Diastereodivergent Enantioselective [8 + 2] Annulation of Tropones and Enals Catalyzed by N-Heterocyclic Carbenes.

N-Heterocyclic carbene catalysts are used for the first time to mediate asymmetric [8 + 2] cycloadditions of enals with tropones. The kinetic [8 + 2] cis-cycloadducts can be epimerized to their trans analogues by simply using increased amounts of base and longer reaction times. Substituted tropones are also tolerated, and the cycloaddition products can be derivatized by hydrogenation or methanolysis. The main stereochemical features of the process have been rationalized by microkinetic modeling based on the results of DFT calculations.

Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts.

Sustainability concerns are the wind in the sails for the development of novel, more selective catalytic processes. Hence, chiral catalysts play a crucial role in the green production of enantioenriched compounds. To further increase the green profile of this approach, the use of solid-supported catalytic species is appealing due to the reduced generation of waste, as well as the possibility of reusing the precious catalyst. Even more attractive is the implementation of flow processes based on these immobilized catalysts, a flexible strategy that allows to generate from milli- to multi-gram amounts of chiral product with a reduced footprint set-up. Herein, we will present the efforts devoted in our laboratory towards the immobilization of chiral catalysts and their use in single-pass, highly enantioselective, flow processes. Proline, diarylprolinols, other aminocatalysts, squaramides, thioureas, phosphoric acids and even chiral ligands and metal-based catalysts constitute our current toolkit of supported species for enantioselective catalysis.

Desymmetrisation of meso-diones promoted by a highly recyclable polymer-supported chiral phosphoric acid catalyst.

A polystyrene-supported BINOL-derived chiral phosphoric acid has been applied to the desymmetrisation of meso-diones to produce enantioenriched cyclohexenones. The catalytic resin has proven highly active and robust, giving rise to Hajos-Parrish or Wieland-Miescher type products in good yields and enantioselectivities, while allowing for extended recycling.

Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable Immobilized Isothiourea.

Higher-order cycloaddition reactions constitute an efficient approach towards the construction of medium to large ring systems. However, enantioselective versions of these transformations remain scarce, which hampers their deployment in medicinal chemistry, or any other discipline in which homochirality is deemed crucial. Herein, we report a novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea-catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The resulting bicyclic compounds can be hydrogenated, but, most remarkably, they can also undergo completely regioselective [4+2] cycloaddition with active dienophiles to give architecturally complex polycyclic compounds in a straightforward manner.

Organocatalytic Enantioselective Continuous-Flow Cyclopropanation.

A set of six solid-supported diarylprolinol catalysts (varying on the anchoring strategy and the type of polymeric support) has been prepared and applied to the enantioselective cyclopropanation reaction. The selected candidate allows implementation of a long flow experiment (48 h) and generates a library of 12 cyclopropanes by sequential flow experiments. The mildness and utility of the method have enabled a telescoped process in which the outstream is directly used in a Wittig flow reaction.

Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches.

Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities.

Polystyrene or Magnetic Nanoparticles as Support in Enantioselective Organocatalysis? A Case Study in Friedel-Crafts Chemistry.

Heterogenized versions of the second-generation MacMillan imidazolidin-4-one are described for the first time. This versatile organocatalyst has been supported on 1% DVB Merrifield resin and Fe3O4 magnetic nanoparticles through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The resulting catalytic materials have been successfully applied to the asymmetric Friedel-Crafts alkylation of indoles with α,ß-unsaturated aldehydes. While both catalytic systems can be easily recovered and admit repeated recycling, the polystyrene-based catalyst shows higher stability and provides better stereoselectivities.

H-Bond-Directing Organocatalyst for Enantioselective [4 + 2] Cycloadditions via Dienamine Catalysis.

An efficient, highly regio- and stereoselective [4 + 2] cycloaddition reaction to generate tetrahydropyranopyrazole frameworks has been developed. To this end, a dienamine-based catalytic strategy that relies on the H-bond-directing effect of the hydroxy group of a dinaphthylprolinol-type aminocatalyst has been used. This enables the synthesis of multifunctionalized heterocyclic derivatives with three contiguous stereocenters in good yields and excellent enantioselectivities.

Highly enantioselective cross-aldol reactions of acetaldehyde mediated by a dual catalytic system operating under site isolation.

Polystyrene-supported (PS) diarylprolinol catalysts 1 a (Ar = phenyl) and 1 b (Ar = 3,5-bis(trifluoromethyl)phenyl) have been developed. Operating under site-isolation conditions, PS-1 a/1 b worked compatibly with PS-bound sulfonic acid catalyst 2 to promote deoligomerization of paraldehyde and subsequent cross-aldol reactions of the resulting acetaldehyde in one pot, affording aldol products in high yields with excellent enantioselectivities. The effect of water on the performance of the catalytic system has been studied and its optimal amount (0.5 equiv) has been determined. The dual catalytic system (1/2) allows repeated recycling and reuse (10 cycles). The potential of this methodology is demonstrated by a two-step synthesis of a phenoperidine analogue (68% overall yield; 98% ee) and by the preparation of highly enantioenriched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5, key intermediates in the synthesis of a variety of druglike structures.

Photoswitchable thioureas for the external manipulation of catalytic activity.

A series of azobenzene-based thiourea catalysts have been developed with the aim of achieving control over the catalytic activity by the use of light. The conceptual design of these systems relies on the inactivation by means of intramolecular hydrogen bonding, only likely to take place in one of their isomeric forms. After fine structure modulation of the catalyst a substantial difference in activity has been observed between the irradiated and the nonirradiated reaction. Furthermore, the system allowed in situ manipulation of the catalyst activity during the course of a given experiment.

Enantioselective continuous-flow production of 3-indolylmethanamines mediated by an immobilized phosphoric acid catalyst.

A polystyrene-supported 1,1'-bi-2-naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel-Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a broad range of 3-indolylmethanamines (19 examples) in high yields and excellent enantioselectivities (up to 98 % enantiomeric excess) after short reaction times under very convenient reaction conditions (RT in dichloromethane). Moreover, repeated recycling (14 cycles) was possible with no substantial loss in catalytic performance and the system could be adapted to a continuous-flow operation (6 h). Finally, the applicability of the system was further confirmed by rapid access to a library of compounds with three points of diversity in a single continuous-flow experiment that involved sequential pumping of different substrate combinations.

Continuous flow, highly enantioselective Michael additions catalyzed by a PS-supported squaramide.

A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recycled up to 10 times without any decrease in enantioselectivity (average 96% ee) and adapted to continuous flow operation (24 h). A single flow experiment involving six different nitroalkenes in a sequential manner highlights the applicability of this methodology for rapid access to chemical diversity.

Dienamine-mediated inverse-electron-demand hetero-diels-alder reaction by using an enantioselective H-bond-directing strategy.

Giving directions: optically active dihydropyrans bearing three contiguous stereogenic centers can be efficiently prepared by the title reaction. High stereo- and regiocontrol can be achieved by employing a bifunctional H-bond-directing aminocatalyst.

Polystyrene-supported (2S)-(-)-3-exo-piperazinoisoborneol: an efficient catalyst for the batch and continuous flow production of enantiopure alcohols.

A polystyrene-supported analog (PS-PIB) of 3-exo-morpholinoisoborneol (MIB), designed for increased chemical stability, has been synthesized and used as a ligand in the asymmetric alkylation of aldehydes with Et(2)Zn. The supported ligand turned out to be highly active and enantioselective for a broad scope of substrates (92-99% ee), allowing repeated recycling. A single-pass, continuous flow process implemented with PS-PIB shows only a marginal decrease in conversion after 30 h of operation.

Asymmetric organocatalytic formal [2 + 2]-cycloadditions via bifunctional H-bond directing dienamine catalysis.

A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo- and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual activation of α,ß-unsaturated aldehydes and nitroolefins by amino- and hydrogen-bonding catalysis, respectively. A new bifunctional squaramide-based aminocatalyst has been designed and synthesized in order to enable such an activation strategy. The potential and scope of the reaction are demonstrated, and computational studies which account for the stereochemical outcome are presented.

Copper-free intramolecular alkyne-azide cycloadditions leading to seven-membered heterocycles.

Treatment of alk-2-ynyl derivatives of enantiopure phenylglycidol with NaN(3) triggers a cascade reaction consisting of stereospecific and regioselective epoxide ring opening followed by intramolecular azide-alkyne cycloaddition under strictly metal-free conditions. This simple one-pot procedure allows a fast buildup of molecular complexity, generating a wide array of triazolooxazepinols, triazolodiazepinols, and triazolothiazepinols.

Catalytic enantioselective oxaziridination.

The first catalytic enantioselective synthesis of oxaziridines is presented. The oxidation of aryl and alkyl aldimines with m-CPBA under organocatalytic conditions using cinchona alkaloid-derived catalysts furnished optically active oxaziridines in good yields and high enantioselectivities (up to 94% ee). Mechanistic investigations indicate a stepwise enantioselective oxidation process.