The preparation of enantiomerically pure compounds has become a stringent requirement for pharmaceutical synthesis. [1] In this context, asymmetric catalysis is probably the most attractive procedure for the synthesis of active pharmaceutical ingredients (APIs) due to environmental, operational, and economic benefits.3,4-Dihydropyrazino[1,2-a]indol-1(2H)-ones 1 (see Scheme 1) have attracted much attention due to the broad scope of their biological activities (that is, their antifungal properties, noncompetitive antihistamine activity, and specific inhibition of serotonergic receptors).[2] Moreover, recent patents reported the effectiveness of the corresponding 1,2,3,4-tetrahydropyrazino[1,2-a]indoles 2 (Scheme 1) as antiobesity agents and in the treatment and prevention of noninsulin-dependent diabetes. [3] From these studies, the importance of the absolute configuration of the stereocenters on the pharmacological activity emerged clearly. Moreover, since the piperazine compounds 2 are readily obtainable from 1,[3] the development of an effective stereoselective synthetic route to pyrazino-indol-1-ones 1 would be extremely valuable. The use of chiral pools and the resolution of racemates are the only synthetic routes to 1 and 2 to date. [3][4][5] During our ongoing research addressing the functionalization of polycyclic indoles, [6] we recently communicated an efficient Pd-catalyzed approach to tetrahydro-b-carbolines through regio-and enantioselective C3-allylic nucleophilic alkylation (up to 97 % ee).[7] Unfortunately, all our attempts to exploit such an approach to perform enantioselective indolyl-N1 ring-closing reactions were unsuccessful. Herein, we describe the first highly enantioselective synthesis of molecular motifs of type 1 through a phase-transfer-catalyzed [8] aza-Michael addition.[9]The employment of a metal-free approach [10] stems from our recent findings on the intramolecular base-catalyzed synthesis of 1, from readily available precursors 3 (Scheme 2).[11] However, the use of Lewis acid catalysis in the present ring-closing reaction failed, probably due to the poor electrophilic character of the a,b-unsaturated ester and to low catalyst turnover as a result of starting material/ product inhibition (that is, a metallo-poisoning effect exerted by the strongly coordinating amide group). Searching for an enantioselective variant, we firstly turned our attention to chiral organic bases such as the Cinchona alkaloids and sparteine, which gave disappointing results in the cyclizations of 3 a (X = H; toluene, reflux, 48 h, 0 % ee). We reasoned that the unsatisfactory stereoinduction could be ascribable to the formation of flexible and not sufficiently tight ion pairs between the ammonium salt of the quinuclidine ring and the nucleophilic indolate intermediate (Figure 1 a).
