Asymmetric Synthesis DOI: 10.1002/anie.200803610 Catalytic Asymmetric Aminoallylation of Aldehydes: A Catalytic Enantioselective Aza-Cope Rearrangement** Magnus Rueping* and Andrey P. Antonchick Efficient catalytic enantioselective variants of many signifi- cant organic reactions have been developed, including biocatalytic and metal-catalyzed processes, but increasingly also organocatalytic methods. Sigmatropic rearrangements are among the fundamental methods for the preparation of complex organic molecules and have found widespread application in the synthesis of biologically relevant molecules and natural products. A variety of catalytic asymmetric sigmatropic rearrangements have already been reported. [1] Most are based on the use of chiral metal complexes; however, individual organocatalytic enantioselective variants have also been described in which chiral secondary amines, [2] cinchona alkaloids, [3] and guanidium salts [4] serve as the catalysts. Surprisingly, no successful catalytic enantioselective aza-Cope rearrangement has been reported to date, [5] despite the importance of the corresponding products in synthetic organic chemistry. Given the relevance of sigmatropic rear- rangements and the resulting products, as well as the limited success in the development of an asymmetric version, we viewed the development of an asymmetric aminoallylation of aldehydes [6] on the basis of a catalytic enantioselective 2-aza- or 2-azonia-Cope rearrangement as an important goal [Eq. (1)]. Such a transformation would provide an efficient route to optically active homoallylic amines, which are particularly useful building blocks for the synthesis of natural products [7] and valuable precursors of other organic com- pounds, including b-amino acids, aminoalcohols, aminoep- oxides, pyrrolidines, and piperidines. [8, 9] Herein, we report the development of a catalytic asymmetric aminoallylation of aldehydes on the basis of a condensation–rearrangement sequence. In continuation of our studies on the organocatalyzed activation of imines [10] and carbonyl compounds, [11] and on the basis of our experience in asymmetric ion-pair and hydrogen- bond catalysis, we decided to examine a phosphoric acid catalyzed 2-aza-Cope rearrangement (Scheme 1). In planning our reaction, we assumed that the aminoallylation of an aldehyde 2 with an amine 3 under the catalysis of a phosphoric acid diester 1 would result initially in the formation of an iminium ion in the form of a chiral ion pair A. We further anticipated that activation by the Brønsted acid would be strong enough to accelerate the following aza-Cope rearrangement to the adduct B. Subsequent reprotonation should then provide the desired optically active homoallylic amine 4 with regeneration of the chiral Brønsted acid 1. Our initial experiments revealed that Brønsted acid catalyzed Cope rearrangements can be performed with 1,1- diaryl homoallylic amines 3 in combination with aldehydes 2 and a catalytic amount of diphenyl phosphoric acid diester. Hence, in our attempt to develop an asymmetric variant of the transformation we investigated the application of various chiral phosphoric acid diesters 1a–o as catalysts (Table 1). [12–14] We observed the best results with regard to the enantiomeric ratio of the product with (R)-3,3’-bis- (naphthyl)octahydrobinol (1h) as the catalyst (Table 1, entry 8). To further optimize the reaction conditions, we varied the solvent, the concentration of the reaction mixture, the reaction temperature, and the catalyst loading and found that the Brønsted acid catalyzed enantioselective Cope rearrangement can be performed in various aprotic solvents. Scheme 1. Brønsted acid catalyzed aza-Cope rearrangement. [*] Prof. Dr. M. Rueping, Dr. A. P. Antonchick Degussa Endowed Professorship Institute of Organic Chemistry und Chemical Biology Goethe University Frankfurt am Main Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany) Fax: (+ 49) 69-798-29248 E-mail: m.rueping@chemie.uni-frankfurt.de [**] We acknowledge Evonik Degussa and the DFG (Priority Program Organocatalysis) for financial support. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200803610. Communications 10090  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 10090 –10093