基-1，2-二苯乙醇合成，并质子化各种具有良好到中等对映选择性的α-单烷基环烷酮锂烯醇。…对映体选择性的提高在以锂盐为添加剂的(S，S)-酰亚胺不对称质子化反应中，观察到了更多的前手性锂烯醇酸酯。例如，在5当量的溴化锂存在下，在Et_2O中生成相应的2-正戊基环戊酮，并与(S，S)-酰亚胺在THF中质子化，得到了接近定量产率90%的2-正戊基环戊酮。2-甲基环己酮与光学活性的1-环己基乙胺衍生的(S)-或(R)-酰亚胺的反应比(S，S)-或(R，R)-亚胺具有更高的对映选择性。值得注意的是，对映体选择性高度依赖于酰亚胺的环己烷基取代基的空间膨胀。这些手性酰亚胺进一步成功地应用于手性烯醇的非对映选择性质子化反应。当(-)-薄荷酮的锂离子被(S，S)-亚胺或(R)-亚胺质子化时，主要产物为顺酮。与(R，R)-亚胺或(S)-亚胺反应有较高的反式选择性。使用催化量的手性亚胺和化学计量的非手性质子源实现了这种非对映选择性质子化的催化过程。较少

Asymmetric protonation of prochiral metal enolates is an effective route to optically active carbonyl compounds. Although a number of groups have made important contributions to the continuing progress in this process, most of these are the reactions of enolates having polar groups including amino, hydroxyl, or phenyl groups, and there have been few satisfactory reports on the asymmetric induction of enolates of simple ketones such as 2-methylcyclohexanone. We have already reported that the new chiral proton source, (S,S) -or (R,R) -imide, which possesses an asymmetric 2-oxazoline ring, can be easily prepared from Kemp's tricarboxylic acid and (1R,2S) -or (1S,2R) -2-amino-1,2-diphenylethanol, and protonates various lithium enolates of alpha-monoalkylatedcycloalkanones with excellent to moderate enantioselectivity.In this research, we further examined the asymmetric protonation of simple prochiral metal enolates with the chiral imide and related imides. An increase in enantioselectivity … More was observed in the asymmetric protonation of prochiral lithium enolates with (S,S) -imide using lithium salt as an additive. For example, (R) -enriched 2-n-pentylcyclopentanone was obtained in a nearly quantitative yield with 90% ee when the corresponding lithium enolate was generated in the presence of 5 equiv of LiBr in Et_2O and was protonated with (S,S) -imide in THF.Higher enantioselectivity was observed for the reaction of lithium enolate of 2-methylcyclohexanone with optically active 1-cyclohexylethylamine derived (S) -or (R) -imide, which possesses a chiral amide group, than with (S,S) - or (R,R) -imide. Noteworthy was the fact that the enantioselectivity was highly dependent on the steric bulkiness of alkyl substituents of cyclohexane ring of the imide. These chiral imides were further successfully applied to a diastereoselective protonation of a chiral enolate. When the lithium enolate of (-) -menthone was protonated by (S,S) -imide or (R) -imide, cis-ketone was the major product formed. In contrast, a high trans-selectivity was obtained for the reaction with (R,R) -imide or (S) -imide. The catalytic process of this diastereoselective protonation has been realized using a catalytic amount of these chiral imides and stoichiometric amount of an achiral proton source. Less