The enantioselective Brønsted acid catalyzed 1,2-addition to imines has emerged as a powerful metal-free method to access functionalized chiral amines.[1] Chiral phosphoric acids have proven to be highly effective catalysts in aza-Friedel-Crafts, hydrocyanation, Mannich, reduction, and other 1,2-addition reactions. [2, 3] In a limited number of cases, the resulting amine products have been converted into pharmaceutically relevant or natural product precursors.[2c,f, 3o] However, a subsequent tandem or one-pot process using the amine as a nucleophile has rarely been exploited. The research groups of Rueping and Gong independently developed an elegant Brønsted acid catalyzed tandem Mannich/aza-Michael addition of an enolized a,b-unsaturated ketone and imine for the asymmetric synthesis of isoquinuclidines. [3a,e] More recently, chiral piperidines have been prepared by Terada and co-workers in a tandem aza-ene type reaction/cyclization sequence.[3k]We envisioned that another class of heterocycles, chiral 1,3-disubstituted isoindolines 3, could be rapidly accessed from bifunctional substrates 1 containing an imine and Michael acceptor (Scheme 1). An e-iminoenoate 1 could react in a Brønsted acid catalyzed 1,2-addition with a nucleophile (NuH) to afford a chiral amine 2, which could react further in an intramolecular aza-Michael addition.Chiral isoindolines, particularly 1-isoindolylcarboxylic acids 4 (R 1 = CO 2 H) and 1-substituted isoindolin-3-ones 5, are common substructures in a variety of natural products [4] and pharmaceuticals.[5] Access to 1-and 1,3-substituted isoindolines 4 and 5 is hampered by the fact that only a limited number of synthetic procedures exist for their preparation.[6] Moreover, few reports describe routes to enantiomerically pure isoindolines. Resolutions [7] and chiralauxiliary-based methods [8] are dominant avenues to enantiomerically enriched isoindolyl derivatives 4-6. Several articles detail the metal-catalyzed asymmetric synthesis of 1-substituted isoindolines 4 and 1-substituted isoindolin-3-ones 5. [9] To the best of our knowledge, there are no existing metal-or organocatalyzed asymmetric syntheses of 1,3-disubstituted isoindolines 6.We report herein the first catalytic diastereo-and enantioselective synthesis of 1,3-disubstituted isoindolines using a one-pot, two-step process consisting of a chiral Brønsted acid catalyzed aza-Friedel-Crafts reaction and a base-catalyzed intramolecular aza-Michael addition. Moreover, these investigations led to the discovery of a Brønsted acid catalyzed stereoablative kinetic resolution [10] that occurs in tandem to the Friedel-Crafts reaction and amplifies the enantiomeric ratios of the isoindoline products.Indoles 8 and N-tosyliminoenoates 9 were selected as the nucleophilic and electrophilic components, respectively, for this reaction (Scheme 2). In the first instance, indole (8 a) and iminoenoate 9 a were exposed to several chiral binaphthol-(BINOL)-derived phosphoric acids (e.g. 7 a, X = OH). These catalysts were found to be completely inert,...
Die enantioselektive Brønsted-Säure-katalysierte 1,2-Addition an Imine hat sich als eine leistungsstarke metallfreie Methode zur Herstellung von funktionalisierten Aminen entwickelt.[1] Hierbei haben sich chirale Phosphorsäuredi-ester als sehr effiziente Katalysatoren in Aza-Friedel-Crafts-, Hydrocyanierungs-, Mannich-, Reduktions-und anderen 1,2-Additionsreaktionen erwiesen. [2, 3] In einigen Fällen wurden die entstandenen Amine in Vorläufer für Mehrstufensynthesen pharmazeutisch relevanter Verbindungen oder Naturstoffe umgewandelt.[ Wir interessierten uns für eine andere Art von Heterocyclen, nämlich die chiralen 1,3-disubstituierten Isoindoline 3, die aus difunktionellen Substraten 1, die ein Imin und einen Michael-Akzeptor enthalten, einfach zugänglich sein sollten (Schema 1). Ein e-Iminoenoat 1 könnte in einer Brønsted-Säure-katalysierten 1,2-Addition mit einem Nucleophil (NuH) zu einem chiralen Amin 2 reagieren, das in einer intramolekularen Aza-Michael-Addition weiter reagieren könnte.Chirale Isoindoline, vor allem 1-Isoindolylcarbonsäuren 4 (R 1 = CO 2 H) und 1-substituierte Isoindolin-3-one 5, sind charakteristische Strukturelemente in einer Vielzahl von Naturstoffen [4] und Arzneimitteln.[5] Der Zugang zu 1-und 1,3-substituierten Isoindolinen 4 und 5 wird durch die Tatsache erschwert, dass es nur eine beschränkte Zahl von Verfahren zur Synthese dieser Verbindungen gibt.[6] Darüber hinaus gibt es nur wenige Methoden zur Herstellung enantiomerenreiner Isoindoline. Racematspaltungen [7] und Methoden mit chiralen Auxiliaren [8] bilden die Mehrzahl der Zugangsmöglichkeiten zu enantiomerenangereicherten Isoindolylderivaten 4, 5 und 6. Mehrere Artikel beschreiben die metallkatalysierte asymmetrische Synthese von 1-substituierten Isoindolinen 4 und 1-substituierten Isoindolin-3-onen 5.[9] Unseres Wissens gibt es bisher keine metall-oder organokatalysierten asymmetrischen Synthesen von 1,3-disubstituierten Isoindolinen 6.Wir berichten nun von der ersten katalytischen diastereound enantioselektiven Synthese von 1,3-disubstituierten Isoindolinen in einem Eintopf-Zweistufenverfahren, bestehend aus einer Brønsted-Säure-katalysierten Aza-FriedelCrafts-Reaktion und einer basenkatalysierten intramolekularen Aza-Michael-Addition. Außerdem führten diese Untersuchungen zur Entdeckung einer Brønsted-Säure-katalysierten stereoablativen kinetischen Racematspaltung, [10] die parallel zur Friedel-Crafts-Reaktion verläuft und die Enantiomerenverhältnisse der Isoindoline verbessert.Indole 8 und N-Tosyliminoenoate 9 wurden als nucleophile bzw. elektrophile Reaktionspartner für diese Reaktion gewählt (Schema 2). In einer ersten Versuchsreihe wurden Indol (8 a) und Iminoenoat 9 a mit unterschiedlichen von
Biocatalytic asymmetric reductions have been key steps in the synthesis of 1,1-dimethoxy-2-propanone, catalyzed by suitable ketoreductases to (S)- and (R)-1,1-dimethoxy-2-propanol, obtained in ≥99.9% ee and excellent yield. Removal of the protecting group gave the (S)- and (R)-lactaldehydes in excellent yield and purity.
SummaryThe first organocatalytic asymmetric synthesis of smyrindiol, by using an (S)-proline catalyzed enantioselective intramolecular aldol reaction as the key step, is described. Smyrindiol was synthesized from commercially available 2,4-dihydroxybenzaldehyde in 15 steps, with excellent stereoselectivity (de = 99%, ee = 99%). In the course of this total synthesis a new and mild coumarin assembly was developed.
Isoindole derivatives R 0140Asymmetric Broensted Acid Catalyzed Isoindoline Synthesis: Enhancement of Enantiomeric Ratio by Stereoablative Kinetic Resolution. -The asymmetric synthesis of 1,3-disubstituted isoindolines is based on a metal-free one-pot Broensted acid catalyzed Friedel-Crafts/base-catalyzed aza-Michael addition sequence of bifunctional ε-iminoenoates and indoles. A Broensted acid catalyzed stereoablative kinetic resolution occurs in tandem to the Friedel-Crafts reaction: the enantiomeric ratios increase to excellent levels with enhanced reaction time; however, the yields decrease.-(ENDERS*, D.; NARINE, A. A.; TOULGOAT, F.; BISSCHOPS, T.; Angew.
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