2010

ABSTRACT:

A catalytic enantioselective synthesis of dihydrofurans has been developed. 1,3-Dicarbonyl derivatives react with (E)-β,β-bromonitrostyrenes in the presence of a chiral bifunctional thiourea catalyst providing mild and efficient access to diverse polysubstituted dihydrofurans in good yields and enantioselectivities. We have developed a new enantioselective Michael addition-nucleophilic substitution reaction that enables the formation of trans-tetrasubstituted dihydrofuranes from easily accessible diketones and (E)-β,β-bromonitrostyrenes. The reactions proceed in good yields, with good enantioselectivities and with high functional group tolerance. Furthermore, this methodology demonstrates that β,β-bromonitrostyrenes are useful dielectrophilic synthons in the field of asymmetric organocatalysis.

ABSTRACT:

A simple and efficient continuous-flow hydroarylation of arenes and heteroarenes using various styrenes in conjunction with a heterogeneous catalyst has been developed. Additionally, this method has been successfully extended to the hydroalkylation of styrenes by employing 1,3-dicarbonyl compounds as the nucleophile. Multigram quantities of diarylmethanes have been prepared using this new microwave flow method. We have developed a simple and efficient continuous-flow hydroarylation of arenes and heteroarenes using various styrenes and employing a heterogeneous catalyst. The reactions were sequentially introduced into the flow cell and performed several times without having to change the catalyst. This procedure provided a series of valuable 1,1-diarylalkanes in good yields. Additionally, this method has been efficiently applied to the hydroalkylation of styrenes with 1,3-dicarbonyl compounds. Scale up of this method was readily achieved providing an efficient method for the preparation of diarylmethanes in multigram quantities. The technology presented is beneficial compared to classical batch reactions in particular with regard to continuously harvesting product, the fast optimization of reaction parameters, and restriction of by-product formation, in particular styrene dimerization and polymerization.

ABSTRACT:

(E)-β-Bromonitrostyrenes react with enaminones in water to afford pyrroles in excellent yields. The domino reaction constitutes a new, mild, and environmentally benign process for the fast and efficient synthesis of diverse pyrroles. We have developed a facile and mild synthesis of trisubstituted pyrroles by reaction of enaminones with β-bromonitrostyrenes. This method constitutes a new approach for the synthesis of diverse pyrroles, in which β-bromonitrostyrenes have been used as a trifunctional synthon. Additionally, the reaction can be carried out in water as a cheap and environmentally benign solvent, and a simple purification step provides the products in good yields after very short reaction times. This method is extremely efficient and can be conducted on a larger scale at low cost making it an ideal alternative to existing methods.

ABSTRACT:

A highly enantioselective metal-free reduction of 3H-indoles has been developed. This Brønsted acid catalyzed transfer hydrogenation of indole derivatives with Hantzsch dihydropyridine as the hydrogen source constitutes an efficient method for the synthesis of various optically active indolines with high enantioselectivities. We developed the first metal-free enantioselective Brønsted acid catalyzed transfer hydrogenation of 3H-indoles. The mild reaction conditions, low catalyst loading, and high enantioselectivities render this transformation an attractive approach to optically active indolines.

ABSTRACT:

The first catalytic enantioselective synthesis of benzodiazepinones employing an efficient hydrogenation protocol has been developed. The corresponding products are obtained in good yields, with excellent enantioselectivities and broad functional group tolerance. In addition, a one-pot procedure involving in situ generation of benzodiazepin-2-ones followed by asymmetric reduction is presented. We have developed a highly enantioselective, hydrogenation of 1H-[1,5]benzodiazepin-2(3H)-ones. This method represents the first enantioselective reduction of these substrates and provides the corresponding valuable biologically active 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones, which resemble cyclic β-amino acids, in good yields and with excellent enantioselectivities (87–99% ee). Furthermore, we were able to extend this method to conduct an efficient one-pot reaction involving a condensation reaction followed by the catalytic enantioselective hydrogenation. It should also be noted that the metal-free hydrogenation is also compatible with various halogenation patterns enabling easy variation of both the aryl substituent as well as the benzodiazapinone core. A further benefit of this method is that the nitro functionality has been shown to be entirely stable under the reaction conditions described. Thus, attractive features of this transformation include the mild reaction conditions, operational simplicity and practicability, a broad substrate scope and functional group tolerance.

ABSTRACT:

A biologically inspired reaction design leads to the development of the first highly enantioselective Brønsted acid catalysed reaction in aqueous solution. We have developed the first highly enantioselective Brønsted acid catalysed reaction using water as a reaction medium employing the principle of hydrophobic hydration. Further, it represents the first example in the field of organocatalysis of a non-covalent asymmetric induction conducted in a pure aqueous reaction solvent. This enantioselective Brønsted acid catalysed activation, previously considered impossible, provides, in the transfer hydrogenation described, an efficient route to 2-substituted tetrahydroquinolines or cyclic amines in good yields and with excellent enantioselectivities. The ecologically and economically advantageous reaction medium, water, further simplifies this already practical method and makes this reduction an attractive synthesis possibility for optically active tetrahydroquinolines and amines. Application on an industrial scale is also possible as the synthetic and biocatalytic recycling of dihydroypyridines in water is already feasible. Water as a reaction medium no longer excludes asymmetric Brønsted acid catalysis and it is only a question of time until further examples in this area are developed.

ABSTRACT:

A highly enantioselective organocatalytic transfer hydrogenation enabling the synthesis of both 6-fluoro-2-methyltetrahydroquinoline and 7,8-difluoro-3-methyl-benzoxazine has been developed. We describe the development of an Brønsted acid catalysed asymmetric organocatalytic transfer hydrogenation as a simple and straightforward method to access both valuable key intermediates 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline and 7,8-difluoro-3-methyldihydrobenzoxazine. These reactions proceed with excellent stereoinduction and can be performed with low catalyst loadings under mild reaction conditions. The resulting chiral building blocks were subsequently used in the metal-free synthesis of the valuable drugs (R)-flumequine and (R)-levofloxacine.

ABSTRACT:

Effective metal-catalyzed benzylations of 4-hydroxycoumarin have been developed. Employing a low amount of a cheap, nontoxic, and air-stable catalyst the 3-alkylated hydroxycoumarins were isolated in high yields after short reaction times. Applying this new methodology two widely used anticoagulants phenprocoumon and coumatetralyl were synthesized applying mild reaction conditions.

ABSTRACT:

A new methodology for the immobilization of chiral Brønsted acids has been developed. The resulting heterogeneous organocatalysts have been employed in multiple consecutive catalysis cycles in the asymmetric organocatalytic transfer hydrogenation. The new catalyst system can not only be easily recovered from the reaction mixture in a tea-bag approach but it can also be easily reused in several catalytic cycles without loss of reactivity and selectivity.

ABSTRACT:

The development of efficient Friedel–Crafts alkylations of arenes and heteroarenes using only catalytic amounts of a Lewis acid has gained much attention over the last decade. The new catalytic approaches described in this review are favoured over classical Friedel–Crafts conditions as benzyl-, propargyl- and allyl alcohols, or styrenes, can be used instead of toxic benzyl halides. Additionally, only low catalyst loadings are needed to provide a wide range of products. Following a short introduction about the origin and classical definition of the Friedel–Crafts reaction, the review will describe the different environmentally benign substrates which can be applied today as an approach towards greener processes. Additionally, the first diastereoselective and enantioselective Friedel–Crafts-type alkylations will be highlighted.

ABSTRACT:

The first highly enantioselective reduction of both quinoxalines as well as quinoxalinones was developed. The new method can effectively be applied in the transformation of diverse aryl-substituted quinoxalines and quinoxalinones into the biologically and pharmacologically relevant 2-tetrahydroquinoxalines and 3-dihydroquinoxalinones with excellent enantioselectivities (up to 98 % ee). The mild organocatalytic reaction conditions also allow various halogenation patterns, which may be useful for further derivatization. In contrast to existing synthetic routes, the method we have developed is not based on the introduction of chiral residues but rather provides the desired optically active products by a simple, direct, and fast enantioselective reduction step, which will be useful for application in the synthesis of fine chemicals, as well as agro- and pharmaceutical products.

ABSTRACT:

The first enantioselective domino Mannich–ketalization reaction of o-hydroxy benzaldimines with electron-rich alkenes was developed. The new reaction sequence provides an easy and direct access to optically pure 4-aminobenzopyrans in good yields with excellent enantiomeric ratios (up to e.r. 98:2). Our newly developed reaction nicely complements Akiyama′s previously reported Brønsted acid catalyzed reaction of aldimines with dihydrofurans and dihydropyrans which lead to tetrahydroquinolines. However, our reaction results in the enantioselective synthesis of biologically relevant furanobenzopyrans and pyranobenzopyrans. The reaction sequence proceeds under mild reaction conditions in the presence of an air-stable chiral N-triflylphosphoramide catalyst and represent a first example of a Mannich–ketalization reaction in asymmetric domino catalysis.

ABSTRACT:

The development of a bifunctional cinchona-based, thiourea-catalyzed, enantioselective domino reaction of cyclohexa-1,2-dione with variously substituted β-nitrostyrenes, which provides complex, polyfunctionalized bicyclo[3.2.1]octan-8-ones was reported. In this efficient domino Michael–Henry reaction diverse β-nitrostyrenes can be successfully applied and the bicyclic products, containing four stereogenic centers of which two may be neighboring quaternary stereocenters, can be isolated in good yields with excellent enantioselectivities (91–97 % ee). Furthermore, we demonstrate the significance of a bifunctional activation mode compared to a base-catalyzed activation in order to gain high enantiocontrol. With regard to the mechanism, we reveal a base-induced epimerization in this unprecedented domino reaction, which provides the opportunity to control the predominant formation of one of the diastereomers. It is notable that this can be achieved by using just 0.5–1.0 mol % catalyst, allowing low cost, ready access to complex enantiopure compounds that can be applied as valuable chiral building blocks in synthetic organic and medicinal chemistry.

ABSTRACT:

Asymmetric catalysis is a key feature of modern synthetic organic chemistry. Traditionally, different combinations of ligands and metals are used to perform highly enantioselective reactions. Since the renaissance of organocatalysis in the early 2000s, tremendous improvement in the field of metal-free catalysis has been achieved. Recently, the combination of transition metals and organocatalysts has allowed the development of new protocols enabling transformations that could not previously be realized. This article aims to present the latest contributions in the field of combined chiral Brønsted acid and metal catalyzed reactions, highlighting the advantages of these catalytic systems as well as describing the uncertainties regarding the molecular structure of the catalytically active species and the reaction mechanisms.

ABSTRACT:

Recently, 1,1′-bi-2-naphthol (BINOL)-based N-triflylphosphoramides emerged as a new class of potent Brønsted acid catalysts. In this paper we describe the efficient synthesis of various BINOL-based N-triflylphosphoramides and their calcium salts. Furthermore, X-ray crystal structure analysis combined with energy-dispersive X-ray spectroscopy (EDX) measurements confirmed that the synthesised chiral N-triflylphosphoramides are highly acidic metal-free catalysts. The calcium salts arise from column chromatography and can be used in asymmetric Ca-catalysis. Further reaction with strong acids results in the BINOL-based N-triflylphosphoramides which act as strong chiral Brønsted acids which can be applied in carbonyl activations.