Asymmetric Michael Reaction Catalyzed by Proline Lithium Salt: Efficient Synthesis of L‐Proline and Isoindoloisoquinolinone Derivatives

Abstract

Enamine catalysis has emerged as a powerful method for the potential application of carbonyl activation in asymmetric catalysis. Since List, Lerner, and Barbas first reported the proline-catalyzed direct aldol reaction, many pyrrolidine-type and imidazolidinone-type chiral amine catalysts have been developed with highly effective stereoinduction. In most cases, these catalysts were designed by increasing the steric bulk on the pyrrolidine moiety, 5] such as in the Jorgensen–Hayashi catalyst. By contrast, when amino acid metal salts were employed as enamine catalysts, the stereoselectivity was hardly controlled through shielding one face of the enamine intermediate. The seminal work of the Yamaguchi group, who employed a proline rubidium catalyst, as well as the groups of Feng, Reiser, and others, have demonstrated that amino acid metal salts are attractive alternatives to organocatalysts and other metalbased catalysts. Lithium, the closest congener of hydrogen, can form lithium-bonding interactions that are analogous to hydrogen-bonding interactions but with stronger bonding ability. We believe that the suitable combination of proline and lithium would facilitate reactions that proline alone cannot. The asymmetric Michael addition of unmodified aldehydes to nitroalkenes has attracted much attention because the installation of the formyl and nitro groups in a single step allows subsequent versatile transformations. Moreover, the Michael reaction has also been widely used as one of the steps in cascade reactions that allows for the construction of molecular complexity in a single procedure. Since Barbas and co-workers reported the first example of the asymmetric addition of an unmodified aldehyde to a nitroalkene, the groups of Alexakis, Wang, Hayashi, Palomo, Jacobsen, Chen, and Loh, among many others, have developed a series of efficient secondary and thio ACHTUNGTRENNUNG(urea)-primary amines to improve the stereoselectivity and substrate scope of this reaction. Although these reported methods can afford good-to-excellent diastereoand enantioselectivities, the need for a large excess of Michael donors, as well as the use of expensive and not readily available catalysts, seriously limit the application of this reaction on a large scale, especially on an industrial scale. To overcome these limitations, the immobilization of organocatalysts has been pursued to facilitate product separation and catalyst reuse. However, this approach has always led to a decrease in the reaction activity and enantioselectivity. Very recently, the Wennemers group successfully lowed the catalyst loading to as little as 0.1 mol% following kinetic studies. Moreover, the groups of Ni and Wang described highly efficient reusable catalysts for the excellent diastereoand enantioselective Michael reaction. Although significant progress has been made, the development of lowmolecular-weight, inexpensive, and readily available catalysts for the highly stereoselective Michael reaction with various linear, a-branched, and unsaturated aldehydes as donors is still of significance. Herein, we report a highly stereoselective Michael addition of aldehydes to nitroalkenes catalyzed by proline lithium salt. Remarkably, the asymmetric Michael reaction could be scaled up to 50 mmol with 23:1 d.r. and 90% ee. Furthermore, the useful building blocks were successfully transformed into biologically important l-proline and isoindoloisoquinolinone derivatives on the gram scale. The asymmetric Michael addition of n-butylaldehyde (1a) to nitrostyrene (2a) was selected as a model reaction for our initial optimization studies (Table 1). Preliminary experiments identified l-proline lithium salt as a suitable catalyst (see the Supporting Information, Table S1, entry 1), whereas other secondary amino acid metal salts gave inferior results with respect to the yields and stereoselectivities (Table 1, entries 2–5). The primary acid lithium salts showed minimal catalytic activity under the same reaction conditions (Table 1, entries 6 and 7), which may be attributed to the unfavorable equilibrium between the imine and the secondary enamine. When l-proline was employed as the catalyst, no Michael adduct was obtained (Table 1, entry 8). Then, the effect of water on the reaction was studied (Table 1, entries 9–12). The results indicated that a small amount of water was essential to obtaining a high yield (Table 1, entry 1 versus entry 11); however, the diastereoand enantioselectivities decreased with an increased amount of water (Table 1, entry 1 versus entries 9 and 10). The presence of molecular sieves during the catalytic reaction de[a] K. Xu, S. Zhang, Y. Hu, Z. Zha, Prof. Z. Wang Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry University of Science and Technology of China Hefei, Anhui, 230026 (P. R. China) Fax: ACHTUNGTRENNUNG(+86)551-3631760 E-mail : zwang3@ustc.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201202409.