LUETTGEN, K.; NARINE, A. A.; Synthesis 2007, 7, 959-980; Inst. Org. Chem., RWTH Aachen, D-52074 Aachen, Germany; Eng.) -Lindner 27-226

Nature utilizes simple C2 and C3 building blocks, such as dihydroxyacetone phosphate (DHAP), phosphoenolpyruvate (PEP), and the "active aldehyde" in various enzyme-catalyzed carbon-carbon bond formations to efficiently build up complex organic molecules. In this Perspective, we describe the transition from using enantiopure chemical synthetic equivalents of these building blocks, employing our SAMP/RAMP hydrazone methodology and metalated chiral alpha-amino nitriles, to the asymmetric organocatalytic versions developed in our laboratory. Following this biomimetic strategy, the DHAP equivalent 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) has been used in the proline-catalyzed synthesis of carbohydrates, aminosugars, carbasugars, polyoxamic acid, and various sphingosines. Proline-catalyzed aldol reactions involving a PEP-like equivalent have also allowed for the asymmetric synthesis of ulosonic acid precursors. By mimicking the "active aldehyde" nucleophilic acylations in Nature catalyzed by the thiamine-dependent enzyme, transketolase, enantioselective N-heterocyclic carbene-catalyzed benzoin and Stetter reactions have been developed. Finally, based on Nature's use of domino reactions to convert simple building blocks into complex and highly functionalized molecules, we report on our development of biomimetic asymmetric multicomponent domino reactions which couple enamine and iminium catalysis.

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,...

Mutants of the Micromonospora viridifaciens sialidase, Y370E and Y370F, are catalytically active retaining enzymes that operate by different mechanisms. Previous substitutions with smaller amino acids, including Y370D, yielded inverting sialidases. At least one water molecule can fit into the active-site cavity of this mutant and act as a nucleophile from the face opposite the leaving group (Biochemistry 2003, 42, 12 682). Thus, addition of a CH(2) unit (Asp versus Glu) changes the mechanism from inversion back to retention of configuration. Based on Brønsted beta(lg) values, it is proposed that the Y370E mutant reacts by a double-displacement mechanism (beta(lg) on k(cat)/K(m) -0.36+/-0.04) with Glu370 acting as the nucleophile. However, the Y370F mutant (beta(lg) on k(cat)/K(m) -0.79+/-0.12) reacts via a dissociative transition state. The crystal structure of the Y370F mutant complexed with 2-deoxy-2,3-dehydro-N-acetylneuraminic acid shows no significant active-site perturbation relative to the wild-type enzyme.

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