Asymmetric alkylations of electron-rich arenes such as indoles are of great importance for the synthesis of many natural products and pharmaceuticals.[1] Hence, different approaches have been undertaken to develop catalytic enantioselective additions of indoles to a,b-unsaturated carbonyl compounds. To date, these have been based on the application of chiral transition-metal complexes [2] or secondary amines, the latter of which function through covalent activation, forming intermediary iminium ions. [3] In this context the use of b,g-unsaturated a-keto esters is of particular interest since they not only exhibit a higher reactivity but also can be functionalized readily to the corresponding amino acids or a-hydroxy acids.Given the frequent occurrence of the indole core structure in biologically active substances and natural products [4] together with the possibility of activating carbonyl functionalities with chiral Brønsted acids, [5][6] the development of an enantioselective, metal-free, noncovalently catalyzed Friedel-Crafts alkylation of indoles appeared to be of great significance. This would not only be the first example of such an organocatalyzed transformation, but more importantly it would give simple and direct access to optically pure a-keto and a-amino acids. We report here on the development of such a reaction, a highly enantioselective Brønsted acid catalyzed addition of indoles to a,b-unsaturated carbonyl compounds.In continuing studies on the Bønsted acid catalyzed asymmetric Nazarov cyclization of divinyl ketones [5] [Eq. (1)], we assumed that an enantioselective FriedelCrafts alkylation of indoles through the noncovalent activation of a-keto esters using N-triflylphosphoramides [Eq. (2)] should also be feasible. Therefore, our investigations started with the examination of the Brønsted acid catalyzed addition of N-methylindole (1 a) to the a-keto ester 2 a. While no reaction was observed when weak Brønsted acids, such as carbonic acids or diphenyl phosphate, were used, catalytic amounts of N-triflylphosphoramide 5 a resulted in product formation. However, in addition to the desired 1,4-addition product 3 a, the bisindole 4 a was isolated as the main product (Scheme 1).The Lewis or Brønsted acid catalyzed formation of bisindoles starting from aldehydes, ketones, and 1,2-diketones is well known, [7] and several naturally occurring alkaloids contain this structural element.[8] However, the remarkable regioselectivity observed in the reaction of indoles with b,gunsaturated a-keto esters favoring the 1,2-addition with the generation of bisindole 4 a has not previously been reported. Figure 1 shows the X-ray crystal structure of 4 a. In contrast to all previously reported bisindoles, 4 a exhibits atropisomerism as a result of the rotation barrier about the bonds to the quaternary carbon bond. The bisindole atropisomers are not only observed in the X-ray crystal structure but can also be Scheme 1. Brønsted acid catalyzed reaction of N-methylindole (1 a) with a-keto ester 2 a to form bisindole 4 a.
An efficient, metal-free Brønsted acidcatalyzed, enantioselective hydrocyanation of ketoimines has been developed. This BINOL phosphate-catalyzed Strecker reaction provides the corresponding amino nitriles, precursors of quaternary amino acids, in good isolated yields and enantioselectivities. Additionally, we demonstrate that chiral diols, such as TADDOL, are effective enantioselective catalysts for the hydrogen-bond activation of aldimines.Keywords: amino acids; BINOL phosphate; Brønsted acid; hydrocyanation; Strecker reaction; TADDOL The addition of hydrogen cyanide to imines, the Strecker reaction, constitutes one of the most direct and practical methods for the synthesis of a-amino acids and derivatives.[1] As a result, considerable effort has been devoted towards the development of asymmetric Strecker reactions. [2,3] In addition to various metal-catalyzed hydrocyanations, [4] promising metal-free enantioselective variants [5] have been described. Recently, we reported that chiral Brønsted acids [6,7] are efficient catalysts for highly enantioselective processes, including the hydrogenation of ketoimines, [8a,b] benzoxazines, benzthiazines, benzoxazinones [8c] and quinolines, [9] as well as direct MannichMichael reactions, [10] or the hydrocyanation of aldimines (Scheme 1). [11] In this reaction the aldimine is protonated by a chiral BINOL phosphate 1 which leads to the formation of a chiral iminium ion, a chiral ion pair. Subsequent addition of HCN results in formation of the corresponding amino nitrile and the regenerated Brønsted acid catalyst. [11] Based on our previous results and observations, we herein report the application of yet another metalfree catalyst, the chiral TADDOL, for the hydrocyanation of aldimines. Furthermore, we describe the BINOL phosphate-catalyzed asymmetric Strecker reaction of ketoimines, which is generally not only more difficult to achieve as compared to the hydrocyanation of aldimines, [4h-j,5d] but additionally leads to the formation of valuable quaternary amino acids.We initially started our investigation with the exploration of various BINOL phosphates 1a-f in the hydrocyanation of ketoimine 4 (Table 1). The best results with regard to reactivity and selectivity were obtained with catalytic amounts of 1a (5 mol %) providing amino nitrile 5 in 70 % ee (Table 1, entry 1). All other tested BINOL phosphate catalysts gave inferior results which is in agreement with our earlier developed Brønsted acid-catalyzed reactions where sterically more congested 3,3'-aryl substituents on the BINOL skeleton gave generally better results. All cyanation reactions were performed in toluene at À40 8C with 1.5 equivs. of in situ generated HCN. [12] Other cyanide sources tested, such as trimethylsilyl cyanide or acetone cyanohydrin did not lead to the desired products.Further examinations concentrated on the solvent employed, as it was previously shown to have an important impact on reactivity and selectivity in Brønst-ed acid-catalyzed transformations. In accordance with the BINOL...
Professor Dieter Seebach zum 70. Geburtstag gewidmet Asymmetrische Alkylierungen elektronenreicher Arene wie der Indole sind von großer Bedeutung für die Synthese vieler Natur-und Arzneistoffe.[1] Dementsprechend gab es schon eine Reihe von Versuchen, Indole enantioselektiv an a,bungesättigte Carbonylverbindungen zu addieren. Die Ansät-ze beruhen bisher vor allem auf dem Einsatz chiraler Über-gangsmetallkomplexe [2] oder chiraler sekundärer Amine, wobei die letztgenannten durch Bildung eines intermediären Iminiumions eine kovalente Aktivierung bewirken.[3] Der Einsatz b,g-ungesättigter a-Ketoester ist in diesem Zusammenhang von besonderem Interesse, da diese nicht nur reaktiver als die üblichen Enone sind, sondern sich auch leicht zu Aminosäuren oder a-Hydroxycarbonsäuren weiter funktionalisieren lassen.Eine enantioselektive, metallfreie, nicht kovalent katalysierte Friedel-Crafts-Alkylierung von Indolen war für uns aus zwei Gründen von Bedeutung: Zum einen ist das Indolgrundgerüst in biologisch aktiven Wirk-und Naturstoffen weit verbreitet, [4] und zum anderen wollten wir eine Methode entwickeln, nach der sich Carbonylverbindungen mithilfe chiraler Brønsted-Säuren aktivieren lassen.[5-6] Dies wäre das erste Beispiel einer solchen organokatalytischen Transformation und würde zudem einen einfachen und direkten Zugang zu den entsprechenden enantiomerenreinen a-Ketound a-Aminosäuren eröffnen.Wir berichten hier von der Entwicklung einer solchen Reaktion: einer hoch enantioselektiven Brønsted-Säure-katalysierten Addition von Indolen an a,b-ungesättigte Carbonylverbindungen. In Anlehnung an die kürzlich von uns beschriebene Brønsted-Säure-katalysierte asymmetrische Nazarov-Cyclisierung von Divinylketonen [5] [Gl. (1) Die Lewis-oder Brønsted-Säure-katalysierte Synthese von Bisindolen aus Aldehyden, Ketonen oder 1,2-Diketonen ist bekannt, [7] und eine Reihe von Alkaloid-Naturstoffen enthält dieses Strukturelement.[8] Die bemerkenswerte Regioselektivität bei der Reaktion von Indolen mit b,g-ungesättigten a-Ketoestern zugunsten der 1,2-Addition unter Bildung des Bisindols 4 a ist jedoch neu. Abbildung 1 zeigt die Molekülstruktur von 4 a im Einkristall. 4 a weist -anders als Schema 1. Brønsted-Säure-katalysierte Reaktion von N-Methylindol (1 a) mit dem a-Ketoester 2 a unter Bildung des Bisindols 4 a.
The enantioselective synthesis of 2-aryl-substituted 2,3-dihydroquinolin-4-ones, a class of heterocyclic compounds with interesting biological activities, has been achieved through a Brønsted acidcatalyzed enantioselective intramolecular Michael addition. The products are available in moderate to high yields and with good enantioselectivities.
Nitriles Q 0520 Metal-Free, Enantioselective Strecker Reactions Catalyzed by Chiral BINOL and TADDOL Catalysts. -The Broensted acid catalyzed hydrocyanation of ketoimines provides amino nitriles in good isolated yields and enantioselectivities. Additionally first results concerning the application of metal-free chiral TADDOL for the hydrocyanation of aldimines are described. -(RUEPING*, M.; SUGIONO, E.; MORETH, S. A.; Adv. Synth. Catal. 349 (2007) 4-5, 759-764; Inst. Org. Chem. Chem. Biol., Univ. Frankfurt, D-60438 Frankfurt/M., Germany; Eng.) -Bartels 29-075
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