Alfa'-oxy enones and pyrrolidin-2,3-diones as efficient new templates in asymmetric organocatalytic Michael reactions

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Highly efficient and recoverable dendritic organocatalyst from click chemistry for the asymmetric michael addition of ketones to nitroolefins without the use of organic solvent

A series Of pyrrolidine-triazole based dendritic catalysts have been synthesized and applied directly in the asymmetric Michael addition of ketones to nitroolefins without the use of an organic solvent. Good yields (up to 99%), and high diastereoselectivities (up to syn/anti = 45:1) and enantioselectivities (up to 95% ee) have been obtained. Furthermore. the third generation catalyst can be reused at least five times without significant loss of catalytic activity. (C) 2008 Elsevier Ltd. All rights reserved.

Michael Reactions of the Anions generated by the Metal-Ammonia Reduction of Benzoic Acids.

A novel method for the construction of carboncarbon bonds is described in which anions obtained by the metal-ammonia reduction of benzoic acid and its derivatives undergo ready Michael reaction with methyl crotonate to give the addition products.

Catalytic Asymmetric Michael Addition/Cyclization Cascade Reaction of 3-Isothiocyanatooxindoles with Nitro Olefins

The first organocatalytic asymmetric reaction of 3-isothiocyanatooxindoles with nitro olefins has been developed by using a cinchonidine-derived bifunctional catalyst. The resulting products, highly functionalized 3,2-pyrrolidinyl-substituted spirooxindole derivatives, were obtained in high yields with good diastereo- and enantioselectivities (up to dr >20:1 and er = 96:4). This Michael addition/cyclization cascade reaction employs monosubstituted nitro olefins and complements the Zn-II-catalyzed variant, which is only applicable to disubstituted nitro olefins.

Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids

Nitrogen-containing heterocycles, such as indolines and pyrroloindolines, are prevalent in a variety of diverse natural products, many of which exhibit remarkable biological activities. These frameworks have inspired innovative research aimed at discovering novel methods for their stereoselective preparation.

We have developed an enantioselective synthesis of pyrroloindolines based on a formal (3 + 2) cycloaddition of indoles and 2-amidoacrylates. This reaction is promoted by (R)-BINOL•SnCl₄; this complex is a Lewis acid-assisted Brønsted acid that effects a highly face-selective catalyst-controlled protonation of an enolate. Mechanistic studies also determined that the initial product of this reaction is an indolinium ion, which upon aqueous workup undergoes cyclization to the pyrroloindoline.

Based on this result, we investigated alternative nucleophiles to trap the indolinium ion. First, addition of sodium borohydride to the optimized reaction conditions yields indoline-containing amino acid derivatives.

Next, carbon nucleophiles were explored. Indole substrates incorporating a tethered alkene were exposed to the conditions for the formal (3 + 2) cycloaddition, resulting in a conjugate addition/asymmetric protonation/Prins cyclization cascade. In this transformation, the indolinium ion is attacked by the olefin, and the resulting carbocation is quenched by a chloride ion. Zirconium tetrachloride was found to be the optimal Lewis acid. Stoichiometric proton and chloride sources were also found to be crucial for reactivity.

Asymmetric Michael addition of aldehydes to nitroolefins catalyzed by L-prolinamide derivatives using phenols as co-catalysts

The asymmetric Michael addition of aldehydes to nitroolefins was investigated using L-prolinamide derivatives of 2-(2'-piperidinyl)pyridine as catalyst and a variety of phenols as co-catalyst. Extensive screening toward the effect of prolinamides, phenols, and solvents on this transformation revealed that a combination of (S)-2-(2'-piperidinyl)pyridine-derived trans-4-hydroxy-L-prolinamide 2c, (S)-1,1'-bi-2-naphthol, and dichloromethane was a promising system. This system was shown to be amenable to a rich variety of aldehydes and nitroolefins and afforded the nitroaldehyde products with excellent yield, enantiomeric excess (up to 99%) and diastereoselectivity ratio (up to 99/1), even in the case of 1 mol % catalyst loading and 1.5 equiv of aldehydes.

A homo-proline tetrazole as an improved organocatalyst for the asymmetric Michael addition of carbonyl compounds to nitro-olefins

A new homo-proline tetrazole derivative 7 has been prepared and shown to have improved properties for achieving asymmetric Michael addition of carbonyl compounds to nitro-olefins.

Synthesis and metal complexes of C2 symmetric ligands obtained from (R)-(+)-Betti and dialdehydes for asymmetric induction reactions

The aim of this master’s research thesis was the employment of an enantiopure 1,3-aminoalcohol, the 1-(α-aminobenzyl)-2-naphthol, known as Betti base, for the synthesis of some novel compounds which show a C2 symmetry. Some of these compounds, after derivatization, were used as ligands in association with transition metals to prepare some catalysts for enantioselective catalytic reactions. Some aminoalcohol (Salan-type) derivatives of these compounds were obtained upon reduction and in some cases it was possible to obtain complexes with transition metals such as Mn, Ni, Co and Cu. Furthermore a novel 6-membered analogue bisoxazoline ligand, 2,6-bis((R)-1-Phenyl-1H-naphtho[1,2-e][1,3]oxazin-3-yl)pyridine, was obtained and from it two Cu-complexes were prepared. The metal complexes were employed in some reactions to test the asymmetric induction, which was in some cases up to discrete values.

Microwave-Assisted Phospha-Michael Reactions with Internal Alkenes

The atom efficient phospha-Michael reaction between bis 4-methylphenyl phosphine oxide and several activated internal alkenes has been shown to occur under microwave irradiation without added solvent or catalyst. The alkenes used for this study were ethyl 4-nitrocinnamate, two chalcones ((E)-3-(4-methoxy-phenyl)-1-(4- nitrophenyl)-prop-2-en-1-one and (E)-1-(4-methoxyphenyl)-3-(3-nitro-phenyl)-prop-2- en-1-one), and 2-phenylmethylene-propanedinitrile. In the case of ethyl 4-nitrocinnamate, reaction with bis 4-methylphenyl phosphine oxide for sixty minutes at 130 °C yielded the desired phospha-Michael product in a 55% yield after purification. Varying the location of the nitro group on the phenyl rings of the chalcones did not seem to have a large effect on their reactivity. By NMR, both chalcones seemed to react to the same extent when the reaction times and temperatures were held constant. Interestingly, a phospha-Michael reaction was observed at a reaction temperature of 65°C for experiments involving 2- phenyl-methylene-propanedinitrile while the other substrates required a reaction temperature of 130 °C. Similar experiments were carried out with bis mesityl phosphine oxide and two internal alkenes: 2-phenylmethylene-propanedinitrile and ethyl-2-cyano-3- methyl-2-butenoate. These experiments did not yield any of the predicted phospha- Michael products, which suggest steric limitations to the Michael donor for this reaction.

Synthesis of α,β-diamino acid derivatives via asymmetric Mannich reactions of glycine imino esters catalyzed by a chiral phosphoramidite·silver complex

AgOTf·phosphoramidite complexes efficiently catalyze the enantioselective Mannich-type reaction between benzophenone-imine glycine methyl ester and N-tosyl aldimines in the absence of a base. The corresponding syn-adducts, which are the direct precursors of α,β-diamino acids, are obtained with moderate to good syn-diastereoselectivities (up to 9:1) and high enantioselectivities (up to 99% ee).

Asymmetric electrocyclic reactions

This critical review offers an overview of asymmetric electrocyclic processes, where diastereo- or enantioselectivity is a consequence of the influence of a chiral component (be it substrate or catalyst) on the electrocyclic bond-forming process (195 references). © 2011 The Royal Society of Chemistry.

Catalytic Asymmetric Direct Vinylogous Michael Addition of gamma-Aryl-Substituted Deconjugated Butenolides to Nitroolefins and N-Phenylmaleimide

Direct asymmetric vinylogous Michael reactions of gamma-aryl-substituted deconjugated butenolides with nitroolefins and N-phenylmaleimide are described using bifunctional thiourea derivatives as the catalyst. The resulting butenolide derivatives containing adjacent quaternary and tertiary stereocenters are obtained in good yields (54-90%) and with excellent enantioselectivities (er up to 99:1) and high diastereoselectivities (dr up to > 20:1).

Highly efficient asymmetric hetero-Diels-Alder reactions of carbonyl compounds catalyzed by Lewis acid platinum complexes of conformationally flexible NUPHOS-type diphosphines

Conformationally flexible NUPHOS-type diphosphines have been resolved as their diastereopure platinum BINOLate complexes delta- and lambda-[(NUPHOS)Pt{(S)-BINOL}] and the corresponding enantiopure Lewis acids delta- and lambda-[(NUPHOS)Pt(OTf)(2)], being generated by protonation with trifluoromethanesulfonic acid, act as highly efficient catalysts for the hetero-Diels-Alder reaction of nonactivated conjugated dienes with aryl glyoxals and glyoxylate esters, giving ee's as high as 99%.

Catalytic asymmetric desymmetrization approaches to enantioenriched cyclopentanes

Catalytic asymmetric desymmetrization represents an excellent strategy for accessing highly functionalized chiral building blocks. However, the application of desymmetrization for the synthesis of enantio-enriched cyclopentane derivatives remained limited, when compared to chiral cyclohexanes. We have recently developed a desymmetrization protocol for prochiral 2,2-disubstituted cyclopentene-1,3-diones by direct catalytic asymmetric vinylogous nucleophilic addition of deconjugated butenolides. In this perspective, we give an overview of asymmetric desymmetrization reactions leading to enantioenriched cyclopentanes and their derivatives. The focus is kept confined to the diverse nature of reactions used for this purpose. A brief discussion on the potential future directions is also provided.

Synthesis of new bis-BINOLs linked by a 2,2 '-bipyridine bridge

A series of new G-symmetric chiral ligands 8, 9, 11 and 12, consisting of two binaphthyl units linked by a 2,2'-bipyridine bridge, has been synthesized via Suzuki cross-coupling reactions.